Detection of Neanderthal Adaptively Introgressed Genetic Variants That Modulate Reporter Gene Expression in Human Immune Cells
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Detection of Neanderthal Adaptively Introgressed Genetic Variants That Modulate Reporter Gene Expression in Human Immune Cells. / Jagoda, Evelyn; Xue, James R.; Reilly, Steven K.; Dannemann, Michael; Racimo, Fernando; Huerta-Sanchez, Emilia; Sankararaman, Sriram; Kelso, Janet; Pagani, Luca; Sabeti, Pardis C.; Capellini, Terence D.
In: Molecular Biology and Evolution, Vol. 39, No. 1, msab304, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Detection of Neanderthal Adaptively Introgressed Genetic Variants That Modulate Reporter Gene Expression in Human Immune Cells
AU - Jagoda, Evelyn
AU - Xue, James R.
AU - Reilly, Steven K.
AU - Dannemann, Michael
AU - Racimo, Fernando
AU - Huerta-Sanchez, Emilia
AU - Sankararaman, Sriram
AU - Kelso, Janet
AU - Pagani, Luca
AU - Sabeti, Pardis C.
AU - Capellini, Terence D.
PY - 2022
Y1 - 2022
N2 - Although some variation introgressed from Neanderthals has undergone selective sweeps, little is known about its functional significance. We used a Massively Parallel Reporter Assay (MPRA) to assay 5,353 high-frequency introgressed variants for their ability to modulate the gene expression within 170 bp of endogenous sequence. We identified 2,548 variants in active putative cis-regulatory elements (CREs) and 292 expression-modulating variants (emVars). These emVars are predicted to alter the bindingmotifs of important immune transcription factors, are enriched for associations with neutrophil and white blood cell count, and are associated with the expression of genes that function in innate immune pathways including inflammatory response and antiviral defense. We combined theMPRA data with other data sets to identify strong candidates to be driver variants of positive selection including an emVar that may contribute to protection against severe COVID-19 response. We endogenously deleted two CREs containing expression-modulation variants linked to immune function, rs11624425 and rs80317430, identifying their primary genic targets as ELMSAN1, and PAN2 and STAT2, respectively, three genes differentially expressed during influenza infection. Overall, we present the first database of experimentally identified expression-modulating Neanderthal-introgressed alleles contributing to potential immune response in modern humans.
AB - Although some variation introgressed from Neanderthals has undergone selective sweeps, little is known about its functional significance. We used a Massively Parallel Reporter Assay (MPRA) to assay 5,353 high-frequency introgressed variants for their ability to modulate the gene expression within 170 bp of endogenous sequence. We identified 2,548 variants in active putative cis-regulatory elements (CREs) and 292 expression-modulating variants (emVars). These emVars are predicted to alter the bindingmotifs of important immune transcription factors, are enriched for associations with neutrophil and white blood cell count, and are associated with the expression of genes that function in innate immune pathways including inflammatory response and antiviral defense. We combined theMPRA data with other data sets to identify strong candidates to be driver variants of positive selection including an emVar that may contribute to protection against severe COVID-19 response. We endogenously deleted two CREs containing expression-modulation variants linked to immune function, rs11624425 and rs80317430, identifying their primary genic targets as ELMSAN1, and PAN2 and STAT2, respectively, three genes differentially expressed during influenza infection. Overall, we present the first database of experimentally identified expression-modulating Neanderthal-introgressed alleles contributing to potential immune response in modern humans.
KW - neandertal
KW - introgression
KW - massively parallel reporter assay
KW - positive selection
KW - adaptation
KW - immune
KW - SCREEN REVEALS
KW - NUCLEAR-FACTOR
KW - KAPPA-B
KW - GENOME
KW - TRANSCRIPTION
KW - SELECTION
KW - ADAPTATION
KW - LANDSCAPE
KW - ADMIXTURE
KW - LINKS
U2 - 10.1093/molbev/msab304
DO - 10.1093/molbev/msab304
M3 - Journal article
C2 - 34662402
VL - 39
JO - Molecular Biology and Evolution
JF - Molecular Biology and Evolution
SN - 0737-4038
IS - 1
M1 - msab304
ER -
ID: 291295688