publications | Bruce Rannala

2024

SystBiol
Bayesian Inference Under the Multispecies Coalescent with Ancient DNA Sequences

Anna A Nagel, Tomáš Flouri, Ziheng Yang, and Bruce Rannala

Systematic Biology, Jul 2024

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Ancient DNA (aDNA) is increasingly being used to investigate questions such as the phylogenetic relationships and divergence times of extant and extinct species. If aDNA samples are sufficiently old, expected branch lengths (in units of nucleotide substitutions) are reduced relative to contemporary samples. This can be accounted for by incorporating sample ages into phylogenetic analyses. Existing methods that use tip (sample) dates infer gene trees rather than species trees, which can lead to incorrect or biased inferences of the species tree. Methods using a multispecies coalescent (MSC) model overcome these issues. We developed an MSC model with tip dates and implemented it in the program bpp. The method performed well for a range of biologically realistic scenarios, estimating calibrated divergence times and mutation rates precisely. Simulations suggest that estimation precision can be best improved by prioritizing sampling of many loci and more ancient samples. Incorrectly treating ancient samples as contemporary in analyzing simulated data, mimicking a common practice of empirical analyses, led to large systematic biases in model parameters, including divergence times. Two genomic datasets of mammoths and elephants were analyzed, demonstrating the method’s empirical utility.
@article{10.1093/sysbio/syae047, author = {Nagel, Anna A and Flouri, Tomáš and Yang, Ziheng and Rannala, Bruce}, title = {{Bayesian Inference Under the Multispecies Coalescent with Ancient DNA Sequences}}, journal = {Systematic Biology}, pages = {syae047}, year = {2024}, month = jul, issn = {1063-5157}, doi = {10.1093/sysbio/syae047}, url = {https://doi.org/10.1093/sysbio/syae047}, }
ScienceAdvances
Early detection of highly transmissible viral variants using phylogenomics

Michael R. May, and Bruce Rannala

Science Advances, Jul 2024

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As demonstrated by the SARS-CoV-2 pandemic, the emergence of novel viral strains with increased transmission rates poses a serious threat to global health. Statistical models of genome sequence evolution may provide a critical tool for early detection of these strains. Using a novel stochastic model that links transmission rates to the entire viral genome sequence, we study the utility of phylogenetic methods that use a phylogenetic tree relating viral samples versus count-based methods that use case counts of variants over time exclusively to detect increased transmission rates and identify candidate causative mutations. We find that phylogenies in particular can detect novel transmission-enhancing variants very soon after their origin and may facilitate the development of early detection systems for outbreak surveillance. Phylogenetic trees of viruses facilitate the early detection of highly transmissible variants of concern.
@article{doi:10.1126/sciadv.adk7623, author = {May, Michael R. and Rannala, Bruce}, title = {Early detection of highly transmissible viral variants using phylogenomics}, journal = {Science Advances}, volume = {10}, number = {33}, pages = {eadk7623}, year = {2024}, doi = {10.1126/sciadv.adk7623}, url = {https://www.science.org/doi/abs/10.1126/sciadv.adk7623}, }

2023

PNAS
Model misspecification misleads inference of the spatial dynamics of disease outbreaks

Jiansi Gao, Michael R May, Bruce Rannala, and Brian R Moore

Proceedings of the National Academy of Sciences, Jul 2023

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Epidemiology has been transformed by the advent of Bayesian phylodynamic models that allow researchers to infer the geographic history of pathogen dispersal over a set of discrete geographic areas [1, 2]. These models provide powerful tools for understanding the spatial dynamics of disease outbreaks, but contain many parameters that are inferred from minimal geographic information (i.e., the single area in which each pathogen was sampled). Consequently, inferences under these models are inherently sensitive to our prior assumptions about the model parameters. Here, we demonstrate that the default priors used in empirical phylodynamic studies make strong and biologically unrealistic assumptions about the underlying geographic process. We provide empirical evidence that these unrealistic priors strongly (and adversely) impact commonly reported aspects of epidemiological studies, including: 1) the relative rates of dispersal between areas; 2) the importance of dispersal routes for the spread of pathogens among areas; 3) the number of dispersal events between areas, and; 4) the ancestral area in which a given outbreak originated. We offer strategies to avoid these problems, and develop tools to help researchers specify more biologically reasonable prior models that will realize the full potential of phylodynamic methods to elucidate pathogen biology and, ultimately, inform surveillance and monitoring policies to mitigate the impacts of disease outbreaks.
@article{gao2023model, title = {Model misspecification misleads inference of the spatial dynamics of disease outbreaks}, author = {Gao, Jiansi and May, Michael R and Rannala, Bruce and Moore, Brian R}, journal = {Proceedings of the National Academy of Sciences}, volume = {120}, number = {11}, pages = {e2213913120}, year = {2023}, doi = {10.1073/pnas.2213913120}, publisher = {National Academy of Sciences}, }
Bioinformatics
PrioriTree: a utility for improving phylodynamic analyses in BEAST

Jiansi Gao, Michael R May, Bruce Rannala, and Brian R Moore

Bioinformatics, Jul 2023

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Phylodynamic methods are central to studies of the geographic and demographic history of disease outbreaks. Inference under discrete-geographic phylodynamic models—which involve many parameters that must be inferred from minimal information—is inherently sensitive to our prior beliefs about the model parameters. We present an interactive utility, PrioriTree, to help researchers identify and accommodate prior sensitivity in discrete-geographic inferences. Specifically, PrioriTree provides a suite of functions to generate input files for—and summarize output from—BEAST analyses for performing robust Bayesian inference, data-cloning analyses and assessing the relative and absolute fit of candidate discrete-geographic (prior) models to empirical datasets.
@article{gao2023prioritree, title = {PrioriTree: a utility for improving phylodynamic analyses in BEAST}, author = {Gao, Jiansi and May, Michael R and Rannala, Bruce and Moore, Brian R}, journal = {Bioinformatics}, volume = {39}, number = {1}, pages = {btac849}, year = {2023}, url = {https://academic.oup.com/bioinformatics}, doi = {10.1093/bioinformatics/btac849}, publisher = {Oxford University Press}, }
Genetics
An efficient exact algorithm for identifying hybrids using population genomic sequences

Sneha Chakraborty, and Bruce Rannala

Genetics, Jul 2023

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The identification of individuals that have a recent hybrid ancestry (between populations or species) has been a goal of naturalists for centuries. Since the 1960s, codominant genetic markers have been used with statistical and computational methods to identify F1 hybrids and backcrosses. Existing hybrid inference methods assume that alleles at different loci undergo independent assortment (are unlinked or in population linkage equilibrium). Genomic datasets include thousands of markers that are located on the same chromosome and are in population linkage disequilibrium which violate this assumption. Existing methods may therefore be viewed as composite likelihoods when applied to genomic datasets and their performance in identifying hybrid ancestry (which is a model-choice problem) is unknown. Here, we develop a new program Mongrail that implements a full-likelihood Bayesian hybrid inference method that explicitly models linkage and recombination, generating the posterior probability of different F1 or F2 hybrid, or backcross, genealogical classes. We use simulations to compare the statistical performance of Mongrail with that of an existing composite likelihood method (NewHybrids) and apply the method to analyze genome sequence data for hybridizing species of barred and spotted owls.
@article{chakraborty2023efficient, title = {An efficient exact algorithm for identifying hybrids using population genomic sequences}, doi = {10.1093/genetics/iyad011}, author = {Chakraborty, Sneha and Rannala, Bruce}, journal = {Genetics}, pages = {iyad011}, year = {2023}, publisher = {Oxford University Press}, }
SystBiol
Estimation of species divergence times in presence of cross-species gene flow

George P Tiley, Tomás Flouri, Xiyun Jiao, Jelmer W Poelstra, Bo Xu, and 4 more authors

Systematic Biology, Mar 2023

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Cross-species introgression can have significant impacts on phylogenomic reconstruction of species divergence events. Here, we used simulations to show how the presence of even a small amount of introgression can bias divergence time estimates when gene flow is ignored in the analysis. Using advances in analytical methods under the multispecies coalescent (MSC) model, we demonstrate that by accounting for incomplete lineage sorting and introgression using large phylogenomic data sets this problem can be avoided. The multispecies-coalescent-with-introgression (MSci) model is capable of accurately estimating both divergence times and ancestral effective population sizes, even when only a single diploid individual per species is sampled. We characterize some general expectations for biases in divergence time estimation under three different scenarios: 1) introgression between sister species, 2) introgression between non-sister species, and 3) introgression from an unsampled (i.e., ghost) outgroup lineage. We also conducted simulations under the isolation-with-migration (IM) model, and found that the MSci model assuming episodic gene flow was able to accurately estimate species divergence times despite high levels of continuous gene flow. We estimated divergence times under the MSC and MSci models from two published empirical datasets with previous evidence of introgression, one of 372 target-enrichment loci from baobabs (Adansonia), and another of 1,000 transcriptome loci from fourteen species of the tomato relative, Jaltomata. The empirical analyses not only confirm our findings from simulations, demonstrating that the MSci model can reliably estimate divergence times, but also show that divergence time estimation under the MSC can be robust to the presence of small amounts of introgression in empirical datasets with extensive taxon sampling.
@article{tiley2023, author = {Tiley, George P and Flouri, Tomás and Jiao, Xiyun and Poelstra, Jelmer W and Xu, Bo and Zhu, Tianqi and Rannala, Bruce and Yoder, Anne D and Yang, Ziheng}, title = {Estimation of species divergence times in presence of cross-species gene flow}, journal = {Systematic Biology}, year = {2023}, month = mar, issn = {1063-5157}, doi = {10.1093/sysbio/syad015}, }
RSocInterface
Bayesian phylogenetic inference of HIV latent lineage ages using serial sequences

Anna A Nagel, and Bruce Rannala

J. R. Soc. Interface, Mar 2023

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HIV evolves rapidly within individuals, allowing phylogenetic studies to infer histories of viral lineages on short time scales. Latent HIV sequences are an exception to this rapid evolution, as their transcriptional inactivity leads to negligible mutation rates compared with non-latent HIV lineages. This difference in mutation rates generates potential information about the times at which sequences entered the latent reservoir, providing insight into the dynamics of the latent reservoir. A Bayesian phylogenetic method is developed to infer integration times of latent HIV sequences. The method uses informative priors to incorporate biologically sensible bounds on inferences (such as requiring sequences to become latent before being sampled) that many existing methods lack. A new simulation method is also developed, based on widely used epidemiological models of within-host viral dynamics, and applied to evaluate the new method—showing that point estimates and credible intervals are often more accurate than existing methods. Accurate estimates of latent integration dates are crucial in relating integration times to key events during HIV infection, such as treatment initiation. The method is applied to publicly available sequence data from four HIV patients, providing new insights regarding the temporal pattern of latent integration.
@article{Nagel2023, author = {Nagel, Anna A and Rannala, Bruce}, title = {Bayesian phylogenetic inference of HIV latent lineage ages using serial sequences}, journal = {J. R. Soc. Interface}, year = {2023}, doi = {10.1098/rsif.2023.0022}, }
PNAS
Efficient Bayesian inference under the multispecies coalescent with migration

Tomáš Flouri, Xiyun Jiao, Jun Huang, Bruce Rannala, and Ziheng Yang

Proceedings of the National Academy of Sciences, Mar 2023

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Analyses of genome sequence data have revealed pervasive interspecific gene flow and enriched our understanding of the role of gene flow in speciation and adaptation. Inference of gene flow using genomic data requires powerful statistical methods. Yet current likelihood-based methods involve heavy computation and are feasible for small datasets only. Here, we implement the multispecies-coalescent-with-migration model in the Bayesian program bpp, which can be used to test for gene flow and estimate migration rates, as well as species divergence times and population sizes. We develop Markov chain Monte Carlo algorithms for efficient sampling from the posterior, enabling the analysis of genome-scale datasets with thousands of loci. Implementation of both introgression and migration models in the same program allows us to test whether gene flow occurred continuously over time or in pulses. Analyses of genomic data from Anopheles mosquitoes demonstrate rich information in typical genomic datasets about the mode and rate of gene flow.
@article{Flouri2023, author = {Flouri, Tomáš and Jiao, Xiyun and Huang, Jun and Rannala, Bruce and Yang, Ziheng}, title = {Efficient Bayesian inference under the multispecies coalescent with migration}, journal = {Proceedings of the National Academy of Sciences}, volume = {120}, number = {44}, pages = {e2310708120}, year = {2023}, doi = {10.1073/pnas.2310708120}, }

2022

MBE
New phylogenetic models incorporating interval-specific dispersal dynamics improve inference of disease spread

Jiansi Gao, Michael R May, Bruce Rannala, and Brian R Moore

Molecular Biology and Evolution, Mar 2022

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Phylodynamic methods reveal the spatial and temporal dynamics of viral geographic spread, and have featured prominently in studies of the COVID-19 pandemic. Virtually all such studies are based on phylodynamic models that assume—despite direct and compelling evidence to the contrary—that rates of viral geographic dispersal are constant through time. Here, we: (1) extend phylodynamic models to allow both the average and relative rates of viral dispersal to vary independently between pre-specified time intervals; (2) implement methods to infer the number and timing of viral dispersal events between areas; and (3) develop statistics to assess the absolute fit of discrete-geographic phylodynamic models to empirical datasets. We first validate our new methods using simulations, and then apply them to a SARS-CoV-2 dataset from the early phase of the COVID-19 pandemic. We show that: (1) under simulation, failure to accommodate interval-specific variation in the study data will severely bias parameter estimates; (2) in practice, our interval-specific discrete-geographic phylodynamic models can significantly improve the relative and absolute fit to empirical data; and (3) the increased realism of our interval-specific models provides qualitatively different inferences regarding key aspects of the COVID-19 pandemic—revealing significant temporal variation in global viral dispersal rates, viral dispersal routes, and the number of viral dispersal events between areas—and alters interpretations regarding the efficacy of intervention measures to mitigate the pandemic.
@article{gao2022new, title = {New phylogenetic models incorporating interval-specific dispersal dynamics improve inference of disease spread}, author = {Gao, Jiansi and May, Michael R and Rannala, Bruce and Moore, Brian R}, journal = {Molecular Biology and Evolution}, volume = {39}, number = {8}, pages = {msac159}, year = {2022}, doi = {10.1093/molbev/msac159}, publisher = {Oxford University Press} }
MBE
Bayesian phylogenetic inference using relaxed-clocks and the multispecies coalescent

Tomáš Flouri, Jun Huang, Xiyun Jiao, Paschalia Kapli, Bruce Rannala, and 1 more author

Molecular Biology and Evolution, Mar 2022

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The multispecies coalescent (MSC) model accommodates both species divergences and within-species coalescent and provides a natural framework for phylogenetic analysis of genomic data when the gene trees vary across the genome. The MSC model implemented in the program BPP assumes a molecular clock and the Jukes–Cantor model, and is suitable for analyzing genomic data from closely related species. Here we extend our implementation to more general substitution models and relaxed clocks to allow the rate to vary among species. The MSC-with-relaxed-clock model allows the estimation of species divergence times and ancestral population sizes using genomic sequences sampled from contemporary species when the strict clock assumption is violated, and provides a simulation framework for evaluating species tree estimation methods. We conducted simulations and analyzed two real datasets to evaluate the utility of the new models. We confirm that the clock-JC model is adequate for inference of shallow trees with closely related species, but it is important to account for clock violation for distant species. Our simulation suggests that there is valuable phylogenetic information in the gene-tree branch lengths even if the molecular clock assumption is seriously violated, and the relaxed-clock models implemented in BPP are able to extract such information. Our Markov chain Monte Carlo algorithms suffer from mixing problems when used for species tree estimation under the relaxed clock and we discuss possible improvements. We conclude that the new models are currently most effective for estimating population parameters such as species divergence times when the species tree is fixed.
@article{flouri2022bayesian, title = {Bayesian phylogenetic inference using relaxed-clocks and the multispecies coalescent}, author = {Flouri, Tom{\'a}{\v{s}} and Huang, Jun and Jiao, Xiyun and Kapli, Paschalia and Rannala, Bruce and Yang, Ziheng}, journal = {Molecular Biology and Evolution}, volume = {39}, number = {8}, pages = {msac161}, year = {2022}, doi = {10.1093/molbev/msac161}, publisher = {Oxford University Press} }

2021

EcolMon
The cost of ectoparasitism in cliff swallows declines over 35 years

Charles R Brown, Stacey L Hannebaum, Valerie A O’Brien, Catherine E Page, Bruce Rannala, and 5 more authors

Ecological Monographs, Mar 2021

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Host–parasite dynamics often vary over time, brought about by changes in the parasite’s virulence or the host’s ability to resist or tolerate the parasite. Although virulence evolution in microparasites is well studied, we know little about temporal change in the pathogenicity of macroparasites such as blood-feeding insects. Using data collected over 35 yr, we report a reduction in pathogenicity of the hematophagous swallow bug (Cimex vicarius) on its Cliff Swallow (Petrochelidon pyrrhonota) host. Relative to experimentally fumigated, parasite-free nests, the negative effects of bugs on nestling swallow body mass and survival were less in the later years of the study than in the earlier years, and the negative relationship between nestling body mass and bug abundance became weaker over time. The survival of adult birds exposed to swallow bugs increased throughout the study, while survival of birds from parasite-free nests decreased over time. Swallow bug abundance per nest, bug body size, and bug age ratios did not change during the study. Between-colony transmission of bugs showed less immigration into larger colonies than in earlier studies, but there was no net change in transmission. Cliff Swallows did not reduce their exposure to bugs over time by being more likely to avoid infested nest or colony sites. Parents increased the number of food deliveries to their offspring over time in the presence of parasites, but the total amount of food delivered was unchanged. The reduced cost of swallow bug ectoparasitism does not seem related to changes in parasite narrow-sense virulence, the host’s avoidance of parasites, the presence of alternative hosts for bugs, or climate-driven phenological mismatches. The results probably reflect the Cliff Swallow’s evolving of greater tolerance to swallow bugs, brought about by the bird’s shift from natural cliff nesting sites to artificial structures that may harbor more bugs than natural cliffs. This study shows that hosts can respond relatively rapidly to high levels of parasitism, and provides support for models that suggest the evolution of tolerance should be expected in some host–parasite systems.
@article{brown2021cost, title = {The cost of ectoparasitism in cliff swallows declines over 35 years}, author = {Brown, Charles R and Hannebaum, Stacey L and O’Brien, Valerie A and Page, Catherine E and Rannala, Bruce and Roche, Erin A and Wagnon, Gigi S and Knutie, Sarah A and Moore, Amy T and Brown, Mary B}, journal = {Ecological Monographs}, volume = {91}, number = {2}, pages = {e01446}, doi = {10.1002/ecm.1446}, year = {2021} }

