Segmental Duplications and Genetic Disease

Abstract The human genome contains many different types of repetitive DNA elements that vary by size and copy number. Segmental duplications (SDs) are one such class of repetitive elements that are relatively large in size, have low copy number in the genome and their copies share high levels of sequence identity with each other. These characteristic features of SDs make them excellent substrates for genomic rearrangements, resulting from aberrant recombination between the highly identical copies. Several of the genomic rearrangements mediated by SDs lead to copy number variations of large genomic regions containing many genes. Consequently, SD‐mediated rearrangements are often associated with genetic diseases that manifest as syndromes characterised by multiple congenital anomalies due to dosage imbalance of one or more genes. Key Concepts Segmental duplications are repetitive DNA elements in the human genome. Segmental duplications mediate genomic rearrangements associated with many genomic diseases. Segmental duplications mediate genomic rearrangements via nonallelic homologous recombination (NAHR), or they can stimulate or promote rearrangements via nonhomologous end‐joining (NHEJ) or replication‐based mechanism (RBM). Segmental duplications have been associated with both recurrent and nonrecurrent chromosomal rearrangements including microdeletions, microduplications, translocations, inversions and other complex rearrangements. Segmental duplications have played an important role in the human genome evolution, genetic variation and disease predisposition.