Auton, A. et al. A global reference for human genetic variation. Nature 526, 68–74 (2015).
Orita, M., Suzuki, Y., Sekiya, T. & Hayashi, K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 5, 874–879 (1989).
Wang, D. G. et al. Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. Science 280, 1077–1082 (1998).
Altshuler, D., Donnelly, P. & The International HapMap Consortium.A haplotype map of the human genome. Nature 437, 1299–1320 (2005).
Alkan, C., Coe, B. P. & Eichler, E. E. Genome structural variation discovery and genotyping. Nat. Rev. Genet. 12, 363–376 (2011).
Ho, S. S., Urban, A. E. & Mills, R. E. Structural variation in the sequencing era. Nat. Rev. Genet. 21, 171–189 (2020).
Kosugi, S. et al. Comprehensive evaluation of structural variation detection algorithms for whole genome sequencing. Genome Biol. 20, 117 (2019).
Feuk, L., Carson, A. R. & Scherer, S. W. Structural variation in the human genome. Nat. Rev. Genet. 7, 85–97 (2006).
Sudmant, P. H. et al. An integrated map of structural variation in 2,504 human genomes. Nature 526, 75–81 (2015). This paper describes the phase 3 SV release of the 1000 Genomes Project, which provided an unprecedented level of insight into the diversity of SVs in the global human population and has stood as one of the gold-standard multi-ancestry data sets in the SV field over the subsequent decade.
Korbel, J. O. et al. Paired-end mapping reveals extensive structural variation in the human genome. Science 318, 420–426 (2007).
Riggs, E. R. et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet. Med. 22, 245–257 (2020).
Jacobs, P. A., Baikie, A. G., Court Brown, W. M. & Strong, J. A. The somatic chromosomes in mongolism. Lancet 1, 710 (1959).
Tjio, J. H. & Levan, A. The chromosome number of man. Hereditas 42, 1–6 (1956).
Warburton, D. De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints. Am. J. Hum. Genet. 49, 995–1013 (1991).
Cohen, A. J. et al. Hereditary renal-cell carcinoma associated with a chromosomal translocation. N. Engl. J. Med. 301, 592–595 (1979).
Funderburk, S. J., Spence, M. A. & Sparkes, R. S. Mental retardation associated with “balanced” chromosome rearrangements. Am. J. Hum. Genet. 29, 136–141 (1977).
Hou, J.-W., Wang, T.-R. & Chuang, S.-M. An epidemiological and aetiological study of children with intellectual disability in Taiwan. J. Intellect. Disabil. Res. 42, 137–143 (1998).
Knight, S. J. L. et al. Subtle chromosomal rearrangements in children with unexplained mental retardation. Lancet 354, 1676–1681 (1999).
Iafrate, A. J. et al. Detection of large-scale variation in the human genome. Nat. Genet. 36, 949–951 (2004).
Sebat, J. et al. Large-scale copy number polymorphism in the human genome. Science 305, 525–528 (2004).
Redon, R. et al. Global variation in copy number in the human genome. Nature 444, 444–454 (2006).
Conrad, D. F. et al. Origins and functional impact of copy number variation in the human genome. Nature 464, 704–712 (2010).
McCarroll, S. A. et al. Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat. Genet. 40, 1166–1174 (2008).
Conrad, D. F., Andrews, T. D., Carter, N. P., Hurles, M. E. & Pritchard, J. K. A high-resolution survey of deletion polymorphism in the human genome. Nat. Genet. 38, 75–81 (2006).
Mills, R. E. et al. Mapping copy number variation by population-scale genome sequencing. Nature 470, 59–65 (2011).
Hehir-Kwa, J. Y. et al. A high-quality human reference panel reveals the complexity and distribution of genomic structural variants. Nat. Commun. 7, 12989 (2016).
Sudmant, P. H. et al. Global diversity, population stratification, and selection of human copy-number variation. Science 349, aab3761 (2015).
Collins, R. L. et al. A structural variation reference for medical and population genetics. Nature 581, 444–451 (2020). This paper describes the initial SV component of the gnomAD, which is a widely adopted reference resource for evaluating the frequencies and distributions of genetic variation in the human population.
Abel, H. J. et al. Mapping and characterization of structural variation in 17,795 human genomes. Nature 583, 83–89 (2020).
Almarri, M. A. et al. Population structure, stratification, and introgression of human structural variation. Cell 182, 189–199 (2020).
Byrska-Bishop, M. et al. High-coverage whole-genome sequencing of the expanded 1000 Genomes Project cohort including 602 trios. Cell 185, 3426–3440 (2022).
Miga, K. H. et al. Telomere-to-telomere assembly of a complete human X chromosome. Nature 585, 79–84 (2020).
Chaisson, M. J. P. et al. Multi-platform discovery of haplotype-resolved structural variation in human genomes. Nat. Commun. 10, 1784 (2019). In this study, members of the HGSVC apply an exhaustive combination of genomic technologies to thoroughly characterize all SVs present in the genomes of three parent–child trios, which yields one of the most comprehensive SV data sets produced to date for an individual set of genomes.
