NEW YORK – With genome sequence and phenotypic data for more than 3,200 individuals from sites across Japan, a team led by investigators at the RIKEN Center for Integrative Medical Sciences has learned more about the structure, ancestral history, and natural selection in the Japanese population.
The findings appeared in Science Advances on Wednesday.
"This comprehensive genetic dataset enables us to delve into uncharted territories concerning population and medical genetics of the Japanese population," first author Xiaoxi Liu and senior author Chikashi Terao, researchers with the RIKEN Center for Integrative Medical Sciences and Shizuoka General Hospital, said in an email.
As part of the Japanese Encyclopedia of Whole-Genome/Exome Sequencing Library (JEWEL) effort, the researchers performed whole-genome sequencing for 3,256 Biobank Japan (BBJ) participants from seven regions in Japan, generating an average of nearly 26-fold coverage. Within these sequences, they found almost 45.6 million single nucleotide variants and more than 9.1 million small insertions or deletions.
The team analyzed the variants alongside available clinical data from health records and participant surveys, which contained information on everything from prior diagnoses and clinical test results to personal and family histories.
"[E]xtensive efforts have been made to collect and curate deep phenotypes through a review of medical records, follow-up surveys, and examinations in BBJ," the study's authors explained, noting that JEWEL "is enriched with potentially pathogenic variants associated with diseases, and detailed clinical information permits targeted examination of carriers of particular interest."
In total, the investigators identified 371 pathogenic variants found in ClinVar. They also unearthed more than 1,700 new loss-of-function variants (LoF), including almost two dozen gene "knockouts" involving compound heterozygous variants or variants affecting both copies of a given gene.
The team also incorporated available phenotyping data to assess the potential consequences of heterozygous LoF variants affecting genes such as the protein tyrosine phosphatase receptor type D-coding gene PTPRD.
LoF variants in PTPRD, which turned up in half a dozen participants, appeared to have a relatively modest effect on transcript levels, the authors reported. Consequently, the suggested "tolerability to LoF should be evaluated not only at the gene level but also at the transcript level," they wrote.
When the investigators used the data to analyze population structure and ancestry, meanwhile, they saw signs that three main groups contributed ancestry to the individuals profiled, arguing against a dual ancestry proposed in the past.
"Historically, the dual-structure model, which posits that the Japanese population was formed through the admixture of the Jomon and Yayoi people, has been the predominant framework," Liu and Terao explained. "However, our findings suggest that a tri-ancestral model may provide a better fit based on our data."
Along with ancestral groups that appeared to have ties to a Neolithic Jomon hunter-gatherer group and an ancient group linked to China's Yellow River region, they explained, the genomic data pointed to a previously unappreciated group with higher ancestry contributions to populations in Northeastern Japan.
"This tri-ancestral model could be useful for understanding founder pathogenic mutations in Japanese [people], such as the BRCA1 Leu63Ter founder mutation, which is specific to the Japanese population and was observed predominantly in people of Northeast lineage," Liu and Terao said.
The genome sequence collection also made it possible to take a closer look at sites under selection in the Japanese population, as well as sequences originating from introgression by archaic hominins such as Neanderthals and Denisovans.
The researchers flagged 44 complex trait-associated archaic sequence segments, for example. In particular, they traced a type 2 diabetes-associated region containing the NKX6-1 gene back to Denisovans and unearthed an East Asian-specific introgression of Neanderthal sequences containing a GLP1R variant implicated in type 2 diabetes risk in individuals from Japan but not in those with European ancestry.
"This discovery is particularly relevant considering the development of oral semaglutide, a GLP-1 analog, for treating type 2 diabetes," they explained, adding that the result "underscores the importance of considering archaic genetic variants within specific population contexts."