Human Chromosome 7q1123

The WBS deletion region is comprised of around 1.2 Mb of unique DNA sequence, including at least 24 protein-coding genes, flanked by large LCRs; one on the centromeric side and two on the telomeric side (Fig. 1). These LCRs, which predispose the region to non-allelic homologous recombination (NAHR), are between 300 and 400 kb in size and are comprised of both transcribed and non-transcribed genes and pseudogenes. The structure of each LCR is complex, but has been subdivided into segments of homologous sequence termed blocks A, B, and C (29-31). The centromeric, medial, and telomeric copies of each block can be distin-

Fig. 1. The Williams-Beuren syndrome (WBS) deletion region at 7q11.23. The gene organization of the WBS region is shown, with genes represented as arrows that indicate the orientation of their transcription. A segment containing pseudogenes (SBDSP; SDCRBP) that has been duplicated from 7q11.22 lies adjacent to the centromeric low-copy repeats (LCR). The centromeric, medial and telomeric WBS LCRs are depicted as shaded boxes and expanded below to reveal the genomic structure of each. The locations of the three repeat blocks, designated A, B, and C are shown with their orientation indicated by the direction of the arrow. The individual gene components of the LCRs are shown with different shaded arrows. The actual genes are those that are labeled, while the unlabeled segments represent pseudogenes. The exceptions to this are STAG3L and WBSCR19L, whose actual genes lie outside the region.

Fig. 1. The Williams-Beuren syndrome (WBS) deletion region at 7q11.23. The gene organization of the WBS region is shown, with genes represented as arrows that indicate the orientation of their transcription. A segment containing pseudogenes (SBDSP; SDCRBP) that has been duplicated from 7q11.22 lies adjacent to the centromeric low-copy repeats (LCR). The centromeric, medial and telomeric WBS LCRs are depicted as shaded boxes and expanded below to reveal the genomic structure of each. The locations of the three repeat blocks, designated A, B, and C are shown with their orientation indicated by the direction of the arrow. The individual gene components of the LCRs are shown with different shaded arrows. The actual genes are those that are labeled, while the unlabeled segments represent pseudogenes. The exceptions to this are STAG3L and WBSCR19L, whose actual genes lie outside the region.

guished from each other by single nucleotide differences, or paralagous sequence variants, although the sequence identity can be as high as 99.6% over large stretches of DNA.

The individual blocks are made up of genes and sequences that are present in duplicated copies, both within the WBS region and at other sites on chromosome 7. These genes include general transcription factor 2I (GTF2I), GTF2I repeat domain-containing protein 2 (GTF2IRD2), neutrophil cytosolic factor 1 (NCF1), stromal antigen 3 (STAG3), POM121 membrane glycoprotein (POM121), FK506-binding protein 6 (FKBP6), Williams-Beuren syndrome chromosome region 20 (WBSCR20), tripartite motif-containing 50 (TRIM50), and a number of highly related postmeiotic segregation increased 2-like (PMS2L) genes. Of these, functional copies of WBSCR20, TRIM50, and FKBP6 are disrupted or deleted near the centromeric breakpoint. GTF2I is always disrupted or deleted at the telomeric breakpoint, with NCF1 and GTF2IRD2 variably deleted depending on the location of the distal deletion breakpoint.

Three STAG3 pseudogenes are present within the LCRs, but the functional copy lies distal to the WBS region at 7q22, along with two other pseudogenes (32). Several POM121 transcription units are also present within the LCRs, but it is unknown which of these corresponds to the functional gene. Further complexity is added by the presence of fusion transcripts between POM121 and Zona pellucida sperm-binding protein 3 (ZP3) (33), which maps close, but distal, to the WBS region (34; http://www.chr7.org/), and numerous other POM121-like sequences scattered throughout the genome. Intriguingly, POM121-like sequences are also found within the LCRs that flank the 22q11.2 deletion region (35).

Gene clusters of highly similar transcription units, the PMS2L genes are also contained within the LCRs. Because of the large number and high homology of these genes, it is still unknown exactly how many exist and which are actively transcribed, but many different transcripts have been demonstrated (36,37). PMS2L gene clusters are also present in two other locations on human chromosome 7; 7q11.22 and 7q22 (5).

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