Audano, P. A. et al. Characterizing the major structural variant alleles of the human genome. Cell 176, 663–675 (2019).
Ebert, P. et al. Haplotype-resolved diverse human genomes and integrated analysis of structural variation. Science 372, eabf7117 (2021).
Porubsky, D. et al. Recurrent inversion polymorphisms in humans associate with genetic instability and genomic disorders. Cell 185, 1986–2005 (2022).
Hallast, P. et al. Assembly of 43 human Y chromosomes reveals extensive complexity and variation. Nature 621, 355–364 (2023).
Halldorsson, B. V. et al. The sequences of 150,119 genomes in the UK Biobank. Nature 607, 732–740 (2022).
All of Us Research Program Genomics Investigators. Genomic data in the All of Us research program. Nature 627, 340–346 (2024).
Nurk, S. et al. The complete sequence of a human genome. Science 376, 44–53 (2022). This seminal publication from the T2T consortium describes the first complete (gapless) sequencing of a single human genome, which marks the beginning of the era of complete human genomes and pangenome graphs.
Wagner, J. et al. Curated variation benchmarks for challenging medically relevant autosomal genes. Nat. Biotechnol. 40, 672–680 (2022).
Hurles, M. E., Dermitzakis, E. T. & Tyler-Smith, C. The functional impact of structural variation in humans. Trends Genet. 24, 238–245 (2008).
Spielmann, M., Lupianez, D. G. & Mundlos, S. Structural variation in the 3D genome. Nat. Rev. Genet. 19, 453–467 (2018).
Beyter, D. et al. Long-read sequencing of 3,622 Icelanders provides insight into the role of structural variants in human diseases and other traits. Nat. Genet. 53, 779–786 (2021). This study is the largest published analysis of SVs based on long-read genome sequencing in a human population to date and demonstrates the value of long-read technologies in identifying and genotyping SVs — especially tandem repeats — associated with human traits and diseases.
Logsdon, G. A., Vollger, M. R. & Eichler, E. E. Long-read human genome sequencing and its applications. Nat. Rev. Genet. 21, 597–614 (2020).
Mahmoud, M. et al. Structural variant calling: the long and the short of it. Genome Biol. 20, 246 (2019).
Chin, C. S. et al. A diploid assembly-based benchmark for variants in the major histocompatibility complex. Nat. Commun. 11, 4794 (2020).
Yi, K. & Ju, Y. S. Patterns and mechanisms of structural variations in human cancer. Exp. Mol. Med. 50, 98 (2018).
Loh, P. R. et al. Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations. Nature 559, 350–355 (2018).
McConnell, M. J. et al. Mosaic copy number variation in human neurons. Science 342, 632–637 (2013).
Handsaker, R. E. et al. Large multiallelic copy number variations in humans. Nat. Genet. 47, 296–303 (2015). This study is a high-quality survey of mCNVs in the human population and includes the initial characterization of ‘runaway haplotypes’ in certain ancestry groups that have undergone a recent expansion in copy number.
Mahmoud, M. et al. Utility of long-read sequencing for All of Us. Nat. Commun. 15, 837 (2024).
Luning Prak, E. T. & Kazazian, H. H. Mobile elements and the human genome. Nat. Rev. Genet. 1, 134–144 (2000).
Stewart, C. et al. A comprehensive map of mobile element insertion polymorphisms in humans. PLoS Genet. 7, e1002236 (2011).
Gardner, E. J. et al. The mobile element locator tool (MELT): population-scale mobile element discovery and biology. Genome Res. 27, 1916–1929 (2017).
Sherman, R. M. et al. Assembly of a pan-genome from deep sequencing of 910 humans of African descent. Nat. Genet. 51, 30–35 (2019).
Kehr, B. et al. Diversity in non-repetitive human sequences not found in the reference genome. Nat. Genet. 49, 588–593 (2017).
Wong, K. H. Y., Levy-Sakin, M. & Kwok, P.-Y. De novo human genome assemblies reveal spectrum of alternative haplotypes in diverse populations. Nat. Commun. 9, 3040 (2018).
Wei, W. et al. Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes. Nature 611, 105–114 (2022).
Fan, H. & Chu, J. Y. A brief review of short tandem repeat mutation. Genomics Proteom. Bioinform. 5, 7–14 (2007).
Willems, T., Gymrek, M., Highnam, G., Mittelman, D. & Erlich, Y. The landscape of human STR variation. Genome Res. 24, 1894–1904 (2014).
Talkowski, M. E. et al. Next-generation sequencing strategies enable routine detection of balanced chromosome rearrangements for clinical diagnostics and genetic research. Am. J. Hum. Genet. 88, 469–481 (2011).
Talkowski, M. E. et al. Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. Cell 149, 525–537 (2012).
Redin, C. et al. The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies. Nat. Genet. 49, 36–45 (2017). This paper is the largest published analysis of balanced chromosomal abnormalities at nucleotide resolution in developmental disorders, which emphasizes the role of this unique class of SVs in the pathogenesis of severe pediatric disorders.
Lowther, C. et al. Balanced chromosomal rearrangements offer insights into coding and noncoding genomic features associated with developmental disorders. Preprint at medRxiv https://doi.org/10.1101/2022.02.15.22270795 (2022).
Chiang, C. et al. Complex reorganization and predominant non-homologous repair following chromosomal breakage in karyotypically balanced germline rearrangements and transgenic integration. Nat. Genet. 44, 390–397, S391 (2012).
Abyzov, A. et al. Analysis of deletion breakpoints from 1,092 humans reveals details of mutation mechanisms. Nat. Commun. 6, 7256 (2015).
Brand, H. et al. Paired-duplication signatures mark cryptic inversions and other complex structural variation. Am. J. Hum. Genet. 97, 170–176 (2015).
Borg, K. et al. Molecular analysis of a constitutional complex genome rearrangement with 11 breakpoints involving chromosomes 3, 11, 12, and 21 and a approximately 0.5-Mb submicroscopic deletion in a patient with mild mental retardation. Hum. Genet. 118, 267–275 (2005).
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).
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).
Quinlan, A. R. & Hall, I. M. Characterizing complex structural variation in germline and somatic genomes. Trends Genet. 28, 43–53 (2012).
Sanders, A. D. et al. Characterizing polymorphic inversions in human genomes by single-cell sequencing. Genome Res. 26, 1575–1587 (2016).
Levy-Sakin, M. et al. Genome maps across 26 human populations reveal population-specific patterns of structural variation. Nat. Commun. 10, 1025 (2019).
Hermetz, K. E. et al. Large inverted duplications in the human genome form via a fold-back mechanism. PLoS Genet. 10, e1004139 (2014).
Collins, R. L. et al. Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome. Genome Biol. 18, 36 (2017).
Kloosterman, W. P. et al. Chromothripsis as a mechanism driving complex de novo structural rearrangements in the germline. Hum. Mol. Genet. 20, 1916–1924 (2011).
Chatron, N. et al. The enrichment of breakpoints in late-replicating chromatin provides novel insights into chromoanagenesis mechanisms. Preprint at bioRxiv https://doi.org/10.1101/2020.07.17.206771 (2020).
Weckselblatt, B., Hermetz, K. E. & Rudd, M. K. Unbalanced translocations arise from diverse mutational mechanisms including chromothripsis. Genome Res. 25, 937–947 (2015).
Liu, P. et al. Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. Cell 146, 889–903 (2011).
Stephens, P. J. et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27–40 (2011). This study reports the first observation of chromothripsis, which ignited entire sub-disciplines within human genetics and cancer genomics focused on identifying and characterizing extremely complex genomic rearrangements.
Cortés-Ciriano, I. et al. Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing. Nat. Genet. 52, 331–341 (2020).
de Pagter, M. S. et al. Chromothripsis in healthy individuals affects multiple protein-coding genes and can result in severe congenital abnormalities in offspring. Am. J. Hum. Genet. 96, 651–656 (2015).
Weckselblatt, B. & Rudd, M. K. Human structural variation: mechanisms of chromosome rearrangements. Trends Genet. 31, 587–599 (2015).
Carvalho, C. M. & Lupski, J. R. Mechanisms underlying structural variant formation in genomic disorders. Nat. Rev. Genet. 17, 224–238 (2016).
Gu, W., Zhang, F. & Lupski, J. R. Mechanisms for human genomic rearrangements. Pathogenetics 1, 4 (2008).
Lieber, M. R. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu. Rev. Biochem. 79, 181–211 (2010).
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).
Ottaviani, D., LeCain, M. & Sheer, D. The role of microhomology in genomic structural variation. Trends Genet. 30, 85–94 (2014).
Balachandran, P. et al. Transposable element-mediated rearrangements are prevalent in human genomes. Nat. Commun. 13, 7115 (2022).
Startek, M. et al. Genome-wide analyses of LINE–LINE-mediated nonallelic homologous recombination. Nucleic Acids Res. 43, 2188–2198 (2015).
Zhang, C. Z. et al. Chromothripsis from DNA damage in micronuclei. Nature 522, 179–184 (2015).
Logsdon, G. A. et al. The variation and evolution of complete human centromeres. Nature 629, 136–145 (2024).
Wang, T. et al. The human pangenome project: a global resource to map genomic diversity. Nature 604, 437–446 (2022).
Itsara, A. et al. De novo rates and selection of large copy number variation. Genome Res. 20, 1469–1481 (2010).
Sanders, S. J. et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70, 863–885 (2011).
Sebat, J. et al. Strong association of de novo copy number mutations with autism. Science 316, 445–449 (2007).