2020

MBE
A Bayesian implementation of the multispecies coalescent model with introgression for phylogenomic analysis

Tomáš Flouri, Xiyun Jiao, Bruce Rannala, and Ziheng Yang

Molecular Biology and Evolution, Mar 2020

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Recent analyses suggest that cross-species gene flow or introgression is common in nature, especially during species divergences. Genomic sequence data can be used to infer introgression events and to estimate the timing and intensity of introgression, providing an important means to advance our understanding of the role of gene flow in speciation. Here, we implement the multispecies-coalescent-with-introgression model, an extension of the multispecies-coalescent model to incorporate introgression, in our Bayesian Markov chain Monte Carlo program BPP. The multispecies-coalescent-with-introgression model accommodates deep coalescence (or incomplete lineage sorting) and introgression and provides a natural framework for inference using genomic sequence data. Computer simulation confirms the good statistical properties of the method, although hundreds or thousands of loci are typically needed to estimate introgression probabilities reliably. Reanalysis of data sets from the purple cone spruce confirms the hypothesis of homoploid hybrid speciation. We estimated the introgression probability using the genomic sequence data from six mosquito species in the Anopheles gambiae species complex, which varies considerably across the genome, likely driven by differential selection against introgressed alleles.
@article{flouri2020bayesian, title = {A Bayesian implementation of the multispecies coalescent model with introgression for phylogenomic analysis}, author = {Flouri, Tom{\'a}{\v{s}} and Jiao, Xiyun and Rannala, Bruce and Yang, Ziheng}, journal = {Molecular Biology and Evolution}, volume = {37}, number = {4}, pages = {1211--1223}, year = {2020}, doi = {10.1093/molbev/msz296}, publisher = {Oxford University Press} }
SystBiol
The impact of cross-species gene flow on species tree estimation

Xiyun Jiao, Tomáš Flouri, Bruce Rannala, and Ziheng Yang

Systematic Biology, Mar 2020

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Recent analyses of genomic sequence data suggest cross-species gene flow is common in both plants and animals, posing challenges to species tree estimation. We examine the levels of gene flow needed to mislead species tree estimation with three species and either episodic introgressive hybridization or continuous migration between an outgroup and one ingroup species. Several species tree estimation methods are examined, including the majority-vote method based on the most common gene tree topology (with either the true or reconstructed gene trees used), the UPGMA method based on the average sequence distances (or average coalescent times) between species, and the full-likelihood method based on multilocus sequence data. Our results suggest that the majority-vote method based on gene tree topologies is more robust to gene flow than the UPGMA method based on coalescent times and both are more robust than likelihood assuming a multispecies coalescent (MSC) model with no cross-species gene flow. Comparison of the continuous migration model with the episodic introgression model suggests that a small amount of gene flow per generation can cause drastic changes to the genetic history of the species and mislead species tree methods, especially if the species diverged through radiative speciation events. Estimates of parameters under the MSC with gene flow suggest that African mosquito species in the Anopheles gambiae species complex constitute such an example of extreme impact of gene flow on species phylogeny. [IM; introgression; migration; MSci; multispecies coalescent; species tree.]
@article{jiao2020impact, title = {The impact of cross-species gene flow on species tree estimation}, author = {Jiao, Xiyun and Flouri, Tom{\'a}{\v{s}} and Rannala, Bruce and Yang, Ziheng}, journal = {Systematic Biology}, volume = {69}, number = {5}, pages = {830--847}, year = {2020}, doi = {10.1093/sysbio/syaa001}, publisher = {Oxford University Press} }
PGE
The Multi-species Coalescent Model and Species Tree Inference

Bruce Rannala, Scott V. S. V. Edwards, Adam Leaché, and Ziheng Yang

In Phylogenetics in the Genomic Era, Mar 2020

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The multispecies coalescent (MSC) is an extension of the single-population coalescent model of population genetics to the case of multiple species. The MSC naturally accommodates speciation events (with subsequent genetic isolation between species) and the coalescent process within each species. It provides a framework for analysis of multilocus genomic sequence data from multiple species in a number of inference problems including species tree estimation, accounting for ancestral polymorphism and deep coalescence. Within this framework, the genealogical fluctuations across genes or genomic regions (and the gene tree/species tree conflicts that may result) are not seen as a problem but rather as a source of information for estimating important parameters such as species divergence times, ancestral population sizes, and the timings, directions, and intensities of cross-species introgression or hybridisation events. This chapter outlines the basic theory of the MSC and its important applications in analysis of genomic sequence data, describing the most widely-used full-likelihood and heuristic methods of species tree estimation. We discuss several active areas of research in which we predict future developments will occur, including inference of introgression events on a species phylogeny.
@incollection{rannala:hal-02535622, title = {{The Multi-species Coalescent Model and Species Tree Inference}}, author = {Rannala, Bruce and Edwards, Scott V. S. V. and Leach{\'e}, Adam and Yang, Ziheng}, url = {https://hal.science/hal-02535622}, booktitle = {{Phylogenetics in the Genomic Era}}, editor = {Scornavacca, Celine and Delsuc, Fr{\'e}d{\'e}ric and Galtier, Nicolas}, publisher = {{No commercial publisher | Authors open access book}}, pages = {3.3:1--3.3:21}, year = {2020}, hal_id = {hal-02535622}, hal_version = {v1} }
PGE
Species Delimitation

Bruce Rannala, and Ziheng Yang

In Phylogenetics in the Genomic Era, Mar 2020

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Species delimitation is the process of determining which groups of individual organisms constitute different populations of a single species and which constitute different species. The problem goes back to the earliest days of taxonomy and formalized processes for describing new species exist and are widely used, although the methods are time-intensive and problematic for some species. Genomic data carries extensive information about the degree of genetic isolation among species and about ancient and recent introgression. For this reason, genomic data can play an important role in species delimitation under many existing species concepts. Here we review the history of molecular species delimitation leading up to the current genomic era. We then describe the most widely used computational methods for species delimitation using single-and multi-locus genomic data. Relative strengths and weaknesses of the approaches are discussed and a new method for delimiting species based on empirical criteria is proposed.
@incollection{rannala:hal-02536468, title = {{Species Delimitation}}, author = {Rannala, Bruce and Yang, Ziheng}, url = {https://hal.science/hal-02536468}, booktitle = {{Phylogenetics in the Genomic Era}}, editor = {Scornavacca, Celine and Delsuc, Fr{\'e}d{\'e}ric and Galtier, Nicolas}, publisher = {{No commercial publisher | Authors open access book}}, pages = {5.5:1--5.5:18}, year = {2020}, hal_id = {hal-02536468}, hal_version = {v1} }
PGE
A Tutorial on the Use of BPP for Species Tree Estimation and Species Delimitation

Tomáš Flouri, Bruce Rannala, and Ziheng Yang

In Phylogenetics in the Genomic Era, Mar 2020

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BPP is a Bayesian Markov chain Monte Carlo program for analyzing multilocus sequence data under the multispecies coalescent (MSC) model with and without introgression. Among the analyses that can be conducted are estimation of population size and species divergence times, species tree estimation, species delimitation and estimation of cross-species introgression intensity. The program can also be used to simulate gene trees and sequence alignments under the MSC model with, or without, migration. In this tutorial, we illustrate the use of BPP for species tree estimation and species delimitation. We also provide practical guidelines on running BPP on multicore systems. As BPP is continuously updated, the most up-to-date version of this tutorial, as well as the data files, are available at https://github.com/bpp/bpp-tutorial
@incollection{flouri:hal-02536475, title = {{A Tutorial on the Use of BPP for Species Tree Estimation and Species Delimitation}}, author = {Flouri, Tom{\'a}{\v s} and Rannala, Bruce and Yang, Ziheng}, url = {https://hal.science/hal-02536475}, booktitle = {{Phylogenetics in the Genomic Era}}, editor = {Scornavacca, Celine and Delsuc, Fr{\'e}d{\'e}ric and Galtier, Nicolas}, publisher = {{No commercial publisher | Authors open access book}}, pages = {5.6:1--5.6:16}, year = {2020}, hal_id = {hal-02536475}, hal_version = {v1} }
BCR
Haplotype analysis of the internationally distributed BRCA1 c. 3331_3334delCAAG founder mutation reveals a common ancestral origin in Iberia

Anna Marie De Asis Tuazon, Paul Lott, Mabel Bohórquez, Jennyfer Benavides, Carolina Ramirez, and 6 more authors

Breast Cancer Research, Mar 2020

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Background The BRCA1 c.3331_3334delCAAG founder mutation has been reported in hereditary breast and ovarian cancer families from multiple Hispanic groups. We aimed to evaluate BRCA1 c.3331_3334delCAAG haplotype diversity in cases of European, African, and Latin American ancestry. Methods BC mutation carrier cases from Colombia (n = 32), Spain (n = 13), Portugal (n = 2), Chile (n = 10), Africa (n = 1), and Brazil (n = 2) were genotyped with the genome-wide single nucleotide polymorphism (SNP) arrays to evaluate haplotype diversity around BRCA1 c.3331_3334delCAAG. Additional Portuguese (n = 13) and Brazilian (n = 18) BC mutation carriers were genotyped for 15 informative SNPs surrounding BRCA1. Data were phased using SHAPEIT2, and identical by descent regions were determined using BEAGLE and GERMLINE. DMLE+ was used to date the mutation in Colombia and Iberia. Results The haplotype reconstruction revealed a shared 264.4-kb region among carriers from all six countries. The estimated mutation age was 100 generations in Iberia and that it was introduced to South America early during the European colonization period. Conclusions Our results suggest that this mutation originated in Iberia and later introduced to Colombia and South America at the time of Spanish colonization during the early 1500s. We also found that the Colombian mutation carriers had higher European ancestry, at the BRCA1 gene harboring chromosome 17, than controls, which further supported the European origin of the mutation. Understanding founder mutations in diverse populations has implications in implementing cost-effective, ancestry-informed screening.
@article{tuazon2020haplotype, title = {Haplotype analysis of the internationally distributed {BRCA1 c. 3331}\_{3334delCAAG} founder mutation reveals a common ancestral origin in Iberia}, author = {Tuazon, Anna Marie De Asis and Lott, Paul and Boh{\'o}rquez, Mabel and Benavides, Jennyfer and Ramirez, Carolina and Criollo, Angel and Estrada-Florez, Ana and Mateus, Gilbert and Velez, Alejandro and Carmona, Jenny and others}, journal = {Breast Cancer Research}, volume = {22}, pages = {1--10}, year = {2020}, doi = {10.1186/s13058-020-01341-3}, publisher = {BioMed Central} }
SCIASIA
Effect of SNPs in genes regulating cell cycle control, apoptosis and inflammation on lung cancer susceptibility of northern Thai population

Rattanasak Wongkomonched, Bruce Rannala, Phongtape Wiwatanadate, Somchareon Saeteng, Jatupol Kampuansai, and 1 more author

SCIENCEASIA, Mar 2020

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Northern Thai population has experienced a high incidence of lung cancer and greater rates of mortality over the past several decades. In this study, blood samples and personal information were collected from 91 non-small cell lung cancer patients and 84 cancer-free healthy unrelated volunteers living in northern Thailand. Eight functional SNPs, including cell cycle control (TP53 Pro72Arg, MDM2 T309G, CCND1 G723A, CDKN1A Ser31Arg), apoptosis (FASLG C-844T, FAS G-1378A) and inflammation (TGFB1 T-1347C, TGFB1 Pro10Leu) were genotyped by multiplex allelespecific polymerase chain reactions. Odds ratios (OR) with 95% confidence intervals (CI) were calculated using logistic regression after making adjustments for age, gender and the smoking status of all participating subjects. No significant association between a single SNP and lung cancer risk was observed. However, a combination of TGFB1-1347T and 10Pro allele carriers indicated a significantly increased risk for lung cancer (OR = 2.90, 95% CI = 1.01–8.4, P = 0.049) relative to wild-type genotypes. Among the participants, who had kitchens inside their homes, -1347T allele carriers had significant increase in lung cancer risk (OR = 5.9, 95% CI = 1.32–26.5, P = 0.020) when compared to the TGFB1- 1347 C/C genotype carriers. In conclusion, we have observed a significant association between TGFB1-1347T allele and either TGFB1 10Pro allele or having kitchen inside the house on risk elevation of non-small cell lung cancer among the population of northern Thailand.
@article{wongkomonched2020effect, title = {Effect of SNPs in genes regulating cell cycle control, apoptosis and inflammation on lung cancer susceptibility of northern Thai population}, author = {Wongkomonched, Rattanasak and Rannala, Bruce and Wiwatanadate, Phongtape and Saeteng, Somchareon and Kampuansai, Jatupol and Kangwanpong, Daoroong}, journal = {SCIENCEASIA}, volume = {46}, number = {5}, pages = {568--+}, doi = {10.2306/scienceasia1513-1874.2020.079}, year = {2020}, publisher = {SCIENCE SOCIETY THAILAND PUBLIC INFORMATION DEPT, 73/1 RAMA VI RD, RAJDHEVEE~…} }

2019

SystBiol
The spectre of too many species

Adam D Leaché, Tianqi Zhu, Bruce Rannala, and Ziheng Yang

Systematic Biology, Mar 2019

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Recent simulation studies examining the performance of Bayesian species delimitation as implemented in the BPP program have suggested that BPP may detect population splits but not species divergences and that it tends to over-split when data of many loci are analyzed. Here, we confirm these results and provide the mathematical justifications. We point out that the distinction between population and species splits made in the protracted speciation model (PSM) has no influence on the generation of gene trees and sequence data, which explains why no method can use such data to distinguish between population splits and speciation. We suggest that the PSM is unrealistic as its mechanism for assigning species status assumes instantaneous speciation, contradicting prevailing taxonomic practice. We confirm the suggestion, based on simulation, that in the case of speciation with gene flow, Bayesian model selection as implemented in BPP tends to detect population splits when the amount of data (the number of loci) increases. We discuss the use of a recently proposed empirical genealogical divergence index (gdi) for species delimitation and illustrate that parameter estimates produced by a full likelihood analysis as implemented in BPP provide much more reliable inference under the gdi than the approximate method PHRAPL. We distinguish between Bayesian model selection and parameter estimation and suggest that the model selection approach is useful for identifying sympatric cryptic species, while the parameter estimation approach may be used to implement empirical criteria for determining species status among allopatric populations.
@article{leache2019spectre, title = {The spectre of too many species}, author = {Leach{\'e}, Adam D and Zhu, Tianqi and Rannala, Bruce and Yang, Ziheng}, journal = {Systematic Biology}, volume = {68}, number = {1}, pages = {168--181}, year = {2019}, doi = {10.1093/sysbio/syy051}, publisher = {Oxford University Press} }

2018

MBE
Species tree inference with BPP using genomic sequences and the multispecies coalescent

Tomáš Flouri, Xiyun Jiao, Bruce Rannala, and Ziheng Yang

Molecular Biology and Evolution, Mar 2018

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The multispecies coalescent provides a natural framework for accommodating ancestral genetic polymorphism and coalescent processes that can cause different genomic regions to have different genealogical histories. The Bayesian program BPP includes a full-likelihood implementation of the multispecies coalescent, using transmodel Markov chain Monte Carlo to calculate the posterior probabilities of different species trees. BPP is suitable for analyzing multilocus sequence data sets and it accommodates the heterogeneity of gene trees (both the topology and branch lengths) among loci and gene tree uncertainties due to limited phylogenetic information at each locus. Here, we provide a practical guide to the use of BPP in species tree estimation. BPP is a command-line program that runs on LINUX, MACOSX, and WINDOWS. This protocol shows how to use both BPP 3.4 and BPP 4.0.
@article{flouri2018species, title = {Species tree inference with BPP using genomic sequences and the multispecies coalescent}, author = {Flouri, Tom{\'a}{\v{s}} and Jiao, Xiyun and Rannala, Bruce and Yang, Ziheng}, journal = {Molecular Biology and Evolution}, volume = {35}, number = {10}, pages = {2585--2593}, year = {2018}, doi = {10.1093/molbev/msy147}, publisher = {Oxford University Press} }

2017

SystBiol
Efficient Bayesian species tree inference under the multispecies coalescent

