Age Estimate of GJB2-p.(Arg143Trp) Founder Variant in Hearing Impairment in Ghana, Suggests Multiple Independent Origins across Populations.
Age Estimate of GJB2-p.(Arg143Trp) Founder Variant in Hearing Impairment in Ghana, Suggests Multiple Independent Origins across Populations.
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DOI：
10.3390/biology11030476
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发表时间：
2022-03-21
期刊：
影响因子：
4.2
通讯作者：
Wonkam A
中科院分区：
文献类型：
--
作者：
Aboagye ET;Adadey SM;Esoh K;Jonas M;de Kock C;Amenga-Etego L;Awandare GA;Wonkam A
GJB2-p.（Arg 143 Trp）创始人突变在不同种族语言和地理背景的许多人群中产生了对该变体的起源和年龄的兴趣，该变体主要与加纳的非综合征性听力障碍相关。询问GJB 2-p的多个可能的独立来源。（Arg 143 Trp）变异，我们估计年龄的变异在加纳贝叶斯推断，使用连锁标记的全外显子组测序数据从听力受损无关的个人谁是纯合子的GJB 2-p。（Arg 143 Trp）变异，和来自同一人群的未受影响的对照。我们估计变异的年龄约为9625年，从一个共同的土著加纳祖先。单倍型背景在加纳听力受损的人显然不同于他们的日本同行。我们在GJB 2-p中观察到低单倍型多样性。（Arg 143 Trp）基因组区域，尽管该区域的重组率相对较高。GJB 2-P（Arg 143 Trp）阳性个体与加纳GJB 2-p没有共同的单倍型。（Arg 143 Trp）阴性对照，以及从1000个基因组中的群体提取的数据没有共同的单倍型，进一步支持GJB 2-p的多个独立起源。（Arg 143 Trp）在全球人群中的分布。间隙连接蛋白β 2（GJB 2）（连接蛋白26）变体通常与非综合征性听力损伤（NSHI）有关。在加纳，GJB 2变体p.（Arg 143 Trp）是NSHI的最大贡献者，在受影响的多重家庭中报告的患病率为25.9%。迄今为止，在非洲大陆，GJB 2-p. Arg 143 Trp仅在加纳报告。利用来自16个分离NSHI的家庭的32个个体的全外显子组测序数据，以及38个具有相同种族语言背景的无关听力对照，我们调查了p.（Arg 143 Trp）在加纳使用连锁标记。利用贝叶斯连锁不平衡基因定位方法，我们估计了GJB 2-p。（Arg 143 Trp）起源于约9625年（385代）前的加纳。一项单倍型分析比较了加纳人和1000个基因组项目的数据，结果显示GJB 2-p。Arg 143 Trp）在加纳和日本人群以及欧洲血统人群中具有不同的单倍型背景，进一步支持了该变体的多个独立起源。此外，我们发现大量的单倍型保守的遗传背景的加纳人与双等位基因GJB 2-p。（Arg 143 Trp）与GJB 2-p相比。来自加纳的听力正常的（Arg 143 Trp）阴性群体，表明GJB 2-p纯合的加纳人群中的该基因组区域存在强烈的进化限制。（Arg143Trp）。本研究评估了GJB 2-p的年龄。（Arg 143 Trp）在9625年，并支持在全球人口中的这种变异的多个独立的起源。
The incidence of the GJB2-p.(Arg143Trp) founder mutation in numerous populations of different ethnolinguistic and geographical backgrounds has generated interest on the provenance and age of the variant, which is predominantly associated with non-syndromic hearing impairment in Ghana. To interrogate the multiple possible independent origins of the GJB2-p.(Arg143Trp) variant, we estimated the age of the variant in Ghana by Bayesian inference, using linked makers in whole-exome sequencing data from hearing-impaired unrelated individuals who are homozygous for the GJB2-p.(Arg143Trp) variant, and nonaffected controls from the same population. We estimated the age of the variant as approximately 9625 years, from a common indigenous Ghanaian ancestor. Haplotype backgrounds in Ghanaian hearing-impaired individuals were apparently different from those of their Japanese counterparts. We observed low haplotype diversity in the GJB2-p.(Arg143Trp) genomic region for homozygous individuals compared to the normal hearing Ghanaian controls, although the recombination rate is relatively high in the region. The GJB2-p.(Arg143Trp)-positive individuals shared no common haplotype with the Ghanaian GJB2-p.(Arg143Trp)-negative controls, and as well as no common haplotype with data extracted from populations in 1000 Genomes, further supporting the multiple independent origins of GJB2-p.(Arg143Trp) in the global population. Gap junction protein beta 2 (GJB2) (connexin 26) variants are commonly implicated in non-syndromic hearing impairment (NSHI). In Ghana, the GJB2 variant p.(Arg143Trp) is the largest contributor to NSHI and has a reported prevalence of 25.9% in affected multiplex families. To date, in the African continent, GJB2-p.(Arg143Trp) has only been reported in Ghana. Using whole-exome sequencing data from 32 individuals from 16 families segregating NSHI, and 38 unrelated hearing controls with the same ethnolinguistic background, we investigated the date and origin of p.(Arg143Trp) in Ghana using linked markers. With a Bayesian linkage disequilibrium gene mapping method, we estimated GJB2-p.(Arg143Trp) to have originated about 9625 years (385 generations) ago in Ghana. A haplotype analysis comparing data extracted from Ghanaians and those from the 1000 Genomes project revealed that GJB2-p.(Arg143Trp) is carried on different haplotype backgrounds in Ghanaian and Japanese populations, as well as among populations of European ancestry, lending further support to the multiple independent origins of the variant. In addition, we found substantial haplotype conservation in the genetic background of Ghanaian individuals with biallelic GJB2-p.(Arg143Trp) compared to the GJB2-p.(Arg143Trp)-negative group with normal hearing from Ghana, suggesting a strong evolutionary constraint in this genomic region in Ghanaian populations that are homozygous for GJB2-p.(Arg143Trp). The present study evaluates the age of GJB2-p.(Arg143Trp) at 9625 years and supports the multiple independent origins of this variant in the global population.
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