Author Archives: Joe Pickrell

An excess of gene expression divergence on the X chromosome in Drosophila embryos: implications for the faster-X hypothesis

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An excess of gene expression divergence on the X chromosome in Drosophila embryos: implications for the faster-X hypothesis

Melek A. Kayserili, Dave T. Gerrard, Pavel Tomancak, Alex T. Kalinka
(Submitted on 5 Sep 2012)

The X chromosome is present as a single copy in the heterogametic sex, and this hemizygosity is expected to drive unusual patterns of evolution on the X relative to the autosomes. For example, the hemizgosity of the X may lead to a lower chromosomal effective population size compared to the autosomes suggesting that the X might be more strongly affected by genetic drift. However, the X may also experience stronger positive selection than the autosomes because recessive beneficial mutations will be more visible to selection on the X where they will spend less time being masked by the dominant, less beneficial allele – a proposal known as the faster-X hypothesis. Thus, empirical studies demonstrating increased genetic divergence on the X chromosome could be indicative of either adaptive or non-adaptive evolution. We measured gene expression in Drosophila species and in D. melanogaster inbred strains for both embryos and adults. In the embryos we found that expression divergence is on average more than 20% higher for genes on the X chromosome relative to the autosomes, but in contrast, in the inbred strains gene expression variation is significantly lower on the X chromosome. Furthermore, expression divergence of genes on Muller’s D element is significantly greater along the branch leading to the obscura sub-group, in which this element segregates as a neo-X chromosome. In the adults, divergence is greatest on the X chromosome for males, but not for females, yet in both sexes inbred strains harbour the lowest level of gene expression variation on the X chromosome. We consider different explanations for our results and conclude that they are most consistent within the framework of the faster-X hypothesis.

Analysis of DNA sequence variation within marine species using Beta-coalescents

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Analysis of DNA sequence variation within marine species using Beta-coalescents

Matthias Steinrücken, Matthias Birkner, Jochen Blath
(Submitted on 4 Sep 2012)

We apply recently developed inference methods based on general coalescent processes to DNA sequence data obtained from various marine species. Several of these species are believed to exhibit so-called shallow gene genealogies, potentially due to extreme reproductive behaviour, e.g. via Hedgecock’s “reproduction sweepstakes”. Besides the data analysis, in particular the inference of mutation rates and the estimation of the (real) time to the most recent common ancestor, we briefly address the question whether the genealogies might be adequately described by so-called Beta coalescents (as opposed to Kingman’s coalescent), allowing multiple mergers of genealogies.
The choice of the underlying coalescent model for the genealogy has drastic implications for the estimation of the above quantities, in particular the real-time embedding of the genealogy

Journal policy change: ESA journals will consider preprints

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Scott Collins, the president of the Ecological Society of America, announced today on Twitter that all ESA journals will now consider papers for publication that have previously been posted on preprint servers like arXiv. We look forward to discussing preprints headed to ESA journals here on Haldane’s Sieve.

[Update] See also here.

Transposable sequence evolution is driven by gene context

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Transposable sequence evolution is driven by gene context

Anna-Sophie Fiston-Lavier, Charles E. Vejnar, Hadi Quesneville
(Submitted on 2 Sep 2012)

Transposable elements (TEs) in eukaryote genomes are quantitatively the main components affecting genome size, structure and expression. The dynamics of their insertion and deletion depend on diverse factors varying in strength and nature along the genome. We address here how TE sequence evolution is affected by neighboring genes and the chromatin status (euchromatin or heterochromatin) at their insertion site. We estimated the rates of evolution of TE sequences in Arabidopsis thaliana, and found that they depend on the distance to the nearest genes: TEs located close to genes evolve faster than those that are more distant. Consequently, TE sequences in heterochromatic regions, which are gene-poor regions, are surprisingly younger and longer than those elsewhere. We present a model of TE sequence dynamics in TE-rich genomes, such as maize and wheat, and in TE-poor genomes such as fly and A. thaliana.

Evolutionary genomics of transposable elements in Saccharomyces cerevisiae

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Evolutionary genomics of transposable elements in Saccharomyces cerevisiae

Martin Carr, Douda Bensasson, Casey M. Bergman
(Submitted on 1 Sep 2012)

