De novo rates and selection of large copy number variation
Open accessAbstract
While copy number variation (CNV) is an active area of research, de novo mutation rates within human populations are not well characterized. By focusing on large (>100 kbp) events, we estimate the rate of de novo CNV formation in humans by analyzing 4394 transmissions from human pedigrees with and without neurocognitive disease. We show that a significant limitation in directly measuring genome-wide CNV mutation is accessing DNA derived from primary tissues as opposed to cell lines. We conservatively estimated the genome-wide CNV mutation rate using single nucleotide polymorphism (SNP) microarrays to analyze whole-blood derived DNA from asthmatic trios, a collection in which we observed no elevation in the prevalence of large CNVs. At a resolution of ∼30 kb, nine de novo CNVs were observed from 772 transmissions, corresponding to a mutation rate of μ = 1.2 × 10−2 CNVs per genome per transmission (μ = 6.5 × 10−3 for CNVs >500 kb). Combined with previous estimates of CNV prevalence and assuming a model of mutation-selection balance, we estimate significant purifying selection for large (>500 kb) events at the genome-wide level to be s = 0.16. Supporting this, we identify de novo CNVs in 717 multiplex autism pedigrees from the AGRE collection and observe a fourfold enrichment (P = 1.4 × 10−3) for de novo CNVs in cases of multiplex autism versus unaffected siblings, suggesting that many de novo CNV mutations contribute a subtle, but significant risk for autism. We observe no parental bias in the origin or transmission of CNVs among any of the cohorts studied.
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The over-representation of large de novo CNVs in ASD has been replicated in studies of 60 to 393 simplex trios.
“The over-representation of large de novo CNVs in ASD has been replicated in studies ranging from 60 to 393 simplex trios (Itsara et al., 2010; Marshall et al., 2008; Pinto et al., 2010)”
From Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism (2011) · cites this paper as Itsara et al., 2010
Subsequent larger studies confirmed a high rate (5-10%) of de novo CNVs in ASD and further clarified the extent of genetic heterogeneity.
“Subsequent studies in larger samples have confirmed a high (5–10%) rate of de novo CNVs in ASD and further elucidated the extent of genetic heterogeneity in ASD (Itsara et al., 2010; Levy et al., 2011; Marshall et al., 2008; Pinto et al., 2010; Sanders et al., 2011).”
From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Itsara et al., 2010
CNVs larger than 10 kb occur at a rate of about 0.01-0.02 per generation.
“CNVs >10 Kb in size occur at a rate of ~0.01–0.02 per generation.(Itsara et al., 2010; Levy et al., 2011; Marshall et al., 2008; Sanders et al., 2011; Sebat et al., 2007).”
From CNVs: Harbingers of a Rare Variant Revolution in Psychiatric Genetics (2012) · cites this paper as Itsara et al., 2010
The control de novo CNV rate of 0.9% is consistent with previous estimates ranging from 0.5% to 3%.
“This rate is consistent with estimates from previous studies ranging from 0.5% to 3% (Conrad et al., 2010, Itsara et al., 2010, Levy et al., 2011, Sebat et al., 2007 and Xu et al., 2008).”
From High frequencies of de novo CNVs in bipolar disorder and schizophrenia (2011) · cites this paper as Itsara et al., 2010
The size difference between SD-mediated and non-SD-mediated de novo CNVs is consistent with prior studies linking CNV size to mutational mechanism.
“Notably, the median size of SD and non-SD-mediated de novo CNVs was 722 kb and 67 kb respectively, consistent with previous studies that have found differences in CNV size related to the underlying mutational mechanism (Itsara et al., 2010 and Stefansson et al., 2008).”
From High frequencies of de novo CNVs in bipolar disorder and schizophrenia (2011) · cites this paper as Itsara et al., 2010
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“, 2011) replicated the association between ASD and de novo CNVs (dnCNVs) (Itsara et al., 2010; Marshall et al., 2008; Sebat et al., 2007) and the role of CNVs at 16p11.”
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“This overrepresentation of large de novo CNVs in ASD has been replicated in three subsequent studies involving cohorts ranging in size from 60 to 393 simplex trios (Itsara et al., 2010; Marshall et al., 2008; Pinto et al., 2010).”
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“…found a higher incidence of new copy-number mutation in autistic children from simplex (only one affected child) ASD families than in typical children or in children from multiplex (multiple affected children) ASD families (Marshall et al., 2008; Sebat et al., 2007; see also Itsara et al., 2010).”
