title: Identification of novel mouse genes conferring posthypoxic pauses.
abstract: Although central to the susceptibility of adult diseases characterized by abnormal rhythmogenesis, characterizing the genes involved is a challenge. We took advantage of the C57BL/6J (B6) trait of hypoxia-induced periodic breathing and its absence in the C57BL/6J-Chr 1(A/J)/NaJ chromosome substitution strain to test the feasibility of gene discovery for this abnormality. Beginning with a genetic and phenotypic analysis of an intercross study between these strains, we discovered three quantitative trait loci (QTLs) on mouse chromosome 1, with phenotypic effects. Fine-mapping reduced the genomic intervals and gene content, and the introgression of one QTL region back onto the C57BL/6J-Chr 1(A/J)/NaJ restored the trait. mRNA expression of non-synonymous genes in the introgressed region in the medulla and pons found evidence for differential expression of three genes, the highest of which was apolipoprotein A2, a lipase regulator; the apo a2 peptide fragment (THEQLTPLVR), highly expressed in the liver, was expressed in low amounts in the medulla but did not correlate with trait expression. This work directly demonstrates the impact of elements on mouse chromosome 1 in respiratory rhythmogenesis.
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, University Hospital Case Medical Center and the Louis Stokes Cleveland DVA Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: C Barton
authors.initials: CB
authors.lastname: Gillombardo
authors.forename: Motoo
authors.initials: M
authors.lastname: Yamauchi
authors.forename: Mark D
authors.initials: MD
authors.lastname: Adams
authors.forename: Jesse
authors.initials: J
authors.lastname: Dostal
authors.forename: Sam
authors.initials: S
authors.lastname: Chai
authors.forename: Michael W
authors.initials: MW
authors.lastname: Moore
authors.forename: Lucas M
authors.initials: LM
authors.lastname: Donovan
authors.forename: Fang
authors.initials: F
authors.lastname: Han
authors.forename: Kingman P
authors.initials: KP
authors.lastname: Strohl
mesh_terms: D000818:Animals; D016633:Apolipoprotein A-II / Q000235:genetics*; D002874:Chromosome Mapping; D005260:Female; D008297:Male; D008526:Medulla Oblongata / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010507:Periodicity; D011149:Pons / Q000378:metabolism; D040641:Quantitative Trait Loci; D012119:Respiration / Q000235:genetics*
chemical_list: D016633:Apolipoprotein A-II