On the Utility of Short Intron Sequences as a Reference for the Detection of Positive and Negative Selection in Drosophila

Parsch, John; Novozhilov, Sergey; Saminadin-Peter, Sarah S.; Wong, Karen M.; Andolfatto, Peter

doi:10.1093/molbev/msq046

Cited by 112 publications

(171 citation statements)

References 62 publications

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“…Our results largely echo previous findings, with the relative hierarchy of divergence across these functional categories of site consistent with that shown in polymorphism. That is, first and second codon position show the least divergence with D. sechellia, which is again consistent with expectation given functional constraint of these sites as well as being consistent with previous studies in Drosophila (Andolfatto 2005;Bachtrog and Andolfatto 2006;Halligan and Keightley 2006;Haddrill et al 2008;Parsch et al 2010). We also recover high levels of divergence for short introns and third codon positions, which are comparatively unconstrained site classes, which also confirms previous results (Andolfatto 2005 Laurent et al 2011).…”

Section: Polymorphism and Divergencesupporting

confidence: 92%

“…In contrast, short introns and third codon positions show the highest level of nucleotide variability, while UTR sequences, intergenic regions, and long introns show intermediate levels of polymorphism. These relative levels of polymorphism across functional categories of site are broadly consistent with previous reports from a variety of Drosophila species including D. miranda (Bachtrog and Andolfatto 2006), D. simulans (Begun et al 2007;Haddrill et al 2008), and D. melanogaster (Andolfatto 2005;Parsch et al 2010;Zeng and Charlesworth 2010).…”

Section: Polymorphism and Divergencesupporting

confidence: 90%

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Inferences of Demography and Selection in an African Population of Drosophila melanogaster

et al. 2013

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It remains a central problem in population genetics to infer the past action of natural selection, and these inferences pose a challenge because demographic events will also substantially affect patterns of polymorphism and divergence. Thus it is imperative to explicitly model the underlying demographic history of the population whenever making inferences about natural selection. In light of the considerable interest in adaptation in African populations of Drosophila melanogaster, which are considered ancestral to the species, we generated a large polymorphism data set representing 2.1 Mb from each of 20 individuals from a Ugandan population of D. melanogaster. In contrast to previous inferences of a simple population expansion in eastern Africa, our demographic modeling of this ancestral population reveals a strong signature of a population bottleneck followed by population expansion, which has significant implications for future demographic modeling of derived populations of this species. Taking this more complex underlying demographic history into account, we also estimate a mean X-linked region-wide rate of adaptation of 6 · 10 211 /site/generation and a mean selection coefficient of beneficial mutations of 0.0009. These inferences regarding the rate and strength of selection are largely consistent with most other estimates from D. melanogaster and indicate a relatively high rate of adaptation driven by weakly beneficial mutations.T HERE is considerable interest in understanding the nature and extent of adaptation in natural populations. Drosophila melanogaster has been the focus of many such studies and a variety of approaches to address this fundamental question have been developed with this system. These include divergence-based methods (e.g., Sattath et al. 2011), polymorphism-based approaches (e.g., Kim and Stephan 2002;Sabeti et al. 2002;Kim and Nielsen 2004;Li and Stephan 2006b;Jensen et al. 2008a), and approaches that use both polymorphism and divergence data (e.g., Fay et al. 2002;Welch 2006;Andolfatto 2007;Macpherson et al. 2007;Shapiro et al. 2007). In some cases, these methods aim to localize putative targets of selection (e.g., Harr et al. 2002;Glinka et al. 2003;Jensen et al. 2007a), while in others the ultimate goal is to generally characterize the average rate and strength of adaptation (Wiehe and Stephan 1993;Li and Stephan 2006a;Andolfatto 2007;Macpherson et al. 2007;Jensen et al. 2008a). These approaches have enjoyed much success, and it is becoming clear that the signatures of both recent and recurrent selection abound in the D. melanogaster genome (for review see Sella et al. 2009).However, demographic history will also leave its signature in the genome, which has the potential to confound inferences of natural selection. Indeed, to effectively investigate models of natural selection, which are of great general interest in evolutionary biology, one must take into account the underlying demographic history of a population. Consequently, understanding demographic history is integr...

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Section: Polymorphism and Divergencesupporting

confidence: 92%

Section: Polymorphism and Divergencesupporting

confidence: 90%

Inferences of Demography and Selection in an African Population of Drosophila melanogaster

et al. 2013

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“…To do this, we computed a synonymous SFS that would be expected under neutrality given this extreme estimate of selection on synonymous sites (see SI Appendix, Text S3, for details). We further assumed that the SFS from short introns has a neutral shape (19,20). We only see a negligible effect on the DFE inference using this predicted neutral SFS compared with Fig.…”