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Genovese, G., Fromer, M., Stahl, E. A., Ruderfer, D. M., Chambert, K., Landén, M., Moran, J. L., Purcell, S. M., Sklar, P., Sullivan, P. F., et al. (2016) · Nature Neuroscience · doi:10.1038/nn.4402 · Cited by 444 · see citing works
The Genetic Landscapes of Autism Spectrum Disorders
Huguet, G., Ey, E., & Bourgeron, T. (2013) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-091212-153431 · Cited by 447 · see citing works
Precise estimates of mutation rate and spectrum in yeast
Zhu, Y. O., Siegal, M. L., Hall, D. W., & Petrov, D. A. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1323011111 · Cited by 421 · see citing works
A cross-disorder dosage sensitivity map of the human genome
Collins, R. L., Glessner, J., Porcu, E., Lepamets, M., Brandon, R. C., Lauricella, C., Han, L., Morley, T. J., Niestroj, L., Ulirsch, J. C., et al. (2022) · Cell · doi:10.1016/j.cell.2022.06.036 · Cited by 377 · see citing works
Goriely, A., & Wilkie, A. O. M. (2012) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2011.12.017 · Cited by 365 · see citing works
Human Copy Number Variation and Complex Genetic Disease
Girirajan, S., Campbell, C. D., & Eichler, E. E. (2011) · Annual Review of Genetics · doi:10.1146/annurev-genet-102209-163544 · Cited by 367 · see citing works
“Itsara and colleagues proposed an alternate model that unifies all these observations by analyzing 717 multiplex pedigrees from the AGRE cohort for de novo CNVs (54).”
Self-citationGene Copy-Number Alterations: A Cost-Benefit Analysis
Tang, Y.-C., & Amon, A. (2013) · Cell · doi:10.1016/j.cell.2012.11.043 · Cited by 348 · see citing works
“Sequencing of human populations revealed that CNVs are rare, occurring at a frequency of less than 1 percent (Itsara et al., 2009) and that they are under strong negative selection (Itsara et al., 2010).”
Genome-wide genetic changes during modern breeding of maize
Jiao, Y., Zhao, H., Ren, L., Song, W., Zeng, B., Guo, J., Wang, B., Liu, Z., Chen, J., Li, W., et al. (2012) · Nature Genetics · doi:10.1038/ng.2312 · Cited by 346 · see citing works
High frequencies of de novo CNVs in bipolar disorder and schizophrenia
Malhotra, D., McCarthy, S., Michaelson, J. J., Vacic, V., Burdick, K. E., Yoon, S., Cichon, S., Corvin, A., Gary, S., Gershon, E. S., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.11.007 · Cited by 325 · see citing works
“5% to 3% (Conrad et al., 2010; Itsara et al., 2010; Levy et al., 2011; Sebat et al., 2007; Xu et al., 2008).”
InfluentialProperties and rates of germline mutations in humans
Campbell, C. D., & Eichler, E. E. (2013) · Trends in Genetics · doi:10.1016/j.tig.2013.04.005 · Cited by 279 · see citing works
“Interestingly, individuals with autism in families with multiple affected individuals also show an increased number of de novo CNVs compared to their siblings even though the multiplex nature of these families would suggest a primarily inherited model of disease[21].”
BackgroundInfluentialSelf-citationThe Emerging Picture of Autism Spectrum Disorder: Genetics and Pathology
Chen, J. A., Peñagarikano, O., Belgard, T. G., Swarup, V., & Geschwind, D. H. (2015) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-012414-040405 · Cited by 254 · see citing works
Mosaicism in health and disease — clones picking up speed
Forsberg, L. A., Gisselsson, D., & Dumanski, J. P. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.145 · Cited by 253 · see citing works
Retention of duplicated genes in evolution
Kuzmin, E., Taylor, J. S., & Boone, C. M. (2021) · Trends in Genetics · doi:10.1016/j.tig.2021.06.016 · Cited by 227 · see citing works
Protein interactome reveals converging molecular pathways among autism disorders
Sakai, Y., Shaw, C. A., Dawson, B. C., Dugas, D. V., Al-Mohtaseb, Z., Hill, D. E., & Zoghbi, H. Y. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002166 · Cited by 226 · see citing works
“Furthermore, there were no deletion events overlapping these three deleted genes nor duplication events overlapping with FLNA loci among the CNV data from 1500 controls (36) that we used for Fig.”
