A Sparse Learning Framework for Joint Effect Analysis of Copy Number Variants

Copy number variants (CNVs), including large deletions and duplications, represent an unbalanced change of DNA segments. Abundant in human genomes, CNVs contribute to a large proportion of human genetic diversity, with impact on many human phenotypes. Although recent advances in genetic studies have shed light on the impact of individual CNVs on different traits, the analysis of joint effect of multiple interactive CNVs lags behind from many perspectives. A primary reason is that the large number of CNV combinations and interactions in the human genome make it computationally challenging to perform such joint analysis. To address this challenge, we developed a novel sparse learning framework that combines sparse learning with biological networks to identify interacting CNVs with joint effect on particular traits. We showed that our approach performs well in identifying CNVs with joint phenotypic effect using simulated data. Applied to a real human genomic dataset from the 1,000 Genomes Project, our approach identified multiple CNVs that collectively contribute to population differentiation. We found a set of multiple CNVs that have joint effect in different populations, and affect gene expression differently in distinct populations. These results provided a collection of CNVs that likely have downstream biomedical implications in individuals from diverse population backgrounds.