Bruce Rannala, and Ziheng Yang

Systematic biology, Mar 2017

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We develop a Bayesian method for inferring the species phylogeny under the multispecies coalescent (MSC) model. To improve the mixing properties of the Markov chain Monte Carlo (MCMC) algorithm that traverses the space of species trees, we implement two efficient MCMC proposals: the first is based on the Subtree Pruning and Regrafting (SPR) algorithm and the second is based on a node-slider algorithm. Like the Nearest-Neighbor Interchange (NNI) algorithm we implemented previously, both new algorithms propose changes to the species tree, while simultaneously altering the gene trees at multiple genetic loci to automatically avoid conflicts with the newly proposed species tree. The method integrates over gene trees, naturally taking account of the uncertainty of gene tree topology and branch lengths given the sequence data. A simulation study was performed to examine the statistical properties of the new method. The method was found to show excellent statistical performance, inferring the correct species tree with near certainty when 10 loci were included in the dataset. The prior on species trees has some impact, particularly for small numbers of loci. We analyzed several previously published datasets (both real and simulated) for rattlesnakes and Philippine shrews, in comparison with alternative methods. The results suggest that the Bayesian coalescent-based method is statistically more efficient than heuristic methods based on summary statistics, and that our implementation is computationally more efficient than alternative full-likelihood methods under the MSC. Parameter estimates for the rattlesnake data suggest drastically different evolutionary dynamics between the nuclear and mitochondrial loci, even though they support largely consistent species trees. We discuss the different challenges facing the marginal likelihood calculation and transmodel MCMC as alternative strategies for estimating posterior probabilities for species trees. [Bayes factor; Bayesian inference; MCMC; multispecies coalescent; nodeslider; species tree; SPR.]
@article{rannala2017efficient, title = {Efficient Bayesian species tree inference under the multispecies coalescent}, author = {Rannala, Bruce and Yang, Ziheng}, journal = {Systematic biology}, volume = {66}, number = {5}, pages = {823--842}, year = {2017}, doi = {10.1093/sysbio/syw119}, publisher = {Oxford University Press} }
MolEcol
Bayesian species identification under the multispecies coalescent provides significant improvements to DNA barcoding analyses

Ziheng Yang, and Bruce Rannala

Molecular Ecology, Mar 2017

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DNA barcoding methods use a single locus (usually the mitochondrial COI gene) to assign unidentified specimens to known species in a library based on a genetic distance threshold that distinguishes between-species divergence from within-species diversity. Recently developed species delimitation methods based on the multispecies coalescent (MSC) model offer an alternative approach to individual assignment using either single-locus or multiloci sequence data. Here, we use simulations to demonstrate three features of an MSC method implemented in the program bpp. First, we show that with one locus, MSC can accurately assign individuals to species without the need for arbitrarily determined distance thresholds (as required for barcoding methods). We provide an example in which no single threshold or barcoding gap exists that can be used to assign all specimens without incurring high error rates. Second, we show that bpp can identify cryptic species that may be misidentified as a single species within the library, potentially improving the accuracy of barcoding libraries. Third, we show that taxon rarity does not present any particular problems for species assignments using bpp and that accurate assignments can be achieved even when only one or a few loci are available. Thus, concerns that have been raised that MSC methods may have problems analysing rare taxa (singletons) are unfounded. Currently, barcoding methods enjoy a huge computational advantage over MSC methods and may be the only approach feasible for massively large data sets, but MSC methods may offer a more stringent test for species that are tentatively assigned by barcoding.
@article{yang2017bayesian, title = {Bayesian species identification under the multispecies coalescent provides significant improvements to DNA barcoding analyses}, author = {Yang, Ziheng and Rannala, Bruce}, journal = {Molecular Ecology}, volume = {26}, number = {11}, pages = {3028--3036}, doi = {10.1111/mec.14093}, year = {2017} }

2016

PLOS1
A glance at recombination hotspots in the domestic cat

Hasan Alhaddad, Chi Zhang, Bruce Rannala, and Leslie A Lyons

PloS one, Mar 2016

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Recombination has essential roles in increasing genetic variability within a population and in ensuring successful meiotic events. The objective of this study is to (i) infer the population-scaled recombination rate (ρ), and (ii) identify and characterize regions of increased recombination rate for the domestic cat, Felis silvestris catus. SNPs (n = 701) were genotyped in twenty-two East Asian feral cats (random bred). The SNPs covered ten different chromosomal regions (A1, A2, B3, C2, D1, D2, D4, E2, F2, X) with an average region size of 850 Kb and an average SNP density of 70 SNPs/region. The Bayesian method in the program inferRho was used to infer regional population recombination rates and hotspots localities. The regions exhibited variable population recombination rates and four decisive recombination hotspots were identified on cat chromosome A2, D1, and E2 regions. As a description of the identified hotspots, no correlation was detected between the GC content and the locality of recombination spots, and the hotspots enclosed L2 LINE elements and MIR and tRNA-Lys SINE elements.
@article{alhaddad2016glance, title = {A glance at recombination hotspots in the domestic cat}, author = {Alhaddad, Hasan and Zhang, Chi and Rannala, Bruce and Lyons, Leslie A}, journal = {PloS one}, volume = {11}, number = {2}, pages = {e0148710}, year = {2016}, doi = {10.1371/journal.pone.0148710}, publisher = {Public Library of Science San Francisco, CA USA} }
PTRSB
Conceptual issues in Bayesian divergence time estimation

Bruce Rannala

Philosophical Transactions of the Royal Society B: Biological Sciences, Mar 2016

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Bayesian inference of species divergence times is an unusual statistical problem, because the divergence time parameters are not identifiable unless both fossil calibrations and sequence data are available. Commonly used marginal priors on divergence times derived from fossil calibrations may conflict with node order on the phylogenetic tree causing a change in the prior on divergence times for a particular topology. Care should be taken to avoid confusing this effect with changes due to informative sequence data. This effect is illustrated with examples. A topology-consistent prior that preserves the marginal priors is defined and examples are constructed. Conflicts between fossil calibrations and relative branch lengths (based on sequence data) can cause estimates of divergence times that are grossly incorrect, yet have a narrow posterior distribution. An example of this effect is given; it is recommended that overly narrow posterior distributions of divergence times should be carefully scrutinized.
@article{rannala2016conceptual, title = {Conceptual issues in Bayesian divergence time estimation}, author = {Rannala, Bruce}, journal = {Philosophical Transactions of the Royal Society B: Biological Sciences}, volume = {371}, number = {1699}, pages = {20150134}, year = {2016}, doi = {10.1098/rstb.2015.0134}, publisher = {The Royal Society} }
PNAS
Critically evaluating the theory and performance of Bayesian analysis of macroevolutionary mixtures

Brian R Moore, Sebastian Höhna, Michael R May, Bruce Rannala, and John P Huelsenbeck

Proceedings of the National Academy of Sciences, Mar 2016

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Bayesian analysis of macroevolutionary mixtures (BAMM) has recently taken the study of lineage diversification by storm. BAMM estimates the diversification-rate parameters (speciation and extinction) for every branch of a study phylogeny and infers the number and location of diversification-rate shifts across branches of a tree. Our evaluation of BAMM reveals two major theoretical errors: (i) the likelihood function (which estimates the model parameters from the data) is incorrect, and (ii) the compound Poisson process prior model (which describes the prior distribution of diversification-rate shifts across branches) is incoherent. Using simulation, we demonstrate that these theoretical issues cause statistical pathologies; posterior estimates of the number of diversification-rate shifts are strongly influenced by the assumed prior, and estimates of diversification-rate parameters are unreliable. Moreover, the inability to correctly compute the likelihood or to correctly specify the prior for rate-variable trees precludes the use of Bayesian approaches for testing hypotheses regarding the number and location of diversification-rate shifts using BAMM.
@article{moore2016critically, title = {Critically evaluating the theory and performance of Bayesian analysis of macroevolutionary mixtures}, author = {Moore, Brian R and H{\"o}hna, Sebastian and May, Michael R and Rannala, Bruce and Huelsenbeck, John P}, journal = {Proceedings of the National Academy of Sciences}, volume = {113}, number = {34}, pages = {9569--9574}, year = {2016}, doi = {10.1073/pnas.1518659113}, publisher = {Proceedings of the National Academy of Sciences} }

2015

CurrZool
The art and science of species delimitation

Bruce Rannala

Current Zoology, Mar 2015

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DNA-based approaches to systematics have changed dramatically during the last two decades with the rise of DNA barcoding methods and newer multi-locus methods for species delimitation. During the last half-decade, partly driven by the new sequencing technologies, the focus has shifted to multi-locus sequence data and the identification of species within the framework of the multi-species coalescent (MSC). In this paper, I discuss model-based Bayesian methods for species delimitation that have been developed in recent years using the MSC. Several approximate methods for species delimitation (and their limitations) are also discussed. Explicit species delimitation models have the advantage of clarifying more precisely what is being delimited and what assumptions we are making in doing so. Moreover, the methods can be very powerful when applied to large multi-locus datasets and thus take full advantage of data generated using today’s technologies.
@article{rannala2015art, title = {The art and science of species delimitation}, author = {Rannala, Bruce}, journal = {Current Zoology}, volume = {61}, number = {5}, pages = {846--853}, year = {2015}, doi = {10.1093/czoolo/61.5.846}, publisher = {Oxford University Press Oxford, UK} }

2014

SystBiol
The influence of gene flow on species tree estimation: a simulation study

Adam D Leaché, Rebecca B Harris, Bruce Rannala, and Ziheng Yang

Systematic biology, Mar 2014

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Gene flow among populations or species and incomplete lineage sorting (ILS) are two evolutionary processes responsible for generating gene tree discordance and therefore hindering species tree estimation. Numerous studies have evaluated the impacts of ILS on species tree inference, yet the ramifications of gene flow on species trees remain less studied. Here, we simulate and analyse multilocus sequence data generated with ILS and gene flow to quantify their impacts on species tree inference. We characterize species tree estimation errors under various models of gene flow, such as the isolation-migration model, the n-island model, and gene flow between non-sister species or involving ancestral species, and species boundaries crossed by a single gene copy (allelic introgression) or by a single migrant individual. These patterns of gene flow are explored on species trees of different sizes (4 vs. 10 species), at different time scales (shallow vs. deep), and with different migration rates. Species trees are estimated with the multispecies coalescent model using Bayesian methods (BEST and *BEAST) and with a summary statistic approach (MPEST) that facilitates phylogenomic-scale analysis. Even in cases where the topology of the species tree is estimated with high accuracy, we find that gene flow can result in overestimates of population sizes (species tree dilation) and underestimates of species divergence times (species tree compression). Signatures of migration events remain present in the distribution of coalescent times for gene trees, and with sufficient data it is possible to identify those loci that have crossed species boundaries. These results highlight the need for careful sampling design in phylogeographic and species delimitation studies as gene flow, introgression, or incorrect sample assignments can bias the estimation of the species tree topology and of parameter estimates such as population sizes and divergence times. [*BEAST; BEST; coalescence; compression; dilation; introgression; MPEST; migration; simulation.]
@article{leache2014influence, title = {The influence of gene flow on species tree estimation: a simulation study}, author = {Leach{\'e}, Adam D and Harris, Rebecca B and Rannala, Bruce and Yang, Ziheng}, journal = {Systematic biology}, volume = {63}, number = {1}, pages = {17--30}, year = {2014}, doi = {10.1093/sysbio/syt049}, publisher = {Oxford University Press} }
G3
The functional significance of common polymorphisms in zinc finger transcription factors

Sarah H Lockwood, Anna Guan, Abigail S Yu, Chi Zhang, Artem Zykovich, and 3 more authors

G3: Genes, Genomes, Genetics, Mar 2014

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Variants that alter the DNA-binding specificity of transcription factors could affect the specificity for and expression of potentially many target genes, as has been observed in several tumor-derived mutations. Here we examined if such trans expression quantitative trait loci (trans-eQTLs) could similarly result from common genetic variants. We chose to focus on the Cys2-His2 class of zinc finger transcription factors because they are the most abundant superfamily of transcription factors in human and have well-characterized DNA binding interactions. We identified 430 SNPs that cause missense substitutions in the DNA-contacting residues. Fewer common missense SNPs were found at DNA-contacting residues compared with non-DNA-contacting residues (P = 0.00006), consistent with possible functional selection against SNPs at DNA-contacting positions. Functional predictions based on zinc finger transcription factor (ZNF) DNA binding preferences also suggested that many common substitutions could potentially alter binding specificity. However, Hardy-Weinberg Equilibrium analysis and examination of seven orthologs within the primate lineage failed to find evidence of trans-eQTLs associated with the DNA-contacting positions or evidence of a different selection pressure on a contemporary and evolutionary timescales. The overall conclusion was that common SNPs that alter the DNA-contacting residues of these factors are unlikely to produce strong trans-eQTLs, consistent with the observations by others that trans-eQTLs in humans tend to be few and weak. Some rare SNPs might alter specificity and remained rare due to purifying selection. The study also underscores the need for large-scale eQTLs mapping efforts that might provide experimental evidence for SNPs that alter the choice of transcription factor binding sites.
@article{lockwood2014functional, title = {The functional significance of common polymorphisms in zinc finger transcription factors}, author = {Lockwood, Sarah H and Guan, Anna and Yu, Abigail S and Zhang, Chi and Zykovich, Artem and Korf, Ian and Rannala, Bruce and Segal, David J}, journal = {G3: Genes, Genomes, Genetics}, volume = {4}, number = {9}, pages = {1647--1655}, year = {2014}, doi = {10.1534/g3.114.012195}, publisher = {Oxford University Press} }

SystBiol

Bayesian species delimitation can be robust to guide-tree inference errors

Chi Zhang, Bruce Rannala, and Ziheng Yang

Systematic Biology, Mar 2014

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@article{zhang2014bayesian,
  title = {Bayesian species delimitation can be robust to guide-tree inference errors},
  author = {Zhang, Chi and Rannala, Bruce and Yang, Ziheng},
  journal = {Systematic Biology},
  volume = {63},
  number = {6},
  pages = {993--1004},
  year = {2014},
  doi = {10.1093/sysbio/syu052},
  publisher = {Oxford University Press}
}

Genetics
Bayesian inference of shared recombination hotspots between humans and chimpanzees

Ying Wang, and Bruce Rannala

Genetics, Mar 2014

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Recombination generates variation and facilitates evolution. Recombination (or lack thereof) also contributes to human genetic disease. Methods for mapping genes influencing complex genetic diseases via association rely on linkage disequilibrium (LD) in human populations, which is influenced by rates of recombination across the genome. Comparative population genomic analyses of recombination using related primate species can identify factors influencing rates of recombination in humans. Such studies can indicate how variable hotspots for recombination may be both among individuals (or populations) and over evolutionary timescales. Previous studies have suggested that locations of recombination hotspots are not conserved between humans and chimpanzees. We made use of the data sets from recent resequencing projects and applied a Bayesian method for identifying hotspots and estimating recombination rates. We also reanalyzed SNP data sets for regions with known hotspots in humans using samples from the human and chimpanzee. The Bayes factors (BF) of shared recombination hotspots between human and chimpanzee across regions were obtained. Based on the analysis of the aligned regions of human chromosome 21, locations where the two species show evidence of shared recombination hotspots (with high BFs) were identified. Interestingly, previous comparative studies of human and chimpanzee that focused on the known human recombination hotspots within the β-globin and HLA regions did not find overlapping of hotspots. Our results show high BFs of shared hotspots at locations within both regions, and the estimated locations of shared hotspots overlap with the locations of human recombination hotspots obtained from sperm-typing studies.
@article{wang2014bayesian, title = {Bayesian inference of shared recombination hotspots between humans and chimpanzees}, author = {Wang, Ying and Rannala, Bruce}, journal = {Genetics}, volume = {198}, number = {4}, pages = {1621--1628}, year = {2014}, doi = {10.1534/genetics.114.168377}, publisher = {Oxford University Press} }
MBE
Unguided species delimitation using DNA sequence data from multiple loci

Ziheng Yang, and Bruce Rannala

Molecular Biology and Evolution, Mar 2014

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A method was developed for simultaneous Bayesian inference of species delimitation and species phylogeny using the multispecies coalescent model. The method eliminates the need for a user-specified guide tree in species delimitation and incorporates phylogenetic uncertainty in a Bayesian framework. The nearest-neighbor interchange algorithm was adapted to propose changes to the species tree, with the gene trees for multiple loci altered in the proposal to avoid conflicts with the newly proposed species tree. We also modify our previous scheme for specifying priors for species delimitation models to construct joint priors for models of species delimitation and species phylogeny. As in our earlier method, the modified algorithm integrates over gene trees, taking account of the uncertainty of gene tree topology and branch lengths given the sequence data. We conducted a simulation study to examine the statistical properties of the method using six populations (two sequences each) and a true number of three species, with values of divergence times and ancestral population sizes that are realistic for recently diverged species. The results suggest that the method tends to be conservative with high posterior probabilities being a confident indicator of species status. Simulation results also indicate that the power of the method to delimit species increases with an increase of the divergence times in the species tree, and with an increased number of gene loci. Reanalyses of two data sets of cavefish and coast horned lizards suggest considerable phylogenetic uncertainty even though the data are informative about species delimitation. We discuss the impact of the prior on models of species delimitation and species phylogeny and of the prior on population size parameters (θ) on Bayesian species delimitation.
@article{yang2014unguided, title = {Unguided species delimitation using DNA sequence data from multiple loci}, author = {Yang, Ziheng and Rannala, Bruce}, journal = {Molecular Biology and Evolution}, volume = {31}, number = {12}, pages = {3125--3135}, year = {2014}, doi = {10.1093/molbev/msu279}, publisher = {Oxford University Press} }

2013

EJHG

Meiotic gene-conversion rate and tract length variation in the human genome

Badri Padhukasahasram, and Bruce Rannala

European Journal of Human Genetics, Mar 2013

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@article{padhukasahasram2013meiotic,
  title = {Meiotic gene-conversion rate and tract length variation in the human genome},
  author = {Padhukasahasram, Badri and Rannala, Bruce},
  journal = {European Journal of Human Genetics},
  pages = {1--8},
  year = {2013},
  doi = {10.1038/ejhg.2013.30},
  publisher = {Nature Publishing Group}
}

