Deep Haplotype Divergence and Long-Range Linkage Disequilibrium at Xp21.1 Provide Evidence That Humans Descend From a Structured Ancestral Population

Garrigan, Daniel; Mobasher, Zahra; Kingan, Sarah B.; Wilder, Jason A.; Hammer, Michael F.

doi:10.1534/genetics.105.041095

Cited by 71 publications

(62 citation statements)

References 42 publications

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“…Our results are consistent with earlier inferences supporting the role of archaic admixture in sub-Saharan Africa based on analyses of coding regions (19) and the Xp21.1 noncoding region (16). Although our estimates of isolation and admixture dates are tentative, the results point to relatively recent genetic exchange with an unknown archaic hominin that diverged from the ancestors of modern humans in the Lower-Middle Pleistocene and remained isolated for several hundred thousand years.…”

Section: Discussionsupporting

confidence: 91%

“…Interestingly, recent studies attest to the existence of Late Stone Age human remains with archaic features in Nigeria (Iwo Eleru) and the Democratic Republic of Congo (Ishango) (30)(31)(32). The observation that populations from many parts of the world, including Africa, show evidence of introgression of archaic variants (6,16,19) suggests that genetic exchange between morphologically divergent forms may be a common feature of human evolution. If so, hybridization may have played a key role in the de novo origin of some our uniquely human traits (33).…”

Section: Discussionmentioning

confidence: 99%

“…Here we use a different strategy to address the question of ancient population structure in Africa. Using multilocus DNA sequence polymorphism data from extant Africans, we analyze patterns of divergence and linkage disequilibrium (LD) to detect the signature of archaic admixture (16)(17)(18). Application of this approach to publicly available sequence data from the Environmental Genome Project found evidence of ancient population structure in both African and non-African populations (19).…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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 possibility to discriminate between these scenarios is to calculate the percentage of congruent mutations, meaning those that occur on the basal branches of a genealogy (Wall 2000). When we applied this approach to the two major BSG clades, a percentage of congruent mutations equal to 34% was obtained; this is lower than previous estimates under a model of ancient population structure, which ranged from 42% to 45% (Barreiro et al 2005;Garrigan et al 2005); also, the TMRCA we estimated for the BSG gene is not unusual (Tishkoff and Verrelli 2003;Garrigan and Hammer 2006), while deep coalescent times are expected when ancient population subdivision is involved. The asymmetric structure of the haplotype genealogy whereby most chromosomes cluster in one clade with a relatively deep coalescent, while a minor branch is accounted for by a small number of less diverged chromosomes is difficult to interpret within a theoretical framework.…”

Section: Bsg (Ok System)contrasting

confidence: 77%

Widespread balancing selection and pathogen-driven selection at blood group antigen genes

Fumagalli¹,

Cagliani²,

Pozzoli³

et al. 2008

Genome Res.

153

141

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Historically, allelic variations in blood group antigen (BGA) genes have been regarded as possible susceptibility factors for infectious diseases. Since host-pathogen interactions are major determinants in evolution, BGAs can be thought of as selection targets. In order to verify this hypothesis, we obtained an estimate of pathogen richness for geographic locations corresponding to 52 populations distributed worldwide; after correction for multiple tests and for variables different from selective forces, significant correlations with pathogen richness were obtained for multiple variants at 11 BGA loci out of 26. In line with this finding, we demonstrate that three BGA genes, namely CD55, CD151, and SLC14A1, have been subjected to balancing selection, a process, rare outside MHC genes, which maintains variability at a locus. Moreover, we identified a gene region immediately upstream the transcription start site of FUT2 which has undergone non-neutral evolution independently from the coding region. Finally, in the case of BSG, we describe the presence of a highly divergent haplotype clade and the possible reasons for its maintenance, including frequency-dependent balancing selection, are discussed. These data indicate that BGAs have been playing a central role in the host-pathogen arms race during human evolutionary history and no other gene category shows similar levels of widespread selection, with the only exception of loci involved in antigen recognition.

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“…32,33 A possibility to discriminate between these two scenarios is to calculate the percentage of congruent mutations, meaning those that occur on the basal branches of a genealogy. 33 When this approach is applied to the two major clades (that is haplogroups 1 and 2), a percentage of congruent mutations equal to 20% is obtained; this is much lower than earlier estimates under a model of ancient population structure that ranged from 42 to 45%, 34,35 suggesting that balancing selection rather than population subdivision is responsible for the maintenance of the two clades. Conversely, the presence of a third minor haplogroup restricted to Africa and with a deeper TMRCA, might be explained by ancient population structure in the African continent.…”

Section: Resultsmentioning

confidence: 92%

A population genetics study of the Familial Mediterranean Fever gene: evidence of balancing selection under an overdominance regime

et al. 2009

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Familial Mediterranean Fever (FMF) is a recessively inherited systemic autoinflammatory disease caused by mutations in the MEFV gene. The frequency of different disease alleles is extremely high in multiple populations from the Mediterranean region, suggesting heterozygote advantage. Here, we characterize the sequence variation and haplotype structure of the MEFV 3 0 gene region (from exon 5 to the 3 0 UTR) in seven human populations. In non-African populations, we observed high levels of nucleotide variation, an excess of intermediate-frequency alleles, reduced population differentiation and a genealogy with two common haplotypes separated by deep branches. These features are suggestive of balancing selection having acted on this region to maintain one or more selected alleles. In line with this finding, an excess of heterozygotes was observed in Europeans and Asians, suggesting an overdominance regime. Our data, together with the earlier demonstration that the MEFV exon 10 has been subjected to episodic positive selection over primate evolution, provide evidence for an adaptive role of nucleotide variation in this gene region. Our data suggest that further studies aimed at clarifying the role of MEFV variants might benefit from the integration of molecular evolutionary and functional analyses.

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Deep Haplotype Divergence and Long-Range Linkage Disequilibrium at Xp21.1 Provide Evidence That Humans Descend From a Structured Ancestral Population

Cited by 71 publications

References 42 publications

Genetic evidence for archaic admixture in Africa

Genetic evidence for archaic admixture in Africa

Widespread balancing selection and pathogen-driven selection at blood group antigen genes

A population genetics study of the Familial Mediterranean Fever gene: evidence of balancing selection under an overdominance regime

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