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Opposing selective forces operating on human-specific duplicated TCAF genes in Neanderthals and humans

Authors :
Alexandra P. Lewis
PingHsun Hsieh
Jason G. Underwood
Yafei Mao
AnneMarie E. Welch
Mitchell R. Vollger
Tzu-Hsueh Huang
Vy Dang
Carl Baker
Stuart Cantsilieris
Katherine M. Munson
Philip C. Dishuck
Evan E. Eichler
Melanie Scofield
Publication Year :
2020
Publisher :
Research Square Platform LLC, 2020.

Abstract

TRP channel-associated factor 1/2 (TCAF1/TCAF2) proteins antagonistically regulate the cold-sensor protein TRPM8 in multiple human tissues. Understanding their significance has been complicated given the locus spans a gap-ridden region with complex segmental duplications in GRCh38. Using long-read sequencing, we sequence-resolve the locus, annotate full-length TCAF models in human and nonhuman primate genomes, and show substantial human-specific TCAF copy number variation. We identify two human super haplogroups, H4 and H5, and establish that TCAF duplications originated ~1.7 million years ago but diversified only in Homo sapiens by recurrent structural mutations that altered TCAF copy number and regulation. Conversely, in all archaic-hominin samples the fixation for a specific H4 haplotype without duplication is likely due to positive selection. The significant, positive effect of H4 on TCAF2 expression in modern-day humans with candidate associations for hypothyroidism, nerve compression, and diabetes suggests TCAF diversification among hominins potentially in response to cold or dietary adaptations.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........69a011de183c5221ac06de6d61b7960c
Full Text :
https://doi.org/10.21203/rs.3.rs-77798/v1