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Journal of Genetics and Genome Research





DOI: 10.23937/2378-3648/1410001



Extremely High Carrier Frequency of the GJB2 Splice Site IVS1+1G>A Mutation in Eastern Siberia is Comparable to the Carrier Frequency of the Sickle Cell Anemia in Africa

Nikolay A. Barashkov1,2*, Aisen V. Solovyev2, Fedor M. Teryutin1,2, Vera G. Pshennikova1,2, Leonid A. Klarov3, Georgii P. Romanov2, Sergey S. Nakhodkin2, Kyunney E. Savvinova2,4, Nyurgun N. Gotovtsev2,4, Natalya A. Solovyeva1, Andrei A. Kozhevnikov5, Lena M. Vasilyeva6, Elvira E. Fedotova6, Maria V. Pak7, Sargylana N. Lekhanova8, Elena V. Zakharova9, Adyum M. Rafailov4, Nikolay V. Luginov3, Anatoliy N. Alexeev10, Olga L. Posukh11,12, Lilya U. Dzhemileva13, Elza K. Khusnutdinova13,14 and Sardana A. Fedorova1,2


1Department of Molecular Genetics, Yakut Scientific Centre of Complex Medical Problems, Siberian Branch of the Russian Academy of Medical Sciences, Yakutsk, Russian Federation
2Laboratory of Molecular Biology, Institute of Natural Sciences, M.K. Ammosov North-Eastern Federal University, Yakutsk, Russian Federation
3Department of Radiology, Republican Hospital #2 - Center of Emergency Medicine, Ministry of Public Health of the Sakha Republic, Yakutsk, Russian Federation
4Institute of Natural Sciences, M.K. Ammosov North-Eastern Federal University, Yakutsk, Russian Federation
5Republican Centre of Professional Pathology, Republican Hospital #2 - Center of Emergency Medicine, Ministry of Public Health of the Sakha Republic, Yakutsk, Russian Federation
6Audiology-Logopaedic Center, Republican Hospital #1 - National Medical Centre, Ministry of Public Health of the Sakha Republic, Yakutsk, Russian Federation
7Department of Pediatric, Medical Institute, M.K. Ammosov North-Eastern Federal University, Yakutsk, Russian Federation
8Department of Normal and Abnormal Anatomy, Operative Surgery with Topographic Anatomy and Forensic Medicine, Medical Institute, M.K. Ammosov North-Eastern Federal University, Yakutsk, Russian Federation
9Institute of Foreign Philology and Regional Studies, M.K. Ammosov North-Eastern Federal University, Yakutsk, Russian Federation
101Institute of Humanitarian Research and Indigenous Peoples of the North, Siberian Branch of the Russian Academy of Sciences, Yakutsk, Russian Federation
11Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation
12Novosibirsk State University, Novosibirsk, Russian Federation
13Department of Genomics, Institute of Biochemistry and Genetics, Ufa Scientific Centre, Russian Academy of Sciences, Ufa, Russian Federation
14Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russian Federation


*Corresponding author: Nikolay A. Barashkov, Department of Molecular Genetics, Yakut Scientific Centre of Complex Medical Problems, Siberian Branch of the Russian Academy of Medical Sciences, Sergelyakhsskoe shosse- 4, Sakha Republic, Russian Federation, 1677010, Tel: +7(4112)-32-19-81, E-mail: barashkov2004@mail.ru
J Genet Genome Res, JGGR-1-001, (Volume 1, Issue 1), Research Article; ISSN: 2378-3648
Received: July 24, 2014 | Accepted: August 02, 2014 | Published: September 01, 2014
Citation: Barashkov NA (2014) Extremely High Carrier Frequency of the GJB2 Splice Site IVS1+1G>A Mutation in Eastern Siberia is Comparable to the Carrier Frequency of the Sickle Cell Anemia in Africa. J Genet Genome Res 1:001. 10.23937/2378-3648/1410001
Copyright: © 2014 Barashkov NA. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.



Abstract

This study presents data on the carrier frequencies of IVS1+1 G>A mutation in GJB2 gene, causing by autosomal recessive form of deafness among various ethno-geographical groups of Yakut population and in a random sample of the Yakuts. 350 DNA samples of hearing individuals from various ethno-geographical groups of Yakut population: Central (n=60), Vilyui (n=60), Northern (n=60) and random samples of Yakuts (n=170) were obtained from the DNA Bank of the Department of Molecular Genetics of Yakut Research Center of Complex Medical Problems of RAMS (Yakutsk, Russian Federation). The average carrier frequency of IVS1+1G>A mutation in Yakut population (n=350) detected was - 10.3%. Extremely high carrier frequency of the splice site IVS1+1G>A mutation in GJB2 gene in the Yakut population is comparable to the carrier frequency of the sickle-cell anemia in Africa, which may indicate a possible selective advantage of carriers of this IVS1+1G>A mutation in subarctic climate.


