Journal Article

Dosage sensitivity is a major determinant of human copy number variant pathogenicity

Rice, Alan M., McLysaght, Aoife

2017

Overview

Human copy number variants (CNVs) account for genome variation an order of magnitude larger than single-nucleotide polymorphisms. Although much of this variation has no phenotypic consequences, some variants have been associated with disease, in particular neurodevelopmental disorders. Pathogenic CNVs are typically very large and contain multiple genes, and understanding the cause of the pathogenicity remains a major challenge. Here we show that pathogenic CNVs are significantly enriched for genes involved in development and genes that have greater evolutionary copy number conservation across mammals, indicative of functional constraints. Conversely, genes found in benign CNV regions have more variable copy number. These evolutionary constraints are characteristic of genes in pathogenic CNVs and can only be explained by dosage sensitivity of those genes. These results implicate dosage sensitivity of individual genes as a common cause of CNV pathogenicity. These evolutionary metrics suggest a path to identifying disease genes in pathogenic CNVs. Copy number variants (CNVs) cause significant genomic variation in humans and may be benign or may cause disease. Here, the authors show that pathogenic CNVs are evolutionarily constrained compared with benign, pointing to dosage sensitivity as a potential cause of disease.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/181/2474 / 631/208/212 / Computational Biology - methods / Datasets as Topic / DNA Copy Number Variations - physiology / Evolution, Molecular / Gene Dosage - physiology / Genes / Genome, Human - physiology / Genomes / Genomics - methods / Humanities and Social Sciences / Humans / Hypotheses / multidisciplinary / Neurodevelopmental Disorders - genetics / Pathogens / Phenotype / Science / Science (multidisciplinary)