Analysis of the cat eye syndrome critical region in humans and the region of conserved synteny in mice: a search for candidate genes at or near the human chromosome 22 pericentromere - PubMed (original) (raw)

Comparative Study

. 2001 Jun;11(6):1053-70.

doi: 10.1101/gr.154901.

P Brinkman-Mills, G S Banting, S A Maier, M A Riazi, L Bridgland, S Hu, B Birren, S Minoshima, N Shimizu, H Pan, T Nguyen, F Fang, Y Fu, L Ray, H Wu, S Shaull, S Phan, Z Yao, F Chen, A Huan, P Hu, Q Wang, P Loh, S Qi, B A Roe, H E McDermid

Affiliations

Comparative Study

Analysis of the cat eye syndrome critical region in humans and the region of conserved synteny in mice: a search for candidate genes at or near the human chromosome 22 pericentromere

T K Footz et al. Genome Res. 2001 Jun.

Abstract

We have sequenced a 1.1-Mb region of human chromosome 22q containing the dosage-sensitive gene(s) responsible for cat eye syndrome (CES) as well as the 450-kb homologous region on mouse chromosome 6. Fourteen putative genes were identified within or adjacent to the human CES critical region (CESCR), including three known genes (IL-17R, ATP6E, and BID) and nine novel genes, based on EST identity. Two putative genes (CECR3 and CECR9) were identified, in the absence of EST hits, by comparing segments of human and mouse genomic sequence around two solitary amplified exons, thus showing the utility of comparative genomic sequence analysis in identifying transcripts. Of the 14 genes, 10 were confirmed to be present in the mouse genomic sequence in the same order and orientation as in human. Absent from the mouse region of conserved synteny are CECR1, a promising CES candidate gene from the center of the contig, neighboring CECR4, and CECR7 and CECR8, which are located in the gene-poor proximal 400 kb of the contig. This latter proximal region, located approximately 1 Mb from the centromere, shows abundant duplicated gene fragments typical of pericentromeric DNA. The margin of this region also delineates the boundary of conserved synteny between the CESCR and mouse chromosome 6. Because the proximal CESCR appears abundant in duplicated segments and, therefore, is likely to be gene poor, we consider the putative genes identified in the distal CESCR to represent the majority of candidate genes for involvement in CES.

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Figures

Figure 1

Figure 1

Molecular and computer-based techniques used to identify genes in the CES critical region.

Figure 2

Figure 2

Putative genes identified in the CES critical region (CESCR) and region of conserved synteny in mouse. Sequenced BACs and PACs (with GenBank accession nos.) are shown above (human) or below (mouse) the size scales. CpG islands in the human sequence, with their size in base pairs, are shown directly below the human size scale. Below this are the identified genes, with genes transcribed centromere to telomere above the chromosome, and genes transcribed telomere to centromere below the chromosome. The hatched section of chromosome 22 represents the region rich in duplications from other regions of the genome. The mouse genes are shown above the mouse size scale and oriented as described above. The banded section represents the portion of mouse chromosome 6 orthologous to human chromosome 12p13.

Figure 3

Figure 3

Percent identity plot calculated by

PipMaker

(see Methods) for the human interval of IL-17R to MIL1 compared with the sequence of the region of conserved synteny from mouse chromosome 6. Gap-free segments demonstrating >50% nucleotide identity are indicated by horizontal black bars below the graphical depictions of interspersed repeats, CpG islands, and gene structures. Exons are numbered from the 5′-most cloned exon. A single gap-free alignment underneath a protein-coding exon indicates the mouse exon size is conserved, and thus the mouse locus maintains a homologous ORF.

Figure 3

Figure 3

Percent identity plot calculated by

PipMaker

(see Methods) for the human interval of IL-17R to MIL1 compared with the sequence of the region of conserved synteny from mouse chromosome 6. Gap-free segments demonstrating >50% nucleotide identity are indicated by horizontal black bars below the graphical depictions of interspersed repeats, CpG islands, and gene structures. Exons are numbered from the 5′-most cloned exon. A single gap-free alignment underneath a protein-coding exon indicates the mouse exon size is conserved, and thus the mouse locus maintains a homologous ORF.

