Segmental duplications are continuous portions of DNA greater than 1 kb in size that occur in two or more copies per haploid genome with the copies sharing more than 90% sequence identity (Scherer et al. 2007). In tandem duplications the duplicated segment of DNA is found immediately adjacent to the ancestral copy in the same orientation. Low

copy repeats (LCRs) refers to sequences of 10 kb or more in size, with at least 95% sequence identity, which are separated by 50 kb to 10 Mb of intervening sequence (Stankiewicz and Lupski 2002). Segmental duplications can be LCRs. A duplicon is a duplication traceable to an ancestral or donor location (Bailey and Eichler 2006).

Variation Project ( edu/) and in the Database of Genomic Variants (http://

An estimated 50% of duplications are strictly intrachromosomal. In comparison with interchromosomal duplications, intrachromosomal duplications tend to be larger (18.5 kb versus 14.8 kb) and a higher proportion contain complete genes (6.2% versus 1.3% for known genes) (Zhang et al. 2005a). Within the long arm of chromosome 22, for example, 9.1% of the sequence has been identified as being involved in segmental duplications: 3.9% occurred between non-homologous chromosomes (interchromosomal) while 6.4% was intrachromosomal (Fig. 6.3) (Bailey et al. 2001).

Analysis of the finished sequence of chromosome 15 showed 8.8% of the euchromatic sequence was composed of segmental duplications of which 50% were purely intrachromosomal, 20% interchromosomal, and 30% both intra- and interchromosomal (Zody et al. 2006). The segmental duplications were broadly clustered into two regions, on the proximal and distal ends of 15q. The 15q11-q13 region is particularly prone to chromosomal rearrangements with recombination among segmental duplications, and associated with a variety of deletions, duplications, triplications, inversions, translocations, and marker chromosomes (Fig. 5.4; Section 5.2.6).

Approximately one-third of duplicated genes are arranged in tandem with a heterogeneous distribution among chromosomes (Fig. 6.4) (Shoja and Zhang 2006). There are thought to be 902 tandemly arranged gene clusters in the human genome, of which 68% have two genes in the tandem array; together, tandemly arranged genes make up 14-17% of all genes in the genome (Shoja and Zhang 2006).

6.2.2 Pericentromeric and subtelomeric regions are hotspots for segmental duplications

In terms of chromosomal regions, pericentromeric regions contain a large proportion of segmental duplications: within 5 Mb of the centromere, 22.7% of bases are segmentally duplicated and thought to account for about one-third of all human duplicated sequence (47.2 out of 152 Mb) (She et al. 2004). A gradient is seen towards the centromere of increasing numbers of interchromo-somal duplications and reduced transcriptional diversity. The rate of duplicative transposition of segments of DNA towards pericentromeric regions has been estimated at six to seven events per million years of primate evolution (She et al. 2004).

A two step process is postulated for the generation of such segmental duplications with an initial duplication event to a pericentromeric region, followed by

Duplicative Transposition
Figure 6.1 Interchromosomal duplications revealed from sequencing the human genome. An example is shown for chromosome 7 with lines to other chromosomes indicating homologous blocks, each comprising at least three genes. From Venter et al. (2001), reprinted with permission from AAAS.

Interchromosomal duplication

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