Evidence for opposing selective forces operating on human-specific duplicated TCAF genes in Neanderthals and humans

PingHsun Hsieh (), Vy Dang, Mitchell R. Vollger, Yafei Mao, Tzu-Hsueh Huang, Philip C. Dishuck, Carl Baker, Stuart Cantsilieris, Alexandra P. Lewis, Katherine M. Munson, Melanie Sorensen, AnneMarie E. Welch, Jason G. Underwood and Evan E. Eichler ()
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PingHsun Hsieh: University of Washington School of Medicine
Vy Dang: University of Washington School of Medicine
Mitchell R. Vollger: University of Washington School of Medicine
Yafei Mao: University of Washington School of Medicine
Tzu-Hsueh Huang: University of Washington School of Medicine
Philip C. Dishuck: University of Washington School of Medicine
Carl Baker: University of Washington School of Medicine
Stuart Cantsilieris: University of Washington School of Medicine
Alexandra P. Lewis: University of Washington School of Medicine
Katherine M. Munson: University of Washington School of Medicine
Melanie Sorensen: University of Washington School of Medicine
AnneMarie E. Welch: University of Washington School of Medicine
Jason G. Underwood: University of Washington School of Medicine
Evan E. Eichler: University of Washington School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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 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. Conversely, in all archaic-hominin samples the fixation for a specific H4 haplotype without duplication is likely due to positive selection. Here, our results of TCAF copy number expansion, selection signals in hominins, and differential TCAF2 expression between haplogroups and high TCAF2 and TRPM8 expression in liver and prostate in modern-day humans imply TCAF diversification among hominins potentially in response to cold or dietary adaptations.

Date: 2021
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DOI: 10.1038/s41467-021-25435-4

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