Saccharomyces cerevisiae is one of the premier model systems for studying the genomics and evolution of transposable elements. The availability of the S. cerevisiae genome led to many insights into its five known transposable element families (Ty1-Ty5) in the years shortly after its completion. However, subsequent advances in bioinformatics tools for analysing transposable elements and the recent availability of genome sequences for multiple strains and species of yeast motivates new investigations into Ty evolution in S. cerevisiae. Here we provide a comprehensive phylogenetic and population genetic analysis of Ty families in S. cerevisiae based on a reannotation of Ty elements in the S288c reference genome. We show that previous annotation efforts have underestimated the total copy number of Ty elements for all known families. In addition, we identify a new family of Ty3-like elements related to the S. paradoxus Ty3p which is composed entirely of degenerate solo LTRs. Phylogenetic analyses of LTR sequences identified three families with short-branch, recently active clades nested among long branch, inactive insertions (Ty1, Ty3, Ty4), one family with essentially all recently active elements (Ty2) and two families with only inactive elements (Ty3p and Ty5). Population genomic data from 38 additional strains of S. cerevisiae show that elements present in active clades are predominantly polymorphic, whereas most of the inactive elements are fixed. Finally, we use comparative genomic data to provide evidence that the Ty2 and Ty3p families have arisen in the S. cerevisiae genome by horizontal transfer. Our results demonstrate that the genome of a single individual contains important information about the state of TE population dynamics within a species and suggest that horizontal transfer may play an important role in shaping the diversity of transposable elements in unicellular eukaryotes.

Our paper: Inference of population splits and mixtures from genome-wide allele frequency data

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[This author post is by Joe Pickrell (@joe_pickrell) on Inference of population splits and mixtures from genome-wide allele frequency data, available from arXiv here]

Early last year, I began working (with Jonathan Pritchard) on methods for using genetics to understand population history. As we describe in our preprint, our approach was to build a parameterized model to describe the patterns of correlation in allele frequencies across populations. This type of approach dates back to brilliant work on building population trees by Luca Cavalli-Sforza, AWF Edwards, and Joe Felsenstein from around 40 years ago. The key to our work is that instead of representing history as a bifurcating tree, we additionally allow “migration events” to model admixture between populations. The output from our model (called TreeMix, and available here) is something like that shown below.

A graph of human population history, allowing 10 migration events. Populations are colored according to geographic region.

We applied this method to both human and dog history, with a mix of both known and novel historical results. I thought here I’d speculate about a couple of the novel results:

1. In the human data (see the graph above), one of the more surprising things to me was the arrow to the Cambodian population. The Cambodians appear to be an admixed population, with ~85% of their ancestry related to other southeast Asian populations (like the Dai) and ~15% of their ancestry from…it’s not totally clear. As you can see in the graph, the source of this admixture appears to be a population not particularly closely related to any other population in these data. So who was this population? A speculation is that this represents ancestry from a population related to the “Ancestral South Indian” population described by Reich et al. (2009), though other sources (e.g. Oceania) are plausible.

2. In the dog data (see Figures 5 and 6 in the pre-print), the most overwhelming signal in the data is that the Basenji, a central African dog breed, appears to trace ~25% of its ancestry to admixture with wolves since domestication. This signal is made somewhat surprising by the fact that there are no wolf populations currently living in Africa, which would seem to be a formidable barrier to admixture with an African dog breed. A hint for what’s going on here is provided by vonHoldt et al. (2010), who show that the basenji have an unusual amount of shared variation with wolves from the Middle East. One speculation, then, is that as the ancestors of the Basenji moved into Africa, they came into contact with Middle Eastern wolves and admixed with them.

Other suggestions for scenarios to explain these results are of course welcome. Overall, I’m hopeful that approaches like TreeMix will eventually supplant “standard” tree-building algorithms for situations in which gene flow is known to occur, though of course further development is necessary before this becomes reality.

Joe Pickrell

Our paper: Blood ties: ABO is a trans-species polymorphism in primates

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[This author post is by Laure Ségurel [a postdoc in the Przeworski Lab] on the paper Blood ties: ABO is a trans-species polymorphism in primates, posted on the arXiv here]

The mysteries of the ABO blood group were first brought to our attention by Carole Ober. When we started working on it, we were mostly surprised by how little was known about the function of such a heavily studied gene and such an important clinical phenotype. Indeed, the expression of A, B and/or O antigens at the surface of some cells is a polymorphic phenotype shared by species as diverse as macaques and baboons in Africa, gibbons in Asia, squirrel monkeys in the Americas and, of course, humans throughout most of the world yet, many questions remain unanswered, such as: What is the biological role of ABO in different cell types? Why did Hominoids evolve toward its expression of blood cells whereas other primates express it only on epithelial/endothelial cells? Why is the O allele at such high frequency only in humans? What are the selective agents responsible for the maintenance of this polymorphism? And why did chimpanzees and bonobos apparently loose the polymorphism?

One question that we became interested in answering with population genetic tools was that of the origin of such blood types. When did the genetic polymorphism first emerge and which species share it identical by descent (as opposed to by convergent evolution)? Answers to these questions could tell us where and when having multiple alleles at this locus became advantageous. We therefore sequenced as many Hominoids, Old World monkeys and New World monkeys we could get our hands on, and, even more interestingly, we started thinking about the expectations under a model of convergent evolution, i.e., one where the AB genetic polymorphism was created independently multiple times in different species (and then maintained by balancing selection in these lineages) versus under a model of trans-species polymorphism, i.e., in which the AB genetic polymorphism arose early in time and was transmitted identical by descent to distinct species. Key to distinguishing the two predictions is the age of different selected alleles within a polymorphic population.

