Increased ultra-rare variant load in an isolated Scottish population impacts exonic and regulatory regions
Increased ultra-rare variant load in an isolated Scottish population impacts exonic and regulatory regions
复制标题
孤立的苏格兰人群中超罕见变异负载的增加影响外显子和监管区域
DOI：
10.1101/809244
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Halachev M
中科院分区：
文献类型：
--
作者：
Halachev M
人类群体分离株提供了历史人口统计学过程对群体遗传学影响的快照。这些数据有助于研究罕见序列变异对生物医学表型的功能影响，因为强烈的遗传漂变可能导致更高频率的变异，否则是罕见的。我们提出了第一个全基因组测序（WGS）研究的维京海盗队列，一个代表性的收集样本从孤立的设得兰群岛人口在北方苏格兰，并探讨其遗传特征相比，大陆苏格兰人口。我们的分析揭示了奠基者效应和遗传漂变在形成维京海盗群体基因组变异中所起的重要作用。在所发现的所有高质量变异中，约有十分之一是维京海盗群体所特有的，或者是在更国际化的对照群体中所见的频率至少高出十倍。多线的证据也表明放松纯化选择在进化历史的设得兰群岛隔离。我们证明了超罕见的维京海盗变异体在外显子区域的富集，我们还首次表明，超罕见的变异体在调控区域，特别是启动子内富集，这表明基因表达模式可能在人类分离株中相对迅速地分化。
Human population isolates provide a snapshot of the impact of historical demographic processes on population genetics. Such data facilitate studies of the functional impact of rare sequence variants on biomedical phenotypes, as strong genetic drift can result in higher frequencies of variants that are otherwise rare. We present the first whole genome sequencing (WGS) study of the VIKING cohort, a representative collection of samples from the isolated Shetland population in northern Scotland, and explore how its genetic characteristics compare to a mainland Scottish population. Our analyses reveal the strong contributions played by the founder effect and genetic drift in shaping genomic variation in the VIKING cohort. About one tenth of all high-quality variants discovered are unique to the VIKING cohort or are seen at frequencies at least ten fold higher than in more cosmopolitan control populations. Multiple lines of evidence also suggest relaxation of purifying selection during the evolutionary history of the Shetland isolate. We demonstrate enrichment of ultra-rare VIKING variants in exonic regions and for the first time we also show that ultra-rare variants are enriched within regulatory regions, particularly promoters, suggesting that gene expression patterns may diverge relatively rapidly in human isolates.