Association Study Between MT-CO3Gene Polymorphisms And High-Altitude Adaptation Among Tibetan Chicken

Genetic variations in mtDNA-encoded cytochrome c oxidase subunit Ⅲ gene (MT-CO3) might play an important role in regulation the kinetics of cytochrome c oxidase (COX) and thus be involved in high-altitude adaptation. However, previous studies about the Tibetan chicken (Gallus gallus) MT-CO3variations responsible to high-altitude adaptation encompassed few or sporadic single nucleotide polymorphisms (SNPs) and the results were rather ambiguous. Hitherto, whether there is an effect of MT-CO3alleles or haplotypes on high altitude adaptation has not yet been tested. To thoroughly assess these relevant issues, we reanalysis of DNA sequence variations in the MT-C03gene of new126Tibetan chickens and146lowland chickens.11nucleotide substitutions were obtained, which defined12haplotypes (H1to H12). One synonymous substitution m.10339A>G (4.76%,6/126) and three non-synonymous mutations m.10118G>A (34.92%,44/126), m.10373A>T (1.59%,2/126) and c.9988C>G (0.79%,1/126) were specific to the Tibetan chicken, which might have functional implications in high-altitude accommodation, suggesting that MT-CO3gene is a mutational hot spot for high-altitude adaptation. But in silico prediction only supported a functional effect of the last substitution. The genetic basis of the high-altitude adaptation among Tibetan chicken is varied of Bar-headed goose’s due to the absence of c.346T>C in total Tibetan chicken individuals. We found evidence for associations of both alleles and haplotypes of MT-CO3with high-altitude adaptation. The distribution of the SNPs m.10084G>A, m.10118G>A, m.10273G>A, m.10339A>G, m.10450C>T and m.10672C>T in Tibetan chickens were significantly different from that in lowland chickens. The persence of the alleles10084G,10273G,10450C and10672C, independently significantly increase the risk of the persence of the high-altitude adaptation in Tibatan chicken. Haplotype analysis showed that H4was positively associated with high-altitude adaptation (Adjusted P-value:0.0007, OR:2.5670,95%CI:1.4930-4.4140), whereas H7, H8and H9were negatively linked to high-altitude adaptation (H7:Adjusted P-value:0.0018, OR:0.1016,95%CI:0.0233-0.4440; H8:Adjusted P-value:0.0118, OR:0.3905,95%CI:0.1910-0.7982; H9:Adjusted P-value:8.0040×10-13, OR:0.0664,95%CI:0.0256-0.1725). Thus, it is plausible to propose that the Tibetan chicken possibly coexists with lowland chickens in H6, undergoes the mutation (m.10084A>G) to H4and disperses to various Tibetan chicken-specific haplotypes as a result. These conclusions advance our understanding of how genetic variations of the MT-CO3gene contribute to Tibetan chicken high-altitude adaptation and unveil many suspected mutations involving in functional modifications, whose specific roles need to be further validated by more reliable methodologies.