Neanderthal introgression in SCN9A impacts mechanical pain sensitivity.
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ABSTRACT:
SUBMITTER: Faux P
PROVIDER: S-EPMC10564861 | biostudies-literature | 2023 Oct
REPOSITORIES: biostudies-literature
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Neanderthal introgression in SCN9A impacts mechanical pain sensitivity.
Faux Pierre P Ding Li L Ramirez-Aristeguieta Luis Miguel LM Chacón-Duque J Camilo JC Comini Maddalena M Mendoza-Revilla Javier J Fuentes-Guajardo Macarena M Jaramillo Claudia C Arias William W Hurtado Malena M Villegas Valeria V Granja Vanessa V Barquera Rodrigo R Everardo-Martínez Paola P Quinto-Sánchez Mirsha M Gómez-Valdés Jorge J Villamil-Ramírez Hugo H Silva de Cerqueira Caio C CC Hünemeier Tábita T Ramallo Virginia V Gonzalez-José Rolando R Schüler-Faccini Lavinia L Bortolini Maria-Cátira MC Acuña-Alonzo Victor V Canizales-Quinteros Samuel S Poletti Giovanni G Gallo Carla C Rothhammer Francisco F Rojas Winston W Schmid Annina B AB Adhikari Kaustubh K Bennett David L DL Ruiz-Linares Andrés A
Communications biology 20231010 1
The Nav1.7 voltage-gated sodium channel plays a key role in nociception. Three functional variants in the SCN9A gene (encoding M932L, V991L, and D1908G in Nav1.7), have recently been identified as stemming from Neanderthal introgression and to associate with pain symptomatology in UK BioBank data. In 1000 genomes data, these variants are absent in Europeans but common in Latin Americans. Analysing high-density genotype data from 7594 Latin Americans, we characterized Neanderthal introgression in ...[more]
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Project description:Hybridization between humans and Neanderthals has resulted in a low level of Neanderthal ancestry scattered across the genomes of many modern-day humans. After hybridization, on average, selection appears to have removed Neanderthal alleles from the human population. Quantifying the strength and causes of this selection against Neanderthal ancestry is key to understanding our relationship to Neanderthals and, more broadly, how populations remain distinct after secondary contact. Here, we develop a novel method for estimating the genome-wide average strength of selection and the density of selected sites using estimates of Neanderthal allele frequency along the genomes of modern-day humans. We confirm that East Asians had somewhat higher initial levels of Neanderthal ancestry than Europeans even after accounting for selection. We find that the bulk of purifying selection against Neanderthal ancestry is best understood as acting on many weakly deleterious alleles. We propose that the majority of these alleles were effectively neutral-and segregating at high frequency-in Neanderthals, but became selected against after entering human populations of much larger effective size. While individually of small effect, these alleles potentially imposed a heavy genetic load on the early-generation human-Neanderthal hybrids. This work suggests that differences in effective population size may play a far more important role in shaping levels of introgression than previously thought.
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2017-05-25 | GSE99265 | GEO
Project description:Eurasians have ~2% Neanderthal ancestry, but we lack a comprehensive understanding of the genome-wide influence of Neanderthal introgression on modern human diseases and traits. Here, we quantify the contribution of introgressed alleles to the heritability of more than 400 diverse traits. We show that genomic regions in which detectable Neanderthal ancestry remains are depleted of heritability for all traits considered, except those related to skin and hair. Introgressed variants themselves are also depleted for contributions to the heritability of most traits. However, introgressed variants shared across multiple Neanderthal populations are enriched for heritability and have consistent directions of effect on several traits with potential relevance to human adaptation to non-African environments, including hair and skin traits, autoimmunity, chronotype, bone density, lung capacity, and menopause age. Integrating our results, we propose a model in which selection against introgressed functional variation was the dominant trend (especially for cognitive traits); however, for a few traits, introgressed variants provided beneficial variation via uni-directional (e.g., lightening skin color) or bi-directional (e.g., modulating immune response) effects.
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