BackgroundMethodRare Inherited and De Novo CNVs Reveal Complex Contributions to ASD Risk in Multiplex Families
Leppä, V., Kravitz, S. N., Martin, C. L., Andrieux, J., Caignec, C. L., Martin‐Coignard, D., DyBuncio, C. T., Sanders, S., Lowe, J. K., Cantor, R. M., et al. (2016) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2016.06.036 · Cited by 217 · see citing works
“Some studies have suggested an excess of maternally inherited pathogenic CNVs,(15,20) but an excess of maternal transmission appears to vary by locus rather than being generalizable.(9,13,16,20) Some studies have included individuals from families with multiple affected children (multiplex families) in a case-control…”
BackgroundAn Evaluation of Copy Number Variation Detection Tools from Whole-Exome Sequencing Data
Tan, R., Wang, Y., Kleinstein, S. E., Liu, Y., Zhu, X., Guo, H., Jiang, Q., Allen, A. S., & Zhu, M. (2014) · Human Mutation · doi:10.1002/humu.22537 · Cited by 217 · see citing works
“Theoretically, most CNVs violating the rule of Mendelian inheritance should be deemed as false positive calls because the real de novo CNV rate is known to be extremely low [Itsara et al., 2010].”
BackgroundRates and Genomic Consequences of Spontaneous Mutational Events in Drosophila melanogaster
Schrider, D. R., Houle, D., Lynch, M., & Hahn, M. W. (2013) · Genetics · doi:10.1534/genetics.113.151670 · Cited by 209 · see citing works
“Thus, we may not have adequate power to detect all deletions of between 10 and 50 bp.”
BackgroundInfluentialFernandez, T. V., Sanders, S., Yurkiewicz, I. R., Ercan‐Sencicek, A. G., Kim, Y.-S., Fishman, D. O., Raubeson, M. J., Song, Y., Yasuno, K., Ho, W. S., et al. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.09.034 · Cited by 207 · see citing works
Age-Related Somatic Structural Changes in the Nuclear Genome of Human Blood Cells
Forsberg, L. A., Rasi, C., Razzaghian, H. R., Pakalapati, G., Waite, L. L., Thibeault, K. S., Ronowicz, A., Wineinger, N. E., Tiwari, H. K., Boomsma, D. I., et al. (2012) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2011.12.009 · Cited by 192 · see citing works
Autism genetics: searching for specificity and convergence
Berg, J. M., & Geschwind, D. H. (2012) · Genome Biology · doi:10.1186/gb-2012-13-7-247 · Cited by 192 · see citing works
Genetic contributions to autism spectrum disorder
Havdahl, A., Niarchou, M., Starnawska, A., Uddin, M., van der Merwe, C., & Warrier, V. (2021) · Psychological Medicine · doi:10.1017/s0033291721000192 · Cited by 193 · see citing works
“A higher global frequency of de novo CNVs is observed in idiopathic autism cases from simplex families (10%) compared to multiplex families (2%) and controls (1%) (Halladay et al., 2015; Itsara et al., 2010; Sebat et al., 2007).”
BackgroundZwaigenbaum, L., Bryson, S. E., Szatmari, P., Brian, J., Smith, I. M., Roberts, W., Vaillancourt, T., & Roncadin, C. (2012) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-012-1515-y · Cited by 178 · see citing works
Somatic mosaicism in healthy human tissues
De, S. (2011) · Trends in Genetics · doi:10.1016/j.tig.2011.03.002 · Cited by 174 · see citing works
Luo, R., Sanders, S. J., Tian, Y., Voineagu, I., Huang, N., Chu, S. H., Klei, L., Cai, C., Ou, J., Lowe, J. K., et al. (2012) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2012.05.011 · Cited by 167 · see citing works
“The pathogenic role of de novo CNVs in ASDs has been previously established.(7,17,43,64,65) Although it has been assumed that underlying changes in gene expression contribute to pathogenicity, this has not been demonstrated previously.”
BackgroundCopy-number changes in evolution: rates, fitness effects and adaptive significance
Katju, V., & Bergthorsson, U. (2013) · Frontiers in Genetics · doi:10.3389/fgene.2013.00273 · Cited by 172 · see citing works
Moreno-De-Luca, D., Sanders, S. J., Willsey, A. J., Mulle, J. G., Lowe, J. K., Geschwind, D. H., State, M. W., Martin, C. L., & Ledbetter, D. H. (2013) · Molecular Psychiatry · doi:10.1038/mp.2012.138 · Cited by 161 · see citing works
“…Project (AGP) sample, a collection of 996 patients with ASD from different countries; 5 and the Autism Genetic Resource Exchange (AGRE) study, 22,23 which focuses on studying multiplex families with ASD (that is, where two or more family members have ASD), including 1835 patients from 1105…”
BackgroundMethodHaasl, R. J., & Payseur, B. A. (2015) · Molecular Ecology · doi:10.1111/mec.13339 · Cited by 157 · see citing works
“2012), and large-scale copy number variants arise at a genomewide rate of 10 2 (Itsara et al. 2010).”
