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.
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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Lupski, J. R. Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet. 14, 417–422 (1998).
Zhang, F., Gu, W., Hurles, M. E. & Lupski, J. R. Copy number variation in human health, disease, and evolution. Annu. Rev. Genom. Hum. Genet. 10, 451–481 (2009).
Mills, R. E. et al. An initial map of insertion and deletion (INDEL) variation in the human genome. Genome Res. 16, 1182–1190 (2006).
Sakofsky, C. J. et al. Break-induced replication is a source of mutation clusters underlying kataegis. Cell Rep. 7, 1640–1648 (2014).
Costantino, L. et al. Break-induced replication repair of damaged forks induces genomic duplications in human cells. Science 343, 88–91 (2014).
Zhang, F. et al. The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans. Nat. Genet. 41, 849–853 (2009).
Carvalho, C. M. et al. Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome. Nat. Genet. 43, 1074–1081 (2011).
Liu, P. et al. Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. Cell. 146, 889–903 (2011). Very complex rearrangements with multiple template switches can be formed constitutively in a one-off event by RBM that is reminiscent of the chromothripsis events that were first described in cancer.
Kloosterman, W. P. et al. Constitutional chromothripsis rearrangements involve clustered double-stranded DNA breaks and nonhomologous repair mechanisms. Cell Rep. 1, 648–655 (2012).
Carvalho, C. M. et al. Replicative mechanisms for CNV formation are error prone. Nat. Genet. 45, 1319–1326 (2013). This work revealed how apparently simple structural variants can actually be highly complex and the complexity revealed by applying multiple experimental techniques to deduce structure and understand the resultant end product of mutation. An unexpectedly high mutational spectrum represented by both SNVs and template switches can be detected in up to 52% of the CNVs at the locus studied.
Carvalho, C. M. et al. Absence of heterozygosity due to template switching during replicative rearrangements. Am. J. Hum. Genet. 96, 555–564 (2015). CNVs generated post-zygotically by replication-based mechanisms can produce triplications that are associated with inversion and long regions of AOH. The importance of this observation relies on the potential implication for human diseases that may include not only dosage-sensitive genes but also unmasking of recessive traits due to the extensive AOH, distorting transmission genetics leading to disease in a family with only a single carrier parent, as well as imprinting disease due to the presence of uniparental disomy (UPD).
Sahoo, T. et al. Concurrent triplication and uniparental isodisomy: evidence for microhomology-mediated break-induced replication model for genomic rearrangements. Eur. J. Hum. Genet. 23, 61–66 (2015).
Wang, Y. et al. Characterization of 26 deletion CNVs reveals the frequent occurrence of micro-mutations within the breakpoint-flanking regions and frequent repair of double-strand breaks by templated insertions derived from remote genomic regions. Hum. Genet. 134, 589–603 (2015).
Coe, B. P. et al. Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nat. Genet. 46, 1063–1071 (2014).
Sudmant, P. H. et al. An integrated map of structural variation in 2,504 human genomes. Nature 526, 75–81 (2015).
Gheldof, N. et al. Structural variation-associated expression changes are paralleled by chromatin architecture modifications. PLoS ONE 8, e79973 (2013).
Ricard, G. et al. Phenotypic consequences of copy number variation: insights from Smith-Magenis and Potocki-Lupski syndrome mouse models. PLoS Biol. 8, e1000543 (2010).
Lupianez, D. G. et al. Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell 161, 1012–1025 (2015).
Campbell, I. M., Shaw, C. A., Stankiewicz, P. & Lupski, J. R. Somatic mosaicism: implications for disease and transmission genetics. Trends Genet. 31, 382–392 (2015).
Weischenfeldt, J., Symmons, O., Spitz, F. & Korbel, J. O. Phenotypic impact of genomic structural variation: insights from and for human disease. Nat. Rev. Genet. 14, 125–138 (2013).
Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).
Bailey, J. A. et al. Recent segmental duplications in the human genome. Science 297, 1003–1007 (2002).
Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525–528 (2004).
Sharp, A. J. et al. Segmental duplications and copy-number variation in the human genome. Am. J. Hum. Genet. 77, 78–88 (2005).
Kurotaki, N., Stankiewicz, P., Wakui, K., Niikawa, N. & Lupski, J. R. Sotos syndrome common deletion is mediated by directly oriented subunits within inverted Sos-REP low-copy repeats. Hum. Mol. Genet. 14, 535–542 (2005).