Section: Resultsmentioning

confidence: 84%

Determining the factors driving selective effects of new nonsynonymous mutations

Kim

Marsden

Lohmueller

2016

Preprint

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The distribution of fitness effects (DFE) of new mutations plays a fundamental role in evolutionary genetics. However, the extent to which the DFE differs across species has yet to be systematically investigated. Furthermore, the biological mechanisms determining the DFE in natural populations remain unclear. Here, we show that theoretical models emphasizing different biological factors at determining the DFE, such as protein stability, back-mutations, species complexity, and mutational robustness make distinct predictions about how the DFE will differ between species. Analyzing amino acid-changing variants from natural populations in a comparative population genomic framework, we find that humans have a higher proportion of strongly deleterious mutations than Drosophila melanogaster. Furthermore, when comparing the DFE across yeast, Drosophila, mice, and humans, the average selection coefficient becomes more deleterious with increasing species complexity. Last, pleiotropic genes have a DFE that is less variable than that of nonpleiotropic genes. Comparing four categories of theoretical models, only Fisher's geometrical model (FGM) is consistent with our findings. FGM assumes that multiple phenotypes are under stabilizing selection, with the number of phenotypes defining the complexity of the organism. Our results suggest that long-term population size and cost of complexity drive the evolution of the DFE, with many implications for evolutionary and medical genomics. T he distribution of fitness effects (DFE) represents the distribution of selection coefficients, s, of random mutations in the genome. Here, s quantifies the relative change in fitness due to the mutation. The DFE plays a fundamental role in evolutionary genetics because it quantifies the amount of deleterious, neutral, and adaptive mutations entering a population (1). Despite the importance and considerable study of the DFE (1-3), the extent to which the DFE in terms of s differs across species has yet to be systematically quantified. Furthermore, the biological factors determining the DFE in different species remain elusive. Several theoretical models propose different mechanisms for the evolution of the DFE (Fig. 1) (4-8). Although each of these models has a reasonable theoretical basis as well as some support from experimental evolution studies or microbial studies, which model best explains differences in the DFE between species has not yet been determined. Nor have these models been tested with genetic variation data from natural populations in higher organisms. Because experimental evolution studies in laboratory organisms often use a homogeneous environment and genetically homogeneous organisms, they may better satisfy some of the assumptions of these theoretical models. However, natural populations may provide different qualitative results due to increased resolution to measure weakly deleterious mutations and the unnatural selection pressure in the laboratory (2, 9). Importantly, five theoretical models for the evolution of the DFE predic...

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“…DaDi calculates a log-likelihood of the fit of a model based on an observed SFS. We estimated the SFS for presumably neutral SNPs in Zambian data using segregating sites in short introns (Parsch et al 2010) from the stringently-filtered data set. We used every site in a short intron of length ,86 bp, with 16 bp removed from the intron start and 6 bp removed from the intron end (Lawrie et al 2013).…”

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confidence: 99%

Elevated Linkage Disequilibrium and Signatures of Soft Sweeps Are Common in Drosophila melanogaster

Garud

Petrov

2016

Genetics

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The extent to which selection and demography impact patterns of genetic diversity in natural populations of Drosophila melanogaster is yet to be fully understood. We previously observed that linkage disequilibrium (LD) at scales of 10 kb in the Drosophila Genetic Reference Panel (DGRP), consisting of 145 inbred strains from Raleigh, North Carolina, measured both between pairs of sites and as haplotype homozygosity, is elevated above neutral demographic expectations. We also demonstrated that signatures of strong and recent soft sweeps are abundant. However, the extent to which these patterns are specific to this derived and admixed population is unknown. It is also unclear whether these patterns are a consequence of the extensive inbreeding performed to generate the DGRP data. Here we analyze LD statistics in a sample of .100 fully-sequenced strains from Zambia; an ancestral population to the Raleigh population that has experienced little to no admixture and was generated by sequencing haploid embryos rather than inbred strains. We find an elevation in long-range LD and haplotype homozygosity compared to neutral expectations in the Zambian sample, thus showing the elevation in LD is not specific to the DGRP data set. This elevation in LD and haplotype structure remains even after controlling for possible confounders including genomic inversions, admixture, population substructure, close relatedness of individual strains, and recombination rate variation. Furthermore, signatures of partial soft sweeps similar to those found in the DGRP as well as partial hard sweeps are common in Zambia. These results suggest that while the selective forces and sources of adaptive mutations may differ in Zambia and Raleigh, elevated long-range LD and signatures of soft sweeps are generic in D. melanogaster.KEYWORDS Drosophila melanogaster; demography; linkage disequilibrium; haplotype homozygosity; selection D ISENTANGLING the effects of demography and selection on patterns of genomic variation remains a central challenge in evolutionary biology. Until recently, inference of demography and selection primarily relied on short genomic fragments sampled from a limited number of individuals (e.g., Pritchard et al. 2000;Molina et al. 2001;Li and Stephan 2006;Thornton and Andolfatto 2006;Gutenkunst et al. 2009;Duchen et al. 2013). While these studies provided important insights into the evolutionary forces acting on populations, they were ultimately limited by both sample size and the physical scale in which patterns of polymorphism and linkage could be investigated. The recent availability of wholegenome sequences from multiple individuals with populations in a variety of species (e.g., Abecasis et al. 2010;Cao et al. 2011;Mackay et al. 2012) is enabling us to examine long-range patterns of linkage disequilibrium (LD) (10 kb), measured either as correlations between pairs of sites or as haplotype homozygosity. LD offers powerful insights into selective and demographic processes shaping genetic variation in a natural populatio...

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On the Utility of Short Intron Sequences as a Reference for the Detection of Positive and Negative Selection in Drosophila

Cited by 112 publications

References 62 publications

Inferences of Demography and Selection in an African Population of Drosophila melanogaster

Inferences of Demography and Selection in an African Population of Drosophila melanogaster

Determining the factors driving selective effects of new nonsynonymous mutations

Elevated Linkage Disequilibrium and Signatures of Soft Sweeps Are Common in Drosophila melanogaster

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