RT Journal Article
SR Electronic
T1 <em>De novo</em> assembly of a Tibetan genome and identification of novel structural variants associated with high altitude adaptation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 753186
DO 10.1101/753186
A1 Ouzhuluobu
A1 Yaoxi He
A1 Haiyi Lou
A1 Chaoying Cui
A1 Lian Deng
A1 Yang Gao
A1 Wangshan Zheng
A1 Yongbo Guo
A1 Xiaoji Wang
A1 Zhilin Ning
A1 Jun Li
A1 Bin Li
A1 Caijuan Bai
A1 Baimakangzhuo
A1 Gonggalanzi
A1 Dejiquzong
A1 Bianba
A1 Duojizhuoma
A1 Shiming Liu
A1 Tianyi Wu
A1 Shuhua Xu
A1 Xuebin Qi
A1 Bing Su
YR 2019
UL http://biorxiv.org/content/early/2019/09/02/753186.abstract
AB Structural variants (SVs) may play important roles in human adaption 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.