Genomic Structural Variants

Volume 838 of the series Methods in Molecular Biology pp 1-27


What Have Studies of Genomic Disorders Taught Us About Our Genome?

  • Alexandra D. SimmonsAffiliated withBiology Department, University of St Thomas
  • , Claudia M. B. CarvalhoAffiliated withDepartment of Molecular and Human Genetics, Baylor College of Medicine
  • , James R. LupskiAffiliated withDepartment of Molecular and Human Genetics, Baylor College of MedicineDepartment of Pediatrics, Baylor College of MedicineTexas Children’s Hospital Email author 

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The elucidation of genomic disorders began with molecular technologies that enabled detection of genomic changes which were (a) smaller than those resolved by traditional cytogenetics (less than 5 Mb) and (b) larger than what could be determined by conventional gel electrophoresis. Methods such as pulsed field gel electrophoresis (PFGE) and fluorescent in situ hybridization (FISH) could resolve such changes but were limited to locus-specific studies. The study of genomic disorders has rapidly advanced with the development of array-based techniques. These enabled examination of the entire human genome at a higher level of resolution, thus allowing elucidation of the basis of many new disorders, mechanisms that result in genomic changes that can result in copy number variation (CNV), and most importantly, a deeper understanding of the characteristics, features, and plasticity of our genome. In this chapter, we focus on the structural and architectural features of the genome, which can potentially result in genomic instability, delineate how mechanisms, such as NAHR, NHEJ, and FoSTeS/MMBIR lead to disease-causing rearrangements, and briefly describe the relationship between the leading methods presently used in studying genomic disorders. We end with a discussion on our new understanding about our genome including: the contribution of new mutation CNV to disease, the abundance of mosaicism, the extent of subtelomeric rearrangements, the frequency of de novo rearrangements associated with sporadic birth defects, the occurrence of balanced and unbalanced translocations, the increasing discovery of insertional translocations, the exploration of complex rearrangements and exonic CNVs. In the postgenomic era, our understanding of the genome has advanced very rapidly as the level of technical resolution has become higher. This leads to a greater understanding of the effects of rearrangements present both in healthy subjects and individuals with clinically relevant phenotypes.

Key words

Copy number variation Recombination Gene dosage Mosaicism Insertional translocation Comparative genomic hybridization