% pubman genre = article @article{item_3365414, title = {{Detection of Neanderthal adaptively introgressed genetic variants that modulate reporter gene expression in human immune cells}}, author = {Jagoda, Evelyn and Xue, James R and Reilly, Steven K and Dannemann, Michael and Racimo, Fernando and Huerta-Sanchez, Emilia and Sankararaman, Sriram and Kelso, Janet and Pagani, Luca and Sabeti, Pardis C and Capellini, Terence D}, language = {eng}, issn = {0737-4038}, doi = {10.1093/molbev/msab304}, publisher = {Oxford University Press}, address = {Oxford}, year = {2022}, date = {2022-01}, abstract = {{Although some variation introgressed from Neanderthals has undergone selective sweeps, little is known about its{\textless}br{\textgreater}functional significance. We used a Massively Parallel Reporter Assay (MPRA) to assay 5,353 high-frequency introgressed{\textless}br{\textgreater}variants for their ability to modulate the gene expression within 170 bp of endogenous sequence. We identified 2,548{\textless}br{\textgreater}variants in active putative cis-regulatory elements (CREs) and 292 expression-modulating variants (emVars). These{\textless}br{\textgreater}emVars are predicted to alter the binding motifs of important immune transcription factors, are enriched for associations{\textless}br{\textgreater}with neutrophil and white blood cell count, and are associated with the expression of genes that function in innate{\textless}br{\textgreater}immune pathways including inflammatory response and antiviral defense. We combined the MPRA data with other data{\textless}br{\textgreater}sets to identify strong candidates to be driver variants of positive selection including an emVar that may contribute to{\textless}br{\textgreater}protection against severe COVID-19 response. We endogenously deleted two CREs containing expression-modulation{\textless}br{\textgreater}variants linked to immune function, rs11624425 and rs80317430, identifying their primary genic targets as ELMSAN1,{\textless}br{\textgreater}and PAN2 and STAT2, respectively, three genes differentially expressed during influenza infection. Overall, we present the{\textless}br{\textgreater}first database of experimentally identified expression-modulating Neanderthal-introgressed alleles contributing to po-{\textless}br{\textgreater}tential immune response in modern humans.}}, journal = {{Molecular Biology and Evolution}}, volume = {39}, number = {1}, eid = {msab304}, }