Phenotypic impact of genomic structural variation: insights from and for human disease

Key Points Recent technological advances in array and sequencing approaches are starting to revolutionize our ability to identify structural variants underlying complex phenotypes. Structural variants are now being associated with an increasing number of normal phenotypic variations, as well as common and rare human diseases. Changes in copy number of genes are overall accompanied by similar changes in mRNA expression, although regulatory mechanisms such as epistasis and autoregulatory feedback mechanisms can buffer against such copy-number changes. Structural variants that are associated with complex phenotypes, such as autism or schizophrenia, can affect both regions associated with variable phenotypes and loci associated with Mendelian disease, which often cause more 'hard-wired' phenotypes. Mice are excellent model systems for delineating the phenotypic consequences of structural variants, owing to their high physiological similarity to (and extensive synteny with) humans, and the availability of advanced genetic tools. They can also be used to analyse developmental, cell-type-specific or tissue-specific phenotypes. Novel integrative approaches, including the use of induced pluripotent stem cells (iPSCs), animal models and computational approaches, will enable the delineation of complex disease phenotypes that are caused by rare de novo structural variants with cell-type-specific effects. With the increased cataloguing of human structural variants, our understanding of their influence on phenotype is ever improving. Here, the influence of structural variants on phenotypes including disease is discussed, and strategies for further characterization are presented. Genomic structural variants have long been implicated in phenotypic diversity and human disease, but dissecting the mechanisms by which they exert their functional impact has proven elusive. Recently however, developments in high-throughput DNA sequencing and chromosomal engineering technology have facilitated the analysis of structural variants in human populations and model systems in unprecedented detail. In this Review, we describe how structural variants can affect molecular and cellular processes, leading to complex organismal phenotypes, including human disease. We further present advances in delineating disease-causing elements that are affected by structural variants, and we discuss future directions for research on the functional consequences of structural variants.