Lappalainen, T., Scott, A. J., Brandt, M. & Hall, I. M. Genomic analysis in the age of human genome sequencing. Cell 177, 70–84 (2019).
Brandler, W. M. et al. Paternally inherited cis-regulatory structural variants are associated with autism. Science 360, 327–331 (2018).
Kloosterman, W. P. et al. Characteristics of de novo structural changes in the human genome. Genome Res. 25, 792–801 (2015).
Feusier, J. et al. Pedigree-based estimation of human mobile element retrotransposition rates. Genome Res. 29, 1567–1577 (2019).
Belyeu, J. R. et al. De novo structural mutation rates and gamete-of-origin biases revealed through genome sequencing of 2,396 families. Am. J. Hum. Genet. 108, 597–607 (2021). This study performed SV analyses from WGS of several thousand parent–child trios, which enabled the most accurate empirical estimates of SV mutation rates in humans to date.
Halman, A. & Oshlack, A. Accuracy of short tandem repeats genotyping tools in whole exome sequencing data. F1000Research 9, 200 (2020).
Mitra, I. et al. Patterns of de novo tandem repeat mutations and their role in autism. Nature 589, 246–250 (2021).
Fu, W., Zhang, F., Wang, Y., Gu, X. & Jin, L. Identification of copy number variation hotspots in human populations. Am. J. Hum. Genet. 87, 494–504 (2010).
Conrad, D. F. & Hurles, M. E. The population genetics of structural variation. Nat. Genet. 39, S30–S36 (2007).
Solís-Moruno, M., Batlle-Masó, L., Bonet, N., Aróstegui, J. I. & Casals, F. Somatic genetic variation in healthy tissue and non-cancer diseases. Eur. J. Hum. Genet. 31, 48–54 (2023).
Yu, X. et al. Digital microfluidics-based digital counting of single-cell copy number variation (dd-scCNV Seq). Proc. Natl Acad. Sci. USA 120, e2221934120 (2023).
Gao, T. et al. A pan-tissue survey of mosaic chromosomal alterations in 948 individuals. Nat. Genet. 55, 1901–1911 (2023).
Li, S., Carss, K. J., Halldorsson, B. V. & Cortes, A. Whole-genome sequencing of half-a-million UK Biobank participants. Preprint at medRxiv https://doi.org/10.1101/2023.12.06.23299426 (2023).
Jun, G. et al. Structural variation across 138,134 samples in the TOPMed consortium. Preprint at bioRxiv https://doi.org/10.1101/2023.01.25.525428 (2023).
Logsdon, G. A. et al. Complex genetic variation in nearly complete human genomes. Preprint at bioRxiv https://doi.org/10.1101/2024.09.24.614721 (2024).
Zhao, X. et al. Expectations and blind spots for structural variation detection from long-read assemblies and short-read genome sequencing technologies. Am. J. Hum. Genet. 108, 919–928 (2021).
Ebler, J. et al. Pangenome-based genome inference allows efficient and accurate genotyping across a wide spectrum of variant classes. Nat. Genet. 54, 518–525 (2022).
Ziaei Jam, H. et al. A deep population reference panel of tandem repeat variation. Nat. Commun. 14, 6711 (2023).
Chen, S. et al. A genomic mutational constraint map using variation in 76,156 human genomes. Nature 625, 92–100 (2024).
Garrison, E. et al. Variation graph toolkit improves read mapping by representing genetic variation in the reference. Nat. Biotechnol. 36, 875–879 (2018).
Itsara, A. et al. Population analysis of large copy number variants and hotspots of human genetic disease. Am. J. Hum. Genet. 84, 148–161 (2009).
Ruderfer, D. M. et al. Patterns of genic intolerance of rare copy number variation in 59,898 human exomes. Nat. Genet. 48, 1107–1111 (2016). This study from the Exome Aggregation Consortium represents one of the first well-powered attempts to quantify both haploinsufficiency and triplosensitivity for all human protein-coding genes.
Jakubosky, D. et al. Discovery and quality analysis of a comprehensive set of structural variants and short tandem repeats. Nat. Commun. 11, 2928 (2020).
Ohno, S. Evolution by Gene Duplication (Springer-Verlag, 1970).
Dumas, L. et al. Gene copy number variation spanning 60 million years of human and primate evolution. Genome Res. 17, 1266–1277 (2007).
Dennis, M. Y. & Eichler, E. E. Human adaptation and evolution by segmental duplication. Curr. Opin. Genet. Dev. 41, 44–52 (2016).
Fiddes, I. T. et al. Human-specific NOTCH2NL genes affect notch signaling and cortical neurogenesis. Cell 173, 1356–1369 (2018).
Giannuzzi, G. et al. The human-specific BOLA2 duplication modifies iron homeostasis and anemia predisposition in chromosome 16p11.2 autism individuals. Am. J. Hum. Genet. 105, 947–958 (2019).
