Analysis of the frequency of heterozygous carriage of six mutations of autosomal recessive diseases among Russian old-settlers of Yakutia

Among the populations of Eastern Siberia, the Russian old-settlers of the village of Russkoe Ustye (Allaikhovsky district of Yakutia) occupy a special place: their origin is relations with people from the old possessions of Novgorod the Great (presumably around 1570). The investigation of the hypotheses of the origin of the people of Russkoe Ustye, are of considerable scientific interest for the study of the colonization process of Northern Eurasia. In this study analysis of the carrier frequency of the six mutations responsible for autosomal-recessive diseases in 30 unrelated individuals from the village of Russkoye Ustye was performed. In the population of the Russkoe Ustye we did not find any heterozygous mutations, which are the cause of phenylketonuria (0/30), Wilson disease (0/30), congenital cataract (0/30), progressive deafness (0/30), and methemoglobinemia (0/30). In this Siberian population with a carrier frequency of 6.7%, the c.35delG mutation of the GJB2 gene (2/30) responsible for autosomal recessive deafness 1 A was detected. The absence of local East-Siberian variants of founder mutations associated with congenital cataract, progressive deafness, and methemoglobinemia, which are prevalent among Turkic-speaking Yakuts, indicates that this Turkic component in population of Russkoe Ustye is absent or represented to a small extent. Increasingly, than the Turkic component in the in population of Russkoe Ustye is represented a common West-Eurasian component, as indicated by the presence of the c.35delG mutation of the GJB2 gene, which is common in Europe. 

1. Alekseev A.N. Pervye russkie poseleniia XVII-XVIII vv na severo-vostoke IAkutii [The first Russian settlements of the 17th-18th centuries. in the north-east of Yakutia]. RAN Sibirskoe otdelenie Institut arkheologii i etnografii [RAS Siberian Branch Institute of Archeology and Ethnography. Executive editor V.E. Larichev. Novosibirsk, 1996: 151 (In Russ.).] ISBN 5-7803-0011-9.

2. Bayazutdinova G.M., Shchagina O.A., Polyakov A.V. Mutatsiia s 3207C A gena ATP7B naibolee chastaia prichina gepatolentikuliarnoi degeneratsii v Rossii chastota i prichina rasprostraneniia [Mutation c.3207C>A of the ATP7B gene is the most common cause of hepatolenticular degeneration in Russia: frequency and cause of distribution]. Meditsinskaia genetika [Medical genetics. 2018; 17(4):2530 (In Russ.).] https://doi.org/10.25557/2073-7998.2018.04.25-30

3. Nikitina S.E. Russkie arkticheskie starozhily Respubliki Sakha IAkutiia problemy sokhraneniia unikalnoi kultury [Russian Arctic old-timers of the Republic of Sakha (Yakutia): problems of preserving a unique culture]. Russkie arkticheskie starozhily IAkutii [Russian Arctic old-timers of Yakutia: Collection of scientific articles. Yakutsk: IGIiPMNS, 2019: 16-33 (In Russ.).]

4. Pshennikova V.G., Romanov G.P., Nikolaeva T.M. [et al]. Novaia nonsens-mutatsiia s 1121G A p Trp374 gena CLIC5 osnovnaia prichina iuvenilnoi autosomno-retsessivnoi formy glukhoty DFNB103 ochagi nakopleniia kotoroi obnaruzheny v arkticheskikh raionakh IAkutii [Novel nonsense mutation c.1121G>A (p.Trp374*) of the CLIC5 gene is the main cause of juvenile autosomal recessive form of deafness (DFNB103), the foci of accumulation of which were found in the Arctic regions of Yakutia]. Meditsinskaia genetika [Medical genetics. 2019; 18(10): 36-48 (In Russ.).]

5. Barashkov N.A., Borisova T.V., Gerasimova A.A. [et al.]. Rekonstruktsiia gaplotipa-osnovatelia s mutatsiei c 644G A p Trp215 gena CLIC5 privodiashchei k iuvenilnoi autosomno-retsessivnoi glukhote DFNB103 v IAkutii [Reconstruction of the founder haplotype with the c.644G>A p.(Trp215*) mutation of the CLIC5 gene leading to juvenile autosomal recessive deafness (DFNB103) in Yakutia]. Meditsinskaia genetika [Medical genetics. 2021, 20 (7): 3-14 (In Russ.).]

6. Chikachev A.G. Russkoe serdtse Arktiki [Russian heart of the Arctic]. Literaturnyi fond Yakutsk: Literary Fund, 2010; 478 (In Russ.).]

7. A common founder for the 35delG GJB2 gene mutation in connexin 26 hearing impairment. / L. Van Laer, P. Coucke, R. F. Mueller [et al.]. Journal of medical genetics. 2001; 38 (8): 515-8.

8. Autosomal recessive cataract (CTRCT18) in the Yakut population isolate of Eastern Siberia: a novel founder variant in the FYCO1 gene /N.A Barashkov, F.A. Konovalov, T.V. Borisova [et al.] // Eur J Hum Genet. 2021;29(6):965-976. doi: 10.1038/s41431-021-00833-w.

9. Eisensmith, R.C. Molecular Genetics of Phenylketonuria: From Molecular Anthropology to Gene Therapy / R.C. Eisensmith, and S.C Woo // Advances in Genetics. 1995; 32: 199-271

10. Genetic diversity within the R408W phenylketonuria mutation lineages in Europe. / O. Tighe, D. Dunican, C.O'Neill [et al] // Hum. Mutat. 2003; 21:387-393

11. High carrier frequency of the 35delG deafness mutation in European populations / P. Gasparini, R. Rabionet, G. Barbujani [et al.] // European Journal of Human Genetics. 2000; 8(1): 19-23.

12. Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. / M.R. Zurfluh, J. Zschocke, M. Lindner [et al]. // Hum. Mutat. 2008; 29: 167-175.

13. Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease / S.Vrabelova, O. Letocha, M. Borsky [et al] // Molecular Genetics and Metabolism. 2005; 86: 277–285.

14. Population frequency and age of c.806C>T mutation in CYB5R3 gene as cause of recessive congenital methemoglobinemia in Yakutia. / N.M. Galeeva, M.I. Voevoda, M.G. Spiridonova [et al] // Genetika. 2013; 49(4): 52330. Russian. doi: 10.7868/s0016675813030065. PMID: 23866629.

15. Robinson, G. Congenital ocular blindness in children, 1945 to 1984 / G. Robinson, J. Jan, C. Kinnis. // American Journal of Diseases of Children. 1987; 141(12): 1321-1324. doi: 10.1001/archpedi.1987.04460120087041

16. Separating the post-Glacial coancestry of European and Asian Y chromosomes wit-hin haplotype R1a. / P.A Underhill, N.M. Myres, S. Rootsi [et al.] // Eur J Hum Genet. 2010; 18(4): 479-484

17. Silent mutations in the phenylalanine hydroxylase gene as an aid to the diagnosis of phenylketonuria / L. Kalaydjieva, B. Dworniczak, C. Aulehla-Scholz [et al] // J. Med. Genet. 1991; 28: 686-690.