Detection of Neanderthal Adaptively Introgressed Genetic Variants That Modulate Reporter Gene Expression in Human Immune Cells

Evelyn Jagoda; James R Xue; Steven K Reilly; Michael Dannemann; Fernando Racimo; Emilia Huerta-Sanchez; Sriram Sankararaman; Janet Kelso; Luca Pagani; Pardis C Sabeti; Terence D Capellini

doi:10.1093/molbev/msab304

Detection of Neanderthal Adaptively Introgressed Genetic Variants That Modulate Reporter Gene Expression in Human Immune Cells

Mol Biol Evol. 2022 Jan 7;39(1):msab304. doi: 10.1093/molbev/msab304.

Authors

Evelyn Jagoda¹, James R Xue^{2

3}, Steven K Reilly^{2

3}, Michael Dannemann^{4

5}, Fernando Racimo⁶, Emilia Huerta-Sanchez^{7

8}, Sriram Sankararaman^{9

10}, Janet Kelso⁴, Luca Pagani^{5

11}, Pardis C Sabeti^{2

3

12

13}, Terence D Capellini^{1

3}

Affiliations

¹ Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA.
² Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
⁵ Estonian Biocentre, Institute of Genomics, University of Tartu, Tartu, Estonia.
⁶ Lundbeck GeoGenetics Centre, The Globe Institute, University of Copenhagen, Copenhagen, Denmark.
⁷ Department of Ecology and Evolutionary Biology, Brown University, Providence, RI, USA.
⁸ Center for Computational Molecular Biology, Brown University, Providence, RI, USA.
⁹ Department of Computer Science, UCLA, Los Angeles, CA, USA.
¹⁰ Department of Human Genetics, UCLA, Los Angeles, CA, USA.
¹¹ Department of Biology, University of Padova, Padova, Italy.
¹² Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹³ Howard Hughes Medical Institute, Chevy Chase, MD, USA.

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 binding motifs 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 the MPRA 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: adaptation; immune; introgression; massively parallel reporter assay; neandertal; positive selection.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Gene Expression
Genetic Variation*
Genome, Human*
Humans
Immunity, Innate / genetics*
Inflammation
Neanderthals* / genetics

Abstract

Publication types

MeSH terms

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