Mechanisms underlying structural variant formation in genomic disorders

By C. Carvalho, J. R. Lupski. Nature reviews genetics, 2016

675 citations recorded by the source corpus.

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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Citations in the corpus

The Sequence of 1504 Mutants in the Model Rice Variety Kitaake Facilitates Rapid Functional Genomic Studies (2017, background): “Structural variants (variants>1 kb) are known to be the cause of some human diseases, such as the well-known Down and Turner syndromes, and are associated with several cancers (Weischenfeldt et al., 2013; Carvalho and Lupski, 2016).”
Haplotype-resolved diverse human genomes and integrated analysis of structural variation (2021, background): “Additionally, 40% of insertions and 29% of deletions show blunt-ended breakpoints or microhomology (<50 bp flanking sequence identity), which is consistent with nonhomologous end joining, microhomology-mediated end joining, or microhomology-mediated break-induced replication (24).”
SVIM: structural variant identification using mapped long reads (2018, background): “The accurate detection of SVs is, besides their diversity, hampered by their association with repeat regions, biases in the sequencing technology and the additional complexity of diploidy (Carvalho and Lupski, 2016; Huddleston and Eichler, 2016; Willems et al., 2014).”
Exosomes maintain cellular homeostasis by excreting harmful DNA from cells (2017, unknown): “Thus, it is very likely that exosomal DNA fragments are generated by the conservative homologous recombination 55 that occurs preferentially in the late S, G2 and M phases of the cell-cycle in pre-senescent cells.”
Detection of mosaic and population-level structural variants with Sniffles2 (2024, unknown): “This allele is generated by a given pair of inverted LCRs telomeric to MECP2 being responsible for 20–30% of the MDS cases 6 , a fraction of which will lead to a more severe clinical phenotype.”
Piercing the dark matter: bioinformatics of long-range sequencing and mapping (2018, background): “Copy number variants (CNVs) are an important subtype of SVs formed by genomic deletions and duplications that have been implicated in several human diseases 65 .”
Structural variant calling: the long and the short of it (2019, background): “…(HR) that leads to an inactivation of BRCA1 and BRCA2 [17, 18]; (iii) gene fusions, such as Her2-positive SKBR3 breast cancer that combines multiple genes across chromosomes [19]; and (iv) alteration of the location of gene regulatory elements, causing changes in the gene expression [4, 20].”
Accurate detection of complex structural variations using single molecule sequencing (2017, unknown): “To establish the performance of NGMLR and Sniffles, we benchmarked them against widely used alternative approaches using simulated reads with SVs added of different sizes and types (Supplementary Notes 3, 4, & 5).”