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.

40 Reads
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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; DOI:10.1534/g3.115.021345 · 3.20 Impact Factor
    • ", 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 . "
    [Show abstract] [Hide abstract]
    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; DOI:10.1105/tpc.15.00349 · 9.34 Impact Factor
  • Source
    • "On the other hand, in ∼ 14–18% of children with developmental delay, a CNV larger than 400 kb may be phenotypically significant [Cooper et al., 2011; Hochstenbach et al., 2011]. Taken together, all classes of germline SVs occur more frequently than germline single nucleotide variations (SNVs), they affect more nucleotides and may have a greater phenotypic impact than SNVs [Stankiewicz and Lupksi, 2010; Campbell and Eichler, 2013]. Complex chromosome rearrangements (CCRs) are a class of SVs that involve more than 2 chromosome breaks and result in exchanges of chromosomal segments. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Complex chromosome rearrangements (CCRs) are currently defined as structural genome variations that involve more than 2 chromosome breaks and result in exchanges of chromosomal segments. They are thought to be extremely rare, but their detection rate is rising because of improvements in molecular cytogenetic technology. Their population frequency is also underestimated, since many CCRs may not elicit a phenotypic effect. CCRs may be the result of fork stalling and template switching, microhomology-mediated break-induced repair, breakage-fusion-bridge cycles, or chromothripsis. Patients with chromosomal instability syndromes show elevated rates of CCRs due to impaired DNA double-strand break responses during meiosis. Therefore, the putative functions of the proteins encoded by ATM , BLM , WRN , ATR , MRE11 , NBS1 , and RAD51 in preventing CCRs are discussed. CCRs may exert a pathogenic effect by either (1) gene dosage-dependent mechanisms, e.g. haploinsufficiency, (2) mechanisms based on disruption of the genomic architecture, such that genes, parts of genes or regulatory elements are truncated, fused or relocated and thus their interactions disturbed – these mechanisms will predominantly affect gene expression – or (3) mixed mutation mechanisms in which a CCR on one chromosome is combined with a different type of mutation on the other chromosome. Such inferred mechanisms of pathogenicity need corroboration by mRNA sequencing. Also, future studies with in vitro models, such as inducible pluripotent stem cells from patients with CCRs, and transgenic model organisms should substantiate current inferences regarding putative pathogenic effects of CCRs. The ramifications of the growing body of information on CCRs for clinical and experimental genetics and future treatment modalities are briefly illustrated with 2 cases, one of which suggests KDM4C (JMJD2C) as a novel candidate gene for mental retardation.
    Molecular syndromology 08/2015; 6(3):109-133. DOI:10.1159/000438812.
Show more


40 Reads