Genomic structural variants (SVs) are a major source of genetic diversity in humans. Although numerous studies explore SV diversity across global populations and their potential impacts, validation using model systems are needed to confirm the reported genotype-phenotype associations. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported variants, many predicted to be functionally important. Our analysis unveils the multifaceted origins of these SVs within the Han population, with approximately 24% emerging at the common ancestor of modern humans. By integrating human population-level phenotypic, metabolic, and immunologic data and two humanized mouse models, we demonstrate the causal roles of two SVs: one SV that emerges at the common ancestor of modern human and Neanderthal and Denisova in GSDMD for bone density and one modern-human-specific SV in WWP2 impacting height, weight, fat, craniofacial phenotypes, and innate immunity. Some of these phenotypes were previously unreported and irreproducible phenotypes in mouse knockout experiments. Our results suggest that the SV in GSDMD could serve as a rapid and cost-effective predictive biomarker for evaluating GSDMD-mediated pyroptosis in multiple organ injuries, including cisplatin-induced acute kidney injury. While initially identified in the Han, the functional conservation from human to mouse, signals of positive natural selection specifically in non-African populations including the Han, and associations with multiple disease risks, suggest that both SVs likely influence local adaptation, phenotypic diversity, and disease susceptibility across many non-African populations.

F.J.S. receives research support from Illumina, Pacbio, Oxford Nanopore and Genentech

This work was supported by the National Natural Science Foundation of China (grants No. 31970563 and 32370686 to S.F., 32271186 to J.T., 32030020 to S.X., and 82100773 to Y.G.) and National Key Research and Development Program of China (2020YFE0201600 and 2021YFC2500202 to S.F. and 2022YFC2505400 and 2022YFC3400203 to Y.G.), the 111 Project (B13016 to S.F. and L.J.). Shanghai Municipal Science and Technology (grant No. 2017SHZDZX01) to L.J., Shanghai Rising-Star Program (22QA1405900 to Y.G.). F.J.S. is supported by NIH grants (1U01HG011758-01, U01 AG058589). This work was also supported by the Human Phenome Data Center at Fudan University.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study complied with all relevant regulations for working with human subjects in China. The Ethics Committee of the School of Life Sciences, Fudan University, Shanghai, China approved the study. Participants were recruited to a project studying physical anthropology diversity in China funded by the Ministry of Science and Technology of the People's Republic of China (2015FY111700). Informed consents were approved by all participants.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors