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.

Enhanced non-eupneic breathing following hypoxic, hypercapnic or hypoxic–hypercapnic gas challenges in conscious mice

“…Whereas C57BL6 mice displayed pronounced increases in f R , Rinx and Rinx/f R upon return to room-air after the HX challenge, f R gradually declined in the Swiss-Webster mice and Rinx and Rinx/f R gradually fell to virtually zero values during the post-HX phase. These dramatic differences in post-HX changes in f R and levels of disordered breathing between C57BL6 and Swiss-Webster mice certainly reinforce extensive knowledge that genetic factors play a vital role in determining ventilatory patterns (Han and Strohl, 2000; Han et al, 2001, 2002; Groeben et al, 2005; Gillombardo et al, 2012). …”

“…Expiration during eupneic breathing is passive and occurs via simple elastic recoil of the lungs (Mitchell et al, 1975; St-John and Paton, 2004; Garcia et al, 2011). In contrast, disordered breathing is characterized by abnormal breaths (disturbed balance of inspiratory and expiratory volume per breath) during rest, and the presence of recurrent spontaneous apneas (pauses), sighs and sniffs, and irregular breaths due to abrupt movements such as grooming and locomotor activity (Han and Strohl, 2000; Han et al, 2001, 2002; Price et al, 2003; Strohl, 2003; Yamauchi et al, 2007, 20008a,b,c, 2010; Chai et al, 2011; Gillombardo et al, 2012; Strohl et al, 2012). …”

“…The genetic bases for sleep disordered breathing in mouse strains have received extensive investigation (Tankersley et al, 1994, 1998, 2000, Tankersley, 2000, 2001, 2003; Han and Strohl, 2000; Han et al, 2001, 2002; Tagaito et al, 2001; Schneider et al, 2003; Strohl, 2003; Tankersley and Broman, 2004; Balbir et al, 2006; Yamauchi et al, 2008b; Gillombardo et al, 2012) as have the neurochemical processes (Tankersley et al, 2002b; Price et al, 2003; Groeben et al, 2005; Yamauchi et al, 2007, 2008a, 2012; Moore et al, 2012, 2014), and structural features of respiratory structures such as the carotid bodies (Yamaguchi et al, 2003, 2006; Chai et al, 2011). …”

“…Moreover, the issue as to whether the actual level of the frequency of breathing ( f R ) is associated with or is essential to the expression of disordered breathing upon return to room-air after HX, HC or H-H challenges is not settled (Han et al, 2001, 2002; Tagaito et al, 2001; Yamauchi et al, 2008a,b, 2010). The analysis of breathing patterns is a complicated process that certain groups have mastered (e.g., Tankersley et al, 1994, 1998, 2000, Tankersley, 2000, 2001, 2003; Han and Strohl, 2000; Han et al, 2001, 2002; Tagaito et al, 2001; Schneider et al, 2003; Strohl, 2003; Tankersley and Broman, 2004; Balbir et al, 2006; Yamauchi et al, 2008b; Gillombardo et al, 2012). One less intense (and less informative) method to examine disordered breathing is the Rejection Index (Rinx) feature in whole body plethysmography systems including the Buxco system recently acquired by Data Sciences International (St. Paul, MN).…”

C57BL/6J mouse apolipoprotein A2 gene is deterministic for apnea

“…In a comparison of A/J to B6 mice intercross breeding and a genomic approach placed the trait of B6 post-hypoxic apneas to a region on mouse Chromosome 1 (Gillombardo et al, 2012). The linkage was to a region identified previously as having an interaction effect of hypoxia and hypercapnia (Tankersley and Broman, 2004).…”