Park, S. S. et al. Structure and evolution of the Smith-Magenis syndrome repeat gene clusters, SMS-REPs. Genome Res. 12, 729–738 (2002).
Jiang, Z. et al. Ancestral reconstruction of segmental duplications reveals punctuated cores of human genome evolution. Nat. Genet. 39, 1361–1368 (2007).
Dittwald, P. et al. NAHR-mediated copy-number variants in a clinical population: mechanistic insights into both genomic disorders and Mendelizing traits. Genome Res. 23, 1395–1409 (2013).
Linardopoulou, E. V. et al. Human subtelomeres are hot spots of interchromosomal recombination and segmental duplication. Nature 437, 94–100 (2005).
Stankiewicz, P. & Lupski, J. R. Genome architecture, rearrangements and genomic disorders. Trends Genet. 18, 74–82 (2002).
Sharp, A. J. et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat. Genet. 38, 1038–1042 (2006). The authors apply the conceptual mechanistic understanding of NAHR to predict genomic instability regions and define five novel genomic disorders. This article provides evidence that comprehending the rules underlying structural variation formation in the human genome is important and provides insights enabling predictions of rearrangement-prone genomic regions.
Nathans, J., Piantanida, T. P., Eddy, R. L., Shows, T. B. & Hogness, D. S. Molecular genetics of inherited variation in human color vision. Science 232, 203–210 (1986).
Beck, C. R. et al. Complex genomic rearrangements at the PLP1 locus include triplication and quadruplication. PLoS Genet. 11, e1005050 (2015).
Beri, S., Bonaglia, M. C. & Giorda, R. Low-copy repeats at the human VIPR2 gene predispose to recurrent and nonrecurrent rearrangements. Eur. J. Hum. Genet. 21, 757–761 (2013).
Ishmukhametova, A. et al. Dissecting the structure and mechanism of a complex duplication-triplication rearrangement in the DMD gene. Hum. Mutat. 34, 1080–1084 (2013).
Soler-Alfonso, C. et al. CHRNA7 triplication associated with cognitive impairment and neuropsychiatric phenotypes in a three-generation pedigree. Eur. J. Hum. Genet. 22, 1071–1076 (2014).
Gu, S. et al. Alu-mediated diverse and complex pathogenic copy-number variants within human chromosome 17 at p13.3. Hum. Mol. Genet. 24, 4061–4077 (2015).
Bauters, M. et al. Nonrecurrent MECP2 duplications mediated by genomic architecture-driven DNA breaks and break-induced replication repair. Genome Res. 18, 847–858 (2008).
Carvalho, C. M. et al. Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching. Hum. Mol. Genet. 18, 2188–2203 (2009).
Inoue, K. et al. Genomic rearrangements resulting in PLP1 deletion occur by nonhomologous end joining and cause different dysmyelinating phenotypes in males and females. Am. J. Hum. Genet. 71, 838–853 (2002).
Small, K. & Warren, S. T. Emerin deletions occurring on both Xq28 inversion backgrounds. Hum. Mol. Genet. 7, 135–139 (1998).
Woodward, K. J. et al. Heterogeneous duplications in patients with Pelizaeus-Merzbacher disease suggest a mechanism of coupled homologous and nonhomologous recombination. Am. J. Hum. Genet. 77, 966–987 (2005).
Boone, P. M. et al. The Alu-rich genomic architecture of SPAST predisposes to diverse and functionally distinct disease-associated CNV alleles. Am. J. Hum. Genet. 95, 143–161 (2014).
Stankiewicz, P. et al. Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. Am. J. Hum. Genet. 84, 780–791 (2009).
Vissers, L. E. et al. Rare pathogenic microdeletions and tandem duplications are microhomology-mediated and stimulated by local genomic architecture. Hum. Mol. Genet. 18, 3579–3593 (2009).
Liu, P. et al. Frequency of nonallelic homologous recombination is correlated with length of homology: evidence that ectopic synapsis precedes ectopic crossing-over. Am. J. Hum. Genet. 89, 580–588 (2011).
Lichten, M., Borts, R. H. & Haber, J. E. Meiotic gene conversion and crossing over between dispersed homologous sequences occurs frequently in Saccharomyces cerevisiae. Genetics 115, 233–246 (1987).
McKusick, V. A. Human genetics. Annu. Rev. Genet. 4, 1–46 (1970).
