The ratio of human X chromosome to autosome diversity is positively correlated with genetic distance from genes

Hammer, Michael F.; Woerner, August E.; Mendez, Fernando L.; Watkins, Joseph C.; Cox, Murray P.; Wall, Jeffrey D.

doi:10.1038/ng.651

Cited by 93 publications

(147 citation statements)

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“…S2) are unlikely to explain this pattern, and rather we argue that the reduced variation on the X chromosome is driven by a combination of more efficient selection against detrimental variants and selection for advantageous recessive mutations. Recent studies in humans have also reported a reduced X/A ratio near genes and interpreted this as HillRobertson effects (10,12,27). Purifying selection is, if anything, marginally stronger on the X chromosome than on autosomes in chimpanzees (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…S1). In humans, X to autosome diversity ratios range from 0.57 (Europeans) to 0.7 (Africans) near genes and between 0.75 (Europeans) and 0.87 (Africans) far away from genes (3,(10)(11)(12). We used the human reference genome to orient SNPs (Methods) and obtain the unfolded site frequency spectrum (SFS) at both synonymous and nonsynonymous sites (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Empirical evidence for increased levels of adaptation in X-linked regions remains elusive (7), except for a unique instance of a newly formed neo-X chromosome in Drosophila miranda (9) and a recent analysis of polymorphism and divergence between Drosophila melanogaster and Drosophila simulans for about 100 genes in X-linked regions (2). In human studies, Xlinked variation is lower than autosomal variation close to genes suggesting that selection affects X chromosomes more than autosomes, but Europeans have a genome-wide relative decrease in Xlinked variation when comparing with Africans, suggesting that genetic drift has specifically affected X chromosome in Europeans (3,(10)(11)(12). Likewise, it has been the subject of much discussion why there is a reduced variation of the X chromosome relative to autosomes in the human-chimpanzee ancestral species (13)(14)(15)(16).…”

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Extensive X-linked adaptive evolution in central chimpanzees

Hvilsom

Qian

Bataillon

et al. 2012

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

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Surveying genome-wide coding variation within and among species gives unprecedented power to study the genetics of adaptation, in particular the proportion of amino acid substitutions fixed by positive selection. Additionally, contrasting the autosomes and the X chromosome holds information on the dominance of beneficial (adaptive) and deleterious mutations. Here we capture and sequence the complete exomes of 12 chimpanzees and present the largest set of protein-coding polymorphism to date. We report extensive adaptive evolution specifically targeting the X chromosome of chimpanzees with as much as 30% of all amino acid replacements being adaptive. Adaptive evolution is barely detectable on the autosomes except for a few striking cases of recent selective sweeps associated with immunity gene clusters. We also find much stronger purifying selection than observed in humans, and in contrast to humans, we find that purifying selection is stronger on the X chromosome than on the autosomes in chimpanzees. We therefore conclude that most adaptive mutations are recessive. We also document dramatically reduced synonymous diversity in the chimpanzee X chromosome relative to autosomes and stronger purifying selection than for the human X chromosome. If similar processes were operating in the human-chimpanzee ancestor as in central chimpanzees today, our results therefore provide an explanation for the much-discussed reduction in the human-chimpanzee divergence at the X chromosome.Pan troglodytes troglodytes | SNP | site frequency spectrum | distribution of fitness effects | faster X Q uantifying the relative importance of purifying, neutral, and positive selection in shaping divergence between species remains a challenge in evolutionary biology. Beneficial mutations are central for understanding evolution by natural selection. However, the rarity of beneficial mutations has frustrated attempts to characterize their most basic genetic properties in higher organisms (1). One way forward is to combine genome-wide surveys of polymorphism within species and between species divergence to estimate the fraction, α, of mutations that have been fixed by positive selection. Empirical studies, particularly in the Drosophila genus show that mutations fixed by positive selection can make up a sizable fraction (>50%) of the divergence between species in gene coding regions (2) but whether these results are general for mammals, for example, remains unclear. Furthermore we still know very little about the distribution of fitness effects (DFE) of these mutations and even less about their dominance in diploid organisms. Theory predicts and recent empirical studies emphasize that the demographic history as well as variation in mutation and recombination rates can blur footprints of molecular adaptation by Darwinian selection (3, 4). This in turn can complicate the inference of DFE and α (5, 6).In that context, contrasting the DFE and rates of adaptation in autosomes versus sex chromosomes is an elegant strategy to infer the genetic properties...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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Extensive X-linked adaptive evolution in central chimpanzees

Hvilsom

Qian

Bataillon

et al. 2012

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

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“…Part of the variation in these ratios is associated with differences in recombination and distance from coding loci (and effects of selection). Hammer et al (2010) found that the adjusted ratio increased from 0.89 to 1.48 as the recombination distance from functional loci increased. Further, Vicoso and Charlesworth (2009) reported an adjusted ratio for nucleotide diversity in Drosophila melanogaster for non-coding regions of X chromosomes: autosomes of 1.57, but the adjusted ratio was 0.97 for regions with similar effective recombination rates on X and autosomes.…”

