Mammalian Genome

, Volume 19, Issue 1, pp 2–14 | Cite as

Gene-environment interactions in a mutant mouse kindred with native airway constrictor hyperresponsiveness

  • Lawrence H. Pinto
  • Emily Eaton
  • Bohao Chen
  • Jonah Fleisher
  • Dmitry Shuster
  • Joel McCauley
  • Dalius Kedainis
  • Sandra M. Siepka
  • Kazuhiro Shimomura
  • Eun-Joo Song
  • Aliya Husain
  • Oren J. Lakser
  • Richard W. Mitchell
  • Maria L. Dowell
  • Melanie Brown
  • Blanca Camoretti-Mercado
  • Robert Naclerio
  • Anne I. Sperling
  • Stephen I. Levin
  • Fred W. Turek
  • Julian Solway
Article

Abstract

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.

Notes

Acknowledgments

This work was supported by NIAID P01 AI 56352 and the Sandler Program for Asthma Research.

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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Lawrence H. Pinto
    • 1
  • Emily Eaton
    • 1
  • Bohao Chen
    • 3
  • Jonah Fleisher
    • 1
  • Dmitry Shuster
    • 1
    • 3
  • Joel McCauley
    • 1
  • Dalius Kedainis
    • 1
  • Sandra M. Siepka
    • 1
  • Kazuhiro Shimomura
    • 1
  • Eun-Joo Song
    • 1
  • Aliya Husain
    • 6
  • Oren J. Lakser
    • 4
  • Richard W. Mitchell
    • 3
  • Maria L. Dowell
    • 4
  • Melanie Brown
    • 4
  • Blanca Camoretti-Mercado
    • 3
  • Robert Naclerio
    • 5
  • Anne I. Sperling
    • 3
  • Stephen I. Levin
    • 2
  • Fred W. Turek
    • 1
  • Julian Solway
    • 3
    • 7
  1. 1.Department of Neurobiology and PhysiologyNorthwestern UniversityEvanstonUSA
  2. 2.Center for Comparative MedicineNorthwestern UniversityEvanstonUSA
  3. 3.Department of MedicineUniversity of ChicagoChicagoUSA
  4. 4.Department of PediatricsUniversity of ChicagoChicagoUSA
  5. 5.Department of SurgeryUniversity of ChicagoChicagoUSA
  6. 6.Department of PathologyUniversity of ChicagoChicagoUSA
  7. 7.University of ChicagoChicagoUSA

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