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

Area of Science:

• Genomics
• Public Health
• Genetic Epidemiology

Background:

• Birth defects pose a global health challenge, complicated by unknown genetic mechanisms and difficulties in prevention.
• Implementing effective reproductive health strategies in China is complex due to the population's significant genomic diversity across ethnic groups.

Purpose of the Study:

• To evaluate the feasibility of a pan-ethnic screening strategy for autosomal recessive (AR) diseases in China.
• To guide future reproductive counseling by analyzing high-quality genetic variants from a large Chinese cohort.
• To identify potential therapeutic targets for AR diseases.

Main Methods:

• Re-analysis of high-quality variants associated with AR diseases from the largest publicly available Chinese population cohort using a bottom-up approach.
• Analysis of gene carrier rates (GCRs) across distinct ethnic groups to identify heterogeneity.
• Exploration of druggable targets based on genomic features and gene functions, including phase separation.

Main Results:

• Substantial heterogeneity in GCRs was observed across Chinese ethnic groups, potentially linked to evolutionary selection.
• Differential variants were noted between the ChinaMAP cohort and the gnomAD East Asian group, influenced by sampling, sequencing, and population structure.
• Phase separation emerged as a potential therapeutic target for AR diseases.
• Most genes shared by at least two populations could inform the design of a pan-ethnic screening application.

Conclusions:

• A pan-ethnic screening strategy for AR diseases in China is feasible, especially as costs decrease.
• Prioritizing AR disease genes based on GCR can inform a tiered screening approach for reproductive health.
• Understanding ethnic-specific genetic variations is crucial for effective public health interventions and genetic counseling.