The functional impact of structural variation in humans

Abstract

Structural variation includes many different types of chromosomal rearrangement and encompasses millions of bases in every human genome. Over the past 3 years, the extent and complexity of structural variation has become better appreciated. Diverse approaches have been adopted to explore the functional impact of this class of variation. As disparate indications of the important biological consequences of genome dynamism are accumulating rapidly, we review the evidence that structural variation has an appreciable impact on cellular phenotypes, disease and human evolution.

Figure 1. Types of structural variant

Eight different types of structural variant are depicted, defined relative to the reference genome sequence

Figure 2. Influence of structural variation on gene regulation

A gene is represented by a set of exons (grey boxes), an enhancer (white box) and repressor (black box). Four general mechanisms by which a Structural Variant can impact upon gene expression are depicted. For each mechanism, an exemplar structural variant (in colour) is shown relative to the central reference gene structure.

Figure 3. Examples of evidence for selection on structural variants

(a) Selection might have favoured an APOBEC3 deletion, (b) an increase in AMY1 copy number in populations with a high starch diet (c) and an inversion polymorphism encompassing a number of genes, including MAPT and a truncated copy of NSF. The presence or absence of evidence for positive selection acting on each variant is summarised on the right hand side: an understanding of the relevant biological effect (Biol. effect), an increased number of offspring (Incr. offsp.), an unusually long haplotype (Long hap.), elevated population differentiation (Pop. Diff.), a skewed allele frequency spectrum (Freq. spec.) or an excess of functional changes (Funct. changes). A ‘-‘ indicates either that there was no evidence or that evidence was not sought.