A paternally imprinted QTL for mature body mass on mouse Chromosome 8

Abstract

Body mass (BM) is a classic polygenic trait that has been extensively investigated to determine the underlying genetic architecture. Many previous studies looking at the genetic basis of variation in BM in murine animal models by quantitative trait loci (QTL) mapping have used crosses between two inbred lines. As a consequence it has not been possible to explore imprinting effects which have been shown to play an important role in the genetic basis of early growth with persistent effects throughout the growth curve. Here we use partially inbred mouse lines to identify QTL for mature BM by applying both Mendelian and Imprinting models. The analysis of an F2 population (n approximately 500) identified a number of QTL at 14, 16, and 18 weeks explaining in total 31.5%, 34.4%, and 30.5% of total phenotypic variation, respectively. On Chromosome 8 a QTL of large effect (14% of the total phenotypic variance at 14 weeks) was found to be explained by paternal imprinting. Although Chromosome 8 has not been previously associated with imprinting effects, features of candidate genes within the QTL confidence interval (CpG islands and direct clustered repeats) support the hypothesis that Insulin receptor substrate 2 may be associated with imprinting, but as yet is unidentified as being so.

Genetic mapping of complex traits by minimizing integrated square errors

“…The ML method cannot identify any significant QTL at the genome level; however, the L 2 E method successfully detects one genome-wide significant QTL at 2 cM to the leftmost proximal marker on the chromosome 8. Coincidently, in 2005, Rance et al [28] reported a significant QTL for the mature mice body mass located at 7 cM to the leftmost proximal marker on the chromosome 8, almost at the same location for the significant QTL identified here. Our finding hence further validates the existence of a significant QTL for mice body mass at the beginning of the chromosome 8.…”

Genome Scan for Parent-of-Origin QTL Effects on Bovine Growth and Carcass Traits

“…Obtaining significant results for body composition traits is consistent with imprinting effects on human adult obesity and body composition (Georges et al, 2003; Gorlova et al, 2003; Dong et al, 2005) and on adult obesity and body composition in mice (Casellas et al, 2009). It is now known that imprinting marks, such as DNA methylation and histone configurations, often persist into adulthood (Gorlova et al, 2003; Christensen et al, 2009; Trowbridge and Orkin, 2010; Woodfine et al, 2011; Wu et al, 2011), and that imprinting may play a physiological role in metabolism and body composition throughout life, thereby contributing both to normal variation and the architecture of complex traits rather than being restricted to prenatal and neonatal effects (Rance et al, 2005; Smith et al, 2006; Cheverud et al, 2008; Casellas et al, 2009; Hager et al, 2009; Garfield et al, 2011). Our current understanding of the function of imprinted genes is overwhelmingly biased toward growth and development (Constancia et al, 2005; Abu-Amero et al, 2006; Delaval et al, 2006; Fowden et al, 2006; Fradin et al, 2006; Smith et al, 2006, 2007; Wu et al, 2006; Jiang et al, 2007; Charalambous et al, 2010) and only recently have we begun to gain a better understanding in mice of the effects of genomic imprinting on physiological traits expressed long after embryogenesis and fetal development (Rance et al, 2005; Cheverud et al, 2008; Casellas et al, 2009; Hager et al, 2009; Garfield et al, 2011).…”

Effects of deficiency of the G protein Gsα on energy and glucose homeostasis

“…Imprinted genes also appear to be involved in postnatal energy metabolism as several diseases caused by mutations in imprinted genes lead to obesity (e.g. Prader-Willi syndrome, pseudohypoparathyroidism type 1A) and population studies have identified a number of chromosomal regions associated with parent-of-origin effects on energy balance in humans (Dong et al, 2005; Gorlova et al, 2003; Lindsay et al, 2001; Rance et al, 2005). The effect of GNAS imprinting on energy balance is consistent with the parental conflict hypothesis, a loss of the paternally expressed XLαs leads to a lean phenotype with increased sympathetic nerve activity and energy expenditure while the oppositely imprinted GNAS gene product G s α leads to obesity due to opposite effects on sympathetic nerve activity and energy expenditure.…”