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

作　　者：Ouzhuluobu Yaoxi He Haiyi Lou Chaoying Cui Lian Deng Yang Gao Wangshan Zheng Yongbo Guo Xiaoji Wang Zhilin Ning Jun Li Bin Li Caijuan Bai Baimakangzhuo Gonggalanzi Dejiquzong Bianba Duojizhuoma Shiming Liu Tianyi Wu Shuhua Xu Xuebin Qi Bing Su 

机构地区：[1]High Altitude Medical Research Center.School of Medicine,Tibetan University,Lhasa 850000.China [2]State Key Laboratory of Genetic Resources and Evolution,Kunming Institute of Zoology.Chinese Academy of Sciences.Kunming 650223,China [3]Chinese Academy of Sciences Key Laboratory of Computational Biology,CAS-MP6 Partner Institute for Computational Biology,Shanghai Institute of Nutrition and Health,Shanghai Institutes for Biological Sciences,University of Chinese Academy of Sciences,Shanghai 200031,China [4]Center for Excellence in Animal Evolution and Genetics.Chinese Academy of Sciences,Kunming 650223,China [5]Fukang Obstetrics.Gynecology and Children Branch Hospital,Tibetan Fukang Hospital,Lhasa 850000,China [6]Center for Disease Control,Tibet Autonomous Region.Lhasa 850000,China [7]National Key Laboratory of High Altitude Medicine,High Altitude Medical Research Institute.Xining 810012,China [8]School of Life Science and Technology,Shanghai Tech University,Shanghai 201210.China [9]Collaborative Innovation Center of Genetics and Development.Shanghai 200438,China [10]Kunming College of Life Science,University of Chinese Academy of Sciences,Beijing 100101,China

出　　处：《National Science Review》2020年第2期391-402,共12页国家科学评论（英文版）

基　　金：supported jointly and equally by grants from the National Natural Science Foundation of China(NSFC)(31621062 to B.S.);the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA20040102 to X.Q.;XDB13000000 to B.S.and S.X.);grants from the NSFC(91631306 to B.S.;31671329to X.Q.;91731303,31525014,31771388 and 31711530221 to S.X.;31460287 and 31660308 to Ou.;31601046 and 31871256to H.L.;31900418 to L.D.);the National Key Research and Development Program of China(2016YFC0906403 to S.X.;2012CB518202 to T.W.);the Program of Shanghai Academic Research Leader(16XD1404700 to S.X.);Shanghai Municipal Science and Technology Major Project(2017SHZDZX01 to S.X.);the UK Royal Society-Newton Advanced Fellowship(NAF\R1\191094 to S.X.);the Science and Technology Commission of Shanghai Municipality(16YF1413900 to H.L.;19YF1455200 to L.D.);the State Key Laboratory of Genetic Resources and Evolution(GREKF17-05 to J.L.);the Provincial Natural Science Foundation of the Tibetan Autonomous Region(XZ2018ZR G-130 to J.L.);Tibetan Fukang Hospital grant(2017-04 to J.L.).

摘　　要：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 detected17 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-a662-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.

关 键 词：long-read sequencing TIBETAN structural VARIANTS genetic ADAPTATION reference GENOME 

分 类 号：Q987[生物学—遗传学]