Intrachromosomal Duplications

Initial identification of chromosome-specific duplications often came about through the study of common microdeletion/micoduplication syndromes, such as Prader-Willi/Angelman syndromes, Williams-Beuren syndrome, Smith-Magenis syndrome, Charcot-Marie-Tooth disease type 1A, and DiGeorge/Velocardiofacial syndrome (5). As more of these syndromes were analyzed, it became apparent that the presence of large and highly homologous segmental duplications flanking these sites of rearrangement was a recurring theme. Available evidence suggests that homology between these duplicated sequences acts as a substrate for unequal meiotic recombination, leading to the deletion, duplication, or inversion of the intervening sequence (Fig. 1). Review of known genomic disorders caused by chromosome-specific duplications shows that these usually involve duplications that are more than 95% similar and 10-500 kb in length, separated by 50 kb to 4 Mb of DNA (5).

Although intrachromosomal duplications are found throughout the euchromatic portions of virtually every human chromosome, some chromosomes, such as 1, 9, 16, 17, and 22, show particularly high concentrations within their most proximal regions (2). In these cases the density of duplication can be such that little or no unique sequence occurs across relatively large stretches (300 kb to 4 Mb) of DNA. The organization of these regions can be complex, with large duplication blocks often composed of smaller modules, which have been derived from different genomic locations. This feature has often led to difficulties in characterizing these regions, necessitating the development of specialized methods to allow these regions to be successfully mapped and sequenced.

Many intrachromosomal duplications also share very high levels of sequence identity, with the majority having more than 95% identity between paralogous copies. In extreme cases, this level of nucleotide identity approaches the frequency of allelic variation found in the genome as a whole (approx 1 base per kilobase) (6). This property further confounds the mapping and identification of individual duplicated segments within the genome, and may also represent a significant impediment in the ability to distinguish true allelic polymorphism from paralogous genomic copies (7-9). Indeed, both gene and single nucleotide polymorphism annotation show significant improvements in accuracy when duplicated sequences are correctly defined within a genome assembly (10). Thus, the correct definition of segmental duplications is an important aspect of achieving high-quality genomic sequence (11).

Fig. 1. Segmental duplications mediate structural rearrangement. Misalignment of paralogous blocks of sequence during meiosis leads to unequal recombination and the deletion or duplication of the intervening sequence. These events may create structural polymorphisms or, if the genes (A,B,C) flanked by the duplications are dosage sensitive, genomic disease. O, centromere; TEL, telomere. (Reproduced with permission from ref. 95.)

Fig. 1. Segmental duplications mediate structural rearrangement. Misalignment of paralogous blocks of sequence during meiosis leads to unequal recombination and the deletion or duplication of the intervening sequence. These events may create structural polymorphisms or, if the genes (A,B,C) flanked by the duplications are dosage sensitive, genomic disease. O, centromere; TEL, telomere. (Reproduced with permission from ref. 95.)

Based on the neutral mutation rate in primates of approx 1.5 x 10-9 substitutions per site per year (12), the high levels of homology observed between many chromosome-specific duplications suggests they have emerged only recently during evolutionary history. Indeed, comparative analysis of different primate lineages has demonstrated that some are species-specific, confirming their dynamic nature (13). In other cases, analysis of the levels of sequence divergence between pairs of duplication in different primates, such as those flanking the common Williams-Beuren syndrome deletion region in 7q11.23 and the large palindromic repeats on long arm of the Y chromosome, has provided evidence that they may also act as substrates for gene conversion (14-16).

Although fluorescence in situ hybridization analysis shows the presence of these duplications in multiple primate species, thus, suggesting they originated before the separation of these lineages, estimates of their evolutionary age based on the rate of nucleotide divergence because of random mutation suggest a much more recent origin (17,18). One explanation for this apparent contradiction is that the homology between pairs ofrepeats acts as a substrate for gene conversion events, thus, homogenizing their sequence and maintaining unexpectedly high levels of identity. Although less likely, an alternative explanation is that some segments of DNA have duplicated to the same genomic location independently in different primate lineages.

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