BackgroundAutism spectrum disorders: from genes to neurobiology
Jeremy Willsey, A., & State, M. W. (2015) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2014.10.015 · Cited by 145 · see citing works
Autism Spectrum Disorder Genetics and the Search for Pathological Mechanisms
Manoli, D. S., & State, M. W. (2021) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2020.20111608 · Cited by 151 · see citing works
Recurrent de novo mutations in neurodevelopmental disorders: properties and clinical implications
Wilfert, A. B., Sulovari, A., Turner, T. N., Coe, B. P., & Eichler, E. E. (2017) · Genome Medicine · doi:10.1186/s13073-017-0498-x · Cited by 144 · see citing works
“reported across four SNP microarray and WGS studies [8, 24, 26, 138].”
BackgroundSelf-citationThe challenges and importance of structural variation detection in livestock
Bickhart, D. M., & Liu, G. E. (2014) · Frontiers in Genetics · doi:10.3389/fgene.2014.00037 · Cited by 143 · see citing works
An evolving view of copy number variants
Lauer, S. L., & Gresham, D. (2019) · Current Genetics · doi:10.1007/s00294-019-00980-0 · Cited by 134 · see citing works
“Improved detection by genome sequencing has revealed how prevalent CNVs are in nature, and that de novo CNVs affect more base pairs of human DNA each generation than point mutations (Itsara et al. 2010).”
BackgroundRecent developments in the genetics of autism spectrum disorders
Murdoch, J. D., & State, M. W. (2013) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2013.02.003 · Cited by 132 · see citing works
Exploring the role of copy number variants in human adaptation
Iskow, R. C., Gökçümen, Ö., & Lee, C. (2012) · Trends in Genetics · doi:10.1016/j.tig.2012.03.002 · Cited by 128 · see citing works
“Furthermore, there is a significant depletion of larger CNVs (>500 kb), which are more likely to overlap with functional regions and potentially disrupt epigenetic patterns, indicating strong purifying selection [37].”
BackgroundRees, E., Walters, J., Chambert, K., O'Dushlaine, C., Szatkiewicz, J., Richards, A. L., Georgieva, L., Mahoney‐Davies, G., Legge, S. E., Moran, J. L., et al. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt540 · Cited by 129 · see citing works
“500 kb CNVs occur de novo (21) as do 9–80% of those at specific schizophrenia-associated loci (15,22).”
BackgroundCharacteristics of de novo structural changes in the human genomePreprint
Kloosterman, W. P., Francioli, L. C., Hormozdiari, F., Marschall, T., Hehir‐Kwa, J. Y., Abdellaoui, A., Lameijer, E.-W., Moed, M. H., Koval, V., Renkens, I., et al. (2015) · Genome Research · doi:10.1101/gr.185041.114 · Cited by 125 · see citing works
“03forCNVslargerthan500bp(Conrad et al. 2010) and 0.012 for CNVs larger than 100 kbp (Itsara et al. 2010) per haploid genome.”
InfluentialSelf-citationBeal, M. A., Yauk, C. L., & Marchetti, F. (2017) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2017.04.001 · Cited by 125 · see citing works
Rare Copy Number Variants Contribute to Congenital Left-Sided Heart Disease
Hitz, M., Perreault, L. L., Marshall, C. R., Zada, Y. F., Davies, R., Yang, S. W., Lionel, A. C., D’Amours, G., Lemyre, E., Cullum, R., et al. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002903 · Cited by 125 · see citing works
“Strengths of our study comprise the stringent, uniform CNV analysis workflow for both the LS-CHD as well as the control cohort, which yielded similar results in respect to reported de novo CNV transmission rates [40].”
ResultThe genetic variability and commonality of neurodevelopmental disease
Coe, B. P., Girirajan, S., & Eichler, E. E. (2012) · American Journal of Medical Genetics Part C Seminars in Medical Genetics · doi:10.1002/ajmg.c.31327 · Cited by 124 · see citing works
“Only 8% of the general population carries a CNV greater than 500 kbp (as opposed to 25% for patients with developmental delay) [Itsara et al., 2010;Cooper et al., 2011].”
BackgroundResultInfluentialSelf-citationLu, P., Han, X., Qi, J., Yang, J., Wijeratne, A., Li, T., & Mā, H. (2011) · Genome Research · doi:10.1101/gr.127522.111 · Cited by 124 · see citing works
“…estimated; for example, one study found that the rate for total genome-wide new large CNVs (>100 Kb) is about 1.2 3 10 2 per genome per transmission (Itsara et al. 2010), and another study reported that most of over 4000 CNVs analyzed had individual rates of ;10 5 per generation (Fu et al. 2010).”
