Segmental duplications: an 'expanding' role in genomic instability and disease

Key Points Segmental duplications are a class of repetitive DNA element in the human genome. Segmental duplications have various sizes and organizational configurations. The different copies of a segmental duplication can share 96–99% nucleotide sequence identity with each other. Segmental duplications have been implicated in the aetiology of chromosomal rearrangements that are associated with several genomic disorders. The chromosomal rearrangements include deletions, interstitial duplications, inversions, supernumerary marker chromosomes and translocations. The genomic disorders include DiGeorge and velocardiofacial syndromes, cat eye syndrome, Prader–Willi and Angelman syndromes, Williams–Beuren syndrome and many more. Many models are proposed to explain the mechanisms involved in segmental-duplication-mediated rearrangements. All of these models are based on misalignment between non-allelic segmental duplications, followed by recombination. Segmental duplications represent an under-appreciated source of genetic change in the human genome. The knowledge that specific genetic diseases are caused by recurrent chromosomal aberrations has indicated that genomic instability might be directly related to the structure of the regions involved. The sequencing of the human genome has directed significant attention towards understanding the molecular basis of such recombination 'hot spots'. Segmental duplications have emerged as a significant factor in the aetiology of disorders that are caused by abnormal gene dosage. These observations bring us closer to understanding the mechanisms and consequences of genomic rearrangement.