Keywords

Autosomal recessive deafness 1A, Eastern Siberia, Sickle-cell anemia, Africa.


Introduction

Recently, it was found that Eastern Siberia, subarctic part of Russia, is the region with the most extensive accumulation of the IVS1+1G>A mutation in the world. As a result of founder effect in the unique Yakut population isolate (Asian background population) [1].

The extremely high carrier frequency of IVS1+1G>A mutation (11,7%) from six investigated populations (Yakuts, Dolgans, Evenks, Evens and Yukaghirs), has been found in Yakut population. The age of mutation was estimated to be approximately 800 years. These findings characterize Eastern Siberia as the region with the most extensive accumulation of IVS1+1G>A mutation in the world as a result of founder effect [1].

However, this extreme rate of carrier frequency could be due to the effect of the sample, as to calculate the carrier frequency was used by two ethno-geographical (Central and Vilyui) groups of Yakuts.

The aim of this study is to analyze of the carrier frequency of the IVS1+1G>A splice site mutation in the extended community sample of the Yakuts, involving northern ethno-geographical groups and random sample of the Yakuts.


Material and Methods

Sample

350 DNA samples of hearing individuals from various ethno-geographical groups of Yakut population: Central (n=60), Vilyui (n=60), Northern (n=60) and random samples of Yakuts (n=170) were obtained from the DNA Bank of the Department of Molecular Genetics of Yakut Research Center of Complex Medical Problems of RAMS (Yakutsk, Russian Federation).

The genomic DNA was extracted from lymphocytes of peripheral blood. Amplification of the coding exon 2 and flanking intronic regions was performed using the following primers: ?x26A-U/Cx26U-L (F 51-TCT-TTT-CCA-GAG-CAA-ACC-GC-3, R 51-GAC-ACG-AAG-ATC-AGC-TGC-AG-31) (285 bp) [2], Cx342U/Cx739-L (F 51-AGG-CCG-ACT-TTG-TCT-GCA-ACA-31, R 51-GTG-GGC-CGG-GAC-ACA-AAG-31) (415 bp), 51-TAT-GTC-ATG-TAC-GAC-GGC-T-31, 51-TCT-AAC-AAC-TGG-GCA-ATG-C-31 (239 bp) [3]. Amplification of the noncoding exon 1 and flanking intronic regions was performed using primers Ex1-F/Ex1-R (F 51- CCG-GGA-AGC-TCT-GAG-GAC-31, R GCA-ACC-GCT-CTG-GGT-CTC-31) with the addition of 10% Betaine (Sigma, USA) [4]. The products of PCR were subject to direct sequencing using the same primers on ABI PRISM 3130XL (Applied Biosystems, USA).

Ethics approval

All testing procedures were conducted with a written informed consent signed by parents. This work was approved by the local bioethics committee at the Yakut Research Center of Complex Medical Problems of Siberian Branch of the Russian Academy of Medical Sciences (Yakutsk, Protocol 16, on April 16, 2009).


Results and Discussion

This study presents data on the carrier frequencies of IVS1+1G>A mutation in GJB2 gene, causing by autosomal recessive form of deafness among various ethno-geographical groups of Yakut population and in a random sample of the Yakuts. In a sample of northern ethno-geographical groups of Yakuts were found 5/60 heterozygotes for the IVS1+1G>A splice site mutation in GJB2 gene, carrier frequency - 8,3% (Table 1). The average carrier frequency of IVS1+1G>A mutation for all population samples Yakuts - 10,3%. In a random Yakut sample was found 17/170 heterozygotes, carrier frequency - 10,0% (Table 1).