BackgroundInfluentialAZFc Deletions and Spermatogenic Failure: A Population-Based Survey of 20,000 Y Chromosomes
Rozen, S., Marszalek, J. D., Irenze, K., Skaletsky, H., Brown, L. G., Oates, R. D., Silber, S. J., Ardlie, K., & Page, D. C. (2012) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2012.09.003 · Cited by 123 · see citing works
Czyż, W., Morahan, J., Ebers, G., & Ramagopalan, S. (2012) · BMC Medicine · doi:10.1186/1741-7015-10-93 · Cited by 120 · see citing works
“Copy number variants (CNVs) accounting for a major portion of the genome, are highly polymorphic and relatively unstable, with mutation rates 100 to 10 000 times higher than single base substitutions[52].”
BackgroundGardner and Sutherland's Chromosome Abnormalities and Genetic Counseling
Gardner, R. J. M., & Amor, D. J. (2018) · doi:10.1093/med/9780199329007.001.0001 · Cited by 118 · see citing works
Breman, A. M., Pursley, A. N., Hixson, P. M., Bi, W., Ward, P. A., Bacino, C. A., Shaw, C. A., Lupski, J. R., Beaudet, A. L., Patel, A., et al. (2012) · Prenatal Diagnosis · doi:10.1002/pd.3861 · Cited by 118 · see citing works
“Conversely, the de novo occurrence of a CNV is not absolute evidence of its pathogenicity, especially considering recent data that estimates the genome-wide de novo CNV rate to be close to 1% per transmission per generation.(69)”
BackgroundPoot, M., & Haaf, T. (2015) · Molecular Syndromology · doi:10.1159/000438812 · Cited by 115 · see citing works
An Organismal CNV Mutator Phenotype Restricted to Early Human Development
Liu, P., Yuan, B., Carvalho, C. M. B., Wüster, A., Walter, K., Zhang, L., Gambin, T., Chong, Z., Campbell, I. M., Coban‐Akdemir, Z., et al. (2017) · Cell · doi:10.1016/j.cell.2017.01.037 · Cited by 115 · see citing works
Self-citationSajan, S. A., Fernández, L., Nieh, S. E., Rider, E., Bukshpun, P., Wakahiro, M. L. J., Christian, S. L., Rivière, J., Sullivan, C. T., Sudi, J., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003823 · Cited by 113 · see citing works
“De novo CNVs in autism were compiled from several studies and are listed in Table S6 [34–39].”
MethodHigh mutational rates of large-scale duplication and deletion in Daphnia pulexPreprint
Keith, N., Tucker, A. E., Jackson, C. E., Sung, W., Lucas‐Lledó, J. I., Schrider, D. R., Schaack, S., Dudycha, J. L., Ackerman, M. S., Younge, A., et al. (2015) · Genome Research · doi:10.1101/gr.191338.115 · Cited by 113 · see citing works
“Because large changes in the order, orientation, and copy number of genomic elements can affect transcriptional regulators and gene dosage, large-scale CNVs can be highly deleterious and may be subject to higher levels of purifying selection than single-base mutations (Itsara et al. 2010).”
BackgroundHochstenbach, R., Buizer‐Voskamp, J. E., Vorstman, J. A. S., & Ophoff, R. A. (2011) · Cytogenetic and Genome Research · doi:10.1159/000332928 · Cited by 110 · see citing works
“simplex families) is significantly higher than the 1–2% in the general population [Sebat et al., 2007; Marshall et al., 2008; Qiao et al., 2009; Itsara et al., 2010].”
BackgroundMethodInfluentialApproaches for identifying germ cell mutagens: Report of the 2013 IWGT workshop on germ cell assays☆
Yauk, C. L., Aardema, M. J., van Benthem, J., Bishop, J. B., Dearfield, K. L., DeMarini, D. M., Dubrova, Y. E., Honma, M., Lupski, J. R., Marchetti, F., et al. (2015) · Mutation Research/Genetic Toxicology and Environmental Mutagenesis · doi:10.1016/j.mrgentox.2015.01.008 · Cited by 112 · see citing works
Assessment of megabase-scale somatic copy number variation using single-cell sequencingPreprint
Knouse, K. A., Wu, J., & Amon, A. (2016) · Genome Research · doi:10.1101/gr.198937.115 · Cited by 112 · see citing works
“Not surprisingly, large CNVs experience negative selection, and their existence in a population is largely due to de novo events (Itsara et al. 2010).”
