Yang Linfeng, Lin Zhe, Gao Yong, Zhang Jianguo, Peng Huanhuan, Li Yaqing, Che Jingang, Zhao Lijian, Zhang Jilin
Hebei Industrial Technology Research Institute of Genomics in Maternal and Child Health, BGI-Shijiazhuang Medical Laboratory, Shijiazhuang, China.
BGI Genomics, BGI-Shenzhen, Shenzhen, China.
NPJ Genom Med. 2023 Nov 20;8(1):38. doi: 10.1038/s41525-023-00383-8.
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.
出生缺陷是对公共卫生系统的全球性威胁。致病性突变难以捉摸的分子机制以及后续预防措施转化不力，阻碍了新生儿异常的缓解。在中国应用适当的策略促进生殖健康尤其具有挑战性，因为中国人口包含许多具有不同遗传背景的民族，基因组多样性复杂。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，我们采用自下而上的方法，对来自中国最大的公开可用人群队列的与常染色体隐性（AR）疾病相关的高质量变异进行了重新分析。对不同民族的基因携带率（GCR）分析表明，由于不同的进化选择，可能存在显著的异质性。抽样人群、测序覆盖范围和潜在的人群结构导致了中国地图集与gnomAD中的东亚群体之间观察到的变异差异。除了GCR的特征外，还根据所研究基因的基因组特征和功能作用，探索了潜在的可药物靶向，表明相分离可能是常染色体隐性疾病的治疗靶点。对不同民族估计的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，至少两个群体共有的大多数基因可用于指导泛民族筛查应用的设计。为此，根据GCR的优先排序提出了一份常染色体隐性疾病基因清单，以制定分层筛查策略。
