International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)

Table of Contents * Complex Genetics * Developmental Genetics * Gene Annotation * Gene Discovery * Genome Sequencing * Functional Genomics * Mutagenesis * Presentations * Verne Chapman Memorial Lecture

Dr David Beier
Brigham & Women's Hospital/Harvard Medical School
20 Shattuck Street
Boston MA 02115 USA

Co-Authors: 1)Herron BJ, 1)Rao C, 1)Peters H, 1)Lu W, 1)Liu S, 2)Bronson RT, 3)Justice MJ, 4)McDonald JD
Institutions: 1)Genetics Division, Brigham and Women's Hospital, Harvard Medical School, 2)Tufts U School of Veterinary Medicine, 3)Baylor College of Medicine, 4)Wichita State University

We are screening embryos derived from mice mutagenized with ENU for recessive phenotypes similar to human congenital defects. 3rd generation progeny are evaluated for developmental anomalies at embryonic d18.5; we thus identify defects in organogenesis that are consistent with survival in utero to late gestation, but which may cause post-natal lethality. Affected progeny are used directly for genetic mapping utilizing our previously described method of interval haplotype analysis. With this strategy we are able to localize the mutation to a single linkage group by genotyping 8-10 affected progeny. In our first study we identified 15 monogenic mutants in 54 families. The addition of a mapping component has proven extremely useful in prioritizing our analyses and expediting characterization. We have mapped 7 loci, identified the causal gene for 2 of the mutants obtained, and demonstrated by exclusion that a number of the unmapped mutations are not new alleles of known mutants with similar phenotypes. One of these is a novel mutation in the Sonic hedgehog signalling pathway. The spectrum of abnormalities found to date is remarkably varied, and many of these disorders are similar to human malformation syndromes. Our results demonstrate that a recessive screen can be extremely productive for the purpose of generating abnormal developmental phenotypes and can be readily managed even in a small laboratory.