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

Abstract

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.

Primate genome architecture influences structural variation mechanisms and functional consequences

“…Because NAHR-mediated SVs are usually larger in size, often intersect genes, and have been implicated in numerous genomic disorders (26,35), these results are relevant to the generation of evolutionary novelty by gene duplication and the formation of pathogenic SVs. The markedly increased number of segmental duplications observed in great ape genomes most likely contributes to the activity of NAHR in these species, implying a direct link between genomic architecture and SV formation mechanism landscapes (12).…”

“…Hence, a proportional relationship between fixed gene duplicate copy number and expression (34) seems to represent an exception rather than a rule. Instead, dosage compensatory mechanisms (6,33) or a lack of cis regulatory sequence context to enable gene duplicate expression in the tissue, where the parental gene is expressed (35,36), may explain the observed relationship between gene expression and gene copy number for whole-gene duplications.…”

Concurrent triplication and uniparental isodisomy: evidence for microhomology-mediated break-induced replication model for genomic rearrangements

“…It has been recently proposed that triplications evolve following one of a number of pathways including nonallelic homologous recombination (NAHR), break-induced replication (BIR), fork stalling and template switching (FoSTES) or microhomology-mediated BIR (MMBIR). [11][12][13][14][15] In contrast to triplication, CCRs typically involve multiple chromosomes with multiple breakpoints and are usually nonrecurrent. [16][17][18] The co-occurrence of an interstitial triplication contiguous distally with segmental isoUPD introduces a new level of complexity to our understanding of the cause, mechanism and phenotypic effect of chromosomal rearrangements.…”

Advances in Computer Simulation of Genome Evolution: Toward More Realistic Evolutionary Genomics Analysis by Approximate Bayesian Computation

“…For example, it can be used to identify local evolutionary processes such as selection regimens (which can vary among genomic regions), to allow ortholog prediction in the presence of events such as LGT, or to improve current methods of gene/species tree reconciliation (e.g., Dalquen et al 2012). Moreover, genomic events can play a significant role in molecular adaptation and speciation phenomena (e.g., Lawrence 1999;Barrick et al 2009), and they have also been associated with genetic diseases (Weischenfeldt et al 2013).…”