Polymorphism of the cold receptor gene TRPM8 in native populations of Siberia: putative selective role of rs11563208 polymorphism in Northeast Asia

The TRPM8 gene encodes the cold-activated receptor TRPM8, which has an important role in cold adaptation as well as in metabolic and immune responses. Previously, it has been found that polymorphic variants of the TRPM8 gene, which are present in human populations, are associated with different cold sensitivity. In the present study we have investigated variability of all exons and adjacent intronic sequences of this gene in samples of native populations of Siberia, including regional groups from Northeastern, Central, Southern and Western parts of Siberia. In 9 out of 21 variable loci revealed, the frequency of the derived alleles accounts for more than 10 % (loci rs28901637, rs11562975, rs10929319, rs28901644, rs7593557, rs12185590, rs10171428, rs11563208, and rs11563071). Different variants of these polymorphic loci, which are most frequent in native Siberians, generate 26 haplotypes. In addition to 7 haplotypes shared by all regional groups and present there at frequencies of 2–28 %, unique haplotypes were found in all regional samples. One of them characterized by derived allele T at rs11563208 locus is very interesting because it is spread at the frequency of 14 % only in Northeast Asia (in Koryaks and Chukchi). A synonymous substitution at rs11563208 locus may have a functional role because the amino acid residue (isoleucine at position 1016 of TRPM8 protein) corresponding to this locus is located in functionally important TRP-domain and, hence, it can influence thermoreception processes. It is assumed that the appearance of the haplotype carrying the rs11563208-T allele may be due to the necessity to counteract the inhibition of TRPM8 receptors by polyunsaturated fatty acids, which are typical of the traditional diet of native people of Northeast Asia (Siberian Eskimo, Chukchi and Koryaks).

gene TRPM8, exome, single nucleotide polymorphisms (SNP), human populations, adaptive evolution

1. Andersson D.A., Nash M., Bevan S. Modulation of the cold-activated channel TRPM8 by lysophospholipids and polyunsaturated fatty acids. J. Neurosci. 2007;27:3347-3355. DOI 10.1523/JNEUROSCI.4846-06.2007.

2. Babenko V.N., Isakova J.T., Talaibekova E.T., Asambaeva D.A., Kobzev V.F., Potapova T.A., Voevoda M.I., Aldashev A.A. Polymorphism in the TRP8 gene in Kyrgyz population: putative association with highland adaptation. Vavilovskii Zhurnal Genetiki i Selektsii = Vavilov Journal of Genetics and Breeding. 2015;19(5):630-637. DOI 10.18699/VJ15.080. (in Russian)

3. Cardona A., Pagani L., Antao T., Lawson D.J., Eichstaedt C.A., Yngvadottir B., Shwe M.T.T., Wee J., Romero I.G., Raj S., Metspalu M., Villems R., Willerslev E., Tyler-Smith C., Malyarchuk B.A., Derenko M.V., Kivisild T. Genome-wide analysis of cold adaption in indigenous Siberian populations. PLoS ONE. 2014;9(5):e98076. DOI 10.1371/journal.pone.0098076.

4. Clemente F.J., Cardona A., Inchley C.E., Peter B.M., Jacobs G., Pagani L., Lawson D.J., Antão T., Vicente M., Mitt M., DeGiorgio M., Faltyskova Z., Xue Y., Ayub Q., Szpak M., Mägi R., Eriksson A., Manica A., Raghavan M., Rasmussen M., Rasmussen S., Willerslev E., Vidal-Puig A., Tyler-Smith C., Villems R., Nielsen R., Metspalu M., Malyarchuk B., Derenko M., Kivisild T. A selective sweep on a deleterious mutation in the CPT1A gene in Arctic populations. Am. J. Hum. Genet. 2014;95:584-589. DOI 10.1016/j.ajhg.2014.09.016.

5. Excoffier L., Laval G., Balding D. Gametic phase estimation over large genomic regions using an adaptive window approach. Hum. Genomics. 2003;1:7-19. DOI 10.1186/1479-7364-1-1-7.

6. Kozyreva T.V., Tkachenko E.Ia., Potapova T.A., Voevoda M.I. Respiratory system response to cooling in subjects with single nucleotide polymorphism rs11562975 in the gene for thermosensitive TRPM8 ion channel. Fiziol. Cheloveka = Human Physiology. 2014;40(2):94-

7. (in Russian)

8. Kozyreva T.V., Tkachenko E.Ia., Potapova T.A., Romashchenko A.G., Voevoda M.I. Single-nucleotide polymorphism rs11562975 of the thermosensitive ion channel TRPM8 gene and human sensitivity to cold and menthol. Fiziol. Cheloveka = Human Physiology. 2011;37(2):71-76. (in Russian)

9. Kozyreva T.V., Voronova I.P. Involvement of neurogenomic regulation in the maintenance of temperature homeostasis in the cold. Vavilovskii Zhurnal Genetiki i Selektsii = Vavilov Journal of Genetics and Breeding. 2014;18(4/3):1100-1109. (in Russian)

10. Lapinski A.G., Malyarchuk B.A., Solovenchuk L.L. Sea mammals triglycerides as an alternative source of omega-3 fatty acids for human consumption. PICES Workshop on the Okhotsk Sea and Adjacent Areas. Vladivostok, 1995;56.