Section: And Z Chromosomesmentioning

confidence: 97%

How closely does genetic diversity in finite populations conform to predictions of neutral theory? Large deficits in regions of low recombination

Frankham

2011

Heredity

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Levels of genetic diversity in finite populations are crucial in conservation and evolutionary biology. Genetic diversity is required for populations to evolve and its loss is related to inbreeding in random mating populations, and thus to reduced population fitness and increased extinction risk. Neutral theory is widely used to predict levels of genetic diversity. I review levels of genetic diversity in finite populations in relation to predictions of neutral theory. Positive associations between genetic diversity and population size, as predicted by neutral theory, are observed for microsatellites, allozymes, quantitative genetic variation and usually for mitochondrial DNA (mtDNA). However, there are frequently significant deviations from neutral theory owing to indirect selection at linked loci caused by balancing selection, selective sweeps and background selection. Substantially lower genetic diversity than predicted under neutrality was found for chromosomes with low recombination rates and high linkage disequilibrium (compared with 'normally' recombining chromosomes within species and adjusted for different copy numbers and mutation rates), including W (median 100% lower) and Y (89% lower) chromosomes, dot fourth chromosomes in Drosophila (94% lower) and mtDNA (67% lower). Further, microsatellite genetic and allelic diversity were lost at 12 and 33% faster rates than expected in populations adapting to captivity, owing to widespread selective sweeps. Overall, neither neutral theory nor most versions of the genetic draft hypothesis are compatible with all empirical results.

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“…Individual identifiers for each of these samples are described in Wall et al (35). Our updated resequence dataset consists of 61 loci in autosomal intergenic regions (36), each z20 kb of primarily single-copy noncoding (i.e., putatively nonfunctional) DNA in regions of medium or high recombination (ρ $ 0.9 cM/ Mb) at least 100 kb away from the nearest gene (37). We used a locus trio design, sequencing three fragments of z2 kb spaced evenly across the region (35).…”

Section: Methodsmentioning

confidence: 99%

Genetic evidence for archaic admixture in Africa

Hammer¹,

Woerner²,

Mendez³

et al. 2011

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

275

215

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A long-debated question concerns the fate of archaic forms of the genus Homo: did they go extinct without interbreeding with anatomically modern humans, or are their genes present in contemporary populations? This question is typically focused on the genetic contribution of archaic forms outside of Africa. Here we use DNA sequence data gathered from 61 noncoding autosomal regions in a sample of three sub-Saharan African populations (Mandenka, Biaka, and San) to test models of African archaic admixture. We use two complementary approximate-likelihood approaches and a model of human evolution that involves recent population structure, with and without gene flow from an archaic population. Extensive simulation results reject the null model of no admixture and allow us to infer that contemporary African populations contain a small proportion of genetic material (z2%) that introgressed z35 kya from an archaic population that split from the ancestors of anatomically modern humans z700 kya. Three candidate regions showing deep haplotype divergence, unusual patterns of linkage disequilibrium, and small basal clade size are identified and the distributions of introgressive haplotypes surveyed in a sample of populations from across sub-Saharan Africa. One candidate locus with an unusual segment of DNA that extends for >31 kb on chromosome 4 seems to have introgressed into modern Africans from a now-extinct taxon that may have lived in central Africa. Taken together our results suggest that polymorphisms present in extant populations introgressed via relatively recent interbreeding with hominin forms that diverged from the ancestors of modern humans in the Lower-Middle Pleistocene.H. sapiens | hybridization I t is now well accepted that anatomically modern humans (AMH) originated in Africa and eventually dispersed to all inhabited parts of the world. What is not known is the extent to which the ancestral population that gave rise to AMH was genetically isolated, and whether archaic hominins made a genetic contribution to the modern human gene pool. Answering these questions has important implications for understanding the way in which adaptations associated with modern traits were assembled in the human genome: do the genes of AMH descend exclusively from a single isolated population, or do our genes descend from divergent ancestors that occupied different ecological niches over a wider geographical range across and outside of the African Pleistocene landscape?The introgression debate is typically framed in terms of interbreeding between AMH and Neandertals in Europe or other archaic forms in Asia. The opportunity for such hybridizations may have existed between 90 and 30 kya, after early modern humans dispersed from Africa and before archaic forms went extinct in Eurasia (1-5). Recent genome-level analyses of ancient DNA suggest that a small amount of gene flow did occur from Neandertals into the ancestors of non-Africans sometime after AMH left Africa (6) and that an archaic "Denisovan" population contributed genetic mat...

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The ratio of human X chromosome to autosome diversity is positively correlated with genetic distance from genes

Cited by 93 publications

References 15 publications

Extensive X-linked adaptive evolution in central chimpanzees

Extensive X-linked adaptive evolution in central chimpanzees

How closely does genetic diversity in finite populations conform to predictions of neutral theory? Large deficits in regions of low recombination

Genetic evidence for archaic admixture in Africa

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