Characterization of structural variation in Tibetans reveals new evidence of high-altitude adaptation and introgression

Abstract

Background Structural variation (SV) acts as an essential mutational force shaping the evolution and function of the human genome. However, few studies have examined the role of SVs in high-altitude adaptation and little is known of adaptive introgressed SVs in Tibetans so far. Results Here, we generate a comprehensive catalog of SVs in a Chinese Tibetan (n = 15) and Han (n = 10) population using nanopore sequencing technology. Among a total of 38,216 unique SVs in the catalog, 27% are sequence-resolved for the first time. We systematically assess the distribution of these SVs across repeat sequences and functional genomic regions. Through genotyping in additional 276 genomes, we identify 69 Tibetan-Han stratified SVs and 80 candidate adaptive genes. We also discover a few adaptive introgressed SV candidates and provide evidence for a deletion of 335 base pairs at 1p36.32. Conclusions Overall, our results highlight the important role of SVs in the evolutionary processes of Tibetans’ adaptation to the Qinghai-Tibet Plateau and provide a valuable resource for future high-altitude adaptation studies.

Ethnic Specificity of Species and Strain Composition of Lactobacillus Populations From Mother–Infant Pairs, Uncovered by Multilocus Sequence Typing

“…Accumulating evidence suggests that a variety of factors, including host genetic background, living environment, and especially dietary differences, may pose different challenges and selection pressures for human gut microbial contents at the microbiome level and individual bacterial group ( Chaplinska et al, 2016 ; Kohl et al, 2018 ; Quan et al, 2021 ). Due to dramatic discrepancy in human lifestyle, selective action of long-term diet patterns may be the main reason that contributed to the difference of gut microbiota of ethnic groups located in different geographical areas ( Beam et al, 2021 ; Couch et al, 2021 ).…”

Population-scale genotyping of structural variation in the era of long-read sequencing

“…Compared to the ubiquitous single nucleotide variation (SNV) and small indels, SVs are numerically fewer but larger in size, therefore having a greater impact on DNA sequences and correspondingly on gene expression and protein functionality [9] , [10] , [11] . As a result, SV has received extensive attention in recent studies on genome evolution [10] , population diversity [12] , demographic history [13] , and genetic adaptation [14] , bringing new insights into population genetics. In addition, SV can act as a genetic factor underlying disease risk [15] and has already been reported to be involved in the tumorigenesis of various cancers [6] , [16] , [17] , especially nested SVs in complex genetic backgrounds [18] , [19] .…”

“…On the other hand, many large-scale whole-genome sequencing (WGS) datasets collected from valuable clinical samples and other specific populations have been established in the SRS era [34] , [35] , [36] , [37] , [38] . Detection of novel SVs identified by LRS in these SRS samples allows better estimation of the allele frequency in local populations, facilitating other genotype-based downstream analyses [12] , [14] , [22] , [33] . As a result, genotyping of SVs in cumulative SRS samples remains a critical issue [33] , [39] , although large-scale SV studies using LRS samples exclusively are emerging [40] , [41] .…”

“…However, alignment against a single reference genome is biased towards the reference allele [22] , [42] , [43] , [44] , [45] , so sequences containing large deviated alternative alleles are prone to mismatches or multiple alignments [46] . As reported in several population-scale SV studies, many of the SVs identified by LRS were classified as homozygous references in SRS samples [12] , [14] , [32] , which severely impacts genotype-based population genetic studies or genome-wide association studies of complex diseases. Therefore, it is of paramount importance to explore new methods to eliminate reference bias to improve genotyping accuracy in population-scale SV studies.…”

The blooming of long-read sequencing reforms biomedical research

“…For example, Xue et al used PacBio HiFi reads to create a high-quality and nearly gap-free diploid genome of zig-zag eel so that they could perform a high-resolution comparison of the homomorphic pair of the sex chromosomes to investigate their recombination and differentiation [ 5 ]. The power of long reads was also shown in characterizing structural variations and repetitive elements [ 6 , 7 ].…”