Syntenic Region in Nonhuman Species

The gene content and order of the WBS deletion region is conserved within the syntenic region of mouse chromosome 5, band G1. As with other chromosome regions involved in genomic disorders, the LCRs seen on human chromosome 7q11.23 are absent in the mouse, but interestingly their positions correspond to evolutionary inversion breakpoints (30) (Fig. 2). This coincidence of LCRs and evolutionary chromosome breakpoints has also been reported in the Smith-Magenis syndrome region on human chromosome 17p11.2 and mouse chromosome 11 (38,39), and in the Prader-Willi/Angelman syndrome region on human chromosome 15q11-q13 and mouse chromosome 7 (40).

Because the LCRs are absent in the mouse, so are the multiple psuedogenes. Any genes or pseudogenes contained within the human LCRs are single copy in the mouse and located either within the WBS syntenic region (in the case of Gtf2i, Gtf2ird2, Ncf1, Wbscr20, Trim50, Pom121, and Fkbp6) or within the region of synteny with their functional human gene copy (Pms2 and Stag3). Of the commonly deleted genes, only one is not present in the mouse— WBSCR23. There is evidence from sequence homology for the presence of this gene in apes but not in Old World monkeys, suggesting that it arose within the last 25 million years (41). The presence of an ape-specific gene within the common deletion raises the intriguing thought that it may contribute to some of the more "human" features seen in WBS, such as gregarious personality or descriptive language, but the expression of WBSCR23 appears to be restricted to the skin and some internal organs, making it unlikely to be involved in the alteration of brain function (42).

The high DNA sequence similarity between the LCRs at 7q11.23 suggests that they appeared only recently, leaving little time for divergence. Although these LCRs are not present in the mouse, there is evidence for their existence in closer relatives of modern humans, most notably the nonhuman primates. Comparative analysis in a variety of species has revealed that the LCRs evolved in the hominoid lineage sometime after the divergence of Old World monkeys, which happened approx 25 million years ago. Macaques (Old World monkeys), like mice, do not have these duplicated segments of DNA present at the syntenic regions of 7q11.23, however, apes such as orangutans and gorillas do show multiple copies of sequences from this region (43). Further expansion of the LCR copy number is estimated to have occurred between 5 and 10 million years ago, because fluorescence in situ hybridization (FISH) analysis of nonhuman primate chromosomes show that the gorilla and chimpanzee have more signals than orangutan and gibbon (43). A more detailed analysis of the LCR sequences using FISH and sequence-specific polymerase chain reaction suggests that the evolution of the LCRs has been complex (43a). In the orangutan and gorilla, two copies of the C-block and two copies of the A-block are present, although not always at the same locus. Even in our closest ancestor, the chimpanzee, there are two C-blocks and two A-blocks, but only one B-block. This indicates that the duplication of the B-block, which contains the highest level of sequence identity within the human LCRs and is the site for the majority of the non-allelic homologous recombinations, was duplicated less than 5 million years ago.

Fig. 2. Synteny between human chromosome 7q11.23 and mouse chromosome 5G. The gene order of both regions is shown and the low-copy repeats present at human 7q11.23 are shaded. The region has undergone an evolutionary inversion between mouse and human as indicated by the dashed lines. Asterisks indicate genes that are present in one species but not the other.

Fig. 2. Synteny between human chromosome 7q11.23 and mouse chromosome 5G. The gene order of both regions is shown and the low-copy repeats present at human 7q11.23 are shaded. The region has undergone an evolutionary inversion between mouse and human as indicated by the dashed lines. Asterisks indicate genes that are present in one species but not the other.

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