Populational pan-ethnic screening panel enabled by deep whole genome sequencing.

IF 4.7 2区 医学 Q1 GENETICS & HEREDITY NPJ Genomic Medicine Pub Date : 2023-11-20 DOI:10.1038/s41525-023-00383-8
Linfeng Yang, Zhe Lin, Yong Gao, Jianguo Zhang, Huanhuan Peng, Yaqing Li, Jingang Che, Lijian Zhao, Jilin Zhang
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Abstract

Birth defect is a global threat to the public health systems. Mitigating neonatal anomalies is hampered by elusive molecular mechanisms of pathogenic mutations and poor subsequent translation into preventative measures. Applying appropriate strategies in China to promote reproductive health is particularly challenging, as the Chinese population compromises complex genomic diversity due to the inclusion of many ethnic groups with distinct genetic backgrounds. To investigate and evaluate the feasibility of implementing a pan-ethnic screening strategy, and guide future reproductive counselling, high-quality variants associated with autosome recessive (AR) diseases derived from the largest publicly available cohort of the Chinese population were re-analysed using a bottom-up approach. The analyses of gene carrier rates (GCRs) across distinct ethnic groups revealed that substantial heterogeneity existed potentially due to diverse evolutionary selection. The sampling population, sequencing coverage and underlying population structure contributed to the differential variants observed between ChinaMAP and the East Asian group in gnomAD. Beyond characteristics of GCR, potential druggable targets were additionally explored according to genomic features and functional roles of investigated genes, demonstrating that phase separation could be a therapeutic target for autosomal recessive diseases. A further examination of estimated GCR across ethnic groups indicated that most genes shared by at least two populations could be utilised to direct the design of a pan-ethnic screening application once sequencing and interpreting costs become negligible. To this end, a list of autosomal recessive disease genes is proposed based on the prioritised rank of GCR to formulate a tiered screening strategy.

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通过深度全基因组测序实现人口泛民族筛选小组。
出生缺陷是对公共卫生系统的全球性威胁。减轻新生儿异常受到难以捉摸的致病突变的分子机制和随后转化为预防措施的不良影响。在中国应用适当的策略来促进生殖健康尤其具有挑战性,因为中国人口由于包含许多具有不同遗传背景的民族而损害了复杂的基因组多样性。为了调查和评估实施泛民族筛查策略的可行性,并指导未来的生殖咨询,使用自下而上的方法重新分析了来自中国人口中最大的公开队列中与常染色体隐性(AR)疾病相关的高质量变异。基因携带率(GCRs)在不同种族间的分析表明,由于不同的进化选择,存在着巨大的异质性。取样人群、测序覆盖范围和潜在人群结构导致了中国地图和东亚人群在gnomAD中观察到的差异变异。除了GCR的特征外,根据所研究基因的基因组特征和功能作用,还探索了潜在的药物靶点,表明相分离可能是常染色体隐性遗传病的治疗靶点。对种族间估计GCR的进一步检查表明,一旦测序和解释成本变得可以忽略不计,至少两个群体共享的大多数基因可以用来指导泛种族筛选应用程序的设计。为此,根据GCR的优先级,提出常染色体隐性遗传病基因列表,制定分级筛查策略。
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来源期刊
NPJ Genomic Medicine
NPJ Genomic Medicine Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
9.40
自引率
1.90%
发文量
67
审稿时长
17 weeks
期刊介绍: npj Genomic Medicine is an international, peer-reviewed journal dedicated to publishing the most important scientific advances in all aspects of genomics and its application in the practice of medicine. The journal defines genomic medicine as "diagnosis, prognosis, prevention and/or treatment of disease and disorders of the mind and body, using approaches informed or enabled by knowledge of the genome and the molecules it encodes." Relevant and high-impact papers that encompass studies of individuals, families, or populations are considered for publication. An emphasis will include coupling detailed phenotype and genome sequencing information, both enabled by new technologies and informatics, to delineate the underlying aetiology of disease. Clinical recommendations and/or guidelines of how that data should be used in the clinical management of those patients in the study, and others, are also encouraged.
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