Genetics
Improved reversible jump algorithms for Bayesian species delimitation

Bruce Rannala, and Ziheng Yang

Genetics, Mar 2013

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Several computational methods have recently been proposed for delimiting species using multilocus sequence data. Among them, the Bayesian method of Yang and Rannala uses the multispecies coalescent model in the likelihood framework to calculate the posterior probabilities for the different species-delimitation models. It has a sound statistical basis and is found to have nice statistical properties in simulation studies, such as low error rates of undersplitting and oversplitting. However, the method suffers from poor mixing of the reversible-jump Markov chain Monte Carlo (rjMCMC) algorithms. Here, we describe several modifications to the algorithms. We propose a flexible prior that allows the user to specify the probability that each node on the guide tree represents a true speciation event. We also introduce modifications to the rjMCMC algorithms that remove the constraint on the new species divergence time when splitting and alter the gene trees to remove incompatibilities. The new algorithms are found to improve mixing of the Markov chain for both simulated and empirical data sets.
@article{rannala2013improved, title = {Improved reversible jump algorithms for Bayesian species delimitation}, author = {Rannala, Bruce and Yang, Ziheng}, journal = {Genetics}, volume = {194}, number = {1}, pages = {245--253}, year = {2013}, doi = {10.1534/genetics.112.149039}, publisher = {Oxford University Press} }
TPGE
Molecular clock dating

Z Yang, and B Rannala

In The Princeton Guide to Evolution, Mar 2013

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This chapter reviews the history of the molecular clock, its impact on molecular evolution, and the controversies surrounding mechanisms of evolutionary rate variation and the application of the clock to date species divergences. We review current molecular clock dating methods, including maximum likelihood and Bayesian methods, with an emphasis on relaxing the clock and on incorporating uncertainties into fossil calibrations.
@incollection{yang2013molecular, author = {Yang, Z and Rannala, B}, editor = {Losos, Jonathon B}, booktitle = {The Princeton Guide to Evolution}, title = {Molecular clock dating}, publisher = {Princeton University Press}, year = {2013} }

2012

NatRevGen
Molecular phylogenetics: principles and practice

Ziheng Yang, and Bruce Rannala

Nature Reviews Genetics, Mar 2012

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Phylogenies are important for addressing various biological questions such as relationships among species or genes, the origin and spread of viral infection and the demographic changes and migration patterns of species. The advancement of sequencing technologies has taken phylogenetic analysis to a new height. Phylogenies have permeated nearly every branch of biology, and the plethora of phylogenetic methods and software packages that are now available may seem daunting to an experimental biologist. Here, we review the major methods of phylogenetic analysis, including parsimony, distance, likelihood and Bayesian methods. We discuss their strengths and weaknesses and provide guidance for their use.
@article{yang2012molecular, title = {Molecular phylogenetics: principles and practice}, author = {Yang, Ziheng and Rannala, Bruce}, journal = {Nature Reviews Genetics}, volume = {13}, number = {5}, pages = {303--314}, year = {2012}, doi = {10.1038/nrg3186}, publisher = {Nature Publishing Group UK London} }
MBE
Tail paradox, partial identifiability, and influential priors in Bayesian branch length inference

Bruce Rannala, Tianqi Zhu, and Ziheng Yang

Molecular Biology and Evolution, Mar 2012

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Recent studies have observed that Bayesian analyses of sequence data sets using the program MrBayes sometimes generate extremely large branch lengths, with posterior credibility intervals for the tree length (sum of branch lengths) excluding the maximum likelihood estimates. Suggested explanations for this phenomenon include the existence of multiple local peaks in the posterior, lack of convergence of the chain in the tail of the posterior, mixing problems, and misspecified priors on branch lengths. Here, we analyze the behavior of Bayesian Markov chain Monte Carlo algorithms when the chain is in the tail of the posterior distribution and note that all these phenomena can occur. In Bayesian phylogenetics, the likelihood function approaches a constant instead of zero when the branch lengths increase to infinity. The flat tail of the likelihood can cause poor mixing and undue influence of the prior. We suggest that the main cause of the extreme branch length estimates produced in many Bayesian analyses is the poor choice of a default prior on branch lengths in current Bayesian phylogenetic programs. The default prior in MrBayes assigns independent and identical distributions to branch lengths, imposing strong (and unreasonable) assumptions about the tree length. The problem is exacerbated by the strong correlation between the branch lengths and parameters in models of variable rates among sites or among site partitions. To resolve the problem, we suggest two multivariate priors for the branch lengths (called compound Dirichlet priors) that are fairly diffuse and demonstrate their utility in the special case of branch length estimation on a star phylogeny. Our analysis highlights the need for careful thought in the specification of high-dimensional priors in Bayesian analyses.
@article{rannala2012tail, title = {Tail paradox, partial identifiability, and influential priors in Bayesian branch length inference}, author = {Rannala, Bruce and Zhu, Tianqi and Yang, Ziheng}, journal = {Molecular Biology and Evolution}, volume = {29}, number = {1}, pages = {325--335}, year = {2012}, doi = {10.1093/molbev/msr210}, publisher = {Oxford University Press} }
SystBiol
Robustness of compound Dirichlet priors for Bayesian inference of branch lengths

Chi Zhang, Bruce Rannala, and Ziheng Yang

Systematic Biology, Mar 2012

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We modified the phylogenetic program MrBayes 3.1.2 to incorporate the compound Dirichlet priors for branch lengths proposed recently by Rannala, Zhu, and Yang (2012. Tail paradox, partial identifiability and influential priors in Bayesian branch length inference. Mol. Biol. Evol. 29:325–335.) as a solution to the problem of branch-length overestimation in Bayesian phylogenetic inference. The compound Dirichlet prior specifies a fairly diffuse prior on the tree length (the sum of branch lengths) and uses a Dirichlet distribution to partition the tree length into branch lengths. Six problematic data sets originally analyzed by Brown, Hedtke, Lemmon, and Lemmon (2010. When trees grow too long: investigating the causes of highly inaccurate Bayesian branch-length estimates. Syst. Biol. 59:145–161) are reanalyzed using the modified version of MrBayes to investigate properties of Bayesian branch-length estimation using the new priors. While the default exponential priors for branch lengths produced extremely long trees, the compound Dirichlet priors produced posterior estimates that are much closer to the maximum likelihood estimates. Furthermore, the posterior tree lengths were quite robust to changes in the parameter values in the compound Dirichlet priors, for example, when the prior mean of tree length changed over several orders of magnitude. Our results suggest that the compound Dirichlet priors may be useful for correcting branch-length overestimation in phylogenetic analyses of empirical data sets.
@article{zhang2012robustness, title = {Robustness of compound Dirichlet priors for Bayesian inference of branch lengths}, author = {Zhang, Chi and Rannala, Bruce and Yang, Ziheng}, journal = {Systematic Biology}, volume = {61}, number = {5}, pages = {779--784}, year = {2012}, doi = {10.1093/sysbio/sys030}, publisher = {Oxford University Press} }

2011

SystBiol
The accuracy of species tree estimation under simulation: a comparison of methods

Adam D Leaché, and Bruce Rannala

Systematic biology, Mar 2011

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Numerous simulation studies have investigated the accuracy of phylogenetic inference of gene trees under maximum parsimony, maximum likelihood, and Bayesian techniques. The relative accuracy of species tree inference methods under simulation has received less study. The number of analytical techniques available for inferring species trees is increasing rapidly, and in this paper, we compare the performance of several species tree inference techniques at estimating recent species divergences using computer simulation. Simulating gene trees within species trees of different shapes and with varying tree lengths ( T ) and population sizes (θ), and evolving sequences on those gene trees, allows us to determine how phylogenetic accuracy changes in relation to different levels of deep coalescence and phylogenetic signal. When the probability of discordance between the gene trees and the species tree is high (i.e., T is small and/or θ is large), Bayesian species tree inference using the multispecies coalescent (BEST) outperforms other methods. The performance of all methods improves as the total length of the species tree is increased, which reflects the combined benefits of decreasing the probability of discordance between species trees and gene trees and gaining more accurate estimates for gene trees. Decreasing the probability of deep coalescences by reducing θ also leads to accuracy gains for most methods. Increasing the number of loci from 10 to 100 improves accuracy under difficult demographic scenarios (i.e., coalescent units ≤ 4 Ne ), but 10 loci are adequate for estimating the correct species tree in cases where deep coalescence is limited or absent. In general, the correlation between the phylogenetic accuracy and the posterior probability values obtained from BEST is high, although posterior probabilities are overestimated when the prior distribution for θ is misspecified.
@article{leache2011accuracy, title = {The accuracy of species tree estimation under simulation: a comparison of methods}, author = {Leach{\'e}, Adam D and Rannala, Bruce}, journal = {Systematic biology}, volume = {60}, number = {2}, pages = {126--137}, year = {2011}, doi = {10.1093/sysbio/syq073}, publisher = {Oxford University Press} }
Genetics
Bayesian population genomic inference of crossing over and gene conversion

Badri Padhukasahasram, and Bruce Rannala

Genetics, Mar 2011

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Meiotic recombination is a fundamental cellular mechanism in sexually reproducing organisms and its different forms, crossing over and gene conversion both play an important role in shaping genetic variation in populations. Here, we describe a coalescent-based full-likelihood Markov chain Monte Carlo (MCMC) method for jointly estimating the crossing-over, gene-conversion, and mean tract length parameters from population genomic data under a Bayesian framework. Although computationally more expensive than methods that use approximate likelihoods, the relative efficiency of our method is expected to be optimal in theory. Furthermore, it is also possible to obtain a posterior sample of genealogies for the data using this method. We first check the performance of the new method on simulated data and verify its correctness. We also extend the method for inference under models with variable gene-conversion and crossing-over rates and demonstrate its ability to identify recombination hotspots. Then, we apply the method to two empirical data sets that were sequenced in the telomeric regions of the X chromosome of Drosophila melanogaster. Our results indicate that gene conversion occurs more frequently than crossing over in the su-w and su-s gene sequences while the local rates of crossing over as inferred by our program are not low. The mean tract lengths for gene-conversion events are estimated to be ∼70 bp and 430 bp, respectively, for these data sets. Finally, we discuss ideas and optimizations for reducing the execution time of our algorithm.
@article{padhukasahasram2011bayesian, title = {Bayesian population genomic inference of crossing over and gene conversion}, author = {Padhukasahasram, Badri and Rannala, Bruce}, journal = {Genetics}, volume = {189}, number = {2}, pages = {607--619}, year = {2011}, doi = {10.1534/genetics.111.130195}, publisher = {Oxford University Press} }

2010

PNAS
Bayesian species delimitation using multilocus sequence data

Ziheng Yang, and Bruce Rannala

Proceedings of the National Academy of Sciences, Mar 2010

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In the absence of recent admixture between species, bipartitions of individuals in gene trees that are shared across loci can potentially be used to infer the presence of two or more species. This approach to species delimitation via molecular sequence data has been constrained by the fact that genealogies for individual loci are often poorly resolved and that ancestral lineage sorting, hybridization, and other population genetic processes can lead to discordant gene trees. Here we use a Bayesian modeling approach to generate the posterior probabilities of species assignments taking account of uncertainties due to unknown gene trees and the ancestral coalescent process. For tractability, we rely on a user-specified guide tree to avoid integrating over all possible species delimitations. The statistical performance of the method is examined using simulations, and the method is illustrated by analyzing sequence data from rotifers, fence lizards, and human populations.
@article{yang2010bayesian, title = {Bayesian species delimitation using multilocus sequence data}, author = {Yang, Ziheng and Rannala, Bruce}, journal = {Proceedings of the National Academy of Sciences}, volume = {107}, number = {20}, pages = {9264--9269}, year = {2010}, doi = {10.1073/pnas.0913022107}, publisher = {National Academy of Sciences} }

2009

PNAS
Population genomic inference of recombination rates and hotspots

Ying Wang, and Bruce Rannala

Proceedings of the National Academy of Sciences, Mar 2009

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As more human genomic data become available, fine-scale recombination rate variation can be inferred on a genome-wide scale. Current statistical methods to infer recombination rates that can be applied to moderate, or large, genomic regions are limited to approximated likelihoods. Here, we develop a Bayesian full-likelihood method using Markov Chain Monte Carlo (MCMC) to estimate background recombination rates and hotspots. The probability model is inspired by the observed patterns of recombination at several genomic regions analyzed in sperm-typing studies. Posterior probabilities and Bayes factors of recombination hotspots along chromosomes are inferred. For moderate-size genomic regions (e.g., with <100 SNPs), the full-likelihood method is used. Larger regions are split into subintervals (typically each having between 20 and 50 markers). The likelihood is approximated based on the genealogies for each subinterval. The background recombination rates, hotspots, and parameters are evaluated by using a parallel computing approach and assuming shared parameters across the subintervals. Simulation analyses show that our method can accurately estimate the variation in recombination rates across genomic regions. In particular, clusters of hotspots can be distinguished even though weaker hotspots are present. The method is applied to SNP data from the HLA region, the MS32, and chromosome 19.
@article{wang2009population, title = {Population genomic inference of recombination rates and hotspots}, author = {Wang, Ying and Rannala, Bruce}, journal = {Proceedings of the National Academy of Sciences}, volume = {106}, number = {15}, pages = {6215--6219}, year = {2009}, doi = {10.1073/pnas.0900418106}, publisher = {National Academy of Sciences} }

2008

ARGHG
Phylogenetic inference using whole genomes

Bruce Rannala, and Ziheng Yang

Annu. Rev. Genomics Hum. Genet., Mar 2008

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The availability of genome-wide data provides unprecedented opportunities for resolving difficult phylogenetic relationships and for studying population genetic processes of mutation, selection, and recombination on a genomic scale. The use of appropriate statistical models becomes increasingly important when we are faced with very large datasets, which can lead to improved precision but not necessarily improved accuracy if the analytical methods have systematic biases. This review provides a critical examination of methods for analyzing genomic datasets from multiple loci, including concatenation, separate gene-by-gene analyses, and statistical models that accommodate heterogeneity in different aspects of the evolutionary process among data partitions. We discuss factors that may cause the gene tree to differ from the species tree, as well as strategies for estimating species phylogenies in the presence of gene tree conflicts. Genomic datasets provide computational and statistical challenges that are likely to be a focus of research for years to come.
@article{rannala2008phylogenetic, title = {Phylogenetic inference using whole genomes}, author = {Rannala, Bruce and Yang, Ziheng}, journal = {Annu. Rev. Genomics Hum. Genet.}, volume = {9}, pages = {217--231}, year = {2008}, doi = {10.1146/annurev.genom.9.081307.164407}, publisher = {Annual Reviews} }
PTRSB
Bayesian inference of fine-scale recombination rates using population genomic data

Ying Wang, and Bruce Rannala

Philosophical Transactions of the Royal Society B: Biological Sciences, Mar 2008

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Recently, several statistical methods for estimating fine-scale recombination rates using population samples have been developed. However, currently available methods that can be applied to large-scale data are limited to approximated likelihoods. Here, we developed a full-likelihood Markov chain Monte Carlo method for estimating recombination rate under a Bayesian framework. Genealogies underlying a sampling of chromosomes are effectively modelled by using marginal individual single nucleotide polymorphism genealogies related through an ancestral recombination graph. The method is compared with two existing composite-likelihood methods using simulated data. Simulation studies show that our method performs well for different simulation scenarios. The method is applied to two human population genetic variation datasets that have been studied by sperm typing. Our results are consistent with the estimates from sperm crossover analysis.
@article{wang2008bayesian, title = {Bayesian inference of fine-scale recombination rates using population genomic data}, author = {Wang, Ying and Rannala, Bruce}, journal = {Philosophical Transactions of the Royal Society B: Biological Sciences}, volume = {363}, number = {1512}, pages = {3921--3930}, year = {2008}, doi = {10.1098/rstb.2008.0172}, publisher = {The Royal Society London} }
CGC
TP53 gene mutations of lung cancer patients in upper northern Thailand and environmental risk factors

Kanokkan Bumroongkit, Bruce Rannala, Patrinee Traisathit, Metawee Srikummool, Yannawan Wongchai, and 1 more author

Cancer Genetics and Cytogenetics, Mar 2008

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TP53 mutations are observed in about 40–70% of lung cancer tissues, and the hot spot codon mutations are in exons 5 through 8. Previous studies revealed that the distinct TP53 mutational pattern between population groups may be due to different racial or exogenous factors. This research aims to identify risk factors that influence TP53 gene mutation in lung cancer patients residing areas with high lung cancer incidence, in the upper northern part of Thailand. Germline TP53 mutational analyses were also performed to determine the inherited cancer predisposition. Exons 5–8 of the TP53 gene were analyzed by sequencing DNA of cancerous tissue and peripheral blood leukocyte samples from 55 non–small lung cell cancer patients. The results showed that the TP53 germline mutation was not found in all patients, indicating that the TP53 germline mutations were not exclusively responsible for cancer predisposition in this group of lung cancer patients. A total of 19 somatic mutations were found in 18 patients. Mutations were predominantly found in exons, with only 10.53% observed at the splice sites of intron 7. No characteristic hot spot codons were observed. The data suggest that TP53 mutations in this study group are induced by exposure to substances other than tobacco smoke. Pesticide exposure or habitation in poorly ventilated houses may instead be related to the tumorigenesis of lung cancer via TP53 mutations.
@article{bumroongkit2008tp53, title = {TP53 gene mutations of lung cancer patients in upper northern Thailand and environmental risk factors}, author = {Bumroongkit, Kanokkan and Rannala, Bruce and Traisathit, Patrinee and Srikummool, Metawee and Wongchai, Yannawan and Kangwanpong, Daoroong}, journal = {Cancer Genetics and Cytogenetics}, volume = {185}, number = {1}, pages = {20--27}, year = {2008}, doi = {10.1016/j.cancergencyto.2008.04.009}, publisher = {Elsevier} }
MBE
Bayesian inference of errors in ancient DNA caused by postmortem degradation

