Genetic studies of Tibetans, an ethnic group with a long-lasting presence on the Tibetan Plateau which is known as the highest plateau in the world, may offer a unique opportunity to understand the biological adaptations of human beings to high-altitude environments. We conducted a genome-wide study of 1,000,000 genetic variants in 46 Tibetans (TBN) and 92 Han Chinese (HAN) for identifying the signals of high-altitude adaptations (HAAs) in Tibetan genomes. We discovered the most differentiated variants between TBN and HAN at chromosome 1q42.2 and 2p21. EGLN1 (or HIFPH2, MIM 606425) and EPAS1 (or HIF2A, MIM 603349), both related to hypoxia-inducible factor, were found most differentiated in the two regions, respectively. Strong positive correlations were also observed between the frequency of TBN-dominant haplotypes in the two gene regions and altitude in East Asian populations. Linkage disequilibrium and further haplotype network analyses of world-wide populations suggested the antiquity of the TBN-dominant haplotypes and long-term persistence of the natural selection. Finally, a “dominant haplotype carrier” hypothesis could describe the role of the two genes in HAA. All of our population genomic and statistical analyses indicate that EPAS1 and EGLN1 are most likely responsible for HAA of Tibetans. Interestingly, one each but not both of the two genes were also identified by three recent studies. We reanalyzed the available data and found the escaped top signal (EPAS1) could be recaptured with data quality control and our approaches. Based on this experience, we call for more attention to be paid to controlling data quality and batch effects introduced in public data integration. Our results also suggest limitations of extended haplotype homozygosity-based method due to its compromised power in case the natural selection initiated long time ago and particularly in genomic regions with recombination hotspots.

Premature ovarian insufficiency (POI) is a major cause of female infertility due to early loss of ovarian function. POI is a heterogeneous condition, and its molecular etiology is unclear. To identify genetic variants associated with POI, here we performed whole-exome sequencing in a cohort of 1,030 patients with POI. We detected 195 pathogenic/likely pathogenic variants in 59 known POI-causative genes, accounting for 193 (18.7%) cases. Association analyses comparing the POI cohort with a control cohort of 5,000 individuals without POI identified 20 further POI-associated genes with a significantly higher burden of loss-of-function variants. Functional annotations of these novel 20 genes indicated their involvement in ovarian development and function, including gonadogenesis (LGR4 and PRDM1), meiosis (CPEB1, KASH5, MCMDC2, MEIOSIN, NUP43, RFWD3, SHOC1, SLX4 and STRA8) and folliculogenesis and ovulation (ALOX12, BMP6, H1-8, HMMR, HSD17B1, MST1R, PPM1B, ZAR1 and ZP3). Cumulatively, pathogenic and likely pathogenic variants in known POI-causative and novel POI-associated genes contributed to 242 (23.5%) cases. Further genotype–phenotype correlation analyses indicated that genetic contribution was higher in cases with primary amenorrhea compared to that in cases with secondary amenorrhea. This study expands understanding of the genetic landscape underlying POI and presents insights that have the potential to improve the utility of diagnostic genetic screenings.

Human genomics is witnessing an ongoing paradigm shift from a single reference sequence to a pangenome form, but populations of Asian ancestry are underrepresented. Here we present data from the first phase of the Chinese Pangenome Consortium, including a collection of 116 high-quality and haplotype-phased de novo assemblies based on 58 core samples representing 36 minority Chinese ethnic groups. With an average 30.65× high-fidelity long-read sequence coverage, an average contiguity N50 of more than 35.63 megabases and an average total size of 3.01 gigabases, the CPC core assemblies add 189 million base pairs of euchromatic polymorphic sequences and 1,367 protein-coding gene duplications to GRCh38. We identified 15.9 million small variants and 78,072 structural variants, of which 5.9 million small variants and 34,223 structural variants were not reported in a recently released pangenome reference¹. The Chinese Pangenome Consortium data demonstrate a remarkable increase in the discovery of novel and missing sequences when individuals are included from underrepresented minority ethnic groups. The missing reference sequences were enriched with archaic-derived alleles and genes that confer essential functions related to keratinization, response to ultraviolet radiation, DNA repair, immunological responses and lifespan, implying great potential for shedding new light on human evolution and recovering missing heritability in complex disease mapping.

Han Chinese, Japanese and Korean, the three major ethnic groups of East Asia, share many similarities in appearance, language and culture etc., but their genetic relationships, divergence times and subsequent genetic exchanges have not been well studied. We conducted a genome-wide study and evaluated the population structure of 182 Han Chinese, 90 Japanese and 100 Korean individuals, together with the data of 630 individuals representing 8 populations wordwide. Our analyses revealed that Han Chinese, Japanese and Korean populations have distinct genetic makeup and can be well distinguished based on either the genome wide data or a panel of ancestry informative markers (AIMs). Their genetic structure corresponds well to their geographical distributions, indicating geographical isolation played a critical role in driving population differentiation in East Asia. The most recent common ancestor of the three populations was dated back to 3000 ~ 3600 years ago. Our analyses also revealed substantial admixture within the three populations which occurred subsequent to initial splits, and distinct gene introgression from surrounding populations, of which northern ancestral component is dominant. These estimations and findings facilitate to understanding population history and mechanism of human genetic diversity in East Asia, and have implications for both evolutionary and medical studies.

Skin color is a well-recognized adaptive trait and has been studied extensively in humans. Understanding the genetic basis of adaptation of skin color in various populations has many implications in human evolution and medicine. Impressive progress has been made recently to identify genes associated with skin color variation in a wide range of geographical and temporal populations. In this review, we discuss what is currently known about the genetics of skin color variation. We enumerated several cases of skin color adaptation in global modern humans and archaic hominins, and illustrated why, when, and how skin color adaptation occurred in different populations. Finally, we provided a summary of the candidate loci associated with pigmentation, which could be a valuable reference for further evolutionary and medical studies. Previous studies generally indicated a complex genetic mechanism underlying the skin color variation, expanding our understanding of the role of population demographic history and natural selection in shaping genetic and phenotypic diversity in humans. Future work is needed to dissect the genetic architecture of skin color adaptation in numerous ethnic minority groups around the world, which remains relatively obscure compared with that of major continental groups, and to unravel the exact genetic basis of skin color adaptation.