Contributions of Protein-Coding and Regulatory Change to Adaptive Molecular Evolution in Murid Rodents

Halligan, Daniel L.; Kousathanas, Athanasios; Ness, Rob W.; Harr, Bettina; Eöry, Lél; Keane, Thomas M.; Adams, David J.; Keightley, Peter D.

doi:10.1371/journal.pgen.1003995

Cited by 113 publications

(240 citation statements)

References 55 publications

Supporting

Mentioning

219

Contrasting

Unclassified

Order By: Relevance

“…This result has implications for endeavors such as attempts to fit models of the effects of deleterious mutations on variability at linked sites to observed patterns of variability across the genome (76,77); use of the population genomics estimate of the DFE could underestimate these effects, especially for regions that are some distance away from the targets of selection, because more strongly deleterious mutations have effects that extend over longer genetic distances than those of weakly selected mutations.…”

Section: Discussionmentioning

confidence: 99%

Causes of natural variation in fitness: Evidence from studies of Drosophila populations

Charlesworth

2015

Proc. Natl. Acad. Sci. U.S.A.

174

256

View full text Add to dashboard Cite

DNA sequencing has revealed high levels of variability within most species. Statistical methods based on population genetics theory have been applied to the resulting data and suggest that most mutations affecting functionally important sequences are deleterious but subject to very weak selection. Quantitative genetic studies have provided information on the extent of genetic variation within populations in traits related to fitness and the rate at which variability in these traits arises by mutation. This paper attempts to combine the available information from applications of the two approaches to populations of the fruitfly Drosophila in order to estimate some important parameters of genetic variation, using a simple population genetics model of mutational effects on fitness components. Analyses based on this model suggest the existence of a class of mutations with much larger fitness effects than those inferred from sequence variability and that contribute most of the standing variation in fitness within a population caused by the input of mildly deleterious mutations. However, deleterious mutations explain only part of this standing variation, and other processes such as balancing selection appear to make a large contribution to genetic variation in fitness components in Drosophila.

show abstract

Section: Discussionmentioning

confidence: 99%

Causes of natural variation in fitness: Evidence from studies of Drosophila populations

Charlesworth

2015

Proc. Natl. Acad. Sci. U.S.A.

174

256

View full text Add to dashboard Cite

show abstract

“…To determine whether we could recapitulate the negative correlation between the zerofold/fourfold ratio and neutral heterozygosity using realistic models of demography and purifying selection, we performed forward in time simulations under the Wright Fisher model in the Poisson Random Field framework (2,52,53). We explored a variety of different distributions of selective effects, including those fit to mouse (54) and human (55) data, as well as several custom distributions (SI Appendix, SI Text).…”

Section: Methodsmentioning

confidence: 99%

Bottlenecks and selective sweeps during domestication have increased deleterious genetic variation in dogs

Marsden

Vecchyo

O’Brien

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

287

348

View full text Add to dashboard Cite

Population bottlenecks, inbreeding, and artificial selection can all, in principle, influence levels of deleterious genetic variation. However, the relative importance of each of these effects on genome-wide patterns of deleterious variation remains controversial. Domestic and wild canids offer a powerful system to address the role of these factors in influencing deleterious variation because their history is dominated by known bottlenecks and intense artificial selection. Here, we assess genome-wide patterns of deleterious variation in 90 whole-genome sequences from breed dogs, village dogs, and gray wolves. We find that the ratio of amino acid changing heterozygosity to silent heterozygosity is higher in dogs than in wolves and, on average, dogs have 2-3% higher genetic load than gray wolves. Multiple lines of evidence indicate this pattern is driven by less efficient natural selection due to bottlenecks associated with domestication and breed formation, rather than recent inbreeding. Further, we find regions of the genome implicated in selective sweeps are enriched for amino acid changing variants and Mendelian disease genes. To our knowledge, these results provide the first quantitative estimates of the increased burden of deleterious variants directly associated with domestication and have important implications for selective breeding programs and the conservation of rare and endangered species. Specifically, they highlight the costs associated with selective breeding and question the practice favoring the breeding of individuals that best fit breed standards. Our results also suggest that maintaining a large population size, rather than just avoiding inbreeding, is a critical factor for preventing the accumulation of deleterious variants.M any of the mutations that arise in genomes are weakly deleterious and reduce fitness but are not always eliminated from the population by purifying natural selection. Consequently, understanding the reasons why deleterious mutations persist in populations and the role of demographic history in this process is of considerable interest (1-9). The radiation of domestic dogs offers a unique opportunity to address these questions. Dogs were originally domesticated from ancestral gray wolf populations >15,000 y ago in a process involving one or more severe population bottlenecks (10-12). The more recent isolation of modern dog breeds, which occurred over the last 300 y, involved additional population bottlenecks, intense artificial selection, and inbreeding Fig. 1A). Although this history is predicted to have resulted in the accumulation of deleterious variants, its specific effect on genomewide patterns of deleterious variation remains unclear.Here, we use complete genome sequencing data from 46 dogs representing 34 breeds, 25 village dogs, and 19 wolves to directly examine patterns of deleterious genetic variation across the dog genome (Dataset S1). Because more than half of these data derive from our own sequencing efforts, this project represents the largest survey of dog...

