Mapping Genome Variants Sheds Light on Genetic and Phenotypic Differentiation in Chinese

Every human being looks different in one way or the other. That’s the work of genetic variations, the ultimate driving force for evolution as well as the cause for many human diseases. Mapping human genetic variants reveals global genetic diversity, and pinpoints causal variants behind genetic disorders. In recent years, several international consortiums, including the International HapMap Project [1], 1000 Genomes Project (1KGP) [2–5], UK10K [6], Genome of the Netherlands (GoNL) [7], 1KJPN [8], and the Chinese Academy of Sciences Precision Medicine Initiative (CASPMI), reported in this issue [9], have all embarked on a journey to characterize the full spectrum of human genetic variants, This has been much powered by high-throughput sequencing technologies, such as next-generation sequencing (NGS), PacBio, and Oxford Nanopore, and bioinformatics algorithms for variant detections. To date millions of variants including single or multiple nucleotide substitutions, indels, and structural variants (SVs) have been detected in genomes of diverse ethnic origins, serving as valuable resources for genome-wide association studies (GWAS) to link genetic loci with diseases and providing guidance to personalized and precision treatments. China has a population of about 1.4 billion, the world’s largest population with rather diverse ethnic groups. Han, the largest ethnic group in China and the world, constitutes about 18% of world population [10]. It is conceivable that characterizing genetic variations in various Chinese ethnic groups shall provide a vital foundation for elucidating the genetic basis of group-specific traits and disease susceptibility. Although variant discovery routinely involves mapping wholegenome or whole-exome sequencing data against the reference genome (GRCh38) of Caucasian genetic background produced by the Human Genome Project, this universal choice of reference genome is not suitable for capturing genetic variants in every ethnic group, calling for population-specific reference genomes or alternatively graph genomes [11]. Therefore, a high-quality Han-specific reference genome is badly needed for mapping Han genetic variants. Although two reference genomes of southern Han Chinese (HX1 and YH) are available, due to the genetic differences between northern and southern Han populations, a specific reference genome for northern Han is desired for categorizing genetic variations for the northerners, but so far nonexistent. Reporting the nearly completed phase I of CASPMI launched in 2016, Du et al. [9] released a whole genome assembly NH1.0 for a northern Han individual combining multiple sequencing technologies including 10X Genomics, PacBio, and Bionano optical mapping. NH1.0 genome (Scaffold N50 of 46.63 Mb) is more continuous than the two existing Chinese genomes HX1 (21.98 Mb) and YH2.0 (20.52 Mb), also with higher integrity at chromosome level [9]. Comparing NH1.0 with GRCh38 reference genome identified 749 novel sequences spanning 4.76 Mb, harboring 2.6 million genetic variants