Comparative mapping of the human 22q11 chromosomal region and the orthologous region in mice reveals complex changes in gene organization

Comparative mapping of the human 22q11 chromosomal region and the orthologous region in mice reveals complex changes in gene organization

Departments of ^*Cell Biology and ^†Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461; and ^‡Mammalian Genetics Laboratory, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, MD 21702

Communicated by Matthew D. Scharff, Albert Einstein College of Medicine, Bronx, NY (received for review September 18, 1997)

Abstract

The region of human chromosome 22q11 is prone to rearrangements. The resulting chromosomal abnormalities are involved in Velo-cardio-facial and DiGeorge syndromes (VCFS and DGS) (deletions), “cat eye” syndrome (duplications), and certain types of tumors (translocations). As a prelude to the development of mouse models for VCFS/DGS by generating targeted deletions in the mouse genome, we examined the organization of genes from human chromosome 22q11 in the mouse. Using genetic linkage analysis and detailed physical mapping, we show that genes from a relatively small region of human 22q11 are distributed on three mouse chromosomes (MMU6, MMU10, and MMU16). Furthermore, although the region corresponding to about 2.5 megabases of the VCFS/DGS critical region is located on mouse chromosome 16, the relative organization of the region is quite different from that in humans. Our results show that the instability of the 22q11 region is not restricted to humans but may have been present throughout evolution. The results also underscore the importance of detailed comparative mapping of genes in mice and humans as a prerequisite for the development of mouse models of human diseases involving chromosomal rearrangements.

Footnotes

↵ § To whom reprint requests should be addressed. e-mail: skoultch{at}aecom.yu.edu.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. D16Ais1–D16Ais24 and D22S1729–D22S1742).
ABBREVIATIONS:

MMU16,

M. musculus chromosome 16;

HSA22q11,

Homo sapiens chromosome 22q11;

VCFS,

Velo-cardio-facial syndrome;

DGS,

DiGeorge syndrome;

CES,

cat eye syndrome;

YAC,

yeast artificial chromosome;

EST,

expressed sequence tagged site;

BL,

Burkitt’s lymphoma;

RFLP,

restriction fragment length polymorphism;

SSLP,

simple sequence length polymorphism