Evidence of maternal QTL affecting growth and obesity in adult mice

Abstract

Most quantitative trait loci (QTL) studies fail to account for the effect that the maternal genotype may have on an individual's phenotypes, even though maternal effect QTL have been shown to account for considerable variation in growth and obesity traits in mouse models. Moreover, the fetal programming theory suggests that maternal effects influence an offspring's adult fitness, although the genetic nature of fetal programming remains unclear. Within this context, our study focused on mapping genomic regions associated with maternal effect QTL by analyzing the phenotypes of chromosomes 2 and 7 subcongenic mice from genetically distinct dams. We analyzed 12 chromosome 2 subcongenic strains that spanned from 70 to 180 Mb with CAST/EiJ donor regions on the background of C57BL/6 J, and 14 chromosome 7 subcongenic strains that spanned from 81 to 111 Mb with BALB/cByJ donor regions on C57BL/6ByJ background. Maternal QTL analyses were performed on the basis of overlapping donor regions between subcongenic strains. We identified several highly significant (P \ 5 9 10 -4 ) maternal QTL influencing total body weight, organ weight, and fat pad weights in both sets of subcongenics. These QTL accounted for 1.9-11.7% of the phenotypic variance for growth and obesity and greatly narrowed the genomic regions associated with the maternal genetic effects. These maternal effect QTL controlled phenotypic traits in adult mice, suggesting that maternal influences at early stages of development may permanently affect offspring performance. Identification of maternal effects in our survey of two sets of subcongenic strains, representing approximately 5% of the mouse genome, supports the hypothesis that maternal effects represent significant sources of genetic variation that are largely ignored in genetic studies.

Disentangling Prenatal and Postnatal Maternal Genetic Effects Reveals Persistent Prenatal Effects on Offspring Growth in Mice

“…We identified maternal-effect QTL on both of the chromosomes (2 and 7) examined in the study by Casellas et al (2009) (see above), although the locations of the chromosome 7 QTL are relatively far apart. The chromosome 2 QTL are in overlapping regions, but the locus identified by Casellas et al (2009) has effects on late adult traits, while meQTL2.2 has effects limited to earlier life, although it is important to note that Casselas et al did not examine newborn or juvenile weights.…”

“…These studies have shown that they are often one of the largest components of variation for traits expressed early in life, with effects generally eroding after weaning (see Wilson and Festa-Bianchet 2009 for a review of persistence), but often persisting at a low level into adulthood (e.g., Riska et al 1984Riska et al , 1985Cowley et al 1989;Jarvis et al 2005;Casellas et al 2009). It is important to keep in mind that most of our understanding of maternal effects has come from studies that used approaches that cannot differentiate between genetic-and environmentally based maternal effects (but exceptions exist; e.g., Wilson …”

“…Most noteworthy is the study by Casellas et al (2009), who mapped maternal effects of two small genomic regions (accounting for 5% of the genome) on adult traits in a subcongenic population of mice. They identified loci in both genomic regions that had apparent maternal effects on adult body size and obesity traits but did not differentiate between pre-and postnatal influences and did not account for genomic imprinting effects, which could have led to the appearance of these apparent maternal effects (Hager et al 2008b).…”

“…The chromosome 2 QTL are in overlapping regions, but the locus identified by Casellas et al (2009) has effects on late adult traits, while meQTL2.2 has effects limited to earlier life, although it is important to note that Casselas et al did not examine newborn or juvenile weights. Interestingly, a previous analysis of QTL affecting litter size in this same population (Peripato et al 2004) identified a locus on chromosome 12 that maps within the physical confidence interval for meQTL12.1.…”

“…Consequently, information on the contribution of maternal genetic effects is generally absent from our picture of genetic architecture. Experiments where maternal genetic effects have been included, such as in the mapping of maternal effects in small chromosomal blocks in subcongenic mice by Casellas et al (2009) and the mapping of litter means in cross-fostered mice by Wolf et al (2002), have suggested that maternal effects may be an important part of genetic architecture, but they have provided limited general insights (see below).…”