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Mechanisms underlying structural variant formation in genomic disorders

Key Points

  • Genomic disorders can be caused by diverse types of structural variants that are generated by different molecular mechanisms.

  • Genomic architectural features can stimulate the formation of 'simple' or 'complex' structural variants.

  • Nonrecurrent rearrangements are frequently associated with complex structural variants.

  • Repeated and repetitive genomic segments may be used in DNA repair, which can increase genomic instability through replication-based mechanisms (RBMs).

  • Iterative template switching during DNA synthesis can generate complex genomic rearrangements (CGRs). CGRs can be mistaken for simple rearrangements owing to technical challenges and the limited resolution capabilities of structural variant detection methods.

Abstract

With the recent burst of technological developments in genomics, and the clinical implementation of genome-wide assays, our understanding of the molecular basis of genomic disorders, specifically the contribution of structural variation to disease burden, is evolving quickly. Ongoing studies have revealed a ubiquitous role for genome architecture in the formation of structural variants at a given locus, both in DNA recombination-based processes and in replication-based processes. These reports showcase the influence of repeat sequences on genomic stability and structural variant complexity and also highlight the tremendous plasticity and dynamic nature of our genome in evolution, health and disease susceptibility.

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Figure 1: Schematic representation of recurrent and nonrecurrent genomic rearrangements observed in genomic disorders.
Figure 2: Nonallelic homologous recombination mechanism.
Figure 3: Replication-based mechanisms generate structural variants and single-nucleotide variants.
Figure 4: Template switches can generate distinct patterns of 'simple' or 'complex' structural variants.
Figure 5: Replication-based mechanisms are error prone.

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Acknowledgements

The authors thank C. R. Beck, S. Gu, P. Stankiewicz and P. J. Hastings for thoughtful comments and helpful discussions. The authors apologize to colleagues and the authors of relevant papers who could not be cited owing to space limitations. The research conducted by the authors was supported in part by the US National Institutes of Neurologic Disorders and Stroke (RO1NS058529), National Human Genome Research Institute/National Heart Blood Lung Institute jointly funded Baylor Hopkins Center for Mendelian Genomics (U54HG006542), National Institute of General Medical Sciences (RO1 GM106373), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (476217/2013-0) and the Young Investigator fellowship (Science without Borders Program) grant 402520/2012-2 to C.M.B.C. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS, NHGRI/NHBLI, NIGMS or NIH.

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Correspondence to James R. Lupski.

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Competing interests

J.R.L. holds stock ownership in 23andMe, Inc. and Lasergen, Inc., is a paid consultant for Regeneron Pharmaceuticals and is a co-inventor on multiple United States and European patents related to molecular diagnostics. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from molecular genetic testing offered in the Baylor-Miraca Medical Genetics Laboratories (BMGL; http://www.bcm.edu/geneticlabs/). J.R.L. is a member of the BMGL advisory board. C.M.B.C. has no competing interests.

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PowerPoint slides

Glossary

Genomic disorders

Conditions that result from rearrangements of the genome rather than base pair changes of DNA, and in which genomic instability results from the endogenous genome architecture.

Structural variants

Variants that include copy number variants and copy number neutral inversions, insertions and translocations in a personal genome compared with a reference genome.

Copy number variants

(CNVs). Alteration in copy number (gain or loss) of a locus resulting in deviation from the normal diploid state.

Single nucleotide variants

(SNVs). A single site in a DNA sequence that differs among individuals.

Chromothripsis

“Shattering of chromosomes”. A single catastrophic event affecting one chromosome and leading to complex rearrangements in cancer.

Absence of heterozygosity

(AOH). Refers to copy number neutral genomic segments that lack heterozygosity for assayed polymorphic markers.

Template switching

Refers to a transient dissociation of the primer and template followed by a re-association to a distinct template during DNA replication. It can occur within the same replication fork (short-distance template switch) or between distinct replication forks (long-distance template switch).

Array comparative genomic hybridization

(aCGH). Microarray-based technique that measures the relative copy number of DNA segments.

Replication-based mechanisms

(RBMs). Replicative non-homologous DNA repair mechanism of single-ended, double-stranded DNA (seDNA).

Rearrangement susceptibility

Regions of the genome prone to structural variation formation.

Mobile elements

A segment of DNA capable of moving into a new genomic position.

Paralogous sequences

Homologous sequences that arose by duplication.

Nonallelic homologous recombination

Nonallelic pairing of paralogous sequences and crossover leading to deletions, duplications and inversions.

Ectopic synapsis

Chromosomal homologue synapses at a nonallelic position.

Fosmid paired-end sequencing

A clone-based method to sequence the ends of fragments with a known size range.

Homeologous sequences

Imperfectly matched paralogous genomic segments.

Microhomologies

Short stretches of shared nucleotide identity present at the junctions of rearranged genomic segments.

Non-homologous end joining

(NHEJ). Double-stranded break (DSB) mechanism of repair that processes the broken DNA ends and joins non-homologous sequences. It repairs the programmed DSBs created in the immune system.

Break-induced replication

(BIR). Homologous recombination pathway that repairs single-ended double-stranded breaks (seDSBs) through the establishment of a unidirectional replication fork.

Microhomology-mediated break-induced replication

(MMBIR). RAD51-independent break-induced replication that relies on microhomology to resume replication.

Serial replication slippage

(SRS). Multiple rounds of slipped strand mispairing at the replication fork.

Fork stalling and template switching

(FoSTeS). Mechanism of template switching between different replication forks.

Chromoanasynthesis

Chromosome reconstitution or chromosome re-assortment. Constitutive complex rearrangements resulting from multiple template switches.

Microhomology-mediated end joining

(MMEJ). An alternative non-homologous end joining mechanism that repairs broken double-stranded breaks using sequence microhomology to join and stabilize DNA end intermediates.

Kataegis

Somatic single-nucleotide mutation clusters or mutation showers in cis.

Breakage–fusion–bridge (BFB) cycles

Processes by which sister chromatids that lack a telomere (breakage) can retrieve them by fusion and the creation of an unstable dicentric chromosome that will be pulled apart during anaphase (bridge). Eventually, the bridge breaks and the cycle starts again until the chromosome is stabilized.

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Carvalho, C., Lupski, J. Mechanisms underlying structural variant formation in genomic disorders. Nat Rev Genet 17, 224–238 (2016). https://doi.org/10.1038/nrg.2015.25

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