Identifying a High Fraction of the Human Genome to be under Selective Constraint Using GERP++

Davydov, Eugene; Goode, David; Sirota, Marina; Cooper, Gregory M.; Sidow, Arend; Batzoglou, Serafim

doi:10.1371/journal.pcbi.1001025

Cited by 1,470 publications

(1,413 citation statements)

References 22 publications

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“…S10). We defined deleterious variants as those amino acid changes that occurred at phylogenetically conserved sites as measured by the Genomic Evolutionary Rate Profiling (GERP) scores (33). Wolves carry significantly more deleterious amino acid changing variants in the heterozygous state than do breed dogs (P < 2 × 10 −5 , Mann-Whitney U test, Fig.…”

Section: Significancementioning

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.

274

341

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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...

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Section: Significancementioning

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.

274

341

View full text Add to dashboard Cite

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“…In contrast, they were significantly depleted in regions with histone methylation/acetylation associated with active gene transcription, especially in regions with high H3K36me3 levels, associated with transcriptional activation and elongation (Ram et al 2011) and at conserved loci (GERP) (Supplemental Fig. S6; Davydov et al 2010). The ClinVar variants, on the other hand, were especially depleted in regions with high H3K9me3 levels, associated with gene repression and silencing.…”

Section: Spectrum Of Functional Elements Of Somatic Mutations Is Simimentioning

confidence: 99%

Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis

et al. 2014

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The somatic mutation burden in healthy white blood cells (WBCs) is not well known. Based on deep whole-genome sequencing, we estimate that approximately 450 somatic mutations accumulated in the nonrepetitive genome within the healthy blood compartment of a 115-yr-old woman. The detected mutations appear to have been harmless passenger mutations: They were enriched in noncoding, AT-rich regions that are not evolutionarily conserved, and they were depleted for genomic elements where mutations might have favorable or adverse effects on cellular fitness, such as regions with actively transcribed genes. The distribution of variant allele frequencies of these mutations suggests that the majority of the peripheral white blood cells were offspring of two related hematopoietic stem cell (HSC) clones. Moreover, telomere lengths of the WBCs were significantly shorter than telomere lengths from other tissues. Together, this suggests that the finite lifespan of HSCs, rather than somatic mutation effects, may lead to hematopoietic clonal evolution at extreme ages.

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“…Because at most, 10% of the genome seems to be under direct evolutionary constraint (18), reduction in diversity to less than 20% of the mean in large regions must mainly result from indirect selection in the form of background selection (negative selection) or hitchhiking (positive selection). We performed calculations based on existing theory (19) to estimate the expected maximal impact of background selection on diversity (details in SI Text).…”

Section: Significancementioning

confidence: 99%

Extreme selective sweeps independently targeted the X chromosomes of the great apes

Nam¹,

Dutheil

Schierup

et al. 2015

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

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The unique inheritance pattern of the X chromosome exposes it to natural selection in a way that is different from that of the autosomes, potentially resulting in accelerated evolution. We perform a comparative analysis of X chromosome polymorphism in 10 great ape species, including humans. In most species, we identify striking megabase-wide regions, where nucleotide diversity is less than 20% of the chromosomal average. Such regions are found exclusively on the X chromosome. The regions overlap partially among species, suggesting that the underlying targets are partly shared among species. The regions have higher proportions of singleton SNPs, higher levels of population differentiation, and a higher nonsynonymous-to-synonymous substitution ratio than the rest of the X chromosome. We show that the extent to which diversity is reduced is incompatible with direct selection or the action of background selection and soft selective sweeps alone, and therefore, we suggest that very strong selective sweeps have independently targeted these specific regions in several species. The only genomic feature that we can identify as strongly associated with loss of diversity is the location of testis-expressed ampliconic genes, which also have reduced diversity around them. We hypothesize that these genes may be responsible for selective sweeps in the form of meiotic drive caused by an intragenomic conflict in male meiosis. X-chromosome evolution | great apes | selective sweeps | ampliconic genes | meiotic drive

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Identifying a High Fraction of the Human Genome to be under Selective Constraint Using GERP++

Cited by 1,470 publications

References 22 publications

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

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

Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis

Extreme selective sweeps independently targeted the X chromosomes of the great apes

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