Human-specific tandem repeat expansion and differential gene expression during primate evolution

Item Type:	Article
Title:	Human-specific tandem repeat expansion and differential gene expression during primate evolution
Creators Name:	Sulovari, A. and Li, R. and Audano, P.A. and Porubsky, D. and Vollger, M.R. and Logsdon, G.A. and Warren, W.C. and Pollen, A.A. and Chaisson, M.J.P. and Eichler, E.E.
Abstract:	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.
Keywords:	Tandem Repeat, STR, VNTR, Tandem Repeat Expansion, Genome Instability, Animals, Primates
Source:	Proceedings of the National Academy of Sciences of the United States of America
ISSN:	0027-8424
Publisher:	National Academy of Sciences
Volume:	116
Number:	46
Page Range:	23243-23253
Date:	12 November 2019
Additional Information:	Ashley D. Sanders is a member of the The Human Genome Structural Variation Consortium. - Copyright © 2019. Published under the PNAS license.
Official Publication:	https://doi.org/10.1073/pnas.1912175116
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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