Ligia M Mateiu, and Bruce H Rannala

Molecular Biology and Evolution, Mar 2008

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Methods for extracting and amplifying sequences using ancient DNA (aDNA) can be prone to errors caused by postmortem modifications of the DNA strand. A new statistical method is developed for predicting errors in aDNA sequences caused by such processes. In addition to the canonical DNA substitution model parameters, a discrete Markov chain is used to describe nucleotide substitutions occurring via postmortem degradation of the aDNA sequences. A computer program, BYPASSR-degr, was developed implementing the method and was used in subsequent analyses of simulated data sets under the new model. Simulation studies show that the new method can be powerful and accurate in identifying damaged sites. The method is applied to analyze aDNA sequences of Etruscans, Adélie penguins, and horses. No significant signals of degradation were observed at any sites of the aDNA sequences we analyzed.
@article{mateiu2008bayesian, title = {Bayesian inference of errors in ancient DNA caused by postmortem degradation}, author = {Mateiu, Ligia M and Rannala, Bruce H}, journal = {Molecular Biology and Evolution}, volume = {25}, number = {7}, pages = {1503--1511}, year = {2008}, doi = {10.1093/molbev/msn095}, publisher = {Oxford University Press} }
BMCEB
Identification and analysis of evolutionary selection pressures acting at the molecular level in five forkhead subfamilies

Christina D Fetterman, Bruce Rannala, and Michael A Walter

BMC Evolutionary Biology, Mar 2008

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Background Members of the forkhead gene family act as transcription regulators in biological processes including development and metabolism. The evolution of forkhead genes has not been widely examined and selection pressures at the molecular level influencing subfamily evolution and differentiation have not been explored. Here, in silico methods were used to examine selection pressures acting on the coding sequence of five multi-species FOX protein subfamily clusters; FoxA, FoxD, FoxI, FoxO and FoxP. Results Application of site models, which estimate overall selection pressures on individual codons throughout the phylogeny, showed that the amino acid changes observed were either neutral or under negative selection. Branch-site models, which allow estimated selection pressures along specified lineages to vary as compared to the remaining phylogeny, identified positive selection along branches leading to the FoxA3 and Protostomia clades in the FoxA cluster and the branch leading to the FoxO3 clade in the FoxO cluster. Residues that may differentiate paralogs were identified in the FoxA and FoxO clusters and residues that differentiate orthologs were identified in the FoxA cluster. Neutral amino acid changes were identified in the forkhead domain of the FoxA, FoxD and FoxP clusters while positive selection was identified in the forkhead domain of the Protostomia lineage of the FoxA cluster. A series of residues under strong negative selection adjacent to the N- and C-termini of the forkhead domain were identified in all clusters analyzed suggesting a new method for refinement of domain boundaries. Extrapolation of domains among cluster members in conjunction with selection pressure information allowed prediction of residue function in the FoxA, FoxO and FoxP clusters and exclusion of known domain function in residues of the FoxA and FoxI clusters. Conclusion Consideration of selection pressures observed in conjunction with known functional information allowed prediction of residue function and refinement of domain boundaries. Identification of residues that differentiate orthologs and paralogs provided insight into the development and functional consequences of paralogs and forkhead subfamily composition differences among species. Overall we found that after gene duplication of forkhead family members, rapid differentiation and subsequent fixation of amino acid changes through negative selection has occurred.
@article{fetterman2008identification, title = {Identification and analysis of evolutionary selection pressures acting at the molecular level in five forkhead subfamilies}, author = {Fetterman, Christina D and Rannala, Bruce and Walter, Michael A}, journal = {BMC Evolutionary Biology}, volume = {8}, pages = {1--13}, year = {2008}, doi = {10.1186/1471-2148-8-261}, publisher = {BioMed Central} }

2007

SystBiol
Inferring speciation times under an episodic molecular clock

Bruce Rannala, and Ziheng Yang

Systematic Biology, Mar 2007

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We extend our recently developed Markov chain Monte Carlo algorithm for Bayesian estimation of species divergence times to allow variable evolutionary rates among lineages. The method can use heterogeneous data from multiple gene loci and accommodate multiple fossil calibrations. Uncertainties in fossil calibrations are described using flexible statistical distributions. The prior for divergence times for nodes lacking fossil calibrations is specified by use of a birth-death process with species sampling. The prior for lineage-specific substitution rates is specified using either a model with autocorrelated rates among adjacent lineages (based on a geometric Brownian motion model of rate drift) or a model with independent rates among lineages specified by a log-normal probability distribution. We develop an infinite-sites theory, which predicts that when the amount of sequence data approaches infinity, the width of the posterior credibility interval and the posterior mean of divergence times form a perfect linear relationship, with the slope indicating uncertainties in time estimates that cannot be reduced by sequence data alone. Simulations are used to study the influence of among-lineage rate variation and the number of loci sampled on the uncertainty of divergence time estimates. The analysis suggests that posterior time estimates typically involve considerable uncertainties even with an infinite amount of sequence data, and that the reliability and precision of fossil calibrations are critically important to divergence time estimation. We apply our new algorithms to two empirical data sets and compare the results with those obtained in previous Bayesian and likelihood analyses. The results demonstrate the utility of our new algorithms.
@article{rannala2007inferring, title = {Inferring speciation times under an episodic molecular clock}, author = {Rannala, Bruce and Yang, Ziheng}, journal = {Systematic Biology}, volume = {56}, number = {3}, pages = {453--466}, year = {2007}, doi = {10.1080/10635150701420643}, publisher = {Oxford University Press} }
SystBiol
Summarizing a posterior distribution of trees using agreement subtrees

Karen A Cranston, and Bruce Rannala

Systematic biology, Mar 2007

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Bayesian inference of phylogeny is unique among phylogenetic reconstruction methods in that it produces a posterior distribution of trees rather than a point estimate of the best tree. The most common way to summarize this distribution is to report the majority-rule consensus tree annotated with the marginal posterior probabilities of each partition. Reporting a single tree discards information contained in the full underlying distribution and reduces the Bayesian analysis to simply another method for finding a point estimate of the tree. Even when a point estimate of the phylogeny is desired, the majority-rule consensus tree is only one possible method, and there may be others that are more appropriate for the given data set and application. We present a method for summarizing the distribution of trees that is based on identifying agreement subtrees that are frequently present in the posterior distribution. This method provides fully resolved binary trees for subsets of taxa with high marginal posterior probability on the entire tree and includes additional information about the spread of the distribution.
@article{cranston2007summarizing, author = {Cranston, Karen A and Rannala, Bruce}, journal = {Systematic biology}, volume = {56}, number = {4}, pages = {578--590}, year = {2007}, doi = {10.1080/10635150701485091}, publisher = {Society of Systematic Zoology} }
Genetics
Inferring somatic mutation rates using the stop-enhanced green fluorescent protein mouse

Simon Ro, and Bruce Rannala

Genetics, Mar 2007

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A new method is developed for estimating rates of somatic mutation in vivo. The stop-enhanced green fluorescent protein (EGFP) transgenic mouse carries multiple copies of an EGFP gene with a premature stop codon. The gene can revert to a functional form via point mutations. Mice treated with a potent mutagen, N-ethyl-N-nitrosourea (ENU), and mice treated with a vehicle alone are assayed for mutations in liver cells. A stochastic model is developed to model the mutation and gene expression processes and maximum-likelihood estimators of the model parameters are derived. A likelihood-ratio test (LRT) is developed for detecting mutagenicity. Parametric bootstrap simulations are used to obtain confidence intervals of the parameter estimates and to estimate the significance of the LRT. The LRT is highly significant (α < 0.01) and the 95% confidence interval for the relative effect of the mutagen (the ratio of the rate of mutation during the interval of mutagen exposure to the rate of background mutation) ranges from a minimum 200-fold effect of the mutagen to a maximum 2000-fold effect.
@article{ro2007inferring, title = {Inferring somatic mutation rates using the stop-enhanced green fluorescent protein mouse}, author = {Ro, Simon and Rannala, Bruce}, journal = {Genetics}, volume = {177}, number = {1}, pages = {9--16}, year = {2007}, doi = {10.1534/genetics.106.069310}, publisher = {Oxford University Press} }

2006

MBE
Bayesian estimation of species divergence times under a molecular clock using multiple fossil calibrations with soft bounds

Ziheng Yang, and Bruce Rannala

Molecular Biology and Evolution, Mar 2006

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We implement a Bayesian Markov chain Monte Carlo algorithm for estimating species divergence times that uses heterogeneous data from multiple gene loci and accommodates multiple fossil calibration nodes. A birth-death process with species sampling is used to specify a prior for divergence times, which allows easy assessment of the effects of that prior on posterior time estimates. We propose a new approach for specifying calibration points on the phylogeny, which allows the use of arbitrary and flexible statistical distributions to describe uncertainties in fossil dates. In particular, we use soft bounds, so that the probability that the true divergence time is outside the bounds is small but nonzero. A strict molecular clock is assumed in the current implementation, although this assumption may be relaxed. We apply our new algorithm to two data sets concerning divergences of several primate species, to examine the effects of the substitution model and of the prior for divergence times on Bayesian time estimation. We also conduct computer simulation to examine the differences between soft and hard bounds. We demonstrate that divergence time estimation is intrinsically hampered by uncertainties in fossil calibrations, and the error in Bayesian time estimates will not go to zero with increased amounts of sequence data. Our analyses of both real and simulated data demonstrate potentially large differences between divergence time estimates obtained using soft versus hard bounds and a general superiority of soft bounds. Our main findings are as follows. (1) When the fossils are consistent with each other and with the molecular data, and the posterior time estimates are well within the prior bounds, soft and hard bounds produce similar results. (2) When the fossils are in conflict with each other or with the molecules, soft and hard bounds behave very differently; soft bounds allow sequence data to correct poor calibrations, while poor hard bounds are impossible to overcome by any amount of data. (3) Soft bounds eliminate the need for “safe” but unrealistically high upper bounds, which may bias posterior time estimates. (4) Soft bounds allow more reliable assessment of estimation errors, while hard bounds generate misleadingly high precisions when fossils and molecules are in conflict.
@article{yang2006bayesian, title = {Bayesian estimation of species divergence times under a molecular clock using multiple fossil calibrations with soft bounds}, author = {Yang, Ziheng and Rannala, Bruce}, journal = {Molecular Biology and Evolution}, volume = {23}, number = {1}, pages = {212--226}, year = {2006}, doi = {10.1093/molbev/msj024}, publisher = {Oxford University Press} }
SystBiol
Inferring complex DNA substitution processes on phylogenies using uniformization and data augmentation

Ligia Mateiu, and Bruce Rannala

Systematic Biology, Mar 2006

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A new method is developed for calculating sequence substitution probabilities using Markov chain Monte Carlo (MCMC) methods. The basic strategy is to use uniformization to transform the original continuous time Markov process into a Poisson substitution process and a discrete Markov chain of state transitions. An efficient MCMC algorithm for evaluating substitution probabilities by this approach using a continuous gamma distribution to model site-specific rates is outlined. The method is applied to the problem of inferring branch lengths and site-specific rates from nucleotide sequences under a general time-reversible (GTR) model and a computer program BYPASSR is developed. Simulations are used to examine the performance of the new program relative to an existing program BASEML that uses a discrete approximation for the gamma distributed prior on site-specific rates. It is found that BASEML and BYPASSR are in close agreement when inferring branch lengths, regardless of the number of rate categories used, but that BASEML tends to underestimate high site-specific substitution rates, and to overestimate intermediate rates, when fewer than 50 rate categories are used. Rate estimates obtained using BASEML agree more closely with those of BYPASSR as the number of rate categories increases. Analyses of the posterior distributions of site-specific rates from BYPASSR suggest that a large number of taxa are needed to obtain precise estimates of site-specific rates, especially when rates are very high or very low. The method is applied to analyze 45 sequences of the alpha 2B adrenergic receptor gene (A2AB) from a sample of eutherian taxa. In general, the pattern expected for regions under negative selection is observed with third codon positions having the highest inferred rates, followed by first codon positions and with second codon positions having the lowest inferred rates. Several sites show exceptionally high substitution rates at second codon positions that may represent the effects of positive selection.
@article{mateiu2006inferring, title = {Inferring complex DNA substitution processes on phylogenies using uniformization and data augmentation}, author = {Mateiu, Ligia and Rannala, Bruce}, journal = {Systematic Biology}, volume = {55}, number = {2}, pages = {259--269}, year = {2006}, doi = {10.1080/10635150500541599}, publisher = {Oxford University Press} }

2005

SystBiol
Branch-length prior influences Bayesian posterior probability of phylogeny

Ziheng Yang, and Bruce Rannala

Systematic Biology, Mar 2005

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The Bayesian method for estimating species phylogenies from molecular sequence data provides an attractive alternative to maximum likelihood with nonparametric bootstrap due to the easy interpretation of posterior probabilities for trees and to availability of efficient computational algorithms. However, for many data sets it produces extremely high posterior probabilities, sometimes for apparently incorrect clades. Here we use both computer simulation and empirical data analysis to examine the effect of the prior model for internal branch lengths. We found that posterior probabilities for trees and clades are sensitive to the prior for internal branch lengths, and priors assuming long internal branches cause high posterior probabilities for trees. In particular, uniform priors with high upper bounds bias Bayesian clade probabilities in favor of extreme values. We discuss possible remedies to the problem, including empirical and full Bayesian methods and subjective procedures suggested in Bayesian hypothesis testing. Our results also suggest that the bootstrap proportion and Bayesian posterior probability are different measures of accuracy, and that the bootstrap proportion, if interpreted as the probability that the clade is true, can be either too liberal or too conservative.
@article{yang2005branch, author = {Yang, Ziheng and Rannala, Bruce}, journal = {Systematic Biology}, volume = {54}, number = {3}, pages = {455--470}, year = {2005}, doi = {10.1080/10635150590945313}, publisher = {Oxford University Press} }
AJHG
In silico analysis of disease-association mapping strategies using the coalescent process and incorporating ascertainment and selection

Ying Wang, and Bruce Rannala

The American Journal of Human Genetics, Mar 2005

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We present a new method for simulating samples of marker haplotypes, genotypes, or diplotypes in case-control studies in which the markers are linked to a disease locus in any specified region of the genome. The method allows realistic features to be incorporated into the simulations, including selection acting on disease alleles, sample ascertainment of disease chromosomes and polymorphic markers, a genetic dominance model of disease expression that allows incomplete penetrance and phenocopies, and an accurate genetic map of recombination rates and hotspots for recombination in the human genome (or, alternatively, an improved method for simulating the distribution of hotspots). The new method uses an approach that combines simulation of the coalescent process for the sampled chromosomes with a diffusion process used to model the evolution of the disease-mutation frequency over time. Examples illustrate how the method may be used to study the expected power of a marker-disease association study.
@article{wang2005silico, title = {In silico analysis of disease-association mapping strategies using the coalescent process and incorporating ascertainment and selection}, author = {Wang, Ying and Rannala, Bruce}, journal = {The American Journal of Human Genetics}, volume = {76}, number = {6}, pages = {1066--1073}, year = {2005}, doi = {10.1086/430472}, publisher = {Cell Press} }
ExpDerm
Evidence from the stop-EGFP mouse supports a niche-sharing model of epidermal proliferative units

Simon Ro, and Bruce Rannala

Experimental dermatology, Mar 2005

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The classical model of epidermal proliferative units (EPUs) postulates that each EPU is composed of a single column of corneocytes plus epidermal cells directly below the column and is maintained by a single stem cell within the unit. Using the stop-enhanced green fluorescent protein (stop-EGFP) transgenic mouse system, we previously showed epidermal stem cell clonal lineages could produce multiple adjacent corneocytes (i.e. epidermal cells belonging to multiple adjacent EPUs), contradicting the classical EPU model. One possible problem with our earlier study was that N-ethyl-N-nitrosourea (ENU) was used to generate mutations for clonal analysis. This could alter the normal environment of the epidermal tissue and might lead to an artificial expansion of stem cell clonal lineages. In this study, we replicate our earlier findings using untreated stop-EGFP mice and relying on spontaneous mutations to generate clonal cell lineages. We propose an alternative to the classical EPU model to explain the dynamic nature of epidermal proliferation. Our niche-sharing model of EPUs allows epidermal cells to horizontally migrate among EPUs, so that multiple stem cells cooperatively maintain a larger proliferative compartment.
@article{ro2005evidence, author = {Ro, Simon and Rannala, Bruce}, journal = {Experimental dermatology}, volume = {14}, number = {11}, pages = {838--843}, year = {2005}, doi = {10.1111/j.1600-0625.2005.00366.x}, publisher = {Munksgaard International Publishers Oxford, UK; Malden, USA} }

Heredity

Closing the gap between rocks and clocks

K Cranston, and B Rannala

Heredity, Mar 2005

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@article{cranston2005closing,
  title = {Closing the gap between rocks and clocks},
  author = {Cranston, K and Rannala, B},
  journal = {Heredity},
  volume = {94},
  number = {5},
  pages = {461--462},
  doi = {10.1038/sj.hdy.6800644},
  year = {2005}
}

2004

SystBiol
Frequentist properties of Bayesian posterior probabilities of phylogenetic trees under simple and complex substitution models

John P Huelsenbeck, and Bruce Rannala

Systematic biology, Mar 2004

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What does the posterior probability of a phylogenetic tree mean? This simulation study shows that Bayesian posterior probabilities have the meaning that is typically ascribed to them; the posterior probability of a tree is the probability that the tree is correct, assuming that the model is correct. At the same time, the Bayesian method can be sensitive to model misspecification, and the sensitivity of the Bayesian method appears to be greater than the sensitivity of the nonparametric bootstrap method (using maximum likelihood to estimate trees). Although the estimates of phylogeny obtained by use of the method of maximum likelihood or the Bayesian method are likely to be similar, the assessment of the uncertainty of inferred trees via either bootstrapping (for maximum likelihood estimates) or posterior probabilities (for Bayesian estimates) is not likely to be the same. We suggest that the Bayesian method be implemented with the most complex models of those currently available, as this should reduce the chance that the method will concentrate too much probability on too few trees.
@article{huelsenbeck2004frequentist, author = {Huelsenbeck, John P and Rannala, Bruce}, journal = {Systematic biology}, volume = {53}, number = {6}, pages = {904--913}, year = {2004}, doi = {10.1080/10635150490522629}, publisher = {Society of Systematic Zoology} }
NatRevGen
The Bayesian revolution in genetics

