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An ancient fecundability-associated polymorphism creates a new GATA2 binding site in a distal enhancer of HLA-F

View ORCID ProfileKatelyn M. Mika, View ORCID ProfileXilong Li, View ORCID ProfileFrancesco J. DeMayo, View ORCID ProfileVincent J. Lynch
doi: https://doi.org/10.1101/245043
Katelyn M. Mika
1Department of Human Genetics, The University of Chicago, 920 E. 58th Street, CLSC 319C, Chicago, IL 60637, USA.
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Xilong Li
2National Institute of Environmental Health Sciences, Department Reproductive & Developmental Biology Laboratory,111 TW Alexander Drive, Research Triangle Park, NC, 27709, USA
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Francesco J. DeMayo
2National Institute of Environmental Health Sciences, Department Reproductive & Developmental Biology Laboratory,111 TW Alexander Drive, Research Triangle Park, NC, 27709, USA
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Vincent J. Lynch
1Department of Human Genetics, The University of Chicago, 920 E. 58th Street, CLSC 319C, Chicago, IL 60637, USA.
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  • For correspondence: vjlynch@uchicago.edu
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Abstract

Variation in female reproductive traits such as fertility, fecundity, and fecundability are heritable in humans, but identifying and functionally characterizing genetic variants associated with these traits has been challenging. Here we explore the functional significance and evolutionary history of a G/A polymorphism of SNP rs2523393, which we have previously shown is an eQTL for the HLA-F gene and significantly associated with fecundability (time to pregnancy). We replicated the association between rs2523393 genotype and HLA-F expression using GTEx data and demonstrate that HLA-F is up-regulated in the endometrium during the window of implantation and by progesterone in decidual stromal cells. Next, we show that the rs2523393 A allele creates a new GATA2 binding site in a progesterone responsive distal enhancer that loops to the HLA-F promoter. Remarkably, we found that the A allele is derived in the human lineage, that G/A polymorphism arose before the divergence of modern and archaic humans, and is segregating at intermediate to high frequencies across human populations. Remarkably, the derived A is also has been identified in a GWAS as a risk allele for multiple sclerosis. These data suggests that the polymorphism is maintained by antagonistic pleiotropy and a reproduction-health tradeoff in human evolution.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted January 08, 2018.
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An ancient fecundability-associated polymorphism creates a new GATA2 binding site in a distal enhancer of HLA-F
Katelyn M. Mika, Xilong Li, Francesco J. DeMayo, Vincent J. Lynch
bioRxiv 245043; doi: https://doi.org/10.1101/245043
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An ancient fecundability-associated polymorphism creates a new GATA2 binding site in a distal enhancer of HLA-F
Katelyn M. Mika, Xilong Li, Francesco J. DeMayo, Vincent J. Lynch
bioRxiv 245043; doi: https://doi.org/10.1101/245043

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