Leveraging shared ancestral variation to detect local introgression

Fang, Lesly Lopez; Vecchyo, Diego Ortega‐Del; McTavish, Emily Jane; Huerta‐Sánchez, Emilia

doi:10.1101/2022.03.21.485082

Cited by 3 publications

(2 citation statements)

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“…CYP2C9 is located within 50 kb of CYP2C8 , and their archaic SNVs show similar frequencies in modern populations ( supplementary table S3, Supplementary Material online) and were thought to have linked archaic haplotypes ( CYP2C9* 2 and CYP2C8* 3), so they may represent one complete archaic haplotype ( Haeggström et al 2022 ). However, none of these three genes were found to be candidates for introgression at a statistically significant level using the D+ statistic ( Lopez Fang et al 2022 , supplementary table S7, Supplementary Material online). It should be noted that these genes are most certainly under ongoing selection across human populations ( Thomas 2007 ), reducing the statistical power of tests designed to operate under neutrality.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, we performed the D+ statistic ( Lopez Fang et al 2022 ) as a test of local introgression for three genes: CYP2C8 , CYP2C9 , and CYP2J2 . We calculated D+ for all combinations of P1 = {YRI}, P2 = {CEU, PEL}, and P3 = {Vindija Neanderthal} where ancestral states were polarized using the ancestral allele calls in the 1000 Genomes Panel.…”

Section: Methodsmentioning

confidence: 99%

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Pharmacogenetic Variation in Neanderthals and Denisovans and Implications for Human Health and Response to Medications

Wroblewski,

Witt,

Lee

et al. 2023

Genome Biology and Evolution

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Modern humans carry both Neanderthal and Denisovan (archaic) genome elements that are part of the human gene pool and affect the life and health of living individuals. The impact of archaic DNA may be particularly evident in pharmacogenes—genes responsible for the processing of exogenous substances such as food, pollutants, and medications—as these can relate to changing environmental effects, and beneficial variants may have been retained as modern humans encountered new environments. However, the health implications and contribution of archaic ancestry in pharmacogenes of modern humans remain understudied. Here, we explore 11 key cytochrome P450 genes (CYP450) involved in 75% of all drug metabolizing reactions in three Neanderthal and one Denisovan individuals and examine archaic introgression in modern human populations. We infer the metabolizing efficiency of these 11 CYP450 genes in archaic individuals and find important predicted phenotypic differences relative to modern human variants. We identify several single nucleotide variants shared between archaic and modern humans in each gene, including some potentially function-altering mutations in archaic CYP450 genes, which may result in altered metabolism in living people carrying these variants. We also identified several variants in the archaic CYP450 genes that are novel and unique to archaic humans as well as one gene, CYP2B6, that shows evidence for a gene duplication found only in Neanderthals and modern Africans. Finally, we highlight CYP2A6, CYP2C9, and CYP2J2, genes which show evidence for archaic introgression into modern humans and posit evolutionary hypotheses that explain their allele frequencies in modern populations.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Pharmacogenetic Variation in Neanderthals and Denisovans and Implications for Human Health and Response to Medications

Wroblewski,

Witt,

Lee

et al. 2023

Genome Biology and Evolution

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The Utility of Ancestral and Derived Allele Sharing for Genome-Wide Inferences of Introgression

Peede

Vecchyo

Huerta‐Sánchez

2022

Preprint

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The past decade has ushered in a resurgence of studies highlighting the importance of introgression throughout the Tree of Life. Several methods exist for detecting and quantifying introgression on a genomic scale, yet the majority of these methods primarily utilize signals of derived allele sharing between donor and recipient populations. In this study, we exploit the fact that introgression will not only result in derived allele sharing but also the reintroduction of ancestral alleles to derive new estimators of the admixture proportion. Using coalescent simulations, we assess the performance of our new methods and the methods proposed in Lopez Fang et al. 2022 to assess the utility of incorporating shared ancestral variation into genome-wide inferences of introgression. Using coalescent theory, simulations, and applying our methods to human and canid data, we find that methods incorporating ancestral allele sharing are comparable to their derived allele sharing counterparts, in turn providing researchers with the opportunity to utilize more of the genomic signature of introgression.

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TheMUC19gene in Denisovans, Neanderthals, and Modern Humans: An Evolutionary History of Recurrent Introgression and Natural Selection

Villanea,

Peede,

Kaufman

et al. 2023

Preprint

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All humans carry a small fraction of archaic ancestry across the genome, the legacy of gene flow from Neanderthals, Denisovans, and other hominids into the ancestors of modern humans. While the effects of Neanderthal ancestry on human fitness and health have been explored more thoroughly, there are fewer examples of adaptive introgression of Denisovan variants. Here, we study the geneMUC19, for which some modern humans carry aDenisovan-likehaplotype.MUC19is a mucin, a glycoprotein that forms gels with various biological functions, from lubrication to immunity. We find the diagnostic variants for theDenisovan-like MUC19haplotype at high frequencies in admixed Latin American individuals among global population, and at highest frequency in 23 ancient Indigenous American individuals, all predating population admixture with Europeans and Africans. We find that some Neanderthals––Vindija and Chagyrskaya––carry theDenisovan-like MUC19haplotype, and that it was likely introgressed into human populations through Neanderthal introgression rather than Denisovan introgression. Finally, we find that theDenisovan-like MUC19haplotype carries a higher copy number of a 30 base-pair variable number tandem repeat relative to theHuman-likehaplotype, and that copy numbers of this repeat are exceedingly high in American populations. Our results suggest that theDenisovan-like MUC19haplotype served as the raw genetic material for positive selection as American populations adapted to novel environments during their movement from Beringia into North and then South America.

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Leveraging shared ancestral variation to detect local introgression

Cited by 3 publications

References 38 publications

Pharmacogenetic Variation in Neanderthals and Denisovans and Implications for Human Health and Response to Medications

Pharmacogenetic Variation in Neanderthals and Denisovans and Implications for Human Health and Response to Medications

The Utility of Ancestral and Derived Allele Sharing for Genome-Wide Inferences of Introgression

TheMUC19gene in Denisovans, Neanderthals, and Modern Humans: An Evolutionary History of Recurrent Introgression and Natural Selection

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