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Title:
Adaptively introgressed Neandertal haplotype at the OAS locus functionally impacts innate immune responses in humans | Genome Biology
Description:
Background The 2’-5’ oligoadenylate synthetase (OAS) locus encodes for three OAS enzymes (OAS1-3) involved in innate immune response. This region harbors high amounts of Neandertal ancestry in non-African populations; yet, strong evidence of positive selection in the OAS region is still lacking. Results Here we used a broad array of selection tests in concert with neutral coalescent simulations to demonstrate a signal of adaptive introgression at the OAS locus. Furthermore, we characterized the functional consequences of the Neandertal haplotype in the transcriptional regulation of OAS genes at baseline and infected conditions. We found that cells from people with the Neandertal-like haplotype express lower levels of OAS3 upon infection, as well as distinct isoforms of OAS1 and OAS2. Conclusions We present evidence that a Neandertal haplotype at the OAS locus was subjected to positive selection in the human population. This haplotype is significantly associated with functional consequences at the level of transcriptional regulation of innate immune responses. Notably, we suggest that the Neandertal-introgressed haplotype likely reintroduced an ancestral splice variant of OAS1 encoding a more active protein, suggesting that adaptive introgression occurred as a means to resurrect adaptive variation that had been lost outside Africa.
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Keywords {🔍}
oas, pubmed, neandertal, haplotype, article, google, scholar, allele, selection, additional, haplotypes, nls, data, frequency, cas, human, samples, introgression, file, central, snps, population, region, found, expression, adaptive, genes, genomes, european, levels, populations, individuals, fig, genome, locus, results, ancestral, genetic, sample, frequencies, table, expected, simulations, model, ancient, macrophages, genomewide, humans, calculated, positive,
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uk/impute/1000gp%20phase%203%20haplotypes%206%20october%202014 }_1=\frac{x_0}{x_0+\left tumor-necrosis-factor-alpha article download pdf quantitative real-time pcr rna-seq library preparation genome-wide statistical framework full size image high-coverage genome sequence mid-log phase prior central oas region comparable present-day frequencies gene-level expression estimates ]={\displaystyle \sum_i^{\left\{hg performing haplotype-based scans gene-level expression data genome-wide sequence data reach genome-wide significance fast model-based estimation present-day human populations 99th genome-wide percentiles present-day samples estimated long-term balancing selection unusually long-range ld transcript-level expression values present-day european samples uk/impute/1000gp_phase3 observed present-day frequency innate immune responses genome-wide genotype data present-day european populations neandertal-introgressed allele encodes similar present-day frequency genome-wide association studies privacy choices/manage cookies estimate genome-wide levels ihs calculated genome-wide wright–fisher neutral model type-ii interferon genes gene expression responses pickrell jk creative commons license single-pulse introgression model innate immune cells �genome-wide scan bi-allelic variants innate immune response empirical haplotype-based tests haplotype-based test statistic taqman gene assays
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headline:Adaptively introgressed Neandertal haplotype at the OAS locus functionally impacts innate immune responses in humans
description:The 2’-5’ oligoadenylate synthetase (OAS) locus encodes for three OAS enzymes (OAS1-3) involved in innate immune response. This region harbors high amounts of Neandertal ancestry in non-African populations; yet, strong evidence of positive selection in the OAS region is still lacking. Here we used a broad array of selection tests in concert with neutral coalescent simulations to demonstrate a signal of adaptive introgression at the OAS locus. Furthermore, we characterized the functional consequences of the Neandertal haplotype in the transcriptional regulation of OAS genes at baseline and infected conditions. We found that cells from people with the Neandertal-like haplotype express lower levels of OAS3 upon infection, as well as distinct isoforms of OAS1 and OAS2. We present evidence that a Neandertal haplotype at the OAS locus was subjected to positive selection in the human population. This haplotype is significantly associated with functional consequences at the level of transcriptional regulation of innate immune responses. Notably, we suggest that the Neandertal-introgressed haplotype likely reintroduced an ancestral splice variant of OAS1 encoding a more active protein, suggesting that adaptive introgression occurred as a means to resurrect adaptive variation that had been lost outside Africa.
datePublished:2016-11-29T00:00:00Z
dateModified:2016-11-29T00:00:00Z
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license:http://creativecommons.org/publicdomain/zero/1.0/
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keywords:
Natural selection
Introgression
Innate immunity
Animal Genetics and Genomics
Human Genetics
Plant Genetics and Genomics
Microbial Genetics and Genomics
Bioinformatics
Evolutionary Biology
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headline:Adaptively introgressed Neandertal haplotype at the OAS locus functionally impacts innate immune responses in humans
description:The 2’-5’ oligoadenylate synthetase (OAS) locus encodes for three OAS enzymes (OAS1-3) involved in innate immune response. This region harbors high amounts of Neandertal ancestry in non-African populations; yet, strong evidence of positive selection in the OAS region is still lacking. Here we used a broad array of selection tests in concert with neutral coalescent simulations to demonstrate a signal of adaptive introgression at the OAS locus. Furthermore, we characterized the functional consequences of the Neandertal haplotype in the transcriptional regulation of OAS genes at baseline and infected conditions. We found that cells from people with the Neandertal-like haplotype express lower levels of OAS3 upon infection, as well as distinct isoforms of OAS1 and OAS2. We present evidence that a Neandertal haplotype at the OAS locus was subjected to positive selection in the human population. This haplotype is significantly associated with functional consequences at the level of transcriptional regulation of innate immune responses. Notably, we suggest that the Neandertal-introgressed haplotype likely reintroduced an ancestral splice variant of OAS1 encoding a more active protein, suggesting that adaptive introgression occurred as a means to resurrect adaptive variation that had been lost outside Africa.
datePublished:2016-11-29T00:00:00Z
dateModified:2016-11-29T00:00:00Z
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license:http://creativecommons.org/publicdomain/zero/1.0/
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Natural selection
Introgression
Innate immunity
Animal Genetics and Genomics
Human Genetics
Plant Genetics and Genomics
Microbial Genetics and Genomics
Bioinformatics
Evolutionary Biology
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