Vissers, L. E. & Stankiewicz, P. Microdeletion and microduplication syndromes. Methods Mol. Biol. 838, 29–75 (2012).
Liu, P. et al. Mechanism, prevalence, and more severe neuropathy phenotype of the Charcot-Marie-Tooth type 1A triplication. Am. J. Hum. Genet. 94, 462–469 (2014).
Ou, Z. et al. Observation and prediction of recurrent human translocations mediated by NAHR between nonhomologous chromosomes. Genome Res. 21, 33–46 (2011).
Robberecht, C., Voet, T., Zamani Esteki, M., Nowakowska, B. A. & Vermeesch, J. R. Nonallelic homologous recombination between retrotransposable elements is a driver of de novo unbalanced translocations. Genome Res. 23, 411–418 (2013).
Dittwald, P. et al. Inverted low-copy repeats and genome instability—a genome-wide analysis. Hum. Mutat. 34, 210–220 (2013).
Golzio, C. & Katsanis, N. Genetic architecture of reciprocal CNVs. Curr. Opin. Genet. Dev. 23, 240–248 (2013).
Turner, D. J. et al. Germline rates of de novo meiotic deletions and duplications causing several genomic disorders. Nat. Genet. 40, 90–95 (2008). In this paper the authors calculate the locus-specific ratio of deletions and duplications by NAHR in male meiosis. The observed higher ratio of deletions versus duplications, 2/1 for autosomes, correlates well with theoretical predictions.
Myers, S., Freeman, C., Auton, A., Donnelly, P. & McVean, G. A common sequence motif associated with recombination hot spots and genome instability in humans. Nat. Genet. 40, 1124–1129 (2008).
Berg, I. L. et al. PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability in humans. Nat. Genet. 42, 859–863 (2010). Variation within the genomic structure of PRDM9 was reported to correlate with the frequency of meiotic recombination in individuals, providing direct evidence for PRDM9 involvement in HR.
Zhang, F. et al. Identification of uncommon recurrent Potocki-Lupski syndrome-associated duplications and the distribution of rearrangement types and mechanisms in PTLS. Am. J. Hum. Genet. 86, 462–470 (2010).
Cooper, G. M. et al. A copy number variation morbidity map of developmental delay. Nat. Genet. 43, 838–846 (2011).
Lam, K. W. & Jeffreys, A. J. Processes of de novo duplication of human alpha-globin genes. Proc. Natl Acad. Sci. USA 104, 10950–10955 (2007).
MacArthur, J. A. et al. The rate of nonallelic homologous recombination in males is highly variable, correlated between monozygotic twins and independent of age. PLoS Genet. 10, e1004195 (2014).
Flores, M. et al. Recurrent DNA inversion rearrangements in the human genome. Proc. Natl Acad. Sci. USA 104, 6099–6106 (2007).
Kidd, J. M. et al. Mapping and sequencing of structural variation from eight human genomes. Nature 453, 56–64 (2008).
Waldman, A. S. & Liskay, R. M. Dependence of intrachromosomal recombination in mammalian cells on uninterrupted homology. Mol. Cell. Biol. 8, 5350–5357 (1988).
Sun, C. et al. Deletion of azoospermia factor a (AZFa) region of human Y chromosome caused by recombination between HERV15 proviruses. Hum. Mol. Genet. 9, 2291–2296 (2000).
Shuvarikov, A. et al. Recurrent HERV-H-mediated 3q13.2-q13.31 deletions cause a syndrome of hypotonia and motor, language, and cognitive delays. Hum. Mutat. 34, 1415–1423 (2013).
Campbell, I. M. et al. Human endogenous retroviral elements promote genome instability via non-allelic homologous recombination. BMC Biol. 12, 74 (2014).
Steinmann, K. et al. Type 2 NF1 deletions are highly unusual by virtue of the absence of nonallelic homologous recombination hotspots and an apparent preference for female mitotic recombination. Am. J. Hum. Genet. 81, 1201–1220 (2007).
Lam, K. W. & Jeffreys, A. J. Processes of copy-number change in human DNA: the dynamics of α-globin gene deletion. Proc. Natl Acad. Sci. USA 103, 8921–8927 (2006).
Mezard, C., Pompon, D. & Nicolas, A. Recombination between similar but not identical DNA sequences during yeast transformation occurs within short stretches of identity. Cell 70, 659–670 (1992).
Callinan, P. A. & Batzer, M. A. Retrotransposable elements and human disease. Genome Dyn. 1, 104–115 (2006).
