Segmental Duplications: A Source of Diversity, Evolution and Disease


Genome mutations represent a source of variability on which selective pressure acts: negative changes are purged from the populations, whereas positive and neutral changes may be fixed. Segmental duplications (SDs) in the human genome trigger mutations such as structural rearrangements (duplications, deletions, inversions and translocations), thus playing a crucial role in human disease and genome evolution. Several human diseases (genomic disorders) are caused by non‐allelic homologous recombination (NAHR) between highly similar SDs, as well as gene‐containing SDs were crucial to survival and adaptation of human species during evolution. Moreover, both from a pathological and an evolutionary point of view, SDs represent critically important regions for acentric fragment rescue during neocentromerization process. In this light, disease and evolution can be considered as ‘two sides of the same coin’, where the coin represents the SD‐mediated chromosomal rearrangements.

Key Concepts

  • Segmental duplications (SDs) create variability in human genome.

  • Mediating non‐allelic homologous recombination (NAHR) segmental duplications mediate chromosomal unbalance.

  • Duplicated genes may show pattern of expression different from ancestral gene.

  • Segmental duplications are the remains of ancestral pericentromeric regions.

  • Neocentromere can generate at loci where ancestral centromere were located.

Keywords: genomic disorders; mammals; variability; polymorphisms; primates; neocentromere

Figure 1. Model representing the formation of copy number variants (CNVs, striped rectangles) and segmental duplications (SDs, solid colour rectangles). Regions harbouring highly identical SDs (green/blue rectangles) undergo NAHR. If not negatively selected, the created microdeletions and microduplications (rectangles with star) represent new CNVs and can be transmitted from generation to generation. The frequency of the duplicated sequence in the population may increase until it becomes fixed, creating a new SD (turquoise rectangle).
Figure 2. Outcomes of interchromosomal NAHR mediated by SDs. Non‐homologous chromosomes are coloured differently with the centromeres shown as black box. Blue and yellow boxes indicate highly identical segmental duplications and arrows indicate their orientation. Stable reciprocal translocations are originated by NAHR between interchromosomal SDs located on the same chromosomal arms (i.e. q‐arm to q‐arm) directly orientated (a) or on different chromosomal arms with inverted orientation (i.e. p‐arm to q‐arm) (b). Conversely, SDs located on the same chromosomal arms in inverted orientation (c) or on different chromosomal arms directly orientation (d) would lead to unstable dicentric and acentric chromosomes, resulting in chromosome breakage and loss, respectively.
Figure 3. Core duplicon model for segmental duplication formation. Duplicative transposition (Duplication event 1) creates a copy of the ancestral locus (core duplicon, CD, in green) to a new locus on the same chromosome, thus generating an intrachromosomal duplication. A following event of duplicative transposition (Duplication event 2) involving the CD and flanking single sequences (empty orange squares) moves these regions to a new locus on a non‐homologous chromosome, thus creating interchromosomal duplications. This step results in an increase of the segmental duplication size now composed by the CD (filled green square) plus flanking sequences (filled orange squares). An additional round of duplication (Duplication event 3) involving further flanking single sequences may create bigger and more complex intra‐ or interchromosomal segmental duplications. The new paralogous sequences share high similarity and can now promote non‐allelic homologous recombination. These events take place at multiple points during the speciation process (before and after) generating both lineage‐specific and shared duplication blocks between closely related species.


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Further Reading

Alkan C, Coe BP and Eichler EE (2011) Genome structural variation discovery and genotyping. Nature Reviews. Genetics 12: 363–376.

Beckmann JS, Estivill X and Antonarakis SE (2007) Copy number variants and genetic traits: closer to the resolution of phenotypic to genotypic variability. Nature Reviews. Genetics 8: 639–646.

Stankiewicz P (2010) Structural variation in the human genome and its role in disease. Annual Review of Medicine 61: 437–455.

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How to Cite close
Catacchio, Claudia R, Chiatante, Giorgia, Anaclerio, Fabio, and Ventura, Mario(Jan 2015) Segmental Duplications: A Source of Diversity, Evolution and Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0020838.pub2]