We therefore compared alleles within humans, orangutans, gibbons, macaques, baboons and colobus monkeys (all polymorphic species for the A and B alleles), and showed that, at least among Hominoids and among Old World monkeys, the observed genetic pattern is not compatible with a model of convergent evolution but on the contrary matches the expectations under a model of a trans-species polymorphism maintained by multi-allelic balancing selection. In other words, the data indicate that the AB polymorphism was present at least around 20 Millions of years ago, if not earlier. Also, interestingly, it seems that the A, B and O functional classes do not provide a complete description of the allelic classes natural selection is acting on, which underscores the need for more detailed functional studies of ABO sub-groups.

By submitting the paper to arXiv, we hope to circulate it to a diverse audience and without delay. In particular, we hope that the study will motivate more experimental/functional work about the role of this polymorphism in immune response, e.g., to pathogen infections.

Laure Ségurel

A sequentially Markov conditional sampling distribution for structured populations with migration and recombination

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A sequentially Markov conditional sampling distribution for structured populations with migration and recombination

Matthias Steinrücken, Joshua S. Paul, Yun S. Song
(Submitted on 25 Aug 2012)

Conditional sampling distributions (CSDs), sometimes referred to as copying models, underlie numerous practical tools in population genomic analyses. Though an important application that has received much attention is the inference of population structure, the explicit exchange of migrants at specified rates has not hitherto been incorporated into the CSD in a principled framework. Recently, in the case of a single panmictic population, a sequentially Markov CSD has been developed as an accurate, efficient approximation to a principled CSD derived from the diffusion process dual to the coalescent with recombination. In this paper, the sequentially Markov CSD framework is extended to incorporate subdivided population structure, thus providing an efficiently computable CSD that admits a genealogical interpretation related to the structured coalescent with migration and recombination. As a concrete application, it is demonstrated empirically that the CSD developed here can be employed to yield accurate estimation of a wide range of migration rates.

An explicit transition density expansion for a multi-allelic Wright-Fisher diffusion with general diploid selection

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An explicit transition density expansion for a multi-allelic Wright-Fisher diffusion with general diploid selection

Matthias Steinrücken, Y. X. Rachel Wang, Yun S. Song
(Submitted on 25 Aug 2012)

Characterizing time-evolution of allele frequencies in a population is a fundamental problem in population genetics. In the Wright-Fisher diffusion, such dynamics is captured by the transition density function, which satisfies well-known partial differential equations. For a multi-allelic model with general diploid selection, various theoretical results exist on representations of the transition density, but finding an explicit formula has remained a difficult problem. In this paper, a technique recently developed for a diallelic model is extended to find an explicit transition density for an arbitrary number of alleles, under a general diploid selection model with recurrent parent-independent mutation. Specifically, the method finds the eigenvalues and eigenfunctions of the generator associated with the multi-allelic diffusion, thus yielding an accurate spectral representation of the transition density. Furthermore, this approach allows for efficient, accurate computation of various other quantities of interest, including the normalizing constant of the stationary distribution and the rate of convergence to this distribution.

Bayesian Methods for Genetic Association Analysis with Heterogeneous Subgroups: from Meta-Analyses to Gene-Environment Interactions

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Bayesian Methods for Genetic Association Analysis with Heterogeneous Subgroups: from Meta-Analyses to Gene-Environment Interactions

Xiaoquan Wen, Matthew Stephens
(Submitted on 4 Nov 2011 (v1), last revised 8 Nov 2011 (this version, v2))

In genetic association analyses, it is often desired to analyze data from multiple potentially-heterogeneous subgroups. The amount of expected heterogeneity can vary from modest (as might typically be expected in a meta-analysis of multiple studies of the same phenotype, for example), to large (e.g. a strong gene-environment interaction, where the environmental exposure defines discrete subgroups). Here, we consider a flexible set of Bayesian models and priors that can capture these different levels of heterogeneity. We provide accurate numerical approaches to compute approximate Bayes Factors for these different models, and also some simple analytic forms which have natural interpretations and, in some cases, close connections with standard frequentist test statistics. These approximations also have the convenient feature that they require only summary-level data from each subgroup (in the simplest case, a point estimate for the genetic effect, and its standard error, from each subgroup). We illustrate the flexibility of these approaches on three examples: an analysis of a potential gene-environment interaction for a recombination phenotype, a large scale meta-analysis of genome-wide association data from the Global Lipids consortium, and a cross-population analysis for expression quantitative trait loci (eQTLs).