Boone, P. M. et al. Alu-specific microhomology-mediated deletion of the final exon of SPAST in three unrelated subjects with hereditary spastic paraplegia. Genet. Med. 13, 582–592 (2011).
Hsiao, M. C. et al. Decoding NF1 intragenic copy-number variations. Am. J. Hum. Genet. 97, 238–249 (2015).
Deininger, P. L. & Batzer, M. A. Alu repeats and human disease. Mol. Genet. Metab. 67, 183–193 (1999).
Stankiewicz, P., Pursley, A. N. & Cheung, S. W. Challenges in clinical interpretation of microduplications detected by array CGH analysis. Am. J. Med. Genet. A 152A, 1089–1100 (2010).
Ottaviani, D., LeCain, M. & Sheer, D. The role of microhomology in genomic structural variation. Trends Genet. 30, 85–94 (2014).
Lee, J. A., Carvalho, C. M. & Lupski, J. R. A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131, 1235–1247 (2007). Long-range template switching leading to complex genomic rearrangements and causing disease was reported. Fork stalling and template switching mechanisms were proposed for the first time to explain the observed unusual breakpoint complexity.
Hastings, P. J., Lupski, J. R., Rosenberg, S. M. & Ira, G. Mechanisms of change in gene copy number. Nat. Rev. Genet. 10, 551–564 (2009).
Pannunzio, N. R., Li, S., Watanabe, G. & Lieber, M. R. Non-homologous end joining often uses microhomology: implications for alternative end joining. DNA Repair (Amst.) 17, 74–80 (2014).
Liu, P., Carvalho, C. M., Hastings, P. J. & Lupski, J. R. Mechanisms for recurrent and complex human genomic rearrangements. Curr. Opin. Genet. Dev. 22, 211–220 (2012).
Slack, A., Thornton, P. C., Magner, D. B., Rosenberg, S. M. & Hastings, P. J. On the mechanism of gene amplification induced under stress in Escherichia coli. PLoS Genet. 2, e48 (2006).
Chen, J. M., Chuzhanova, N., Stenson, P. D., Ferec, C. & Cooper, D. N. Complex gene rearrangements caused by serial replication slippage. Hum. Mutat. 26, 125–134 (2005).
Stephens, P. J. et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell. 144, 27–40 (2011). Chromothripsis was defined and recognized as a one-off event in cancer.
Malkova, A., Ivanov, E. L. & Haber, J. E. Double-strand break repair in the absence of RAD51 in yeast: a possible role for break-induced DNA replication. Proc. Natl Acad. Sci. USA 93, 7131–7136 (1996).
Morrow, D. M., Connelly, C. & Hieter, P. “Break copy” duplication: a model for chromosome fragment formation in Saccharomyces cerevisiae. Genetics 147, 371–382 (1997).
Malkova, A. & Ira, G. Break-induced replication: functions and molecular mechanism. Curr. Opin. Genet. Dev. 23, 271–279 (2013).
Lydeard, J. R., Jain, S., Yamaguchi, M. & Haber, J. E. Break-induced replication and telomerase-independent telomere maintenance require Pol32. Nature 448, 820–823 (2007).
Lydeard, J. R. et al. Break-induced replication requires all essential DNA replication factors except those specific for pre-RC assembly. Genes Dev. 24, 1133–1144 (2010).
Payen, C., Koszul, R., Dujon, B. & Fischer, G. Segmental duplications arise from Pol32-dependent repair of broken forks through two alternative replication-based mechanisms. PLoS Genet. 4, e1000175 (2008). This paper shows that segmental duplications are formed due to DNA synthesis rather than to ectopic homologous recombination and that the underlying mechanism is dependent on the nonessential Polδ subunit, Pol32.
Arlt, M. F., Rajendran, S., Birkeland, S. R., Wilson, T. E. & Glover, T. W. De novo CNV formation in mouse embryonic stem cells occurs in the absence of Xrcc4-dependent nonhomologous end joining. PLoS Genet. 8, e1002981 (2012).
Ira, G. & Haber, J. E. Characterization of RAD51-independent break-induced replication that acts preferentially with short homologous sequences. Mol. Cell. Biol. 22, 6384–6392 (2002).
Hastings, P. J., Ira, G. & Lupski, J. R. A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genet. 5, e1000327 (2009).
