Structural Variation in the Human Genome and its Role in Disease

Department of Molecular, Baylor College of Medicine, Houston, Texas 77030, USA.
Annual review of medicine (Impact Factor: 12.93). 02/2010; 61(1):437-55. DOI: 10.1146/annurev-med-100708-204735
Source: PubMed


During the last quarter of the twentieth century, our knowledge about human genetic variation was limited mainly to the heterochromatin polymorphisms, large enough to be visible in the light microscope, and the single nucleotide polymorphisms (SNPs) identified by traditional PCR-based DNA sequencing. In the past five years, the rapid development and expanded use of microarray technologies, including oligonucleotide array comparative genomic hybridization and SNP genotyping arrays, as well as next-generation sequencing with "paired-end" methods, has enabled a whole-genome analysis with essentially unlimited resolution. The discovery of submicroscopic copy-number variations (CNVs) present in our genomes has changed dramatically our perspective on DNA structural variation and disease. It is now thought that CNVs encompass more total nucleotides and arise more frequently than SNPs. CNVs, to a larger extent than SNPs, have been shown to be responsible for human evolution, genetic diversity between individuals, and a rapidly increasing number of traits or susceptibility to traits; such conditions have been referred to as genomic disorders. In addition to well-known sporadic chromosomal microdeletion syndromes and Mendelian diseases, many common complex traits including autism and schizophrenia can result from CNVs. Both recombination- and replication-based mechanisms for CNV formation have been described.

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    • "A similar proportion of patients exhibit genetic intellectual disability syndromes such as Fragile X syndrome, Rett's syndrome, tuberous sclerosis, Joubert's syndrome, and more (review Geschwind 2008). Over the last decade, mainly because of the advent of exome sequencing, several thousands of genes have been implicated in this disease (Iossifov et al. 2012; Neale et al. 2012; O'Roak et al. 2012a,b; Pagnamenta et al. 2012; Sanders et al. 2012; Talkowski et al. 2012; Casanova 2014; Fromer et al. 2014; Iossifov et al. 2014; Stessman et al. 2014; Butler et al. 2015; Turner et al. 2015; Michaelson et al. 2012) (reviews Beaudet 2007; Abrahams and Geschwind 2008; Geschwind 2008; van de Lagemaat and Grant 2010; Stankiewicz and Lupski 2010; Miles 2011; Schaaf and Zoghbi 2011; Murdoch and State 2013; Stessman et al. 2014; Ronemus et al. 2014; Jeste and Geschwind 2014). The discovery of many genes has been facilitated by the Simons Simplex Collection (Fischbach and Lord 2010), and the accumulating data can be found in the Simons Foundation Autism Research Initiative (SFARI) web site ( "
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    ABSTRACT: Autism Spectrum Disorders (ASD) encompass a group of neurodevelopmental diseases that demonstrate strong heritability, however the inheritance is not simple and many genes have been associated with these disorders. ASD is regarded as a neurodevelopmental disorder, and abnormalities at different developmental stages are part of the disease etiology. This review provides a general background on neuronal migration during brain development and discusses recent advancements in the field connecting ASD and aberrant neuronal migration. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 10/2015; DOI:10.1111/jnc.13403 · 4.28 Impact Factor
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    • "Early studies of 22q11.2 deletions foreshadowed a more general role for rare CNV in understanding the global genetic architecture of schizophrenia in the population (Kirov et al. 2012; Costain et al. 2013; Stankiewicz and Lupski 2010; Lowther et al. 2015; Bassett et al. 2010; Hochstenbach et al. 2011; Costain and Bassett 2012; Zarrei et al. 2015; Rees et al. 2014). "
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    ABSTRACT: Chromosome 22q11.2 microdeletions impart a high but incomplete risk for schizophrenia. Possible mechanisms include genome-wide effects of DGCR8 haploinsufficiency. In a proof-of-principle study to assess the power of this model, we used high quality whole-genome sequencing of nine individuals with 22q11.2 deletions and extreme phenotypes (schizophrenia, or no psychotic disorder at age >50 years). The schizophrenia group had a greater burden of rare damaging variants impacting protein-coding neurofunctional genes, including genes involved in neuron projection (nominal p=0.02, joint burden of three variant types). Variants in the intact 22q11.2 region were not major contributors. Restricting to genes affected by a DGCR8 mechanism tended to amplify between-group differences. Damaging variants in highly conserved long intergenic non-coding RNA genes were also enriched in the schizophrenia group (nominal p=0.04). The findings support the 22q11.2 deletion model as a threshold-lowering first hit for schizophrenia risk. If applied to a larger and thus better-powered cohort, this appears to be a promising approach to identify genome-wide rare variants in coding and non-coding sequence that perturb gene networks relevant to idiopathic schizophrenia. Similarly designed studies exploiting genetic models may prove useful to help delineate the genetic architecture of other complex phenotypes.
    G3-Genes Genomes Genetics 09/2015; 5(11). DOI:10.1534/g3.115.021345 · 3.20 Impact Factor
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    • ", 2009 ; Craddock et al . , 2010 ; Stankiewicz and Lupski , 2010 ; Alvarez and Akey , 2012 ) . In plants , copy number variation has been identified in multiple species and demonstrated to affect important agronomic traits ( Horiguchi et al . "
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    ABSTRACT: Altering gene dosage through variation in gene copy number is a powerful approach to addressing questions regarding gene regulation, quantitative trait loci, and heterosis, but one that is not easily applied to sexually transmitted species. Elite poplar (Populus spp) varieties are created through interspecific hybridization, followed by clonal propagation. Altered gene dosage relationships are believed to contribute to hybrid performance. Clonal propagation allows for replication and maintenance of meiotically unstable ploidy or structural variants and provides an alternative approach to investigating gene dosage effects not possible in sexually propagated species. Here, we built a genome-wide structural variation system for dosage-based functional genomics and breeding of poplar. We pollinated Populus deltoides with gamma-irradiated Populus nigra pollen to produce >500 F1 seedlings containing dosage lesions in the form of deletions and insertions of chromosomal segments (indel mutations). Using high-precision dosage analysis, we detected indel mutations in ∼55% of the progeny. These indels varied in length, position, and number per individual, cumulatively tiling >99% of the genome, with an average of 10 indels per gene. Combined with future phenotype and transcriptome data, this population will provide an excellent resource for creating and characterizing dosage-based variation in poplar, including the contribution of dosage to quantitative traits and heterosis. © 2015 American Society of Plant Biologists. All rights reserved.
    The Plant Cell 08/2015; 27(9):tpc.15.00349. DOI:10.1105/tpc.15.00349 · 9.34 Impact Factor
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