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

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 locus spans a gap-ridden region with complex segmental duplications GRCh38. Using long-read sequencing, we sequence-resolve locus, annotate full-length TCAF models primate genomes, and show substantial human-specific copy number variation. We identify two super haplogroups, H4 H5, establish that originated ~1.7 million years ago but diversified only Homo sapiens by recurrent structural mutations. Conversely, all archaic-hominin samples fixation for specific haplotype without duplication is likely due to positive selection. Here, our results of expansion, selection signals hominins, differential TCAF2 expression between haplogroups high liver prostate modern-day humans imply diversification among hominins potentially response cold or dietary adaptations.