11. Latorre R., Brauchi S., Madrid R., Orio P. A cool channel in cold transduction. Physiology. 2011;26:273-285. DOI 10.1152/physiol.00004.2011.

12. McKemy D.D., Neuhausser W.M., Jullius D. Identification of a cold receptor reveals general role for TRP channels in thermosensation. Nature. 2002;416:52-58. DOI 10.1038/nature719.

13. Naumov D.E., Perelman J.M., Kolosov V.P., Maksimov V.N., Voevoda M.I., Kolosov A.V., Zhou X.D., Li Q. Genetic polymorphism of thermosensitive cation channels TRPM8 as a factor predisposing to cold airway hyperresponsiveness in patients with chronic obstructive lung diseases. Byulleten’ eksperimental’noy biologii i meditsiny = Bulletin of Experimental Biology and Medicine. 2012;45:8-14. (in Russian)

14. Pagani L., Lawson D.J., Jagoda E., MörseburgA., EriksssonA., Mitt M., Clemente F., Hudjashov G., DeGiorgio M., Saag L., WallJ.D., Cardona A., Mägi R., Sayres M.A.W., Kaewert S., Inchley C., Scheib C.L., Järve M., Karmin M., Jacobs G.S., Antao T., Iliescu F.M., Kushniarevich A., Ayub Q., Tyler-Smith C., Xue Y., Yunusbayev B., Tambets K., Mallick C.B., Saag L., Pocheshkhova E., Andriadze G., Muller C., Westaway M.C., Lambert D.M., Zoraqi G., Turdikulova S., Dalimova D., Sabitov Z., Sultana G.N.N., Lachance J., Tishkoff S., Momynaliev K., Isakova J., Damba L.D., Gubina M., Nymadawa P., Evseeva I., Atramentova L., Utevska O., Ricaut F.- X., Brucato N., Sudoyo H., Letellier T., Cox M.P., Barashkov N.A., Škaro V., Mulahasanovic´ L., Primorac D., Sahakyan H., Mormina M., Eichstaedt C.A., Lichman D.V., Abdullah S., Chaubey G., Wee J.T.S., Mihailov E., Karunas A., Litvinov S., Khusainova R., Ekomasova N., Akhmetova V., Khidiyatova I., Marjanović D., Yepiskoposyan L., Behar D.M., Balanovska E., Metspalu A., Derenko M., Malyarchuk B., Voevoda M., Fedorova S.A., Osipova L.P., Lahr M.M., Gerbault P., Leavesley M., Migliano A.B., Petraglia M., Balanovsky O., Khusnutdinova E.K., Metspalu E., Thomas M.G., Manica A., Nielsen R., Villems R., Willerslev E., Kivisild T., Metspalu M. Genomic analyses inform on migration events during the peopling of Eurasia. Nature. 2016;538:238-242. DOI 10.1038/nature19792.

15. Peier A.M., Moqrich A., Hergarden A.C., Reeve A.J., Andersson D.A., Story G.M., Earley T.J., Dragoni I., McIntyre P., Bevan S., Patapoutian A. ATRP channel that senses cold stimuli and menthol. Cell. 2002;108:705-715.

16. Potapova T.A., Yudin N.S., Babenko V.N., Pilipenko I.V., Kobsev V.F., Grigol’kau L.A., Voevoda M.I. Polymorphism for the cold receptor gene TRPM8 in ethnic groups of Siberia and the Far East. Inform. Vestnik VOGiS = The Herald of Vavilov Society for Geneticists and Breeding Scientists. 2008;12(4):749-754. (in Russian)

17. Ramsey S., Delling M., Clapham D.E. An introduction to TRP channels. Annu. Rev. Physiol. 2006;68:619-647.

18. Rohacs T., Lopes C.M., Michailidis I., Logothetis D.E. PI(4,5)P(2) regulates the activation and desensitization of TRPM8 channels through the TRP domain. Nat. Neurosci. 2005;8:626-634. DOI 10.1038/nn1451.

19. Stein R.J., Santos S., Nagatomi J., Hayashi Y., Minnery B.S., Xavier M., Patel A.S., Nelson J.B., Futrell W.J., Yoshimura N., Chancellor M.B., De Miguel F. Cool (TRPM8) and hot (TRPV1) receptors in the bladder and male genital tract. J. Urology. 2004;172(3):1175-1178. DOI 10.1097/01.ju.0000134880.55119.cf.

20. Tsavaler L., Shapero M.H., Morkowski S., Laus R. Trp-p8, a novel prostate-specific gene, is up-regulated in prostate cancer and other malignancies and shares high homology with transient receptor potential calcium channel proteins. Cancer Res. 2001;61(9):3760-3769.

21. Voets T., Droogmans G., Wissenbach U., Janssens A., Flockerzi V., Nilius B. The principle of temperature-dependent gating in coldand heatsensitive TRP channels. Nature. 2004;430:748-754. DOI 10.1038/nature02732.