Chen, J. M., Chuzhanova, N., Stenson, P. D., Ferec, C. & Cooper, D. N. Meta-analysis of gross insertions causing human genetic disease: novel mutational mechanisms and the role of replication slippage. Hum. Mutat. 25, 207–221 (2005).
Smith, C. E., Llorente, B. & Symington, L. S. Template switching during break-induced replication. Nature 447, 102–105 (2007). Another important aspect of the mutagenic nature of BIR was revealed in this work. BIR can undergo multiple rounds of template switching during DSB repair; dispersed repetitive sequences were observed to lead to non-reciprocal translocations.
Tsaponina, O. & Haber, J. E. Frequent interchromosomal template switches during gene conversion in S. cerevisiae. Mol. Cell 55, 615–625 (2014).
Iraqui, I. et al. Recovery of arrested replication forks by homologous recombination is error-prone. PLoS Genet. 8, e1002976 (2012).
Sun, Z. et al. Replicative mechanisms of CNV formation preferentially occur as intrachromosomal events: evidence from Potocki-Lupski duplication syndrome. Hum. Mol. Genet. 22, 749–756 (2013).
Zhang, F., Carvalho, C. M. & Lupski, J. R. Complex human chromosomal and genomic rearrangements. Trends Genet. 25, 298–307 (2009).
Chanda, B. et al. A novel mechanistic spectrum underlies glaucoma-associated chromosome 6p25 copy number variation. Hum. Mol. Genet. 17, 3446–3458 (2008).
Chauvin, A. et al. Elucidation of the complex structure and origin of the human trypsinogen locus triplication. Hum. Mol. Genet. 18, 3605–3614 (2009).
Coccia, M. et al. X-linked cataract and Nance-Horan syndrome are allelic disorders. Hum. Mol. Genet. 18, 2643–2655 (2009).
Giorgio, E. et al. Analysis of LMNB1 duplications in autosomal dominant leukodystrophy provides insights into duplication mechanisms and allele-specific expression. Hum. Mutat. 34, 1160–1171 (2013).
Rugless, M. J. et al. A large deletion in the human α-globin cluster caused by a replication error is associated with an unexpectedly mild phenotype. Hum. Mol. Genet. 17, 3084–3093 (2008).
Bi, W. et al. Increased LIS1 expression affects human and mouse brain development. Nat. Genet. 41, 168–177 (2009).
Liu, P. et al. Copy number gain at Xp22.31 includes complex duplication rearrangements and recurrent triplications. Hum. Mol. Genet. 20, 1975–1988 (2011).
Abyzov, A. et al. Analysis of deletion breakpoints from 1,092 humans reveals details of mutation mechanisms. Nat. Commun. 6, 7256 (2015).
Deem, A. et al. Break-induced replication is highly inaccurate. PLoS Biol. 9, e1000594 (2011). The mutagenic nature of BIR was shown in this yeast system; Polδ was shown to contribute in part to these errors.
Yousefzadeh, M. J. et al. Mechanism of suppression of chromosomal instability by DNA polymerase POLQ. PLoS Genet. 10, e1004654 (2014).
Northam, M. R., Garg, P., Baitin, D. M., Burgers, P. M. & Shcherbakova, P. V. A novel function of DNA polymerase ζ regulated by PCNA. EMBO J. 25, 4316–4325 (2006).
Cherng, N. et al. Expansions, contractions, and fragility of the spinocerebellar ataxia type 10 pentanucleotide repeat in yeast. Proc. Natl Acad. Sci. USA 108, 2843–2848 (2011).
Sakofsky, C. J. et al. Translesion polymerases drive microhomology-mediated break induced replication leading to complex chromosomal rearrangements. Mol. Cell 60, 860–872 (2015).
Nik-Zainal, S. et al. Mutational processes molding the genomes of 21 breast cancers. Cell. 149, 979–993 (2012). Kataegis, the phenomenon of localized hypermutational segments in cis , was defined in cancer.
Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).
Chung, W. H., Zhu, Z., Papusha, A., Malkova, A. & Ira, G. Defective resection at DNA double-strand breaks leads to de novo telomere formation and enhances gene targeting. PLoS Genet. 6, e1000948 (2010).
Wilson, M. A. et al. Pif1 helicase and Polδ promote recombination-coupled DNA synthesis via bubble migration. Nature 502, 393–396 (2013).
Saini, N. et al. Migrating bubble during break-induced replication drives conservative DNA synthesis. Nature 502, 389–392 (2013).
