The variation game: Cracking complex genetic disorders with NGS and omics data.

Tremendous advances in Next Generation Sequencing (NGS) and high-throughput omics methods have brought us one step closer towards mechanistic understanding of the complex disease at the molecular level. In this review, we discuss four basic regulatory mechanisms implicated in complex genetic diseases, such as cancer, neurological disorders, heart disease, diabetes, and many others. The mechanisms, including genetic variations, copy-number variations, posttranscriptional variations, and epigenetic variations, can be detected using a variety of NGS methods. We propose that malfunctions detected in these mechanisms are not necessarily independent, since these malfunctions are often found associated with the same disease and targeting the same gene, group of genes, or functional pathway. As an example, we discuss possible rewiring effects of the cancer-associated genetic, structural, and posttranscriptional variations on the protein-protein interaction (PPI) network centered around P53 protein. The review highlights multi-layered complexity of common genetic disorders and suggests that integration of NGS and omics data is a critical step in developing new computational methods capable of deciphering this complexity.