De novoassembly of a Tibetan genome and identification of novel structural variants associated with high-altitude adaptation

Abstract

Structural variants (SVs) may play important roles in human adaptation to extreme environments such as high altitude but have been under-investigated. Here, combining long-read sequencing with multiple scaffolding techniques, we assembled a high-quality Tibetan genome (ZF1), with a contig N50 length of 24.57 mega-base pairs (Mb) and a scaffold N50 length of 58.80 Mb. The ZF1 assembly filled 80 remaining N-gaps (0.25 Mb in total length) in the reference human genome (GRCh38). Markedly, we detected 17 900 SVs, among which the ZF1-specific SVs are enriched in GTPase activity that is required for activation of the hypoxic pathway. Further population analysis uncovered a 163-bp intronic deletion in the MKL1 gene showing large divergence between highland Tibetans and lowland Han Chinese. This deletion is significantly associated with lower systolic pulmonary arterial pressure, one of the key adaptive physiological traits in Tibetans. Moreover, with the use of the high-quality de novo assembly, we observed a much higher rate of genome-wide archaic hominid (Altai Neanderthal and Denisovan) shared non-reference sequences in ZF1 (1.32%–1.53%) compared to other East Asian genomes (0.70%–0.98%), reflecting a unique genomic composition of Tibetans. One such archaic hominid shared sequence—a 662-bp intronic insertion in the SCUBE2 gene—is enriched and associated with better lung function (the FEV1/FVC ratio) in Tibetans. Collectively, we generated the first high-resolution Tibetan reference genome, and the identified SVs may serve as valuable resources for future evolutionary and medical studies.

The genome sequence of Samia ricini, a new model species of lepidopteran insect

“…These 35 scaffolds totalled 443,618,927 bp, meaning that ~98.5% of the genome was assigned to the chromosomes (Table 2). Because the orientations of the scaffolds were not experimentally determined and sizes of gaps between scaffolds are unknown, chromosome‐scale scaffolding techniques, Hi‐C sequencing (Burton et al., 2013; Dudchenko et al., 2017) or optical mapping (Jiao et al, 2017; Ouzhuluobu et al., 2020) would be desirable.…”

“…These 35 scaffolds totalled 443,618,927 bp, meaning that ~98.5% of the genome was assigned to the chromosomes (Table 2). Because the orientations of the scaffolds were not experimentally determined and sizes of gaps between scaffolds are unknown, chromosome-scale scaffolding techniques, Hi-C sequencing (Burton et al, 2013;Dudchenko et al, 2017) or optical mapping (Jiao et al, 2017;Ouzhuluobu et al, 2020) (Figure 2). Interestingly, although the total length of LINE and its proportion of all repetitive sequences in the genome were similar between S. ricini and B. mori (Figure 2), the components of LINE families were different.…”

Structural variant selection for high-altitude adaptation using single-molecule long-read sequencing

“…1f), the majority of which were low-frequency (allele frequency<0.1, ~58%) and singleton SVs (~29.9%) (Supplementary Table 4). We also compared our Tibetan SV set with the ZF1 SV call set, which was recently collected from a high-quality de novo assembled Tibetan genome based on the SMRT platform 16 . We found that only 15,890 SVs (~17%) in our Tibetan SV reference panel overlapped with the ZF1 SV call set (17,714 SVs) (Supplementary Table 5).…”

Ancient Migrations - The first complete genome assembly, annotation and variants of the Zoroastrian-Parsi community of India

“…Medical genetics has taken a leap forward in personalized medicine with the information of whole genome sequence for inheritable conditions, birth defects and chromosomal disorders 6 . Personalized genome assembly has shed light on the effects that non-genetic, disease-linked etiologies like methylation of CpG base pair islands have on gene availability for transcription 7,8 .…”

“…Medical genetics has taken a leap forward in personalized medicine with the information of whole genome sequence for inheritable conditions, birth defects and chromosomal disorders 6 .…”