Boettger, L. M. et al. Recurring exon deletions in the HP (haptoglobin) gene contribute to lower blood cholesterol levels. Nat. Genet. 48, 359–366 (2016).
Perry, G. H. et al. Diet and the evolution of human amylase gene copy number variation. Nat. Genet. 39, 1256–1260 (2007). This study describes the initial observation that amylase gene copy number differs among human populations, correlates with salivary amylase protein abundance, and mirrors social transitions to agrarianism, collectively comprising one of the most famous examples of human adaptation due to positively selected SVs.
Bolognini, D. et al. Recurrent evolution and selection shape structural diversity at the amylase locus. Nature 634, 617–625 (2024).
Stefansson, H. et al. A common inversion under selection in Europeans. Nat. Genet. 37, 129–137 (2005).
Boettger, L. M., Handsaker, R. E., Zody, M. C. & McCarroll, S. A. Structural haplotypes and recent evolution of the human 17q21.31 region. Nat. Genet. 44, 881–885 (2012).
Marshall, C. R. et al. Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82, 477–488 (2008). This study reported one of the first systematic analyses of balanced and unbalanced chromosomal abnormalities in individuals with autism spectrum disorder, revealing that large SVs are a major contributor to abnormal neurodevelopment.
Cooper, G. M. et al. A copy number variation morbidity map of developmental delay. Nat. Genet. 43, 838–846 (2011).
Coe, B. P. et al. Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nat. Genet. 46, 1063–1071 (2014).
Douard, E. et al. Effect sizes of deletions and duplications on autism risk across the genome. Am. J. Psychiatry 178, 87–98 (2021).
Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434–443 (2020).
Han, L. et al. Functional annotation of rare structural variation in the human brain. Nat. Commun. 11, 2990 (2020).
Chiang, C. et al. The impact of structural variation on human gene expression. Nat. Genet. 49, 692–699 (2017).
Ferraro, N. M. et al. Transcriptomic signatures across human tissues identify functional rare genetic variation. Science 369, eaaz5900 (2020).
Sekar, A. et al. Schizophrenia risk from complex variation of complement component 4. Nature 530, 177–183 (2016).
Gunning, A. C. et al. Recurrent de novo NAHR reciprocal duplications in the ATAD3 gene cluster cause a neurogenetic trait with perturbed cholesterol and mitochondrial metabolism. Am. J. Hum. Genet. 106, 272–279 (2020).
Usdin, K. The biological effects of simple tandem repeats: lessons from the repeat expansion diseases. Genome Res. 18, 1011–1019 (2008).
Vorechovsky, I. Transposable elements in disease-associated cryptic exons. Hum. Genet. 127, 135–154 (2010).
Sundaram, V. et al. Widespread contribution of transposable elements to the innovation of gene regulatory networks. Genome Res. 24, 1963–1976 (2014).
Cao, X. et al. Polymorphic mobile element insertions contribute to gene expression and alternative splicing in human tissues. Genome Biol. 21, 185 (2020).
Liang, L. et al. Complementary Alu sequences mediate enhancer-promoter selectivity. Nature 619, 868–875 (2023).
Middelkamp, S. et al. Molecular dissection of germline chromothripsis in a developmental context using patient-derived iPS cells. Genome Med. 9, 9 (2017).
van Heesch, S. et al. Genomic and functional overlap between somatic and germline chromosomal rearrangements. Cell Rep. 9, 2001–2010 (2014).
Moore, J. E. et al. Expanded encyclopaedias of DNA elements in the human and mouse genomes. Nature 583, 699–710 (2020).
Fudenberg, G. & Pollard, K. S. Chromatin features constrain structural variation across evolutionary timescales. Proc. Natl Acad. Sci. USA 116, 2175–2180 (2019).
Oz-Levi, D. et al. Noncoding deletions reveal a gene that is critical for intestinal function. Nature 571, 107–111 (2019).
Franke, M. et al. Formation of new chromatin domains determines pathogenicity of genomic duplications. Nature 538, 265–269 (2016).
Lupianez, D. G. et al. Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions. Cell 161, 1012–1025 (2015). This study was among the first to demonstrate that SVs can cause Mendelian developmental diseases by altering the three-dimensional chromatin architecture of the genome rather than by direct disruption of coding genes themselves.
Monlong, J. et al. Global characterization of copy number variants in epilepsy patients from whole genome sequencing. PLoS Genet. 14, e1007285 (2018).
D’Haene, E. & Vergult, S. Interpreting the impact of noncoding structural variation in neurodevelopmental disorders. Genet. Med. 23, 34–46 (2021).
Jakubosky, D. et al. Properties of structural variants and short tandem repeats associated with gene expression and complex traits. Nat. Commun. 11, 2927 (2020).