BackgroundThe developmental transcriptome of the human brain: implications for neurodevelopmental disorders
Tebbenkamp, A. T. N., Willsey, A. J., State, M. W., & Šestan, N. (2014) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000069 · Cited by 110 · see citing works
Huguet, G., Schramm, C., Douard, E., Jiang, L., Labbe, A., Tihy, F., Mathonnet, G., Nizard, S., Lemyre, E., Mathieu, A., et al. (2018) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2018.0039 · Cited by 96 · see citing works
Hehir‐Kwa, J. Y., Rodríguez‐Santiago, B., Vissers, L. E. L. M., de Leeuw, N., Pfundt, R., Buitelaar, J. K., Jurado, L. A. P., & Veltman, J. A. (2011) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2011-100147 · Cited by 107 · see citing works
“The overall process summarising the rare de novo CNV identification is illustrated in supplemental figure S1.”
BackgroundResultInfluentialKu, C., Polychronakos, C., Tan, E., Naidoo, N., Yudi Pawitan, Y., Roukos, D. H., Mort, M. E., & Cooper, D. N. (2012) · Molecular Psychiatry · doi:10.1038/mp.2012.58 · Cited by 97 · see citing works
Implementation of genomic arrays in prenatal diagnosis: The Belgian approach to meet the challenges
Vanakker, O. M., Vilain, C. N., Janssens, K., der Aa, N. V., Smits, G., Bandelier, C., Blaumeiser, B., Bulk, S., Caberg, J., Leener, A. D., et al. (2014) · European Journal of Medical Genetics · doi:10.1016/j.ejmg.2014.02.002 · Cited by 98 · see citing works
De Novo Rates and Selection of Schizophrenia-Associated Copy Number Variants
Rees, E., Moskvina, V., Owen, M. J., O'Donovan, M. C., & Kirov, G. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.07.011 · Cited by 94 · see citing works
“To calculate the variances of q and s for each schizophrenia locus we used the equation p(1-p)/n as described in Itsara et al. (2010) (58).”
Population-Scale Sequencing Data Enable Precise Estimates of Y-STR Mutation Rates
Willems, T., Gymrek, M., Poznik, G. D., Tyler‐Smith, C., The 1000 Genomes Project Chromosome Y Group, & Erlich, Y. (2016) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2016.04.001 · Cited by 97 · see citing works
“A host of studies have evaluated the mutation rates of nearly every type of genetic variation, ranging from SNPs(4-7) and short indels(8) to large structural variations.(9) These sequencing studies have concluded that approximately 50-100 de novo mutations arise each generation, most of which are point mutations.”
BackgroundPathogenic or not? Assessing the clinical relevance of copy number variants
Hehir‐Kwa, J. Y., Pfundt, R., Veltman, J. A., & de Leeuw, N. (2013) · Clinical Genetics · doi:10.1111/cge.12242 · Cited by 93 · see citing works
“Precise estimates of the de novo CNV mutation rate varies, but it has been estimated to be 1 in 50 individuals (17, 18).”
BackgroundDauber, A. N., Golzio, C., Guenot, C., Jodelka, F. M., Kibæk, M., Kjærgaard, S., Leheup, B., Martinet, D., Nowaczyk, M. J. M., Rosenfeld, J. A., et al. (2013) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2013.09.010 · Cited by 90 · see citing works
Population-Genetic Properties of Differentiated Human Copy-Number Polymorphisms
Campbell, C. D., Sampas, N., Tsalenko, A., Sudmant, P. H., Kidd, J. M., Malig, M., Vu, T. H., Vives, L., Tsang, P. W. K., Bruhn, L., et al. (2011) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2011.02.004 · Cited by 91 · see citing works
Self-citationvan Daalen, E., Kemner, C., Verbeek, N. E., van der Zwaag, B., Dijkhuizen, T., Rump, P., Houben, R. H., Slot, R. V. ‘., de Jonge, M. V., Staal, W., et al. (2011) · Neurogenetics · doi:10.1007/s10048-011-0297-2 · Cited by 86 · see citing works
“In a recent study of the Autism Genetic Resource Exchange dataset, Itsara and co-workers found a de novo CNV rate in the order of 2% and concluded that de novo CNVs may contribute a significant risk for autism [18].”
