Stratifying variant deleteriousness and trait-modulating effect under human recent adaptation using the FIND model
Existing methods to distinguish deleterious/pathogenic from neutral variants still inadequately capture the full spectrum of genetic variant impact on fitness and disease susceptibility. We introduce the FIND model, which stratifies genetic variants into refined categories based on fitness spectrum and derived allele frequency. FIND demonstrates enhanced resolution in differentiating trait-modulating alleles from those that are deleterious or neutral, delivering higher performance over existing genome-wide methods. Applying FIND to the interpretation of clinical variants demonstrates its substantial potential in reclassifying variants of unknown significance, providing a new tool to explore the complexities of genetic contributions to health.
Authors
- Wenhao Zhou (ORCID: https://orcid.org/0000-0001-8956-7238)
- Xiaoqiong Gu (ORCID: https://orcid.org/0000-0002-9558-4226)
- Xutong Fan (ORCID: https://orcid.org/0000-0001-7056-1995)
- Xianfu Yi
- Pak C. Sham (ORCID: https://orcid.org/0000-0002-2533-7270)
- Miaoxin Li (ORCID: https://orcid.org/0000-0002-4733-0109)
- Xiaobao Dong (ORCID: https://orcid.org/0000-0003-1652-117X)
- Dandan Huang (ORCID: https://orcid.org/0000-0002-2594-8434)
- Xinran Dong
- Zhikun Wu (ORCID: https://orcid.org/0000-0002-4583-7782)
- Jianhua Wang (ORCID: https://orcid.org/0000-0002-9795-9765)
- Shijie Zhang (ORCID: https://orcid.org/0000-0002-9606-9955)
- Mulin Jun Li (ORCID: https://orcid.org/0000-0003-3598-3679)
Institutions
- Sun Yat-sen University (CN)
- Guangzhou Women and Children Medical Center (CN)
- Children's Hospital of Fudan University (CN)
- Tianjin Medical University (CN)
- University of Hong Kong (HK)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Genome biology
- Published
- 2025-10-29
- DOI
- https://doi.org/10.1186/s13059-025-03843-9
- Primary Topic
- Genetic Associations and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- National Key Research and Development Program of China