Poster Presentation Society for Molecular Biology and Evolution Conference 2016

Patterns of gene duplication and loss in the mammalian lineage mirror association with pathogenic CNVs in human (#427)

Alan M Rice 1 , Aoife McLysaght 1
  1. Trinity College Dublin, Dublin, DUBLIN, Ireland

Copy number variations (CNVs) account for genome variation an order of magnitude larger than single nucleotide polymorphisms. While much of this variation has no phenotypic consequences, some variants have been associated with neurodevelopmental disorders including autism, epilepsy, intellectual disability, and schizophrenia. Copy number changes of specific dosage-sensitive genes may be causative of this pathogenicity. To understand these disorders there is a need to identity causative genes, usually performed through case-control association studies. However, identifying specific causative copy number changes remains difficult given study size requirements to achieve the necessary power. Here we show that patterns of gene duplication and loss in the mammalian lineage are associated with human CNV pathogenicity. We found that pathogenic copy number alterations are significantly enriched for genes involved in development and that genes found on pathogenic CNVs have greater copy number conservation across mammals. Conversely, genes found in benign CNV regions have more variable copy number across the tested species, showing greater duplication frequency and more missing orthologs. These results demonstrate that population CNV trends translate to a reciprocal evolutionary pattern where pathogenic variations in copy number are sufficiently deleterious to be selected against. Whether specific genes are dosage-sensitive can be predicted by characteristic evolutionary patterns and hallmarks of selection. We anticipate that these evolutionary metrics will provide insights to regions of the genome of currently-unknown clinical significance. Furthermore, well-established pathogenic regions can be further refined at gene resolution.