BackgroundA genetic model for neurodevelopmental disease
Coe, B. P., Girirajan, S., & Eichler, E. E. (2012) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2012.04.007 · Cited by 79 · see citing works
Self-citationFirst glimpses of the neurobiology of autism spectrum disorder
Sanders, S. J. (2015) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2015.10.002 · Cited by 84 · see citing works
New Ethical Issues for Genetic Counseling in Common Mental Disorders
Gershon, E. S., & Alliey‐Rodriguez, N. (2013) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2013.12121558 · Cited by 85 · see citing works
De novo copy number variants are associated with congenital diaphragmatic hernia
Yu, L., Wynn, J., Ma, L., Guha, S., Mychaliska, G. B., Crombleholme, T. M., Azarow, K. S., Lim, F. Y., Chung, D. H., Potoka, D. A., et al. (2012) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2012-101135 · Cited by 83 · see citing works
Gene Copy-Number Variation in Haploid and Diploid Strains of the Yeast Saccharomyces cerevisiae
Zhang, H., Zeidler, A. F., Song, W., Puccia, C. M., Malc, E. P., Greenwell, P. W., Mieczkowski, P. A., Petes, T. D., & Argueso, J. L. (2013) · Genetics · doi:10.1534/genetics.112.146522 · Cited by 78 · see citing works
Germline Copy Number Variations and Cancer Predisposition
Krepischi, A. C. V., Pearson, P. L., & Rosenberg, C. (2012) · Future Oncology · doi:10.2217/fon.12.34 · Cited by 77 · see citing works
Genetic architecture of reciprocal CNVs
Golzio, C., & Katsanis, N. (2013) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2013.04.013 · Cited by 75 · see citing works
LINE‐1 retrotransposons in healthy and diseased human brain
Suarez, N. A., Macia, Á., & Muotri, A. R. (2017) · Developmental Neurobiology · doi:10.1002/dneu.22567 · Cited by 74 · see citing works
“de novo copy-number variants (CNVs) (Szatmari et al. 2007; Sebat et al. 2007; Ronald and Hoekstra 2011; Pinto et al. 2010; Marshall et al. 2008; Levy et al. 2011; Itsara et al. 2010; Glessner et al. 2009; Bucan et al. 2009).”
Rare Copy Number Variants Are a Common Cause of Short Stature
Zahnleiter, D., Uebe, S., Ekici, A. B., Hoyer, J., Wiesener, A., Wieczorek, D., Kunstmann, E., Reis, A., Doerr, H.-G., Rauch, A. M., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003365 · Cited by 70 · see citing works
“As we expected 6610(23) de novo CNVs per haploid genome per generation in the healthy population [20], the Table 1.”
BackgroundPoot, M., van der Smagt, J. J., Brilstra, E. H., & Bourgeron, T. (2011) · Cytogenetic and Genome Research · doi:10.1159/000334064 · Cited by 69 · see citing works
“…duplications, have been detected with relatively high frequencies by targeted studies of selected patient populations [Koolen et al., 2006; Sharp et al., 2006; Mefford et al., 2008; Slavotinek, 2008] and also in the healthy population [Itsara et al., 2009; Conrad et al., 2010; Itsara et al., 2010].”
BackgroundResultBreckpot, J., Thienpont, B., Arens, Y. H. J. M., Tranchevent, L.-C., Vermeesch, J. R., Moreau, Y., Gewillig, M. H. M. L., & Devriendt, K. (2011) · Cytogenetic and Genome Research · doi:10.1159/000331272 · Cited by 67 · see citing works
“Novel copy number profiling techniques such as aCGH revealed that this no longer holds true at higher resolution: several examples from literature have demonstrated that de novo CNVs found in patients are not necessarily causal [Itsara et al., 2010; Vermeesch et al., 2011], and imbalances 1 100 kb have shown to arise…”
BackgroundDiversity and consequences of structural variation in the human genome
Collins, R. L., & Talkowski, M. E. (2025) · Nature Reviews Genetics · doi:10.1038/s41576-024-00808-9 · Cited by 71 · see citing works
Horpaopan, S., Spier, I., Zink, A. M., Altmüller, J., Holzapfel, S., Laner, A., Vogt, S. L., Uhlhaas, S., Heilmann‐Heimbach, S., Stienen, D., et al. (2014) · International Journal of Cancer · doi:10.1002/ijc.29215 · Cited by 65 · see citing works
DNA polymerase stalling at structured DNA constrains the expansion of short tandem repeats
Murat, P., Guilbaud, G., & Sale, J. (2020) · bioRxiv · doi:10.1186/s13059-020-02124-x · Cited by 57 · see citing works
Sequence and Structural Diversity of Mouse Y Chromosomes
Morgan, A. P., & de Villena, F. P. (2017) · Molecular Biology and Evolution · doi:10.1093/molbev/msx250 · Cited by 62 · see citing works
“2006), and places the mouse Yq among the most labile sequences known in mouse or human (Egan et al. 2007; Itsara et al. 2010; Morgan, Holt, et al. 2016).”
InfluentialLessons from Model Organisms: Phenotypic Robustness and Missing Heritability in Complex Disease
Queitsch, C., Carlson, K. D., & Girirajan, S. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1003041 · Cited by 61 · see citing works
“This observation led to the hypothesis that multiplex autism is due to an inherited predisposition in addition to other co-occurring mutations, including CNVs [3,76].”
