Cloning and Comparative Mapping of the DiGeorge Syndrome Critical Region in the Mouse

doi:10.1006/geno.1998.5414

Genomics

Volume 52, Issue 1, 15 August 1998, Pages 37-43

https://doi.org/10.1006/geno.1998.5414 Get rights and content

Abstract

Chromosome deletions leading to the hemizygous loss of groups of contiguous genes are a major cause of human congenital defects. In some syndromes haploinsufficiency of a single gene causes the majority of the syndromal features, whereas other diseases are thought to be the consequences of a combined haploinsufficiency. In the case of the DiGeorge and velocardiofacial syndromes, caused by deletions within 22q11, the genetic analyses have so far failed to implicate a single gene. By virtue of FISH analysis and the creation of a BAC/P1 genomic clone contig we have mapped 19 murine homologues of genes and nine EST groups from the region deleted in DiGeorge syndrome and found them to be linked on mouse chromosome 16. Rearrangements during the divergence of mouse and human have led to differing gene orders in the two species, with implications for the most appropriate means of mimicking particular human deletions. The map confirms and extends previous analyses and the contig resources toward the generation of targeted deletions in the mouse.

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RanBP1, a velocardiofacial/DiGeorge syndrome candidate gene, is expressed at sites of mesenchymal/epithelial induction
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Comparative sequence analysis of 634 kb of the mouse chromosome 16 region of conserved synteny with the human velocardiofacial syndrome region on chromosome 22q11.2
2000, Genomics
Mouse genomic DNA sequence extending 634 kb on proximal mouse chromosome 16 was compared to the corresponding human sequence from chromosome 22q11.2. Haploinsufficiency for this region results in velocardiofacial syndrome (VCFS) in humans. The mouse region is rearranged into three conserved blocks relative to human, but gene content and position are highly conserved within these blocks. Examination of the boundaries of one of these blocks suggested that the evolutionary chromosomal rearrangement occurred in the mouse lineage, resulting in inactivation of the mouse orthologue of ZNF74. Sequence analysis identified 21 genes and 15 ESTs. These include 2 novel genes, Srec2 and Cals2, and previously undescribed splice variants of several other genes. Exon discovery was carried out using GRAIL2, MZEF, or comparative analysis across 491 kb of conserved mouse and human sequence. Sequence comparison was highly effective, identifying every gene and nearly every exon without the high frequency of false-positive predictions seen when algorithmic methods were used alone. In combination, these procedures identified every gene with no false-positive predictions. Comparative sequence analysis also revealed regions of extensive conservation among noncoding sequences, accounting for 6% of the sequence. A library of such sequences has been established to form a resource for generalized studies of regulatory and structural elements.
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^☆: K. E. DaviesS. M. Tilghman

¹: To whom correspondence should be addressed. Telephone: 44-171-242-9789. Fax: 44-171-831-0488. E-mail:[email protected].

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Regular ArticleCloning and Comparative Mapping of the DiGeorge Syndrome Critical Region in the Mouse☆

Abstract

Am. J. Hum. Genet.

Genomics

Genomics

Gene

Genomics

Cell

Genomics

Genomics

Genomics

Isolation of a zinc finger gene consistently deleted in DiGeorge syndrome

Hum. Mol. Genet.

Comparative mapping of the DiGeorge syndrome region in mouse shows inconsistent gene order and differential degree of gene conservation

Mamm. Genome

Comparative map of 9 chromosome 22q loci in the laboratory mouse

Hum. Mol. Genet.

Cloning a balanced translocation associated with DiGeorge syndrome and identification of a disrupted candidate gene

Nat. Genet.

Progress in the autosomal segmental aneusomy syndromes (SASs): Single or multi-locus disorders

Hum. Mol. Genet.

Isolation of genes from complex sources of mammalian genomic DNA using exon amplification

Nat. Genet.

How many breaks do we need to CATCH on 22q11

Am. J. Hum. Genet.

Isolation of a novel gene from the DiGeorge syndrome critical region with homology toDrosophila

Hum. Mol. Genet.

A technique for radiolabeling DNA restriction endonuclease fragments to high specific radioactivity

Anal. Biochem.

A region of mouse chromosome 16 is syntenic to the DiGeorge, velo-cardio-facial syndrome minimal critical region

Genome Res.

A transcription map of the DiGeorge and velo-cardio-facial syndrome minimal critical region on 22q11

Hum. Mol. Genet.

The DiGeorge syndrome minimal critical region contains a Goosecoid-like (GSCL) homeobox gene, which is expressed early in human development

Am. J. Hum. Genet.

Isolation of a putative transcriptional regulator from the region of 22q11 deleted in DiGeorge syndrome, Shprintzen syndrome and familial congenital heart disease

Hum. Mol. Genet.

Regular Article
Cloning and Comparative Mapping of the DiGeorge Syndrome Critical Region in the Mouse☆