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.

Genome-wide copy number variations in a large cohort of bantu African children

“…CNVs can arise from genomic rearrangements such as deletions, duplications, insertions, inversions, or translocations [ 1 – 3 ] and have been implicated in the etiology of Mendelian disorders as well as complex traits [ 4 ]. Several pediatric disorders resulting from CNVs such as the 22q11 deletion syndrome, the Williams-Beuren syndrome, resulting from a microdeletion in 7q11.23, and the 15q13.3 microdeletion syndromes are characterized by the occurrence of multiple congenital anomalies, including intellectual and developmental disabilities, congenital heart defects, craniofacial dysmorphisms, or abnormalities in the development of other tissues and organs [ 5 – 10 ]. These types of CNVs can alter copy number of dosage-sensitive genes or disrupt regulatory elements, which result in pathogenic outcomes observed in patients [ 11 ].…”

Genome-wide Copy Number Variations in a Large Cohort of Bantu African Children

“…The 22q11 deletion syndrome (previously referred to as DiGeorge/Velocardiofacial Syndrome), the Williams-Beuren syndrome resulting from a microdeletion in 7q11. 23, and the 15q13.3 microdeletion syndrome are examples of disorders that belong to this group of CNV-mediated disorders (8)(9)(10). CNVs may also play a role in the etiology of common, complex diseases and traits including diabetes, asthma, HIV susceptibility, cancer, and phenotypes in immune and environmental responses (11)(12)(13)(14)(15).…”