show abstract

“…New genome sequences from a population sample of Mus musculus castaneus, one of the three subspecies of house mice, and Mus famulus, are combined with the existing rat genome sequence to describe patterns of polymorphism and divergence genome-wide. In this issue of Genetics, Kousathanas et al translate these patterns into conclusions about faster X evolution, whereas Halligan et al (2013) use them to examine the relative roles of protein-coding and cisregulatory variation in adaptation. Kousathanas et al (2014) analyze variation at 700 X-linked genes and 18,110 autosomal genes.…”

mentioning

confidence: 99%

“…Placing the study of faster X in a comparative framework could help identify the underlying mechanisms. Halligan et al (2013) use the genome sequences from M. musculus castaneus, M. famulus, and rat to compare adaptive evolution at protein-coding and cis-regulatory sequences. Noncoding elements conserved across placental mammals are treated as putative cis-regulatory sequences (and abbreviated as CNEs, for "conserved noncoding elements").…”

mentioning

confidence: 99%

“…The selective purging of deleterious mutations also reduces linked diversity, through a process called background selection (Charlesworth et al 1993). Halligan et al (2013) measure diversity in narrow windows around exons and CNEs, using neutral divergence to account for local variation in the mutation rate. Whereas diversity around CNEs fits predictions from background selection models, variation near exons is lower than expected.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Disproportionate Roles for the X Chromosome and Proteins in Adaptive Evolution

Payseur

2014

Genetics

View full text Add to dashboard Cite

A daptation requires genetic variation. A complete understanding of this key evolutionary process includes identification of the mutations that confer adaptive change. High-resolution genetic dissection of particular adaptive phenotypes can pinpoint these mutations, but this is a challenging task and the resulting conclusions are restricted to the traits under consideration.An alternative approach is to examine characteristics of adaptive mutations through the powerful lens of population genetics. By measuring intraspecific polymorphism and interspecific divergence across genomes, evolutionary properties of those mutations targeted by natural selection can be discovered. Under this framework as well, generalities are widely sought and difficult to identify. A useful way to make progress is to compare patterns of adaptive evolution among different categories of loci. Two contrasts are based on the genomic location of mutations: X linked vs. autosomal and protein coding vs. cis-regulatory (i.e., noncoding sequences that affect local gene expression). These contrasts have generated substantial interest because they are tied directly to basic questions about adaptive evolution.The fate of a beneficial mutation should depend on its mode of inheritance. This idea motivates comparisons between rates of adaptive evolution on the X chromosome and the autosomes. Recent, low-frequency recessive mutations are immediately exposed to selection in males when X-linked and are mostly hidden from selection (in heterozygotes) when autosomal. If beneficial mutations are at least partially recessive on average, they will fix faster on the X chromosome (Avery 1984), elevating the rate of evolution relative to autosomal loci. In an influential theoretical article, Charlesworth et al. (1987) quantified this connection between dominance and "faster X" evolution and identified the biological conditions under which it applies. With several assumptions, the relative rates of molecular evolution at X-linked and autosomal loci can even be used to estimate the average dominance of new advantageous mutations, an important quantity in evolutionary biology.The study of faster X evolution is also motivated by a desire to explain the outsized role of the X chromosome in speciation. In a wide variety of species pairs, the sterility and/or inviability of hybrids created by interspecific crosses maps differentially to the X chromosome (Coyne and Orr 2004). This bias seems to reflect a higher density of hybrid incompatibilities involving the X chromosome (Masly and Presgraves 2007).The prediction of faster X evolution has been tested repeatedly by comparing between-species divergence at X-linked and autosomal genes (Meisel and Connallon 2013). The most popular approach calculates the relative rate of substitution at nonsynonymous and synonymous sites, reasoning that nonsynonymous changes will often be targeted by selection. A flurry of studies featuring Drosophila revealed a range of support for faster X evolution (Betancourt et al. 2002;Thornton and ...

show abstract

Contributions of Protein-Coding and Regulatory Change to Adaptive Molecular Evolution in Murid Rodents

Cited by 113 publications

References 55 publications

Causes of natural variation in fitness: Evidence from studies of Drosophila populations

Causes of natural variation in fitness: Evidence from studies of Drosophila populations

Bottlenecks and selective sweeps during domestication have increased deleterious genetic variation in dogs

Disproportionate Roles for the X Chromosome and Proteins in Adaptive Evolution

Contact Info

Product

Resources

About