Donnianni, R. A. & Symington, L. S. Break-induced replication occurs by conservative DNA synthesis. Proc. Natl Acad. Sci. USA 110, 13475–13480 (2013).
Mayle, R. et al. Mus81 and converging forks limit the mutagenicity of replication fork breakage. Science 349, 742–747 (2015). Endonuclease Mus81 was shown to limit the mutagenic synthesis associated with BIR during DNA repair. It also inhibits template switches between interspersed homeologous repeats, including human Alu. This work importantly adds to our understanding of how genomic architecture contributes to increased instability and which factors have evolved to avoid this.
Bacolla, A. et al. Breakpoints of gross deletions coincide with non-B DNA conformations. Proc. Natl Acad. Sci. USA 101, 14162–14167 (2004).
Chen, J. M., Chuzhanova, N., Stenson, P. D., Ferec, C. & Cooper, D. N. Intrachromosomal serial replication slippage in trans gives rise to diverse genomic rearrangements involving inversions. Hum. Mutat. 26, 362–373 (2005).
Bose, P., Hermetz, K. E., Conneely, K. N. & Rudd, M. K. Tandem repeats and G-rich sequences are enriched at human CNV breakpoints. PLoS ONE 9, e101607 (2014).
Walsh, E., Wang, X., Lee, M. Y. & Eckert, K. A. Mechanism of replicative DNA polymerase delta pausing and a potential role for DNA polymerase kappa in common fragile site replication. J. Mol. Biol. 425, 232–243 (2013).
Northam, M. R. et al. DNA polymerases ζ and Rev1 mediate error-prone bypass of non-B DNA structures. Nucleic Acids Res. 42, 290–306 (2014).
Koren, A. et al. Differential relationship of DNA replication timing to different forms of human mutation and variation. Am. J. Hum. Genet. 91, 1033–1040 (2012).
Chen, L. et al. CNV instability associated with DNA replication dynamics: evidence for replicative mechanisms in CNV mutagenesis. Hum. Mol. Genet. 24, 1574–1583 (2015).
Anand, R. P. et al. Chromosome rearrangements via template switching between diverged repeated sequences. Genes Dev. 28, 2394–2406 (2014).
Korbel, J. O. et al. Paired-end mapping reveals extensive structural variation in the human genome. Science 318, 420–426 (2007).
Kidd, J. M. et al. A human genome structural variation sequencing resource reveals insights into mutational mechanisms. Cell 143, 837–847 (2010).
Lam, H. Y. et al. Nucleotide-resolution analysis of structural variants using BreakSeq and a breakpoint library. Nat. Biotechnol. 28, 47–55 (2010).
Shimojima, K. et al. Pelizaeus-Merzbacher disease caused by a duplication-inverted triplication-duplication in chromosomal segments including the PLP1 region. Eur. J. Med. Genet. 55, 400–403 (2012).
del Gaudio, D. et al. Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males. Genet. Med. 8, 784–792 (2006).
Wolf, N. I. et al. Three or more copies of the proteolipid protein gene PLP1 cause severe elizaeus–Merzbacher disease. Brain 128, 743–751 (2005).
McClintock, B. The behavior in successive nuclear divisions of a chromosome broken at meiosis. Proc. Natl Acad. Sci. USA 25, 405–416 (1939).
McClintock, B. The stability of broken ends of chromosomes in Zea Mays. Genetics 26, 234–282 (1941).
Zuffardi, O., Bonaglia, M., Ciccone, R. & Giorda, R. Inverted duplications deletions: underdiagnosed rearrangements?? Clin. Genet. 75, 505–513 (2009).
Hannes, F. et al. Telomere healing following DNA polymerase arrest-induced breakages is likely the main mechanism generating chromosome 4p terminal deletions. Hum. Mutat. 31, 1343–1351 (2010).
Ghezraoui, H. et al. Chromosomal translocations in human cells are generated by canonical nonhomologous end-joining. Mol. Cell 55, 829–842 (2014).
Ballif, B. C., Yu, W., Shaw, C. A., Kashork, C. D. & Shaffer, L. G. Monosomy 1p36 breakpoint junctions suggest pre-meiotic breakage-fusion-bridge cycles are involved in generating terminal deletions. Hum. Mol. Genet. 12, 2153–2165 (2003).
Luo, Y. et al. Diverse mutational mechanisms cause pathogenic subtelomeric rearrangements. Hum. Mol. Genet. 20, 3769–3778 (2011).
