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

Jagoda, E, Xue, JR, Reilly, SK, Dannemann, M, Racimo, F, Huerta-Sanchez, E, Sankararaman, S, Kelso, J, Pagani, L, Sabeti, PC & Capellini, TD 2022, 'Detection of Neanderthal Adaptively Introgressed Genetic Variants That Modulate Reporter Gene Expression in Human Immune Cells', Molecular Biology and Evolution, vol. 39, no. 1, msab304. https://doi.org/10.1093/molbev/msab304

APA

Jagoda, E., Xue, J. R., Reilly, S. K., Dannemann, M., Racimo, F., Huerta-Sanchez, E., Sankararaman, S., Kelso, J., Pagani, L., Sabeti, P. C., & Capellini, T. D. (2022). Detection of Neanderthal Adaptively Introgressed Genetic Variants That Modulate Reporter Gene Expression in Human Immune Cells. Molecular Biology and Evolution, 39(1), [msab304]. https://doi.org/10.1093/molbev/msab304

Vancouver

Jagoda E, Xue JR, Reilly SK, Dannemann M, Racimo F, Huerta-Sanchez E et al. Detection of Neanderthal Adaptively Introgressed Genetic Variants That Modulate Reporter Gene Expression in Human Immune Cells. Molecular Biology and Evolution. 2022;39(1). msab304. https://doi.org/10.1093/molbev/msab304

Author

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. / Detection of Neanderthal Adaptively Introgressed Genetic Variants That Modulate Reporter Gene Expression in Human Immune Cells. In: Molecular Biology and Evolution. 2022 ; Vol. 39, No. 1.

Bibtex

@article{da2e0ffd4dc34116b820a7b31bc3c674,
title = "Detection of Neanderthal Adaptively Introgressed Genetic Variants That Modulate Reporter Gene Expression in Human Immune Cells",
abstract = "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.",
keywords = "neandertal, introgression, massively parallel reporter assay, positive selection, adaptation, immune, SCREEN REVEALS, NUCLEAR-FACTOR, KAPPA-B, GENOME, TRANSCRIPTION, SELECTION, ADAPTATION, LANDSCAPE, ADMIXTURE, LINKS",
author = "Evelyn Jagoda and Xue, {James R.} and Reilly, {Steven K.} and Michael Dannemann and Fernando Racimo and Emilia Huerta-Sanchez and Sriram Sankararaman and Janet Kelso and Luca Pagani and Sabeti, {Pardis C.} and Capellini, {Terence D.}",
year = "2022",
doi = "10.1093/molbev/msab304",
language = "English",
volume = "39",
journal = "Molecular Biology and Evolution",
issn = "0737-4038",
publisher = "Oxford University Press",
number = "1",

}

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