Tuuli Lappalainen
Assistant Professor
Department of Systems Biology
Columbia University Medical Center
Interpreting Functional Variation in Human Genomes by Transcriptome Sequencing
Detailed characterization of cellular effects of genetic variants is essential for understanding biological processes that underlie genetic associations to disease. One approach to address this challenge is to combine genomic data to a cellular phenotype, such as the transcriptome measured by RNA-sequencing. The early population-scale RNA-seq studies such as GEUVADIS are now being complemented by Genotype-Tissue Expression project (GTEx), where we are creating a comprehensive public atlas of genetic effects on the transcriptome across multiple human tissues. From these data, we have characterized common expression quantitative trait loci that associate to gene expression levels, providing a powerful tool to understand genetic architecture of regulatory variation and its role in GWAS associations. A systematic analysis of transcriptome effects of protein-coding loss-of-function SNPs and indels has led to better understanding of nonsense-mediated decay. Finally, transcriptome sequencing has allowed the first multi-tissue characterization of imprinted loci and their tissue-specificity. Altogether, our results demonstrate the power of integrating genome and transcriptome data in understanding genetic variants and its future potential in future medical and clinical applications.
