Transcriptomic signatures across human tissues identify functional rare genetic variation

作者：N. Ferraro, B. Strober, Jonah Einson, Xin Li, F. Aguet, A. Barbeira, S. Castel, Joe R. Davis, A. Hilliard, Bence Kotis, Yoson Park, Alexandra J. Scott, Craig Smail, Emily K. Tsang, K. Ardlie, T. Assimes, Ira M. Hall, H. Im, T. Lappalainen, P. Mohammadi, S. Montgomery, A. Battle · 发表于：Science · 年份：2020 · DOI：10.1126/science.aaz5900 · 被引用次数：150 · 研究领域：Medicine、Biology

Outliers in the human transcriptome reveal the functional effects of rare genetic variants. The great seismic quiet period Every human genome contains tens of thousands of rare genetic variants—which include single nucleotide changes, insertions or deletions, and larger structural variants—and some may have a functional effect. Ferraro et al. examined data from individuals in the Genotype-Tissue Expression (GTEx) project for outliers across tissues caused by gene expression, splicing, and allele-specific expression. Single rare variants were observed that affected the expression and allele-specific expression of multiple genes and, in the case of a gene fusion event, splicing. Experimental and computational validation suggest that many individuals carry more than 50 rare variants that affect transcription in some way. Although most variants were predicted to not affect an individual's phenotype, a small percentage showed likely disease-related associations, emphasizing the importance of studying the impact of rare genetic variation on the transcriptome. Science, this issue p. eaaz5900 INTRODUCTION The human genome contains tens of thousands of rare (minor allele frequency <1%) variants, some of which contribute to disease risk. Using 838 samples with whole-genome and multitissue transcriptome sequencing data in the Genotype-Tissue Expression (GTEx) project version 8, we assessed how rare genetic variants contribute to extreme patterns in gene expression (eOutliers), allelic e...