Mark A Beaumont, and Bruce Rannala

Nature Reviews Genetics, Mar 2004

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Bayesian statistics allow scientists to easily incorporate prior knowledge into their data analysis. Nonetheless, the sheer amount of computational power that is required for Bayesian statistical analyses has previously limited their use in genetics. These computational constraints have now largely been overcome and the underlying advantages of Bayesian approaches are putting them at the forefront of genetic data analysis in an increasing number of areas.
@article{beaumont2004bayesian, title = {The Bayesian revolution in genetics}, author = {Beaumont, Mark A and Rannala, Bruce}, journal = {Nature Reviews Genetics}, volume = {5}, number = {4}, pages = {251--261}, year = {2004}, doi = {10.1038/nrg1318}, publisher = {Nature Publishing Group UK London} }
EMBO
A stop-EGFP transgenic mouse to detect clonal cell lineages generated by mutation

Simon Ro, and Bruce Rannala

EMBO reports, Mar 2004

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The investigation of cell lineages and clonal organization in tissues is facilitated by techniques that allow labelling of clonal cell lineages. Here, we describe a novel transgenic mouse that allows clonal cell lineages to be traced in virtually any tissue. A green fluorescent cell lineage is generated by a random mutation at an enhanced green fluorescent protein gene that carries a premature stop codon, ensuring clonality. The transgenic system allows efficient detection of mutations and stem-cell fate mapping in the epidermis using live mice, as well as in the kidney and liver post-mortem. Cell lineages that descended from single epidermal stem cells were found to be capable of generating three adjacent corneocytes using the system, providing evidence for horizontal migration of epidermal cells between epidermal proliferative units (EPUs), in contrast to the classical EPU model. The transgenic mouse system is expected to provide a novel tool for stem-cell lineage studies.
@article{ro2004stop, title = {A stop-EGFP transgenic mouse to detect clonal cell lineages generated by mutation}, author = {Ro, Simon and Rannala, Bruce}, journal = {EMBO reports}, volume = {5}, number = {9}, pages = {914--920}, year = {2004}, doi = {10.1038/sj.embor.7400218}, publisher = {John Wiley \& Sons, Ltd Chichester, UK} }
Genetics
A novel solution for the time-dependent probability of gene fixation or loss under natural selection

Ying Wang, and Bruce Rannala

Genetics, Mar 2004

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KIMURA (1955b) proposed a solution for the time-dependent probability of fixation, or loss, of a gene under selection. Example calculations suggest the formulas are prone to numerical inaccuracies. An alternative solution is proposed; the correctness of the solution is confirmed by numerically solving the Kolmogorov backward equation and by simulation.
@article{wang2004novel, title = {A novel solution for the time-dependent probability of gene fixation or loss under natural selection}, author = {Wang, Ying and Rannala, Bruce}, journal = {Genetics}, volume = {168}, number = {2}, pages = {1081--1084}, year = {2004}, doi = {10.1534/genetics.104.027797}, publisher = {Oxford University Press} }
LNCS
Simulating a coalescent process with recombination and ascertainment

Ying Wang, and Bruce Rannala

Lecture Notes in Computer Science, Mar 2004

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A new method is presented for use in simulating samples of disease and normal chromosomes bearing multiple linked genetic markers under a neutral model of mutation, genetic drift, and recombination. The method accounts for the potential effects of investigator sampling bias by allowing for ascertainment of chromosomes according to disease status and of markers according to a pre-specified polymorphism cutoff level. The method was implemented in a computer program and applied to study the general effects of disease mutation age (or frequency), levels of marker polymorphism, and sample size, on pairwise LD between markers and a disease mutation. It is shown that the average pairwise LD between a marker and a disease mutation is lower for older, or more prevalent, disease mutations, as expected. The marker polymorphism cutoff level also has an important influence on LD. Potential applications of the method for predicting the power of genome-wide marker-disease association studies are discussed.
@article{wang2004simulating, title = {Simulating a coalescent process with recombination and ascertainment}, author = {Wang, Ying and Rannala, Bruce}, journal = {Lecture Notes in Computer Science}, pages = {84--95}, year = {2004}, doi = {10.1007/978-3-540-24719-7_7}, publisher = {SPRINGER-VERLAG} }

2003

Genetics
Bayesian inference of recent migration rates using multilocus genotypes

Gregory A Wilson, and Bruce Rannala

Genetics, Mar 2003

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A new Bayesian method that uses individual multilocus genotypes to estimate rates of recent immigration (over the last several generations) among populations is presented. The method also estimates the posterior probability distributions of individual immigrant ancestries, population allele frequencies, population inbreeding coefficients, and other parameters of potential interest. The method is implemented in a computer program that relies on Markov chain Monte Carlo techniques to carry out the estimation of posterior probabilities. The program can be used with allozyme, microsatellite, RFLP, SNP, and other kinds of genotype data. We relax several assumptions of early methods for detecting recent immigrants, using genotype data; most significantly, we allow genotype frequencies to deviate from Hardy-Weinberg equilibrium proportions within populations. The program is demonstrated by applying it to two recently published microsatellite data sets for populations of the plant species Centaurea corymbosa and the gray wolf species Canis lupus. A computer simulation study suggests that the program can provide highly accurate estimates of migration rates and individual migrant ancestries, given sufficient genetic differentiation among populations and sufficient numbers of marker loci.
@article{wilson2003bayesian, title = {Bayesian inference of recent migration rates using multilocus genotypes}, author = {Wilson, Gregory A and Rannala, Bruce}, journal = {Genetics}, volume = {163}, number = {3}, pages = {1177--1191}, year = {2003}, doi = {10.1093/genetics/163.3.1177}, publisher = {Oxford University Press} }
Genetics
Bayes estimation of species divergence times and ancestral population sizes using DNA sequences from multiple loci

Bruce Rannala, and Ziheng Yang

Genetics, Mar 2003

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The effective population sizes of ancestral as well as modern species are important parameters in models of population genetics and human evolution. The commonly used method for estimating ancestral population sizes, based on counting mismatches between the species tree and the inferred gene trees, is highly biased as it ignores uncertainties in gene tree reconstruction. In this article, we develop a Bayes method for simultaneous estimation of the species divergence times and current and ancestral population sizes. The method uses DNA sequence data from multiple loci and extracts information about conflicts among gene tree topologies and coalescent times to estimate ancestral population sizes. The topology of the species tree is assumed known. A Markov chain Monte Carlo algorithm is implemented to integrate over uncertain gene trees and branch lengths (or coalescence times) at each locus as well as species divergence times. The method can handle any species tree and allows different numbers of sequences at different loci. We apply the method to published noncoding DNA sequences from the human and the great apes. There are strong correlations between posterior estimates of speciation times and ancestral population sizes. With the use of an informative prior for the human-chimpanzee divergence date, the population size of the common ancestor of the two species is estimated to be ∼20,000, with a 95% credibility interval (8000, 40,000). Our estimates, however, are affected by model assumptions as well as data quality. We suggest that reliable estimates have yet to await more data and more realistic models.
@article{rannala2003bayes, title = {Bayes estimation of species divergence times and ancestral population sizes using DNA sequences from multiple loci}, author = {Rannala, Bruce and Yang, Ziheng}, journal = {Genetics}, volume = {164}, number = {4}, pages = {1645--1656}, year = {2003}, doi = {10.1093/genetics/164.4.1645}, publisher = {Oxford University Press} }
Evolution
Detecting correlation between characters in a comparative analysis with uncertain phylogeny

John P Huelsenbeck, and Bruce Rannala

Evolution, Mar 2003

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The importance of accommodating the phylogenetic history of a group when performing a comparative analysis is now widely recognized. The typical approaches either assume the tree is known without error, or they base inferences on a collection of well-supported trees or on a collection of trees generated under a stochastic model of cladogenesis. However, these approaches do not adequately account for the uncertainty of phylogenetic trees in a comparative analysis, especially when data relevant to the phylogeny of a group are available. Here, we develop a method for performing comparative analyses that is based on an extension of Felsenstein’s independent contrasts method. Uncertainties in the phylogeny, branch lengths, and other parameters are accommodated by averaging over all possible trees, weighting each by the probability that the tree is correct. We do this in a Bayesian framework and use Markov chain Monte Carlo to perform the high-dimensional summations and integrations required by the analysis. We illustrate the method using comparative characters sampled from Anolis lizards.
@article{huelsenbeck2003detecting, title = {Detecting correlation between characters in a comparative analysis with uncertain phylogeny}, author = {Huelsenbeck, John P and Rannala, Bruce}, journal = {Evolution}, volume = {57}, number = {6}, pages = {1237--1247}, year = {2003}, doi = {10.1111/j.0014-3820.2003.tb00332.x}, publisher = {Blackwell Publishing Ltd Oxford, UK} }
Genetics
Likelihood models of somatic mutation and codon substitution in cancer genes

Ziheng Yang, Simon Ro, and Bruce Rannala

Genetics, Mar 2003

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The role of somatic mutation in cancer is well established and several genes have been identified that are frequent targets. This has enabled large-scale screening studies of the spectrum of somatic mutations in cancers of particular organs. Cancer gene mutation databases compile the results of many studies and can provide insight into the importance of specific amino acid sequences and functional domains in cancer, as well as elucidate aspects of the mutation process. Past studies of the spectrum of cancer mutations (in particular genes) have examined overall frequencies of mutation (at specific nucleotides) and of missense, nonsense, and silent substitution (at specific codons) both in the sequence as a whole and in a specific functional domain. Existing methods ignore features of the genetic code that allow some codons to mutate to missense, or stop, codons more readily than others (i.e., by one nucleotide change, vs. two or three). A new codon-based method to estimate the relative rate of substitution (fixation of a somatic mutation in a cancer cell lineage) of nonsense vs. missense mutations in different functional domains and in different tumor tissues is presented. Models that account for several potential influences on rates of somatic mutation and substitution in cancer progenitor cells and allow biases of mutation rates for particular dinucleotide sequences (CGs and dipyrimidines), transition vs. transversion bias, and variable rates of silent substitution across functional domains (useful in detecting investigator sampling bias) are considered. Likelihood-ratio tests are used to choose among models, using cancer gene mutation data. The method is applied to analyze published data on the spectrum of p53 mutations in cancers. A novel finding is that the ratio of the probability of nonsense to missense substitution is much lower in the DNA-binding and transactivation domains (ratios near 1) than in structural domains such as the linker, tetramerization (oligomerization), and proline-rich domains (ratios exceeding 100 in some tissues), implying that the specific amino acid sequence may be less critical in structural domains (e.g., amino acid changes less often lead to cancer). The transition vs. transversion bias and effect of CpG dinucleotides on mutation rates in p53 varied greatly across cancers of different organs, likely reflecting effects of different endogenous and exogenous factors influencing mutation in specific organs.
@article{yang2003likelihood, title = {Likelihood models of somatic mutation and codon substitution in cancer genes}, author = {Yang, Ziheng and Ro, Simon and Rannala, Bruce}, journal = {Genetics}, volume = {165}, number = {2}, pages = {695--705}, year = {2003}, doi = {10.1093/genetics/165.2.695}, publisher = {Oxford University Press} }

Population genetics and cospeciation: from process to pattern

Bruce Rannala, and Yannis Michalakis

Tangled trees: phylogeny, cospeciation and coevolution, Mar 2003

Bib

@article{rannala2003population,
  title = {Population genetics and cospeciation: from process to pattern},
  author = {Rannala, Bruce and Michalakis, Yannis},
  journal = {Tangled trees: phylogeny, cospeciation and coevolution},
  pages = {120--143},
  year = {2003},
  publisher = {The University of Chicago Press}
}

A statistical perspective for reconstructing the history of host-parasite associations

John P Huelsenbeck, Bruce Rannala, and Bret Larget

Tangled trees: phylogeny, co-speciation and co-evolution, Mar 2003

Bib

@article{huelsenbeck2003statistical,
  title = {A statistical perspective for reconstructing the history of host-parasite associations},
  author = {Huelsenbeck, John P and Rannala, Bruce and Larget, Bret},
  journal = {Tangled trees: phylogeny, co-speciation and co-evolution},
  pages = {93--119},
  year = {2003}
}

ELS
Stationary Allele Frequency Distributions

Bruce Rannala

eLS, Mar 2003

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Forces that determine the allele frequencies in natural populations include genetic drift, natural selection, migration and mutation. A balance of opposing forces can, in some cases, cause allele frequencies to approach a stationary distribution over time. The form of this distribution is not influenced by initial allele frequencies, but instead is determined by the relative magnitudes of different evolutionary forces. Statistical distributions are presented for the stationary allele frequencies under several simple population genetic models (including the k alleles symmetrical mutation model and the Wright island model of migration). In addition, the sampling distribution of allele counts under these models are described. The latter is useful when using genetic marker data to estimate population parameters. A population is at genetic equilibrium if evolutionary forces have persisted long enough for a population to have reached the stationary distribution, this is not often the case in nature.
@article{rannala2003stationary, title = {Stationary Allele Frequency Distributions}, author = {Rannala, Bruce}, journal = {eLS}, year = {2003}, publisher = {John Wiley \& Sons, Ltd} }

2002

SystBiol
Identifiability of parameters in MCMC Bayesian inference of phylogeny

Bruce Rannala

Systematic biology, Mar 2002

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Methods for Bayesian inference of phylogeny using DNA sequences based on Markov chain Monte Carlo (MCMC) techniques allow the incorporation of arbitrarily complex models of the DNA substitution process, and other aspects of evolution. This has increased the realism of models, potentially improving the accuracy of the methods, and is largely responsible for their recent popularity. Another consequence of the increased complexity of models in Bayesian phylogenetics is that these models have, in several cases, become overparameterized. In such cases, some parameters of the model are not identifiable; different combinations of nonidentifiable parameters lead to the same likelihood, making it impossible to decide among the potential parameter values based on the data. Overparameterized models can also slow the rate of convergence of MCMC algorithms due to large negative correlations among parameters in the posterior probability distribution. Functions of parameters can sometimes be found, in overparameterized models, that are identifiable, and inferences based on these functions are legitimate. Examples are presented of overparameterized models that have been proposed in the context of several Bayesian methods for inferring the relative ages of nodes in a phylogeny when the substitution rate evolves over time.
@article{rannala2002identifiability, title = {Identifiability of parameters in MCMC Bayesian inference of phylogeny}, author = {Rannala, Bruce}, journal = {Systematic biology}, volume = {51}, number = {5}, pages = {754--760}, year = {2002}, doi = {10.1080/10635150290102429}, publisher = {Society of Systematic Zoology} }
Bioinformatics
DMLE+: Bayesian linkage disequilibrium gene mapping

Jeff P Reeve, and Bruce Rannala

Bioinformatics, Mar 2002

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Summary: The program DMLE+ allows Bayesian inference of the location of a gene carrying a mutation influencing a discrete trait (such as a disease) and/or other parameters of interest (such as mutation age) based on the observed linkage disequilibrium at multiple genetic markers. DMLE+ uses either individual marker genotypes, or haplotypes, integrates over uncertain population allele frequencies, and can incorporate prior information about gene location from an annotated human genome sequence. Availability: DMLE+ is available in both Windows GUI and portable UNIX command line versions at http://dmle.org
@article{reeve2002dmle+, title = {DMLE+: Bayesian linkage disequilibrium gene mapping}, author = {Reeve, Jeff P and Rannala, Bruce}, journal = {Bioinformatics}, volume = {18}, number = {6}, pages = {894--895}, year = {2002}, doi = {10.1093/bioinformatics/18.6.894}, publisher = {Oxford Univ Press} }
PNAS
Disease surveillance in recombining pathogens: multilocus genotypes identify sources of human Coccidioides infections

Matthew C Fisher, Bruce Rannala, Vishnu Chaturvedi, and John W Taylor

Proceedings of the National Academy of Sciences, Mar 2002

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Molecular surveillance of pathogenic microbes works by genotyping isolates with DNA fingerprinting techniques and then using these genotypes to assign individuals to populations. Clonality is assumed in many fingerprinting studies, although this assumption has been shown to be false for many organisms. To accommodate recombining organisms into surveillance programs, methods using population allele frequencies in combination with individual multilocus genotypes are necessary. Here, we develop a statistical method appropriate for haploid recombining microbes that allows individuals to be assigned to populations. We illustrate the usefulness of this technique by inferring the source populations for Coccidioides isolates recovered from patients treated outside the endemic area of Coccidioides sp., the etiological agents of human coccidioidomycosis, but with a travel history including visits to one or more endemic areas.
@article{fisher2002disease, title = {Disease surveillance in recombining pathogens: multilocus genotypes identify sources of human Coccidioides infections}, author = {Fisher, Matthew C and Rannala, Bruce and Chaturvedi, Vishnu and Taylor, John W}, journal = {Proceedings of the National Academy of Sciences}, volume = {99}, number = {13}, pages = {9067--9071}, year = {2002}, doi = {10.1073/pnas.132178099}, publisher = {National Academy of Sciences} }
PSB2003
Joint Bayesian estimation of mutation location and age using linkage disequilibrium

Bruce Rannala, and Jeff P Reeve

In Pacific Symposium on Biocomputing 2003, Mar 2002

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Associations between disease and marker alleles on chromosomes in populations can arise as a consequence of historical forces such as mutation, selection and genetic drift, and is referred to as "linkage disequilibrium" (LD). LD can be used to estimate the map position of a disease mutation relative to a set of linked markers, as well as to estimate other parameters of interest, such as mutation age. Parametric methods for estimating the location of a disease mutation using marker linkage disequilibrium in a sample of normal and affected individuals require a detailed knowledge of population demography, and in particular require users to specify the postulated age of a mutation and past population growth rates. A new Bayesian method is presented for jointly estimating the position of a disease mutation and its age. The method is illustrated using haplotype data for the cystic fibrosis ΔF508 mutation in europe and the DTD mutation in Finland. It is shown that, for these datasets, the posterior probability distribution of disease mutation location is insensitive to the population growth rate when the model is averaged over possible mutation ages using a prior probability distribution for the mutation age based on the population frequency of the disease mutation. Fewer assumptions are therefore needed for parametric LD mapping.
@incollection{rannala2002joint, title = {Joint Bayesian estimation of mutation location and age using linkage disequilibrium}, author = {Rannala, Bruce and Reeve, Jeff P}, booktitle = {Pacific Symposium on Biocomputing 2003}, pages = {526--534}, doi = {10.1142/9789812776303_0049}, year = {2002} }

