The specific features of the thyroid hormone receptor gene THRB polymorphism in indigenous populations of Siberia

Abstract

In the process of adaptation to cold in humans, genes belonging to the thyroid system signaling pathways that regulate thermogenesis, energy expenditure, and metabolic rearrangements are implicated. One such gene is the THRB gene, which encodes the nuclear receptor TRβ, with which the thyroid hormone triiodothyronine (T3) interacts. The activity of thermogenin UCP1 is influenced by the concentration of TRβ-T3 complexes, which serve to uncouple oxidative phosphorylation in mitochondria, thereby enhancing heat production. Consequently, thyroid hormone receptors have been demonstrated to play a significant role in adaptive thermogenesis. In the present study, we conducted a comprehensive analysis of published data on the THRB gene polymorphism in Siberian indigenous populations, with the objective of identifying potential associations between polymorphism variants and adaptation to cold. The analysis of exon and adjacent noncoding regions of the THRB gene revealed a single nucleotide substitution in the protein-coding region (synonymous substitution in the locus rs3752874). All other nucleotide substitutions were detected primarily in 3’-untranslated regions and introns. Analysis of the THRB haplotype distribution revealed two Koryak-specific haplotypes characterized by the rs762175401-A substitution. The results of population screening demonstrated that this substitution is prevalent among the Koryak population, with a frequency of 13.8 %, and is also present in the Siberian Eskimo population. However, in other global populations, the frequency of the rs762175401-A substitution does not exceed 0.05 % (in the Japanese and Koreans) or has even lower values (less than 0.02 %). The analysis of the nucleotide sequence of the THRB gene indicates that the rs762175401 locus is situated in the 3’-untranslated region at position +2 from the terminating codon. It is plausible that this substitution may have led to alterations in translation termination efficiency. In the case of enhanced termination efficiency, it is conceivable that it contributed to an elevated rate of protein synthesis, thereby resulting in an increase in the concentration of TRβ-T3 complexes. The higher frequency of the rs762175401-A variant in the Koryak and Eskimo populations, representing the oldest populations of Northeastern Siberia, is assumed to be due to long-term adaptation of these populations to cold. Keywords: THRB gene, human populations, Siberia, cold adaptation, thyroid system, adaptive thermogenesis