Gene-environment interactions in a mutant mouse kindred with native airway constrictor hyperresponsiveness.
We mutagenized male BTBR mice with N-ethyl-N-nitrosourea and screened 1315 of their G3 offspring for airway hyperresponsiveness. A phenovariant G3 mouse with exaggerated methacholine bronchoconstrictor response was identified and his progeny bred in a nonspecific-pathogen-free (SPF) facility where sentinels tested positive for minute virus of mice and mouse parvovirus and where softwood bedding was used. The mutant phenotype was inherited through G11 as a single autosomal semidominant mutation with marked gender restriction, with males exhibiting almost full penetrance and very few females phenotypically abnormal. Between G11 and G12, facility infection eradication was undertaken and bedding was changed to hardwood. We could no longer detect airway hyperresponsiveness in more than 37 G12 offspring of 26 hyperresponsive G11 males. Also, we could not identify the mutant phenotype among offspring of hyperresponsive G8-G10 sires rederived into an SPF facility despite 21 attempts. These two observations suggest that both genetic and environmental factors were needed for phenotype expression. We suspect that rederivation into an SPF facility or altered exposure to pathogens or other unidentified substances modified environmental interactions with the mutant allele, and so resulted in disappearance of the hyperresponsive phenotype. Our experience suggests that future searches for genes that confer susceptibility for airway hyperresponsiveness might not be able to identify some genes that confer susceptibility if the searches are performed in SPF facilities. Experimenters are advised to arrange for multigeneration constancy of mouse care in order to clone mutant genes. Indeed, we were not able to map the mutation before losing the phenotype.
Pinto
Lawrence H
LH
Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois, 60208, USA.
Eaton
Emily
E
Chen
Bohao
B
Fleisher
Jonah
J
Shuster
Dmitry
D
McCauley
Joel
J
Kedainis
Dalius
D
Siepka
Sandra M
SM
Shimomura
Kazuhiro
K
Song
Eun-Joo
EJ
Husain
Aliya
A
Lakser
Oren J
OJ
Mitchell
Richard W
RW
Dowell
Maria L
ML
Brown
Melanie
M
Camoretti-Mercado
Blanca
B
Naclerio
Robert
R
Sperling
Anne I
AI
Levin
Stephen I
SI
Turek
Fred W
FW
Solway
Julian
J
D000336:Aerosols; D000375:Aging / Q000187:drug effects; D000402:Airway Obstruction / Q000150:complications* / Q000235:genetics*; D000818:Animals; D001772:Blood Cell Count; D016535:Bronchial Hyperreactivity / Q000150:complications* / Q000235:genetics*; D001985:Bronchial Provocation Tests; D004305:Dose-Response Relationship, Drug; D004777:Environment; D005260:Female; D053263:Gene Regulatory Networks; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D016210:Methacholine Chloride / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D016296:Mutagenesis; D010375:Pedigree; D010641:Phenotype; D010991:Plethysmography
D000336:Aerosols; D016210:Methacholine Chloride