Scott, A. J., Chiang, C. & Hall, I. M. Structural variants are a major source of gene expression differences in humans and often affect multiple nearby genes. Genome Res. 31, 2249–2257 (2021). This study reports the most recent SV analyses from the GTEx project, which is the largest and best-powered quantification of the effects of SVs on gene expression in humans available to date.
Rice, A. M. & McLysaght, A. Dosage sensitivity is a major determinant of human copy number variant pathogenicity. Nat. Commun. 8, 14366 (2017).
Aguirre, M., Rivas, M. A. & Priest, J. Phenome-wide burden of copy-number variation in the UK biobank. Am. J. Hum. Genet. 105, 373–383 (2019).
Collins, R. L. et al. A cross-disorder dosage sensitivity map of the human genome. Cell https://doi.org/10.1016/j.cell.2022.06.036 (2022). This study reports the aggregation and systematic analysis of rare CNVs in nearly one million people, enabling genome-wide association scans of rare deletions and duplications for 54 diseases and the construction of well-calibrated haploinsufficiency and triplosensitivity metrics for all autosomal protein-coding genes.
Huang, N., Lee, I., Marcotte, E. M. & Hurles, M. E. Characterising and predicting haploinsufficiency in the human genome. PLoS Genet. 6, e1001154 (2010).
Stankiewicz, P. & Lupski, J. R. Structural variation in the human genome and its role in disease. Annu. Rev. Med. 61, 437–455 (2010).
McCarroll, S. A. Extending genome-wide association studies to copy-number variation. Hum. Mol. Genet. 17, R135–R142 (2008).
Tam, V. et al. Benefits and limitations of genome-wide association studies. Nat. Rev. Genet. 20, 467–484 (2019).
Craddock, N. et al. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature 464, 713–720 (2010).
Mace, A. et al. CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits. Nat. Commun. 8, 744 (2017).
Li, Y. R. et al. Rare copy number variants in over 100,000 European ancestry subjects reveal multiple disease associations. Nat. Commun. 11, 255 (2020).
Glessner, J. T. et al. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459, 569–573 (2009).
Hujoel, M. L. A. et al. Influences of rare copy-number variation on human complex traits. Cell 185, 4233–4248 (2022).
Barton, A. R., Sherman, M. A., Mukamel, R. E. & Loh, P. R. Whole-exome imputation within UK Biobank powers rare coding variant association and fine-mapping analyses. Nat. Genet. 53, 1260–1269 (2021).
Payer, L. M. et al. Structural variants caused by Alu insertions are associated with risks for many human diseases. Proc. Natl Acad. Sci. USA 114, E3984–E3992 (2017).
Kamitaki, N. et al. Complement genes contribute sex-biased vulnerability in diverse disorders. Nature 582, 577–581 (2020).
Zablotsky, B. et al. Prevalence and trends of developmental disabilities among children in the United States: 2009–2017. Pediatrics 144, e20190811 (2019).
Bell, J. et al. A total population study of diagnosed chromosome abnormalities in Queensland, Australia. Clin. Genet. 22, 49–56 (1982).
van Karnebeek, C. D., Jansweijer, M. C., Leenders, A. G., Offringa, M. & Hennekam, R. C. Diagnostic investigations in individuals with mental retardation: a systematic literature review of their usefulness. Eur. J. Hum. Genet. 13, 6–25 (2005).
Verma, R. S. & Dosik, H. Incidence of major chromosomal abnormalities in a referred population for suspected chromosomal aberrations: a report of 357 cases. Clin. Genet. 17, 305–308 (1980).
Wright, C. F. et al. Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data. Lancet 385, 1305–1314 (2015). This study describes the analysis and clinical interpretation of CNVs detected by chromosomal microarray in the Deciphering Developmental Disorders project, which provided one of the most comprehensive estimates of diagnostic yield for CNV testing in paediatric developmental disorders.
Wapner, R. J. et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N. Engl. J. Med. 367, 2175–2184 (2012).
Sajan, S. A. et al. Both rare and de novo copy number variants are prevalent in agenesis of the corpus callosum but not in cerebellar hypoplasia or polymicrogyria. PLoS Genet. 9, e1003823 (2013).
Sanders, S. J. et al. Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron 87, 1215–1233 (2015).
Pinto, D. et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466, 368–372 (2010).
Magenis, R. E., Brown, M. G., Lacy, D. A., Budden, S. & LaFranchi, S. Is Angelman syndrome an alternate result of del(15)(q11q13)? Am. J. Med. Genet. 28, 829–838 (1987).
Driscoll, D., Budarf, M. & Emanuel, B. A genetic etiology for DiGeorge syndrome: consistent deletions and microdeletions of 22q11. Am. J. Hum. Genet. 50, 924 (1992).
Harel, T. & Lupski, J. R. Genomic disorders 20 years on-mechanisms for clinical manifestations. Clin. Genet. 93, 439–449 (2018).