Table 1: Carrier frequency of the IVS1+1G>A mutation in GJB2 gene in Yakut population (Eastern Siberia) View Table 1


The carrier frequency of IVS1+1G>A in the northern ethno-geographical group and in a random sample of the Yakuts are consistent with previously registered (11,7%) extremely high values of carrier frequency of IVS1+1G>A mutation in Yakut population [1]. The lower rate of mutation carriers in the northern group of the Yakuts (8,3%) compared with Vilyuy (10,0%) and Central (13,3%) groups is consistent with the results of haplotype analysis in which the most highest diversity of IVS1+1G>A haplotypes was found in the Central and Vilyuy subpopulations of Yakuts (excluding of the Yakutsk city), indicating that the expansion of mutant chromosomes on the territory of the Sakha Republic had started from the Lena-Amga interfluves area (Central district) [1]. Extremely high carrier frequency of the splice site mutation IVS1+1G>A in Yakuts (8,3-13,3%) living in Eastern Siberia in conditions of extreme continental climate can be explained not only by stochastic factors in the population dynamics and founder effect, shown earlier using different systems, such as STR-[1], and SNP-markers [4]. The selective advantage of heterozygous carriers of pathological alleles inherited autosomal-recessive disease known from classic example of sickle- cell anemia [5], common in Africa, South and South-East Asia (not uncommon in the Middle East and southern Europe) [6,7], as well as in the America [8]. Geographic stratification of the sickle-cell indicating an extremely high frequency of this disease near the equator [9], and evidence of the genetic adaptation of human populations to other common diseases in these regions - malaria [10]. The findings of the extremely high prevalence of mutations in the GJB2 gene splice site in Eastern Siberia (in some sub-populations of the Yakuts to 13,3%) is comparable with the frequency of heterozygous carriers of sickle cell anemia in Africa (HbS allele), where the carrier frequency of HbS allele was higher than 10% registered only in certain areas, sub-Saharan Africa (Figure 1) [11]. Extreme values of the frequency of heterozygous carriers of a mutation IVS1+1G>A GJB2 in the gene in Yakut population may indicate a possible selective advantage of carriers of this mutation in a subarctic climate [12-14].



Figure 1: The spatial distribution of the carriers frequency of Autosomal recessive deafness 1A in Eastern Siberia [1], comparison with the carriers frequency of sickle-cell anemia in the equatorial region [11] (using with the program SURFER 8.0 Golden Software Ink) View Figure 1




The spatial distribution of the carriers frequency of Autosomal recessive deafness 1A in Eastern Siberia.



Acknowledgements

We thank all patients and blood sample donors who have contributed to this study. This study was supported by the Russian Foundation for Basic Research (12-04-00342-?, 12-04-98520-r_vostok_a, 12-04-31230-mol_a, 14-04-01741_A), Integration project of SB RAS ? 92 "Ethnogeny of indigenous peoples in Siberia and North Asia: comparative, historical, ethno -social and genomic analysis”, the Sakha Republic President Grant #80 for Young Researchers for 2014 year, Scientific and Educational Foundation for Young Scientists of Republic of Sakha (Yakutia) for 2014 year, Project #6.656.2014/K of Ministry of Education and Science of Russia, by grant #30 (2013-2015) of RAS Program «Fundamental Sciences for Medicine».


References
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  4. Soloviev AV, Barashkov NA, Djemileva LY, Posukh OL, Teryutin FM, et al. (2013) Blochnaya architectura preodkovogo gaplotipa mutatsii saita splaisinga IVS1+1G>A gena GJB2 (Cx26), v popyliasii yakutov (po dannim 7 SNP-markerov). International Conference «High-throughput sequencing in genomics» HGS-2013: 81.

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  7. Weatherall DJ, Clegg JB (2001) Inherited haemoglobin disorders: an increasing global health problem. See comment in PubMed Commons below Bull World Health Organ 79: 704-712.

  8. Lazarin GA, Haque IS, Nazareth S, Iori K, Patterson AS, et al. (2013) An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. See comment in PubMed Commons below Genet Med 15: 178-186.

  9. Piel FB, Patil AP, Howes RE, Nyangiri OA, Gething PW, et al. (2010) Global distribution of the sickle cell gene and geographical confirmation of the malaria hypothesis. See comment in PubMed Commons below Nat Commun 1: 104.

  10. ALLISON AC (1957) Malaria in carriers of the sickle-cell trait and in newborn children. See comment in PubMed Commons below Exp Parasitol 6: 418-447.

  11. Piel FB, Patil AP, Howes RE, Nyangiri OA, Gething PW, et al. (2013) Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. See comment in PubMed Commons below Lancet 381: 142-151.

  12. Kelley PM, Harris DJ, Comer BC, Askew JW, Fowler T, et al. (1998) Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss. See comment in PubMed Commons below Am J Hum Genet 62: 792-799.

  13. Sirmaci A, Akcayoz-duman D, Tekin M (2006) The c. IVS1+1G>A mutation in the GJB2 gene is prevalent and large deletions involving the GJB6 gene are not present in the Turkish population. J Genet 85: 213-216.

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