Yatsenko, S. A. et al. Human subtelomeric copy number gains suggest a DNA replication mechanism for formation: beyond breakage-fusion-bridge for telomere stabilization. Hum. Genet. 131, 1895–1910 (2012).
Lowden, M. R., Flibotte, S., Moerman, D. G. & Ahmed, S. DNA synthesis generates terminal duplications that seal end-to-end chromosome fusions. Science 332, 468–471 (2011).
Hermetz, K. E. et al. Large inverted duplications in the human genome form via a fold-back mechanism. PLoS Genet. 10, e1004139 (2014).
Conrad, D. F. et al. Mutation spectrum revealed by breakpoint sequencing of human germline CNVs. Nat. Genet. 42, 385–391 (2010).
King, D. A. et al. Mosaic structural variation in children with developmental disorders. Hum. Mol. Genet. 24, 2733–2745 (2015).
Poduri, A., Evrony, G. D., Cai, X. & Walsh, C. A. Somatic mutation, genomic variation, and neurological disease. Science 341, 1237758 (2013).
Merla, G. et al. Submicroscopic deletion in patients with Williams-Beuren syndrome influences expression levels of the nonhemizygous flanking genes. Am. J. Hum. Genet. 79, 332–341 (2006).
Chaignat, E. et al. Copy number variation modifies expression time courses. Genome Res. 21, 106–113 (2011).
Stranger, B. E. et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315, 848–853 (2007).
Shapiro, J. A. Molecular model for the transposition and replication of bacteriophage Mu and other transposable elements. Proc. Natl Acad. Sci. USA 76, 1933–1937 (1979).
Koolen, D. A. et al. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat. Genet. 38, 999–1001 (2006).
Ballif, B. C. et al. Expanding the clinical phenotype of the 3q29 microdeletion syndrome and characterization of the reciprocal microduplication. Mol. Cytogenet. 1, 8 (2008).
Mochizuki, J. et al. Alu-related 5q35 microdeletions in Sotos syndrome. Clin. Genet. 74, 384–391 (2008).
Rosenfeld, J. A. et al. Further evidence of contrasting phenotypes caused by reciprocal deletions and duplications: duplication of NSD1 causes growth retardation and microcephaly. Mol. Syndromol. 3, 247–254 (2013).
Antonell, A. et al. Partial 7q11.23 deletions further implicate GTF2I and GTF2IRD1 as the main genes responsible for the Williams–Beuren syndrome neurocognitive profile. J. Med. Genet. 47, 312–320 (2010).
Berg, J. S. et al. Speech delay and autism spectrum behaviors are frequently associated with duplication of the 7q11.23 Williams-Beuren syndrome region. Genet. Med. 9, 427–441 (2007).
Beunders, G. et al. A triplication of the Williams–Beuren syndrome region in a patient with mental retardation, a severe expressive language delay, behavioural problems and dysmorphisms. J. Med. Genet. 47, 271–275 (2010).
Cheroki, C. et al. Genomic imbalances associated with mullerian aplasia. J. Med. Genet. 45, 228–232 (2008).
Nogueira, S. I. et al. Atypical 22q11.2 deletion in a patient with DGS/VCFS spectrum. Eur. J. Med. Genet. 51, 226–230 (2008).
Yamagishi, H., Garg, V., Matsuoka, R., Thomas, T. & Srivastava, D. A molecular pathway revealing a genetic basis for human cardiac and craniofacial defects. Science 283, 1158–1161 (1999).
Potocki, L. et al. Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. Am. J. Hum. Genet. 80, 633–649 (2007).
Zhang, F. et al. Mechanisms for nonrecurrent genomic rearrangements associated with CMT1A or HNPP: rare CNVs as a cause for missing heritability. Am. J. Hum. Genet. 86, 892–903 (2010).
Venturin, M. et al. Evidence for non-homologous end joining and non-allelic homologous recombination in atypical NF1 microdeletions. Hum. Genet. 115, 69–80 (2004).
Small, K., Iber, J. & Warren, S. T. Emerin deletion reveals a common X-chromosome inversion mediated by inverted repeats. Nat. Genet. 16, 96–99 (1997).
Fusco, F. et al. Genomic architecture at the Incontinentia Pigmenti locus favours de novo pathological alleles through different mechanisms. Hum. Mol. Genet. 21, 1260–1271 (2012).
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.
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.
- 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.
“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.
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.
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.
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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