Weiss, L. A. et al. Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 358, 667–675 (2008). This study reports the initial discovery of reciprocal CNVs at the 16p11.2 chromosomal locus and autism spectrum disorder; this 16p11.2 CNV is now recognized as one of the single most common genetic causes of abnormal human neurodevelopment.
McCarthy, S. E. et al. Microduplications of 16p11.2 are associated with schizophrenia. Nat. Genet. 41, 1223–1227 (2009).
Nuttle, X. et al. Emergence of a Homo sapiens-specific gene family and chromosome 16p11.2 CNV susceptibility. Nature 536, 205–209 (2016).
Smolen, C. & Girirajan, S. The gene dose makes the disease. Cell 185, 2850–2852 (2022).
Kurotaki, N. et al. Haploinsufficiency of NSD1 causes Sotos syndrome. Nat. Genet. 30, 365–366 (2002).
Wilson, H. L. et al. Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms. J. Med. Genet. 40, 575–584 (2003).
Lopez-Rivera, E. et al. Genetic drivers of kidney defects in the DiGeorge syndrome. N. Engl. J. Med. 376, 742–754 (2017).
Lindsay, E. A. et al. Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice. Nature 410, 97–101 (2001). This study was one of the first to demonstrate that loss of a single gene (TBX1) within a larger genomic disorder CNV locus (22q11.2 deletion) is individually associated with one of the constituent phenotypes commonly observed in CNV carrier patients, which provided important empirical evidence for an oligogenic basis of genomic disorders.
Iyer, J. et al. Pervasive genetic interactions modulate neurodevelopmental defects of the autism-associated 16p11.2 deletion in Drosophila melanogaster. Nat. Commun. 9, 2548 (2018).
Singh, M. D. et al. NCBP2 modulates neurodevelopmental defects of the 3q29 deletion in Drosophila and Xenopus laevis models. PLoS Genet. 16, e1008590 (2020).
Pizzo, L. et al. Functional assessment of the “two-hit” model for neurodevelopmental defects in Drosophila and X. laevis. PLoS Genet. 17, e1009112 (2021).
Girirajan, S. et al. Phenotypic heterogeneity of genomic disorders and rare copy-number variants. N. Engl. J. Med. 367, 1321–1331 (2012).
Albers, C. A. et al. Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome. Nat. Genet. 44, 435–439 (2012).
Davies, R. W. et al. Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome. Nat. Med. 26, 1912–1918 (2020).
Owen, D. et al. Effects of pathogenic CNVs on physical traits in participants of the UK Biobank. BMC Genomics 19, 867 (2018).
Gilissen, C. et al. Genome sequencing identifies major causes of severe intellectual disability. Nature 511, 344–347 (2014).
Werling, D. M. et al. An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder. Nat. Genet. 50, 727–736 (2018).
Turner, T. N. et al. Genomic patterns of de novo mutation in simplex autism. Cell 171, 710–722 (2017).
Turro, E. et al. Whole-genome sequencing of patients with rare diseases in a national health system. Nature 583, 96–102 (2020).
Poultney, C. S. et al. Identification of small exonic CNV from whole-exome sequence data and application to autism spectrum disorder. Am. J. Hum. Genet. 93, 607–619 (2013).
Kazazian, H. H. Jr. et al. Haemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man. Nature 332, 164–166 (1988).
Satterstrom, F. K. et al. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Cell 180, 568–584 (2020).
Coe, B. P. et al. Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity. Nat. Genet. 51, 106–116 (2019).
Fromer, M. et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 506, 179–184 (2014).
Fu, J. M. et al. Rare coding variation provides insight into the genetic architecture and phenotypic context of autism. Nat. Genet. 54, 1320–1331 (2022).
Shanta, O., Noor, A. & Sebat, J. The effects of common structural variants on 3D chromatin structure. BMC Genomics 21, 95 (2020).
Allou, L. et al. Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator. Nature 592, 93–98 (2021).
Aneichyk, T. et al. Dissecting the causal mechanism of X-linked dystonia-parkinsonism by integrating genome and transcriptome assembly. Cell 172, 897–909 (2018).
Maia, N., Nabais Sá, M. J., Melo-Pires, M., de Brouwer, A. P. M. & Jorge, P. Intellectual disability genomics: current state, pitfalls and future challenges. BMC Genomics 22, 909 (2021).
de Ligt, J. et al. Diagnostic exome sequencing in persons with severe intellectual disability. N. Engl. J. Med. 367, 1921–1929 (2012).
Kaplanis, J. et al. Evidence for 28 genetic disorders discovered by combining healthcare and research data. Nature 586, 757–762 (2020).
Miller, D. T. et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am. J. Hum. Genet. 86, 749–764 (2010).
Schaefer, G. B. & Mendelsohn, N. J. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet. Med. 15, 399–407 (2013).
Gardner, E. J. et al. Contribution of retrotransposition to developmental disorders. Nat. Commun. 10, 4630 (2019).
Torene, R. I. et al. Mobile element insertion detection in 89,874 clinical exomes. Genet. Med. 22, 974–978 (2020).