Figure 3

Figure 3

Percent identity plot calculated by

PipMaker

(see Methods) for the human interval of IL-17R to MIL1 compared with the sequence of the region of conserved synteny from mouse chromosome 6. Gap-free segments demonstrating >50% nucleotide identity are indicated by horizontal black bars below the graphical depictions of interspersed repeats, CpG islands, and gene structures. Exons are numbered from the 5′-most cloned exon. A single gap-free alignment underneath a protein-coding exon indicates the mouse exon size is conserved, and thus the mouse locus maintains a homologous ORF.

Figure 3

Figure 3

Percent identity plot calculated by

PipMaker

(see Methods) for the human interval of IL-17R to MIL1 compared with the sequence of the region of conserved synteny from mouse chromosome 6. Gap-free segments demonstrating >50% nucleotide identity are indicated by horizontal black bars below the graphical depictions of interspersed repeats, CpG islands, and gene structures. Exons are numbered from the 5′-most cloned exon. A single gap-free alignment underneath a protein-coding exon indicates the mouse exon size is conserved, and thus the mouse locus maintains a homologous ORF.

Figure 3

Figure 3

Percent identity plot calculated by

PipMaker

(see Methods) for the human interval of IL-17R to MIL1 compared with the sequence of the region of conserved synteny from mouse chromosome 6. Gap-free segments demonstrating >50% nucleotide identity are indicated by horizontal black bars below the graphical depictions of interspersed repeats, CpG islands, and gene structures. Exons are numbered from the 5′-most cloned exon. A single gap-free alignment underneath a protein-coding exon indicates the mouse exon size is conserved, and thus the mouse locus maintains a homologous ORF.

Figure 4

Figure 4

Genomic structure of the genes in the CES critical region (CESCR). Exons and introns are not shown to scale, but sizes in bp are given below the exons and above the introns. Exons are numbered from the 5′-most cloned exon; additional undiscovered exons may exist. ORFs are shown in black, 5′ UTRs in white, 3′ UTRs in grey. No significant ORFs have yet been predicted for CECR3, CECR7, or_CECR8_, hence all the exons are shown in white. Only one exon of CECR9 is currently known, therefore it was not included in this figure. CECR1 and BID were published previously (Footz et al. 1998; Riazi et al. 2000). CECR2 will be published elsewhere.

Figure 5

Figure 5

Expression analysis of genes in the CES critical region (CESCR). Genes are positioned in order along the chromosome, with Northern blots adjacent to them. The hatched section of chromosome 22 represents the region rich in duplications from other regions of the genome. For each Northern blot, a control probing with β-actin or GAPD is shown. Numbers beside the Northern blots indicate sizes in kb. (He) Heart; (Br) brain; (Pl) placenta; (Lu) lung; (Li) liver; (Sk) skeletal muscle; (Ki) kidney; (Pa) pancreas; (Mu) muscle; (Ut) uterus; (Co) colon; (Sm) small intestine; (Bl) bladder; (St) stomach; (Sp) spleen; (Th) thyroid; (Pr) prostate; (Te) testis; (Ov) ovary; (Pe) peripheral blood leukocytes.

Figure 6

Figure 6

Analysis of the proximal 400 kb of the human contig, showing duplications indicative of pericentromeric regions. Repeat-masked genomic sequence was compared with the Homo sapiens subset of the nonredundant (nr) and high-throughput genomic sequence database (htgs) databases. Identity to fully or partially sequenced paralogous clones is indicated as blocks between regions apparently unique to chromosome 22, with the known chromosomal locations identified. An individual chromosome may not show paralogy over the entire block. (UL) Unlocalized clones. The analysis was performed on May 10, 2000, when 80.8% of the genome was represented by draft (61.9%) and/or finished (18.9%) sequence (

http://www.ncbi.nlm.nih.gov/genome/seq/page.cgi?F=HsHome.html&ORG=Hs

). Additional paralogous segments may be found as the genome sequence is finished.

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