Polygenic and Pleiotropic Adaptation of Yaks to High Altitudes: A Genome-Wide Study of Hematological and Physiological Traits.

Abstract

Hematological adaptation is critical for oxygen transport at high altitudes. While hemoglobin concentration is well-studied, yak (Bos grunniens) hematology versus lowland cattle remains under-explored. We analyzed blood phenotypes from 1244 plateau yaks and 154 lowland cattle. Yaks exhibited elevated hemoglobin, hematocrit, and lymphocyte counts, but reduced platelet counts and monocyte/neutrophil percentages among other parameters, indicating distinct hypoxia adaptation. Using genome-wide association studies (GWAS) and composite of multiple signals (CMS), we identified 6485 selection-associated single-nucleotide variants (SNVs) linked to 43 hematological traits (average 6.85% variance explained). These included 172 yak-selected genes (YSGs), with SLIT3, FSTL5, and PCDH15 showing top pleiotropic effects (SLIT3 regulates immune function and oxygen transport). Thirty-eight YSGs influenced multiple traits, and six (SLIT3, FSTL5, PCDH15, PRIM2, CDH13, HLA-DQB1) overlap with genes under selection in Tibetan highlanders. Crucially, unlike hemoglobin attenuation in humans and other species, yaks show elevated hemoglobin, suggesting an alternative adaptive strategy. Cross-species analysis revealed 76 YSG orthologues affect 13 human blood traits, indicating highland species are likely to have selected the same set of genes for hypoxia adaptation. Our findings demonstrate polygenic, pleiotropic mechanisms underpinning yak adaptation, providing a genomic framework for high-altitude biology and conservation.