Pfundt, R. et al. Detection of clinically relevant copy-number variants by exome sequencing in a large cohort of genetic disorders. Genet. Med. 19, 667–675 (2017).
Vissers, L. et al. A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Genet. Med. 19, 1055–1063 (2017).
Lowther, C. et al. Systematic evaluation of genome sequencing as a first-tier diagnostic test for prenatal and pediatric disorders. Am. J. Hum. Genet. 110, 1454–1469 (2023).
Lord, J. et al. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet 393, 747–757 (2019).
Talkowski, M. E. et al. Clinical diagnosis by whole-genome sequencing of a prenatal sample. N. Engl. J. Med. 367, 2226–2232 (2012).
Sanchis-Juan, A. Complex structural variants resolved by short-read and long-read whole genome sequencing in Mendelian disorders. Genome Med. 10, 95 (2018).
Wahlster, L. et al. Familial thrombocytopenia due to a complex structural variant resulting in a WAC-ANKRD26 fusion transcript. J. Exp. Med. 218, e20210444 (2021).
Witt, D. et al. Genome sequencing identifies complex structural MLH1 variant in unsolved Lynch syndrome. Mol. Genet. Genom. Med. 11, e2151 (2023).
Lilleväli, H. et al. Genome sequencing identifies a homozygous inversion disrupting QDPR as a cause for dihydropteridine reductase deficiency. Mol. Genet. Genom. Med. 8, e1154 (2020).
Pagnamenta, A. T. et al. The impact of inversions across 33,924 families with rare disease from a national genome sequencing project. Am. J. Hum. Genet. 111, 1140–1164 (2024).
Höps, W. et al. Impact and characterization of serial structural variations across humans and great apes. Nat. Commun. 15, 8007 (2024).
Khera, A. V. et al. Whole genome sequencing to characterize monogenic and polygenic contributions in patients hospitalized with early-onset myocardial infarction. Circulation 139, 1593–1602 (2019).
Depienne, C. & Mandel, J.-L. 30 years of repeat expansion disorders: what have we learned and what are the remaining challenges? Am. J. Hum. Genet. 108, 764–785 (2021).
Garrison, E. & Guarracino, A. Unbiased pangenome graphs. Bioinformatics 39, btac743 (2023).
Li, H., Feng, X. & Chu, C. The design and construction of reference pangenome graphs with minigraph. Genome Biol. 21, 265 (2020).
Morales, J. et al. A joint NCBI and EMBL-EBI transcript set for clinical genomics and research. Nature 604, 310–315 (2022).
GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science 369, 1318–1330 (2020).
Eggertsson, H. P. et al. GraphTyper2 enables population-scale genotyping of structural variation using pangenome graphs. Nat. Commun. 10, 5402 (2019).
Chen, S. et al. Paragraph: a graph-based structural variant genotyper for short-read sequence data. Genome Biol. 20, 291 (2019).
Samocha, K. E. et al. A framework for the interpretation of de novo mutation in human disease. Nat. Genet. 46, 944–950 (2014).
Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016).
Scully, R., Panday, A., Elango, R. & Willis, N. A. DNA double-strand break repair-pathway choice in somatic mammalian cells. Nat. Rev. Mol. Cell Biol. 20, 698–714 (2019).
Venner, E. et al. Whole-genome sequencing as an investigational device for return of hereditary disease risk and pharmacogenomic results as part of the All of Us Research Program. Genome Med. 14, 34 (2022).
Taliun, D. et al. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. Nature 590, 290–299 (2021).
Sherman, M. A. et al. Large mosaic copy number variations confer autism risk. Nat. Neurosci. 24, 197–203 (2021).
Riggs, E. R. et al. Towards an evidence-based process for the clinical interpretation of copy number variation. Clin. Genet. 81, 403–412 (2012).
Amberger, J. S., Bocchini, C. A., Schiettecatte, F., Scott, A. F. & Hamosh, A. OMIM.org: Online Mendelian Inheritance in Man (OMIM(R)), an online catalog of human genes and genetic disorders. Nucleic Acids Res. 43, D789–D798 (2015).
Uddin, M. et al. A high-resolution copy-number variation resource for clinical and population genetics. Genet. Med. 17, 747–752 (2015).
Zarrei, M. et al. Gene copy number variation and pediatric mental health/neurodevelopment in a general population. Hum. Mol. Genet. 32, 2411–2421 (2023).
Maxwell, E. K. et al. Profiling copy number variation and disease associations from 50,726 DiscovEHR Study exomes. Preprint at bioRxiv https://doi.org/10.1101/119461 (2017).
Babadi, M. et al. GATK-gCNV enables the discovery of rare copy number variants from exome sequencing data. Nat. Genet. 55, 1589–1597 (2023).
Collins, R. L. The Landscape and Consequences of Structural Variation in the Human Genome. Thesis, Harvard University (2022).
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