BackgroundInfluentialAhn, J. W., Bint, S., Bergbaum, A., Mann, K., Hall, R. P., & Ogilvie, C. M. (2013) · Molecular Cytogenetics · doi:10.1186/1755-8166-6-16 · Cited by 60 · see citing works
Harper, K. M., Hiramoto, T., Tanigaki, K., Kang, G., Suzuki, G., Trimble, W. S., & Hiroi, N. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds180 · Cited by 59 · see citing works
Dong, T., He, J., Wang, S., Wang, L., Cheng, Y., & Zhong, Y. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1602152113 · Cited by 60 · see citing works
Arlt, M. F., Rajendran, S., Birkeland, S. R., Wilson, T. E., & Glover, T. W. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002981 · Cited by 56 · see citing works
“05 per meiosis [6,15,16,17].”
Cyr, A. B., Nimmakayalu, M. A., Longmuir, S. Q., Patil, S. R., Keppler‐Noreuil, K. M., & Shchelochkov, O. A. (2011) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.34120 · Cited by 55 · see citing works
Lawson, L. P., Joshi, R., Barbaro, J., & Dissanayake, C. (2018) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-018-3516-y · Cited by 56 · see citing works
The fine-scale architecture of structural variants in 17 mouse genomes
Yalcin, B., Wong, K., Bhomra, A., Goodson, M., Keane, T., Adams, D. J., & Jonathan Flint, C. (2012) · Genome biology · doi:10.1186/gb-2012-13-3-r18 · Cited by 53 · see citing works
Leveraging large genomic datasets to illuminate the pathobiology of autism spectrum disorders
Searles, V. B., Wang, B., & State, M. W. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-020-0768-y · Cited by 52 · see citing works
ESRRA-C11orf20 Is a Recurrent Gene Fusion in Serous Ovarian Carcinoma
Salzman, J., Marinelli, R. J., Wang, P., Green, A. E., Nielsen, J. S., Nelson, B. H., Drescher, C. W., & Brown, P. O. (2011) · PLoS Biology · doi:10.1371/journal.pbio.1001156 · Cited by 52 · see citing works
“Several characteristics of the ESRRA-C11orf20 rearrangement reinforce themes emerging from high-resolution studies of both normal human genetic variation [33,34] and cancer-specific genomic alterations.”
BackgroundNon‐syndromic language delay in a child with disruption in the Protocadherin11X/Y gene pair
Speevak, M. D., & Farrell, S. A. (2011) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.31186 · Cited by 49 · see citing works
“Themutation rate of de novo copy number changes of less than 500Kb in size in this population is 3–10 times the rate seen in unaffected controls [Lakshmi et al., 2007; Itsara et al., 2010].”
Background
- Authors
- Itsara, A., Wu, H., Smith, J. D., Nickerson, D. A., Romieu, I., London, S. J., & Eichler, E. E.
- Affiliations
- University of Washington (US)
- National Institutes of Health (US)
- Instituto Nacional de Salud Pública (MX)
- Howard Hughes Medical Institute (US)
- ORCID
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2010-09-14
- Volume
- 20
- Issue
- 11
- Pages
- 1469-1481
- ISSN
- 1088-9051 (ISSN-L)
- PMC
- PMC2963811
- OpenAlex
- W2158959870
- Cited by
- 328
- References
- 65
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 9 · 2023: 9 · 2022: 8 · 2021: 14 · 2020: 16 · 2019: 10 · 2018: 43 · 2017: 19 · 2016: 30 · 2015: 25 · 2014: 25 · 2013: 36 · 2012: 43
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genome Research (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Department of Health and Human Services
- Autism Speaks
- Simons Foundation
- Simons Foundation Autism Research Initiative (137578)
- Consejo Nacional de Ciencia y Tecnología (26206-M)
- National Institutes of Health (26206-M)
- National Institute of Mental Health (U24MH081810)
- National Institute of General Medical Sciences (T32GM007266)
- National Institute of Environmental Health Sciences (26206-M, ES049019, ES025045, ZIAES049019, ZIAES025045)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
- Keywords
- copy number variation, de novo mutations, mutation rate, purifying selection, mutation-selection balance, autism spectrum disorder, human pedigrees, SNP array, parental bias
- MeSH terms
- Adolescent, Asthma, Autistic Disorder, Base Sequence, Child, Child, Preschool, Female, Gene Frequency, Humans, Male, Pedigree, Selection, Genetic, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Genome-Wide Association Study, DNA Copy Number Variations
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