Random mutagenesis of proximal mouse chromosome 5 uncovers predominantly embryonic lethal mutations.
A region-specific ENU mutagenesis screen was conducted to elucidate the functional content of proximal mouse Chr 5. We used the visibly marked, recessive, lethal inversion Rump White (Rw) as a balancer in a three-generation breeding scheme to identify recessive mutations within the approximately 50 megabases spanned by Rw. A total of 1003 pedigrees were produced, representing the largest inversion screen performed in mice. Test-class animals, homozygous for the ENU-mutagenized proximal Chr 5 and visibly distinguishable from nonhomozygous littermates, were screened for fertility, hearing, vestibular function, DNA repair, behavior, and dysmorphology. Lethals were identifiable by failure to derive test-class animals within a pedigree. Embryonic lethal mutations (total of 34) were overwhelmingly the largest class of mutants recovered. We characterized them with respect to the time of embryonic death, revealing that most act at midgestation (8.5-10.5) or sooner. To position the mutations within the Rw region and to guide allelism tests, we performed complementation analyses with a set of new and existing chromosomal deletions, as well as standard recombinational mapping on a subset of the mutations. By pooling the data from this and other region-specific mutagenesis projects, we calculate that the mouse genome contains approximately 3479-4825 embryonic lethal genes, or about 13.7%-19% of all genes.
Wilson
Lawriston
L
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Ching
Yung-Hao
YH
Farias
Michael
M
Hartford
Suzanne A
SA
Howell
Gareth
G
Shao
Hongguang
H
Bucan
Maja
M
Schimenti
John C
JC
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002875:Chromosomes / Q000187:drug effects; D047108:Embryonic Development / Q000235:genetics*; D005038:Ethylnitrosourea / Q000633:toxicity; D005260:Female; D005298:Fertility / Q000235:genetics; D005804:Genes, Lethal; D005816:Genetic Complementation Test; D005865:Gestational Age; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D016296:Mutagenesis; D009154:Mutation; D014724:Vestibular Function Tests
D005038:Ethylnitrosourea