2001

AJHG
High-resolution multipoint linkage-disequilibrium mapping in the context of a human genome sequence

Bruce Rannala, and Jeff P Reeve

The American Journal of Human Genetics, Mar 2001

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A new method is presented for fine-scale linkage disequilibrium (LD) mapping of a disease mutation; it uses multiple linked single-nucleotide polymorphisms, restriction-fragment-length polymorphisms, or microsatellite markers and incorporates information from an annotated human genome sequence (HGS) and from a human mutation database. The method takes account of population demographic effects, using Markov chain Monte Carlo methods to integrate over the unknown gene genealogy and gene coalescence times. Information about the relative frequency of disease mutations in exons, introns, and other regions, from mutational databases, as well as assumptions about the completeness of the gene annotation, are used with an annotated HGS, to generate a prior probability that a mutation lies at any particular position in a specified region of the genome. This information is updated with information about mutation location, from LD at a set of linked markers in the region, to generate the posterior probability density of the mutation location. The performance of the method is evaluated by simulation and by analysis of a data set for diastrophic dysplasia (DTD) in Finland. The DTD disease gene has been positionally cloned, so the actual location of the mutation is known and can be compared with the position predicted by our method. For the DTD data, the addition of information from an HGS results in disease-gene localization at a resolution that is much higher than that which would be possible by LD mapping alone. In this case, the gene would be found by sequencing a region < 7 kb in size.
@article{rannala2001high, title = {High-resolution multipoint linkage-disequilibrium mapping in the context of a human genome sequence}, author = {Rannala, Bruce and Reeve, Jeff P}, journal = {The American Journal of Human Genetics}, volume = {69}, number = {1}, pages = {159--178}, year = {2001}, doi = {10.1086/321279}, publisher = {Cell Press} }
AJPH
Finding genes influencing susceptibility to complex diseases in the post-genome era

Bruce Rannala

American journal of pharmacogenomics, Mar 2001

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During the last decade, hundreds of genes that harbor mutations causing simple Mendelian disorders have been identified using a combination of linkage analysis and positional cloning techniques. Traditional approaches to gene mapping have been largely unsuccessful in mapping genes influencing so-called ‘complex’ genetic diseases, however, because of low power and other factors. Complex genetic diseases do not display simple Mendelian patterns of inheritance, although genes do have an influence and close relatives of probands consequently have an increased risk. These disorders are thought to be due to the combined effects of variation at multiple interacting genes and the environment. Complex diseases have a significant impact on human health because of their high population incidence (unlike simple Mendelian disorders, which tend to be rare). New techniques are being developed aimed specifically at mapping genes conferring susceptibility to complex diseases. A project aimed at mapping genes influencing susceptibility to a complex disease may be undertaken in several stages: establishing a genetic basis for the disease in one or more populations; measuring the distribution of gene effects; studying statistical power using models; carrying out marker-based mapping studies using linkage or association. Quantitative genetic models can be used to estimate the heritability of a complex (polygenic) disease, as well as to predict the distribution of gene effects and to test whether one or more quantitative trait loci (QTLs) exist. Such models can be used to predict the power of different mapping approaches, but are often unrealistic and therefore provide only approximate predictions. Linkage analyses, association studies and family-based association tests are all hindered by low power and other specific problems. Association studies tend to be more powerful but can generate spurious associations due to population admixture. Alternative strategies for association mapping include the use of recent founder populations or unique isolated populations that are genetically homogeneous, and the use of unlinked markers (so-called genomic controls) to assign different regions of the genome of an admixed individual to particular source populations. Linkage disequilibrium observed in a sample of unrelated affected and normal individuals can also be used to fine-map a disease susceptibility locus in a candidate region. New Bayesian strategies make use of an annotated human genome sequence to further refine the position of a candidate disease susceptibility locus.
@article{rannala2001finding, title = {Finding genes influencing susceptibility to complex diseases in the post-genome era}, author = {Rannala, Bruce}, journal = {American journal of pharmacogenomics}, volume = {1}, pages = {203--221}, year = {2001}, doi = {10.2165/00129785-200101030-00005}, publisher = {Springer International Publishing} }

PNAS

Commentary: Methylation patterns and mathematical models reveal dynamics of stem cell turnover in the human colon

Simon Ro, and Bruce Rannala

Proceedings of the National Academy of Sciences, Mar 2001

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@article{ro2001methylation,
  title = {Commentary: Methylation patterns and mathematical models reveal dynamics of stem cell turnover in the human colon},
  author = {Ro, Simon and Rannala, Bruce},
  journal = {Proceedings of the National Academy of Sciences},
  volume = {98},
  number = {19},
  pages = {10519--10521},
  doi = {10.1073/pnas.201405498},
  year = {2001},
  publisher = {The National Academy of Sciences}
}

HumMut
Using linked markers to infer the age of a mutation

Bruce Rannala, and Giorgio Bertorelle

Human mutation, Mar 2001

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Advances in sequencing and genotyping technologies over the last decade have enabled geneticists to easily characterize genetic variation at the nucleotide level. Hundreds of genes harboring mutations associated with genetic disease have now been identified by positional cloning. Using variation at closely linked genetic markers, it is possible to predict the times in the past at which particular mutations arose. Such studies suggest that many of the rare mutations underlying human genetic disorders are relatively young. Studies of variation at genetic markers linked to particular mutations can provide insights into human geographic history, and historical patterns of natural selection and disease, that are not available from other sources. We review two approaches for estimating allele age using variation at linked genetic markers. A phylogenetic approach aims to reconstruct the gene tree underlying a sample of chromosomes carrying a particular mutation, obtaining a “direct” estimate of allele age from the age of the root of this tree. A population genetic approach relies on models of demography, mutation, and/or recombination to estimate allele age without explicitly reconstructing the gene tree. Phylogenetic methods are best suited for studies of ancient mutations, while population genetic methods are better suited for studies of recent mutations. Methods that rely on recombination to infer the ages of alleles can be fine-tuned by choosing linked markers at optimal map distances to maximize the information available about allele age. A limitation of methods that rely on recombination is the frequent lack of a fine-scale linkage map. Maximum likelihood and Bayesian methods for estimating allele age that rely on intensive numerical computation are described, as well as “composite” likelihood and moment-based methods that lead to simple estimators. The former provide more accurate estimates (particularly for large samples of chromosomes) and should be employed if computationally practical. Hum Mutat 18:87–100, 2001. © 2001 Wiley-Liss, Inc.
@article{rannala2001using, title = {Using linked markers to infer the age of a mutation}, author = {Rannala, Bruce and Bertorelle, Giorgio}, journal = {Human mutation}, volume = {18}, number = {2}, pages = {87--100}, year = {2001}, doi = {10.1002/humu.1158}, publisher = {John Wiley \& Sons, Inc. New York} }

2000

Science
Accommodating phylogenetic uncertainty in evolutionary studies

John P Huelsenbeck, Bruce Rannala, and John P Masly

Science, Mar 2000

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Many evolutionary studies use comparisons across species to detect evidence of natural selection and to examine the rate of character evolution. Statistical analyses in these studies are usually performed by means of a species phylogeny to accommodate the effects of shared evolutionary history. The phylogeny is usually treated as known without error; this assumption is problematic because inferred phylogenies are subject to both stochastic and systematic errors. We describe methods for accommodating phylogenetic uncertainty in evolutionary studies by means of Bayesian inference. The methods are computationally intensive but general enough to be applied in most comparative evolutionary studies.
@article{huelsenbeck2000accommodating, title = {Accommodating phylogenetic uncertainty in evolutionary studies}, author = {Huelsenbeck, John P and Rannala, Bruce and Masly, John P}, journal = {Science}, volume = {288}, number = {5475}, pages = {2349--2350}, doi = {10.1126/science.288.5475.2349}, year = {2000}, publisher = {American Association for the Advancement of Science} }
ARGHG
Estimating allele age

Montgomery Slatkin, and Bruce Rannala

Annual Review of Genomics and Human Genetics, Mar 2000

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The age of an allele can be estimated both from genetic variation among different copies (intra-allelic variation) and from its frequency. Estimates based on intra-allelic variation follow from the exponential decay of linkage disequilibrium because of recombination and mutation. The confidence interval depends both on the uncertainty in recombination and mutation rates and on randomness of the genealogy of chromosomes that carry the allele (the intra-allelic genealogy). Several approximate methods to account for variation in the intra-allelic genealogy have been derived. Allele frequency alone also provides an estimate of age. Estimates based on frequency and on intra-allelic variability can be combined to provide a more accurate estimate or can be contrasted to show that an allele has been subject to natural selection. These methods have been applied to numerous cases, including alleles associated with cystic fibrosis, idiopathic torsion dystonia, and resistance to infection by HIV. We emphasize that estimates of allele age depend on assumptions about demographic history and natural selection.
@article{slatkin2000estimating, title = {Estimating allele age}, author = {Slatkin, Montgomery and Rannala, Bruce}, journal = {Annual Review of Genomics and Human Genetics}, volume = {1}, number = {1}, pages = {225--249}, year = {2000}, doi = {10.1146/annurev.genom.1.1.225}, publisher = {Annual Reviews 4139 El Camino Way, PO Box 10139, Palo Alto, CA 94303-0139, USA} }
Evolution
A Bayesian framework for the analysis of cospeciation

John P Huelsenbeck, Bruce Rannala, and Bret Larget

Evolution, Mar 2000

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Information on the history of cospeciation and host switching for a group of host and parasite species is contained in the DNA sequences sampled from each. Here, we develop a Bayesian framework for the analysis of cospeciation. We suggest a simple model of host switching by a parasite on a host phylogeny in which host switching events are assumed to occur at a constant rate over the entire evolutionary history of associated hosts and parasites. The posterior probability density of the parameters of the model of host switching are evaluated numerically using Markov chain Monte Carlo. In particular, the method generates the probability density of the number of host switches and of the host switching rate. Moreover, the method provides information on the probability that an event of host switching is associated with a particular pair of branches. A Bayesian approach has several advantages over other methods for the analysis of cospeciation. In particular, it does not assume that the host or parasite phylogenies are known without error; many alternative phylogenies are sampled in proportion to their probability of being correct.
@article{huelsenbeck2000bayesian, title = {A Bayesian framework for the analysis of cospeciation}, author = {Huelsenbeck, John P and Rannala, Bruce and Larget, Bret}, journal = {Evolution}, volume = {54}, number = {2}, pages = {352--364}, year = {2000}, doi = {10.1111/j.0014-3820.2000.tb00039.x}, publisher = {Blackwell Publishing Ltd Oxford, UK} }
GenEpi
Methods for multipoint disease mapping using linkage disequilibrium

Bruce Rannala, and Montgomery Slatkin

Genetic Epidemiology, Mar 2000

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Abstract A disease-associated mutation arises on a single chromosome such that alleles at linked markers are initially in complete linkage disequilibrium (LD) with the mutation. LD can be used as a tool for high-resolution mapping of the position of a disease mutation relative to a set of linked marker loci. When more than two linked marker loci are considered, developing a maximum likelihood approach is a challenging mathematical problem. To reduce the complexity, approximate and composite likelihood (CL) methods have been developed for multipoint LD mapping that use simplified models of population history, or of recombination, that ignore some of the statistical dependence among disease chromosomes and among marker loci. We describe the relationship among several composite likelihood methods for multipoint LD mapping, and suggest an alternative CL method that takes better account of the statistical dependence among marker loci. Genet. Epidemiol. 19(Suppl 1):S71–S77, 2000. © 2000 Wiley-Liss, Inc.
@article{rannala2001, author = {Rannala, Bruce and Slatkin, Montgomery}, title = {Methods for multipoint disease mapping using linkage disequilibrium}, journal = {Genetic Epidemiology}, volume = {19}, number = {S1}, pages = {S71-S77}, doi = {10.1002/1098-2272(2000)19:1+<::AID-GEPI11>3.0.CO;2-D}, year = {2000} }

Using stratigraphic information in phylogenetics

JOHN P Huelsenbeck, BRUCE Rannala, and JJ Wiens

Phylogenetic analysis of morphological data. Smithsonian Institution Press, Washington, DC, Mar 2000

Bib

@article{huelsenbeck2000using,
  title = {Using stratigraphic information in phylogenetics},
  author = {Huelsenbeck, JOHN P and Rannala, BRUCE and Wiens, JJ},
  journal = {Phylogenetic analysis of morphological data. Smithsonian Institution Press, Washington, DC},
  pages = {165--191},
  year = {2000}
}

Genetics
Methods for estimating gene frequencies and detecting selection in bacterial populations

Bruce Rannala, Wei-Gang Qiu, and Daniel E Dykhuizen

Genetics, Mar 2000

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Recent breakthroughs in molecular technology, most significantly the polymerase chain reaction (PCR) and in situ hybridization, have allowed the detection of genetic variation in bacterial communities without prior cultivation. These methods often produce data in the form of the presence or absence of alleles or genotypes, however, rather than counts of alleles. Using relative allele frequencies from presence-absence data as estimates of population allele frequencies tends to underestimate the frequencies of common alleles and overestimate those of rare ones, potentially biasing the results of a test of neutrality in favor of balancing selection. In this study, a maximum-likelihood estimator (MLE) of bacterial allele frequencies designed for use with presence-absence data is derived using an explicit stochastic model of the host infection (or bacterial sampling) process. The performance of the MLE is evaluated using computer simulation and a method is presented for evaluating the fit of estimated allele frequencies to the neutral infinite alleles model (IAM). The methods are applied to estimate allele frequencies at two outer surface protein loci (ospA and ospC) of the Lyme disease spirochete, Borrelia burgdorferi, infecting local populations of deer ticks (Ixodes scapularis) and to test the fit to a neutral IAM.
@article{rannala2000methods, title = {Methods for estimating gene frequencies and detecting selection in bacterial populations}, author = {Rannala, Bruce and Qiu, Wei-Gang and Dykhuizen, Daniel E}, journal = {Genetics}, volume = {155}, number = {2}, pages = {499--508}, year = {2000}, doi = {10.1093/genetics/158.3.1387}, publisher = {Oxford University Press} }

1999

Evolution
Insight into speciation from historical demography in the phytophagous beetle genus Ophraella

L Lacey Knowles, Douglas J Futuyma, Walter F Eanes, and Bruce Rannala

Evolution, Mar 1999

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Speciation in phytophagous insects is commonly associated with shifts in host use. Using a phylogenetic framework to identify recently diverged taxa that have undergone a radical host shift, this study focuses on how reconstruction of the historical demography of a species, in conjunction with branching patterns between species, provides insight into mode of speciation. Analyses of mitochondrial cytochrome oxidase I sequences indicate that the leaf beetle Ophraella communa exhibits significant population structure, as shown by patterns of genealogical relationships among mitochondrial haplotypes and high FST-values. However, the absence of regional localization of old clades of haplotypes, negative Tajima’s D, and unimodal rather than bimodal frequency distribution of the number of pairwise differences between sequences suggests an absence of long-term barriers to gene flow. Furthermore, we found no evidence of isolation by distance. This pattern of genetic variation is consistent with episodes of gene flow on a large geographic scale, perhaps owing to Pleistocene changes in climate. Ophraella communa and its sister species O. bilineata diverged during the early Pleistocene. The evidence of dynamic population structure in O. communa, potentially including episodic but massive gene flow, suggests that reproductive isolation evolved quite rapidly on a localized geographic scale, because speciation would probably have been reversed by gene flow if the evolution of reproductive isolation had been prolonged. That is, gene flow occasioned by range shifts during the Pleistocene would likely have interrupted speciation unless it occurred very rapidly. Sequence diversity implies a large effective population size (> 106) in both O. communa and O. bilineata. However, a model based on a drastic bottleneck did not have a lower likelihood than a model with no bottleneck, simply because the time since speciation has been great enough for coalescence to a single ancestor that existed after the speciation event. Sequence diversity in itself, without reference to the time since speciation, cannot provide evidence on the demography of speciation.
@article{knowles1999insight, title = {Insight into speciation from historical demography in the phytophagous beetle genus Ophraella}, author = {Knowles, L Lacey and Futuyma, Douglas J and Eanes, Walter F and Rannala, Bruce}, journal = {Evolution}, volume = {53}, number = {6}, pages = {1846--1856}, doi = {10.1111/j.1558-5646.1999.tb04567.x}, year = {1999} }

1998

Taxon sampling and the accuracy of large phylogenies

Bruce Rannala, John P Huelsenbeck, Ziheng Yang, and Rasmus Nielsen

Systematic Biology, Mar 1998

Bib

@article{rannala1998taxon,
  title = {Taxon sampling and the accuracy of large phylogenies},
  author = {Rannala, Bruce and Huelsenbeck, John P and Yang, Ziheng and Nielsen, Rasmus},
  journal = {Systematic Biology},
  volume = {47},
  number = {4},
  pages = {702--710},
  year = {1998},
  publisher = {Oxford University Press, Society of Systematic Biologists}
}

