Human genomics. Effect of predicted protein-truncating genetic variants on the human transcriptome.

Rivas MA, Pirinen M, Conrad DF, Lek M, Tsang EK, Karczewski KJ, Maller JB, Kukurba KR, DeLuca DS, Fromer M, Ferreira PG, Smith KS, Zhang R, Zhao F, Banks E, Poplin R, Ruderfer DM, Purcell SM, Tukiainen T, Minikel EV, Stenson PD, Cooper DN, Huang KH, Sullivan TJ, Nedzel J, GTEx Consortium , Geuvadis Consortium , Bustamante CD, Li JB, Daly MJ, Guigo R, Donnelly P, Ardlie K, Sammeth M, Dermitzakis ET, McCarthy MI, Montgomery SB, Lappalainen T, MacArthur DG

Science 348 (6235) 666-669 [2015-05-08; online 2015-05-09]

Accurate prediction of the functional effect of genetic variation is critical for clinical genome interpretation. We systematically characterized the transcriptome effects of protein-truncating variants, a class of variants expected to have profound effects on gene function, using data from the Genotype-Tissue Expression (GTEx) and Geuvadis projects. We quantitated tissue-specific and positional effects on nonsense-mediated transcript decay and present an improved predictive model for this decay. We directly measured the effect of variants both proximal and distal to splice junctions. Furthermore, we found that robustness to heterozygous gene inactivation is not due to dosage compensation. Our results illustrate the value of transcriptome data in the functional interpretation of genetic variants.

NGI Uppsala (SNP&SEQ Technology Platform)

National Genomics Infrastructure

PubMed 25954003

DOI 10.1126/science.1261877

Crossref 10.1126/science.1261877

pii: 348/6235/666
pmc: PMC4537935
mid: NIHMS712687
dbGaP: phs000424.v3.p1
dbGaP: phs000424.v5.p1
dbGaP: phs000424.v6.p1