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Neanderthal introgression reintroduced functional alleles lost in the human out of Africa bottleneck

View ORCID ProfileDavid C. Rinker, View ORCID ProfileCorinne Simonti, Evonne McArthur, Douglas Shaw, Emily Hodges, View ORCID ProfileJohn Anthony Capra
doi: https://doi.org/10.1101/533257
David C. Rinker
Department of Biological Sciences, Vanderbilt University, Nashville, TN, 37235, USA;
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  • For correspondence: david.rinker@vanderbilt.edu
Corinne Simonti
Department of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, 30332, USA;
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  • For correspondence: c.simonti@gmail.com
Evonne McArthur
Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN 37235, USA;
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  • For correspondence: evonne.mcarthur@vanderbilt.edu
Douglas Shaw
Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN 37235, USA;
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  • For correspondence: douglas.m.shaw@vanderbilt.edu
Emily Hodges
Department of Biochemistry, Vanderbilt University, Nashville, TN, 37235, USA
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  • For correspondence: emily.hodges@vanderbilt.edu
John Anthony Capra
Department of Biological Sciences, Vanderbilt University, Nashville, TN, 37235, USA;
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  • For correspondence: tony.capra@vanderbilt.edu
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Abstract

Neanderthal ancestry remains across modern Eurasian genomes, and introgressed sequences influence diverse phenotypes, including immune, skin, and neuropsychiatric diseases. Interpretation of introgressed sequences has focused on alleles derived in the Neanderthal lineage. Here, we demonstrate that Neanderthal introgression also reintroduced thousands of ancestral hominin alleles lost in the Eurasian out of Africa bottleneck. Combining evolutionary simulations, expression quantitative trait loci (eQTL), massively parallel reporter assay (MPRA) data, and in vitro validation, we show that reintroduced alleles (RAs) have different fitness effects than Neanderthal-derived alleles (NDAs) and that some RAs regulate gene expression independent of NDAs. Illustrating the broad potential influence of RAs, we find that over 70% of known phenotype associations with NDAs are equally associated with RAs. Finally, we discover enrichment for RA eQTL activity in several tissues, with strongest enrichment in the brain. In summary, our study reveals that Neanderthal introgression supplied Eurasians with many lost functional variants and demonstrates that RAs must be considered when evaluating the effects of introgression.

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Posted January 29, 2019.
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Neanderthal introgression reintroduced functional alleles lost in the human out of Africa bottleneck
David C. Rinker, Corinne Simonti, Evonne McArthur, Douglas Shaw, Emily Hodges, John Anthony Capra
bioRxiv 533257; doi: https://doi.org/10.1101/533257
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Neanderthal introgression reintroduced functional alleles lost in the human out of Africa bottleneck
David C. Rinker, Corinne Simonti, Evonne McArthur, Douglas Shaw, Emily Hodges, John Anthony Capra
bioRxiv 533257; doi: https://doi.org/10.1101/533257

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