Abstract
Mutations in the GJB2 gene are known to be a major cause of autosomal recessive deafness 1A (OMIM 220290). The most common pathogenic variants of the GJB2 gene have a high ethno-geographic specificity in their distribution, being attributed to a founder effect related to the Neolithic migration routes of Homo sapiens. The c.-23 + 1G > A splice site variant is frequently found among deaf patients of both Caucasian and Asian origins. It is currently unknown whether the spread of this mutation across Eurasia is a result of the founder effect or if it could have multiple local centers of origin. To determine the origin of c.-23 + 1G > A, we reconstructed haplotypes by genotyping SNPs on an Illumina OmniExpress 730 K platform of 23 deaf individuals homozygous for this variant from different populations of Eurasia. The analyses revealed the presence of common regions of homozygosity in different individual genomes in the sample. These data support the hypothesis of the common founder effect in the distribution of the c.-23 + 1G > A variant of the GJB2 gene. Based on the published data on the c.-23 + 1G > A prevalence among 16,177 deaf people and the calculation of the TMRCA of the modified f2-haplotypes carrying this variant, we reconstructed the potential migration routes of the carriers of this mutation around the world. This analysis indicates that the c.-23 + 1G > A variant in the GJB2 gene may have originated approximately 6000 years ago in the territory of the Caucasus or the Middle East then spread throughout Europe, South and Central Asia and other regions of the world.
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Code availability
Bioinformatic analyses were done with publicly available software packages as described in the methods. Custom codes to aid in variant filtering are available upon request.
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Acknowledgements
We thank all patients and blood sample donors who have contributed to this study. The authors are grateful to Anatoly N. Alekseev, Chandana Basu Mallik and Georgii P. Romanov for helpful comments on previous versions of this manuscript.
Funding
This study was supported by the Yakut Science Centre of Complex Medical Problems project: “Study of the genetic structure and burden of hereditary pathology of populations of the Republic of Sakha (Yakutia)”, the Ministry of Science and Higher Education of the Russian Federation (FSRG-2020-0016), the Russian Foundation for Basic Research (#18-05-60035_Arctika, # 20-015-00328_A, #19-34-60023_Perspektiva), the Russian State Budjet program No 0259-2021-0014, the European Union through the European Regional Development Fund (Project No. 2014-2020.4.01.15-0012) and IUT 24 Research Funding of the Institutional Estonian Ministry of Education and Research.
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Conceptualization: AVS, AK, NAB and SAF. Funding acquisition: SAF, AVS, VGP, OLP, and EM. Methodology: AVS and SAF. Project administration: SAF, NAB, MM, EKH, and AP. Resources: EB, M.B-Kh, MRL, TGM, GM, LK, and FMT. Visualization: AVS. Writing—original draft: AVS and NAB. Writing—review and editing: OLP, AK, and SAF.
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Solovyev, A.V., Kushniarevich, A., Bliznetz, E. et al. A common founder effect of the splice site variant c.-23 + 1G > A in GJB2 gene causing autosomal recessive deafness 1A (DFNB1A) in Eurasia. Hum Genet 141, 697–707 (2022). https://doi.org/10.1007/s00439-021-02405-w
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DOI: https://doi.org/10.1007/s00439-021-02405-w