Genomic analysis of inherited hearing loss in the Palestinian population
Genomic analysis of inherited hearing loss in the Palestinian population
复制标题
巴勒斯坦人口遗传性听力损失的基因组分析
DOI：
10.1073/pnas.2009628117
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发表时间：
2020-08-18
影响因子：
11.1
通讯作者：
Kanaan, Moien N.
中科院分区：
文献类型：
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作者：
Abu Rayyan, Amal;Kamal, Lara;Kanaan, Moien N.
整个群体的共同表型的遗传特征既揭示了该地区该表型的原因，也揭示了以家庭为基础的、全群体的基因组分析对基因和突变发现的能力。我们描述了整个巴勒斯坦人口听力损失的遗传学特征，招募了来自西岸和加沙所有地区的491个家庭的2198名参与者。在没有听力损失史的巴勒斯坦家庭中，我们估计56%的听力损失是遗传性的，44%是非遗传性的。对于绝大多数(87%)遗传性听力损失家庭，基于小组的基因组DNA测序，然后是大家族的分离分析和参与者RNA的转录分析，能够识别致病基因和突变，包括在遥远的非编码区。听力损失的遗传异质性在基因和等位基因方面都是惊人的：337个被解决的家庭在48个不同的基因中存在143个不同的突变。对于每四个已解决的家系中就有一个，转录改变突变是负责的等位基因。这些突变中有许多是神秘的，要么是剪接增强子或消音器的外显子改变，要么是深度内含子事件。在转录效应的电子分析中进行了实验校准，得出了对剪接的影响，甚至对可访问组织中未表达的基因的突变的高度可信的推断。人群中大多数(58%)的听力损失可归因于血缘关系。鉴于近亲婚姻的持续下降，遗传性听力损失在下一代可能会更加罕见。
The genetic characterization of a common phenotype for an entire population reveals both the causes of that phenotype for that place and the power of family-based, population-wide genomic analysis for gene and mutation discovery. We characterized the genetics of hearing loss throughout the Palestinian population, enrolling 2,198 participants from 491 families from all parts of the West Bank and Gaza. In Palestinian families with no prior history of hearing loss, we estimate that 56% of hearing loss is genetic and 44% is not genetic. For the great majority (87%) of families with inherited hearing loss, panel-based genomic DNA sequencing, followed by segregation analysis of large kindreds and transcriptional analysis of participant RNA, enabled identification of the causal genes and mutations, including at distant noncoding sites. Genetic heterogeneity of hearing loss was striking with respect to both genes and alleles: The 337 solved families harbored 143 different mutations in 48 different genes. For one in four solved families, a transcription-altering mutation was the responsible allele. Many of these mutations were cryptic, either exonic alterations of splice enhancers or silencers or deeply intronic events. Experimentally calibrated in silico analysis of transcriptional effects yielded inferences of high confidence for effects on splicing even of mutations in genes not expressed in accessible tissue. Most (58%) of all hearing loss in the population was attributable to consanguinity. Given the ongoing decline in consanguineous marriage, inherited hearing loss will likely be much rarer in the next generation.