AJHG
Likelihood analysis of disequilibrium mapping, and related problems

Bruce Rannala, and Montgomery Slatkin

The American Journal of Human Genetics, Mar 1998

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In this paper a theory is developed that provides the sampling distribution of alleles at a diallelic marker locus closely linked to a low-frequency allele that arose as a single mutant. The sampling distribution provides a basis for maximum-likelihood estimation of either the recombination rate, the mutation rate, or the age of the allele, provided that the two other parameters are known. This theory is applied to (1) the data of Hästbacka et al., to estimate the recombination rate between a locus associated with diastrophic dysplasia and a linked RFLP marker; (2) the data of Risch et al., to estimate the age of a presumptive allele causing idiopathic distortion dystonia in Ashkenazi jews; and (3) the data of Tishkoff et al., to estimate the date at which, at the CD4 locus, non-African lineages diverged from African lineages. We conclude that the extent of linkage disequilibrium can lead to relatively accurate estimates of recombination and mutation rates and that those estimates are not very sensitive to parameters, such as the population age, whose values are not known with certainty. In contrast, we also conclude that, in many cases, linkage disequilibrium may not lead to useful estimates of allele age, because of the relatively large degree of uncertainly in those estimates.
@article{rannala1998likelihood, title = {Likelihood analysis of disequilibrium mapping, and related problems}, author = {Rannala, Bruce and Slatkin, Montgomery}, journal = {The American Journal of Human Genetics}, volume = {62}, number = {2}, pages = {459--473}, doi = {10.1086/301709}, year = {1998}, publisher = {Cell Press} }
PNAS
Using rare mutations to estimate population divergence times: a maximum likelihood approach

Giorgio Bertorelle, and Bruce Rannala

Proceedings of the National Academy of Sciences, Mar 1998

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In this paper we propose a method to estimate by maximum likelihood the divergence time between two populations, specifically designed for the analysis of nonrecurrent rare mutations. Given the rapidly growing amount of data, rare disease mutations affecting humans seem the most suitable candidates for this method. The estimator RD, and its conditional version RDc, were derived, assuming that the population dynamics of rare alleles can be described by using a birth–death process approximation and that each mutation arose before the split of a common ancestral population into the two diverging populations. The RD estimator seems more suitable for large sample sizes and few alleles, whose age can be approximated, whereas the RDc estimator appears preferable when this is not the case. When applied to three cystic fibrosis mutations, the estimator RD could not exclude a very recent time of divergence among three Mediterranean populations. On the other hand, the divergence time between these populations and the Danish population was estimated to be, on the average, 4,500 or 15,000 years, assuming or not a selective advantage for cystic fibrosis carriers, respectively. Confidence intervals are large, however, and can probably be reduced only by analyzing more alleles or loci.
@article{bertorelle1998using, title = {Using rare mutations to estimate population divergence times: a maximum likelihood approach}, author = {Bertorelle, Giorgio and Rannala, Bruce}, journal = {Proceedings of the National Academy of Sciences}, volume = {95}, number = {26}, pages = {15452--15457}, doi = {10.1073/pnas.95.26.15452}, year = {1998}, publisher = {The National Academy of Sciences} }

Linkage Disequilibrium Mapping and Parkinson’s Disease

Bruce Rannala, and Mongomery Slatkin

Science, Mar 1998

Bib

@article{rannala1998linkage,
  title = {Linkage Disequilibrium Mapping and Parkinson's Disease},
  author = {Rannala, Bruce and Slatkin, Mongomery},
  journal = {Science},
  volume = {280},
  number = {5361},
  pages = {175--175},
  year = {1998},
  publisher = {American Association for the Advancement of Science}
}

1997

PNAS
Detecting immigration by using multilocus genotypes

Bruce Rannala, and Joanna L Mountain

Proceedings of the National Academy of Sciences, Mar 1997

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Immigration is an important force shaping the social structure, evolution, and genetics of populations. A statistical method is presented that uses multilocus genotypes to identify individuals who are immigrants, or have recent immigrant ancestry. The method is appropriate for use with allozymes, microsatellites, or restriction fragment length polymorphisms (RFLPs) and assumes linkage equilibrium among loci. Potential applications include studies of dispersal among natural populations of animals and plants, human evolutionary studies, and typing zoo animals of unknown origin (for use in captive breeding programs). The method is illustrated by analyzing RFLP genotypes in samples of humans from Australian, Japanese, New Guinean, and Senegalese populations. The test has power to detect immigrant ancestors, for these data, up to two generations in the past even though the overall differentiation of allele frequencies among populations is low.
@article{rannala1997detecting, title = {Detecting immigration by using multilocus genotypes}, author = {Rannala, Bruce and Mountain, Joanna L}, journal = {Proceedings of the National Academy of Sciences}, volume = {94}, number = {17}, pages = {9197--9201}, year = {1997}, doi = {10.1073/pnas.94.17.9197}, publisher = {The National Academy of Sciences of the USA} }
MBE
Bayesian phylogenetic inference using DNA sequences: a Markov Chain Monte Carlo method

Ziheng Yang, and Bruce Rannala

Molecular Biology and Evolution, Mar 1997

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An improved Bayesian method is presented for estimating phylogenetic trees using DNA sequence data. The birth-death process with species sampling is used to specify the prior distribution of phylogenies and ancestral speciation times, and the posterior probabilities of phylogenies are used to estimate the maximum posterior probability (MAP) tree. Monte Carlo integration is used to integrate over the ancestral speciation times for particular trees. A Markov Chain Monte Carlo method is used to generate the set of trees with the highest posterior probabilities. Methods are described for an empirical Bayesian analysis, in which estimates of the speciation and extinction rates are used in calculating the posterior probabilities, and a hierarchical Bayesian analysis, in which these parameters are removed from the model by an additional integration. The Markov Chain Monte Carlo method avoids the requirement of our earlier method for calculating MAP trees to sum over all possible topologies (which limited the number of taxa in an analysis to about five). The methods are applied to analyze DNA sequences for nine species of primates, and the MAP tree, which is identical to a maximum-likelihood estimate of topology, has a probability of approximately 95%.
@article{yang1997bayesian, title = {Bayesian phylogenetic inference using DNA sequences: a Markov Chain Monte Carlo method}, author = {Yang, Ziheng and Rannala, Bruce}, journal = {Molecular Biology and Evolution}, volume = {14}, number = {7}, doi = {10.1093/oxfordjournals.molbev.a025811}, pages = {717--724}, year = {1997} }
Science
Phylogenetic methods come of age: testing hypotheses in an evolutionary context

John P Huelsenbeck, and Bruce Rannala

Science, Mar 1997

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The use of molecular phylogenies to examine evolutionary questions has become commonplace with the automation of DNA sequencing and the availability of efficient computer programs to perform phylogenetic analyses. The application of computer simulation and likelihood ratio tests to evolutionary hypotheses represents a recent methodological development in this field. Likelihood ratio tests have enabled biologists to address many questions in evolutionary biology that have been difficult to resolve in the past, such as whether host-parasite systems are cospeciating and whether models of DNA substitution adequately explain observed sequences.
@article{huelsenbeck1997phylogenetic, title = {Phylogenetic methods come of age: testing hypotheses in an evolutionary context}, author = {Huelsenbeck, John P and Rannala, Bruce}, journal = {Science}, volume = {276}, number = {5310}, pages = {227--232}, year = {1997}, doi = {10.1126/science.276.5310.227}, publisher = {American Association for the Advancement of Science} }
Evolution
Statistical tests of host-parasite cospeciation

John P Huelsenbeck, Bruce Rannala, and Ziheng Yang

Evolution, Mar 1997

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A history of cospeciation (synchronous speciation) among ecologically associated, but otherwise distantly related, species is often revealed by a strong correspondence of their phylogenies. In this paper, we present several tests of cospeciation that use maximum‐likelihood and Bayesian methods of phylogenetic estimation. The hypotheses tested include: (1) topological agreement of phylogenies for coevolving groups; (2) identical speciation times of associated species; and (3) identical evolutionary rates in genes of associated species. These tests are applied to examine a possible instance of host‐parasite coevolution among pocket gophers and lice using mitochondrial COI DNA sequences. The observed differences between gopher and louse trees cannot be explained by sampling error and are consistent with a rate of host switching about one‐third the host speciation rate. A subset of the gopher‐louse data is consistent with a common history of evolution (i.e., the topologies and speciation times are identical). However, the relative rate of nucleotide substitution is two to four times higher in the lice than in the gophers.
@article{huelsenbeck1997statistical, title = {Statistical tests of host-parasite cospeciation}, author = {Huelsenbeck, John P and Rannala, Bruce and Yang, Ziheng}, journal = {Evolution}, volume = {51}, number = {2}, pages = {410--419}, doi = {10.1111/j.1558-5646.1997.tb02428.x}, year = {1997}, publisher = {Blackwell Publishing Inc Malden, USA} }

Estimating the age of alleles by use of intraallelic variability.

Montgomery Slatkin, and Bruce Rannala

American journal of human genetics, Mar 1997

Bib

@article{slatkin1997estimating,
  title = {Estimating the age of alleles by use of intraallelic variability.},
  author = {Slatkin, Montgomery and Rannala, Bruce},
  journal = {American journal of human genetics},
  volume = {60},
  number = {2},
  pages = {447},
  year = {1997},
  publisher = {Elsevier}
}

Paleobiology
Maximum likelihood estimation of phylogeny using stratigraphic data

John P Huelsenbeck, and Bruce Rannala

Paleobiology, Mar 1997

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The stratigraphic distribution of fossil species contains potential information about phylogeny because some phylogenetic trees are more consistent with the distribution of fossils in the rock record than others. A maximum likelihood estimator of phylogeny is derived using an explicit mathematical model of fossil preservation. The method assumes that fossil preservations within lineages follow an independent Poisson process, but can be extended to include other preservation models. The performance of the method was examined using Monte Carlo simulation. The performance of the maximum likelihood estimator of topology increases with an increase in the preservation rate. The method is biased, like other methods of phylogeny estimation, when the rate of fossil preservation is low; estimated trees tend to be more asymmetrical than the true tree. The method appears to perform well as a tree rooting criterion even when preservation rates are low. We suggest several possible extensions of the method to address other questions about the nature of fossil preservation and the process of speciation and extinction over time and space.
@article{huelsenbeck1997maximum, title = {Maximum likelihood estimation of phylogeny using stratigraphic data}, author = {Huelsenbeck, John P and Rannala, Bruce}, journal = {Paleobiology}, volume = {23}, number = {2}, pages = {174--180}, doi = {10.1017/S0094837300016778}, year = {1997}, publisher = {Cambridge University Press} }

Gene genealogy in a population of variable size

Bruce Rannala

Heredity, Mar 1997

Bib

@article{rannala1997gene,
  title = {Gene genealogy in a population of variable size},
  author = {Rannala, Bruce},
  journal = {Heredity},
  volume = {78},
  number = {4},
  pages = {417--423},
  year = {1997},
  publisher = {Nature Publishing Group}
}

The sampling distribution of disease-associated alleles

Montgomery Slatkin, and Bruce Rannala

Genetics, Mar 1997

Bib

@article{slatkin1997sampling,
  title = {The sampling distribution of disease-associated alleles},
  author = {Slatkin, Montgomery and Rannala, Bruce},
  journal = {Genetics},
  volume = {147},
  number = {4},
  pages = {1855--1861},
  year = {1997},
  publisher = {Oxford University Press}
}

On the genealogy of a rare allele

Bruce Rannala

Theoretical population biology, Mar 1997

Bib

@article{rannala1997genealogy,
  title = {On the genealogy of a rare allele},
  author = {Rannala, Bruce},
  journal = {Theoretical population biology},
  volume = {52},
  number = {3},
  pages = {216--223},
  year = {1997},
  publisher = {Academic Press}
}

1996

JME
Probability distribution of molecular evolutionary trees: a new method of phylogenetic inference

Bruce Rannala, and Ziheng Yang

Journal of Molecular Evolution, Mar 1996

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A new method is presented for inferring evolutionary trees using nucleotide sequence data. The birth-death process is used as a model of speciation and extinction to specify the prior distribution of phylogenies and branching times. Nucleotide substitution is modeled by a continuous-time Markov process. Parameters of the branching model and the substitution model are estimated by maximum likelihood. The posterior probabilities of different phylogenies are calculated and the phylogeny with the highest posterior probability is chosen as the best estimate of the evolutionary relationship among species. We refer to this as the maximum posterior probability (MAP) tree. The posterior probability provides a natural measure of the reliability of the estimated phylogeny. Two example data sets are analyzed to infer the phylogenetic relationship of human, chimpanzee, gorilla, and orangutan. The best trees estimated by the new method are the same as those from the maximum likelihood analysis of separate topologies, but the posterior probabilities are quite different from the bootstrap proportions. The results of the method are found to be insensitive to changes in the rate parameter of the branching process.
@article{rannala1996probability, title = {Probability distribution of molecular evolutionary trees: a new method of phylogenetic inference}, author = {Rannala, Bruce and Yang, Ziheng}, journal = {Journal of Molecular Evolution}, volume = {43}, pages = {304--311}, doi = {10.1007/BF02338839}, year = {1996}, publisher = {Springer-Verlag} }

Estimating gene flow in island populations

Bruce Rannala, and JA Hartigan

Genetics Research, Mar 1996

Bib

@article{rannala1996estimating,
  title = {Estimating gene flow in island populations},
  author = {Rannala, Bruce and Hartigan, JA},
  journal = {Genetics Research},
  volume = {67},
  number = {2},
  pages = {147--158},
  year = {1996},
  publisher = {Cambridge University Press}
}

The sampling theory of neutral alleles in an island population of fluctuating size

Bruce Rannala

Theoretical population biology, Mar 1996

Bib

@article{rannala1996sampling,
  title = {The sampling theory of neutral alleles in an island population of fluctuating size},
  author = {Rannala, Bruce},
  journal = {Theoretical population biology},
  volume = {50},
  number = {1},
  pages = {91--104},
  year = {1996},
  publisher = {Academic Press}
}

1995

Ectoparasites reduce long-term survival of their avian host

Charles R Brown, Mary Bomberger Brown, and Bruce Rannala

Proceedings of the Royal Society of London. Series B: Biological Sciences, Mar 1995

Bib

@article{brown1995ectoparasites,
  title = {Ectoparasites reduce long-term survival of their avian host},
  author = {Brown, Charles R and Brown, Mary Bomberger and Rannala, Bruce},
  journal = {Proceedings of the Royal Society of London. Series B: Biological Sciences},
  volume = {262},
  number = {1365},
  pages = {313--319},
  year = {1995},
  publisher = {The Royal Society London}
}

Colony choice in birds: models based on temporally invariant site quality

Charles R Brown, and Bruce Rannala

Behavioral Ecology and Sociobiology, Mar 1995

Bib

@article{brown1995colony,
  title = {Colony choice in birds: models based on temporally invariant site quality},
  author = {Brown, Charles R and Rannala, Bruce},
  journal = {Behavioral Ecology and Sociobiology},
  volume = {36},
  pages = {221--228},
  year = {1995},
  publisher = {Springer-Verlag}
}

Identity by descent in island-mainland populations.

Bruce Rannala, and JA Hartigan

Genetics, Mar 1995

Bib

@article{rannala1995identity,
  title = {Identity by descent in island-mainland populations.},
  author = {Rannala, Bruce and Hartigan, JA},
  journal = {Genetics},
  volume = {139},
  number = {1},
  pages = {429--437},
  year = {1995},
  publisher = {Oxford University Press}
}

Polymorphic characters and phylogenetic analysis: a statistical perspective

Bruce Rannala

Systematic Biology, Mar 1995

Bib

@article{rannala1995polymorphic,
  title = {Polymorphic characters and phylogenetic analysis: a statistical perspective},
  author = {Rannala, Bruce},
  journal = {Systematic Biology},
  volume = {44},
  number = {3},
  pages = {421--429},
  year = {1995},
  publisher = {Oxford University Press, Society of Systematic Biologists}
}

1994

Relatedness and conflict over optimal group size

Bruce H Rannala, and Charles R Brown

Trends in ecology & evolution, Mar 1994

Bib

@article{rannala1994relatedness,
  title = {Relatedness and conflict over optimal group size},
  author = {Rannala, Bruce H and Brown, Charles R},
  journal = {Trends in ecology \& evolution},
  volume = {9},
  number = {4},
  pages = {117--119},
  year = {1994},
  publisher = {Elsevier Current Trends}
}

1992

Comparative evolutionary genetics of trematode parasites (Plagiorchiidae) and their anuran hosts

BH Rannala

Canadian Journal of Zoology, Mar 1992

Bib

@article{rannala1992comparative,
  title = {Comparative evolutionary genetics of trematode parasites (Plagiorchiidae) and their anuran hosts},
  author = {Rannala, BH},
  journal = {Canadian Journal of Zoology},
  volume = {70},
  number = {5},
  pages = {993--1000},
  year = {1992},
  publisher = {NRC Research Press}
}

1991

Evidence for host allozymes present on electrophoretic gels of trematode parasites (Digenea: Plagiorchiiformes).

Bruce H Rannala

The Journal of parasitology, Mar 1991

Bib

@article{rannala1991evidence,
  title = {Evidence for host allozymes present on electrophoretic gels of trematode parasites (Digenea: Plagiorchiiformes).},
  author = {Rannala, Bruce H},
  journal = {The Journal of parasitology},
  volume = {77},
  number = {5},
  pages = {805--808},
  year = {1991}
}

1990

Genetic distance and parasite taxonomy

Bruce H Rannala

The Journal of parasitology, Mar 1990

Bib

@article{rannala1990genetic,
  title = {Genetic distance and parasite taxonomy},
  author = {Rannala, Bruce H},
  journal = {The Journal of parasitology},
  volume = {76},
  number = {6},
  pages = {929--930},
  year = {1990}
}

Electrophoretic evidence concerning the relationship between Haplometrana and Glypthelmins (Digenea: Plagiorchiiformes)

Bruce H Rannala

The Journal of parasitology, Mar 1990

Bib

@article{rannala1990electrophoretic,
  title = {Electrophoretic evidence concerning the relationship between Haplometrana and Glypthelmins (Digenea: Plagiorchiiformes)},
  author = {Rannala, Bruce H},
  journal = {The Journal of parasitology},
  pages = {746--748},
  year = {1990},
  publisher = {JSTOR}
}