@article{114d01a8949645149a593a71c1ab6279,
title = "Impacts of Neanderthal-Introgressed Sequences on the Landscape of Human Gene Expression",
abstract = "Regulatory variation influencing gene expression is a key contributor to phenotypic diversity, both within and between species. Unfortunately, RNA degrades too rapidly to be recovered from fossil remains, limiting functional genomic insights about our extinct hominin relatives. Many Neanderthal sequences survive in modern humans due to ancient hybridization, providing an opportunity to assess their contributions to transcriptional variation and to test hypotheses about regulatory evolution. We developed a flexible Bayesian statistical approach to quantify allele-specific expression (ASE) in complex RNA-seq datasets. We identified widespread expression differences between Neanderthal and modern human alleles, indicating pervasive cis-regulatory impacts of introgression. Brain regions and testes exhibited significant downregulation of Neanderthal alleles relative to other tissues, consistent with natural selection influencing the tissue-specific regulatory landscape. Our study demonstrates that Neanderthal-inherited sequences are not silent remnants of ancient interbreeding but have measurable impacts on gene expression that contribute to variation in modern human phenotypes.",
keywords = "RNA-seq, allele-specific expression, archaic hominin, evolution, gene flow, gene regulation, introgression",
author = "McCoy, {Rajiv C.} and Jon Wakefield and Akey, {Joshua M.}",
note = "Funding Information: We thank Joshua Schraiber for assistance estimating the proportions of mutations arising pre- and post-introgression. Thank you to Timothy Sullivan, Stephane Castel, Tuuli Lappalainen, and the GTEx Laboratory, Data Analysis, and Coordinating Center (LDACC). Thanks also to Thomas Montine, Benjamin Vernot, and members of the Akey lab for helpful feedback. R.C.M. is supported by NIH/NHGRI training grant 5T32HG000035-22 to the University of Washington. This work is also partially supported by NIH grant R01GM110068 to J.M.A. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the NIH. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI\SAIC-Frederick (SAIC-F) subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171), and Science Care (X10S172). The LDACC was funded through a contract (HHSN268201000029C) to The Broad Institute. Biorepository operations were funded through an SAIC-F subcontract to Van Andel Institute (10ST1035). Additional data repository and project management were provided by SAIC-F (HHSN261200800001E). The Brain Bank was supported by supplements to University of Miami grants DA006227 and DA033684 and to contract N01MH000028. Statistical Methods development grants were made to the University of Geneva (MH090941 and MH101814), the University of Chicago (MH090951, MH090937, MH101820, MH101825), the University of North Carolina–Chapel Hill (MH090936 and MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University St. Louis (MH101810), and the University of Pennsylvania (MH101822). J.M.A. is a paid consultant of Glenview Capital. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = feb,
day = "23",
doi = "10.1016/j.cell.2017.01.038",
language = "English (US)",
volume = "168",
pages = "916--927.e12",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "5",
}