Human-specific tandem repeat expansion and differential gene expression during primate evolution
Authors: Sulovari Arvis , Li Ruiyang , Audano Peter A. , Porubsky David , Vollger Mitchell R. , Logsdon Glennis A. ,   Human Genome Structural Variation Consortium, Warren Wesley C. , Pollen Alex A. , Chaisson Mark J. P. , Eichler Evan E. , Chaisson Mark J.P. , Sanders Ashley D. , Zhao Xuefang , Malhotra Ankit , Porubsky David , Rausch Tobias , Gardner Eugene J. , Rodriguez Oscar L. , Guo Li , Collins Ryan L. , Fan Xian , Wen Jia , Handsaker Robert E. , Fairley Susan , Kronenberg Zev N. , Kong Xiangmeng , Hormozdiari Fereydoun , Lee Dillon , Wenger Aaron M. , Hastie Alex R. , Antaki Danny , Anantharaman Thomas , Audano Peter A. , Brand Harrison , Cantsilieris Stuart , Cao Han , Cerveira Eliza , Chen Chong , Chen Xintong , Chin Chen-Shan , Chong Zechen , Chuang Nelson T. , Lambert Christine C. , Church Deanna M. , Clarke Laura , Farrell Andrew , Flores Joey , Galeey Timur , Gorkin David U. , Gujral Madhusudan , Guryev Victor , Heaton William Haynes , Korlach Jonas , Kumar Sushant , Kwon Jee Young , Lam Ernest T. , Lee Jong Eun , Lee Joyce , Lee Wan-Ping , Lee Sau Peng , Li Shantao , Marks Patrick , Viaud-Martinez Karine , Meiers Sascha , Munson Katherine M. , Navarro Fabio C.P. , Nelson Bradley J. , Nodzak Conor , Noor Amina , Kyriazopoulou-Panagiotopoulou Sofia , Pang Andy W.C. , Qiu Yunjiang , Rosanio Gabriel , Ryan Mallory , Stütz Adrian , Spierings Diana C.J. , Ward Alistair , Welch AnneMarie E. , Xiao Ming , Xu Wei , Zhang Chengsheng , Zhu Qihui , Zheng-Bradley Xiangqun , Lowy Ernesto , Yakneen Sergei , McCarroll Steven , Jun Goo , Ding Li , Koh Chong Lek , Ren Bing , Flicek Paul , Chen Ken , Gerstein Mark B. , Kwok Pui-Yan , Lansdorp Peter M. , Marth Gabor T. , Sebat Jonathan , Shi Xinghua , Bashir Ali , Ye Kai , Devine Scott E. , Talkowski Michael E. , Mills Ryan E. , Marschall Tobias , Korbel Jan O. , Eichler Evan E. , Lee Charles 
Published: October 2019

Short tandem repeats (STRs) and variable number tandem repeats (VNTRs) are important sources of natural and disease-causing variation, yet they have been problematic to resolve in reference genomes and genotype with short-read technology. We created a framework to model the evolution and instability of STRs and VNTRs in apes. We phased and assembled 3 ape genomes (chimpanzee, gorilla, and orangutan) using long-read and 10x Genomics linked-read sequence data for 21,442 human tandem repeats discovered in 6 haplotype-resolved assemblies of Yoruban, Chinese, and Puerto Rican origin. We define a set of 1,584 STRs/VNTRs expanded specifically in humans, including large tandem repeats affecting coding and noncoding portions of genes (e.g.,MUC3A,CACNA1C). We show that short interspersed nuclear element–VNTR–Alu(SVA) retrotransposition is the main mechanism for distributing GC-rich human-specific tandem repeat expansions throughout the genome but with a bias against genes. In contrast, we observe that VNTRs not originating from retrotransposons have a propensity to cluster near genes, especially in the subtelomere. Using tissue-specific expression from human and chimpanzee brains, we identify genes where transcript isoform usage differs significantly, likely caused by cryptic splicing variation within VNTRs. Using single-cell expression from cerebral organoids, we observe a strong effect for genes associated with transcription profiles analogous to intermediate progenitor cells. Finally, we compare the sequence composition of some of the largest human-specific repeat expansions and identify 52 STRs/VNTRs with at least 40 uninterrupted pure tracts as candidates for genetically unstable regions associated with disease.