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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 x 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.

In a previous study we characterized the B6.CAST-(D2Mit329-D2Mit457)N(6) (B62D) congenic strain, which possesses CAST/EiJ (CAST) chromosome 2 donor alleles from 74 to 180 Mbp on a C57BL6/J (B6) background. This strain exhibited significant decreases in body weight and adiposity attributable to the weight gain 2 (Wg2) quantitative trait locus (QTL). To refine the location of Wg2, we used a two-stage genetic dissection strategy consisting of a B62D x B6 backcross, which mapped Wg2 to the proximal portion of the B62D donor region, followed by the development of seven overlapping subcongenic F(2) intercrosses targeting the Wg2 genomic interval. Surprisingly, five of the seven intercrosses displayed significant differences, dependent on genotype, in body weight and/or fat pad mass. These effects were the result of at least four independent QTLs that were named Wg2a, b, c, and d. In contrast to the lean and low body weight phenotype of the B62D parental strain, mice homozygous for CAST congenic alleles (cast/cast) at Wg2a were significantly heavier at 6 and 9 weeks of age, while cast/cast mice at Wg2c had higher levels of total fat. Consistent with the prior observed effects of Wg2, cast/cast mice at Wg2b displayed significant decreases in 6- and 9-week body weight as well as a decrease in total fat pad mass. All of the QTLs had additive effects on body composition except Wg2d, which displayed underdominance for total fat mass. Significant differences in weight and adiposity were also observed in genetically identical b6/b6 homozygous mice across the panel of subcongenics, suggesting either maternal or paternal contributions to body composition. These data represent a significant advancement toward the identification of mouse chromosome 2 growth and obesity quantitative trait genes.

Previous speed congenic analysis has suggested that the expression of growth and obesity quantitative trait loci (QTL) on distal mouse chromosomes (MMU) 2 and 11, segregating between the CAST/EiJ (CAST) and C57BL/6J-hg/hg (HG) strains, is dependent on sex. To confirm, fine map, and further evaluate QTL x sex interactions, we constructed congenic by recipient F2 crosses for the HG.CAST-(D2Mit329-D2Mit457)N(6) (HG2D) and HG.CAST-(D11Mit260-D11Mit255)N(6) (HG11) congenic strains. Over 700 F2 mice were densely genotyped and phenotyped for a panel of 40 body and organ weight, skeletal length, and obesity-related traits at 9 weeks of age. Linkage analysis revealed 20 QTL affecting a representative subset of phenotypes in HG2DF2 and HG11F2 mice. The effect of sex was quantified by comparing two linear models: the first model included sex as an additive covariate and the second incorporated sex as an additive and an interactive covariate. Of the 20 QTL, 8 were sex biased, sex specific, or sex antagonistic. Most traits were regulated by single QTL; however, two closely linked loci were identified for five traits in HG2DF2 mice. Additionally, the confidence intervals for most QTL were significantly reduced relative to the original mapping results, setting the stage for quantitative trait gene (QTG) discovery. These results highlight the importance of assessing the contribution of sex in complex trait analyses.

Background: High growth (hg) modifier and background independent quantitative trait loci (QTL) affecting growth, adiposity and carcass composition were previously identified on mouse chromosomes (MMU) 1, 2, 5, 8, 9, 11 and 17. To confirm and further characterize each QTL, two panels of speed congenic strains were developed by introgressing CAST/EiJ (CAST) QTL alleles onto either mutant C57Bl/6J-hg/hg (HG) or wild type C57Bl/6J (B6) genetic backgrounds., Results: The first speed congenic panel was developed by introgressing four overlapping donor regions spanning MMU2 in its entirety onto both HG and B6 backgrounds, for a total of eight strains. Phenotypic characterization of the MMU2 panel confirmed the segregation of multiple growth and obesity QTL and strongly suggested that a subset of these loci modify the effects of the hg deletion. The second panel consisted of individual donor regions on an HG background for each QTL on MMU1, 5, 8, 9, 11 and 17. Of the six developed strains, five were successfully characterized and displayed significant differences in growth and/or obesity as compared to controls. All five displayed phenotypes similar to those originally attributed to each QTL, however, novel phenotypes were unmasked in several of the strains including sex-specific effects., Conclusion: The speed congenic strains developed herein constitute an invaluable genomic resource and provide the foundation to identify the specific nature of genetic variation influencing growth and obesity.

Lines of mice selected for many generations for high or low growth in several laboratories around the world have been collected, and from these, inbred lines are being developed by recurrent full-sib mating in Edinburgh. There are seven high selected lines and four low lines (each low line is from the same base population as one of the high lines), and the histories of each are summarized. Mean body weight of males at 70 days of age in the Edinburgh laboratory in the heaviest inbred line (77 g) is 4.8-fold higher than in the lightest line (16 g), and 1.9-fold higher than in the least extreme high line (41 g). Litter size, food intake, and fat content also differ substantially. These inbred extreme selected lines are a uniquely valuable resource for QTL or gene mapping, candidate gene identification, and elucidation of epistatic effects.

A genome-wide scan was performed in order to identify Quantitative Trait Loci (QTL) associated with growth in a population segregating high growth (hg), a partially recessive mutation that enhances growth rate and body size in the mouse. A sample of 262 hg/hg mice was selected from a C57BL/6J-hg/hg x CAST/EiJ F2 cross and typed with 79 SSLP markers distributed across the genome. Eight significant loci were identified through interval mapping. Loci on Chromosomes (Chrs) 2 and 8 affected the growth rate of F2 mice. Loci on Chr 2 and 11 affected growth rate and carcass lean mass (protein and ash). A locus on Chr 9 modified femur length and another one in Chr 17 affected both carcass lean mass and femur length, but none of these had significant effects on growth rate. Loci on Chrs 5 and 9 modified carcass fat content. Additive effects were positive for C57BL/6J alleles, except for the two loci affecting carcass fatness. Typing of selected markers in 274 +/+ F2 mice revealed significant interactions between hg and other growth QTL, which were detected as changes in gene action (additive or dominant) and in allele substitution effects. Knowledge about interactions between loci, especially when major genes are involved, will help in the identification of positional candidate genes and in the understanding of the complex genetic regulation of growth rate and body size in mammals.

The attainment of a specific mature body size is one of the most fundamental differences among species of mammals. Moreover, body size seems to be the central factor underlying differences in traits such as growth rate, energy metabolism and body composition. An important proportion of this variability is of genetic origin. The goal of the genetic analysis of animal growth is to understand its "genetic architecture", that is the number and position of loci affecting the trait, the magnitude of their effects, allele frequencies and types of gene action. In this review, the different strategies developed to identify and characterize genes involved in the regulation of growth in the mouse are described, with emphasis on the methods developed to map loci contributing to the regulation of quantitative traits (QTLs).

Characterizing causal molecular defects in mouse models of overgrowth or dwarfism helps to identify the key genes and pathways that regulate the growth process. We report here the molecular basis for high growth (hg), a spontaneous mutation that causes a 30-50% increase in postnatal growth. We conclude that hg is an allele of the suppressor of cytokine signaling 2 (Socs2), a member of a family of regulators of cytokine signal transduction. We demonstrate mapping of Socs2 to the hg region, lack of Socs2 mRNA expression, a disruption of the Socs2 locus in high-growth (HG) mice, and a similarity of phenotypes of HG mice and Socs2(-/-) mice generated by gene targeting. Characteristics of the HG phenotype suggest that Socs2 deficiency affects growth prenatally and postnatally most likely through deregulating the growth hormone (GH)/insulin-like growth factor I (IGF1). These results demonstrate a critical role for Socs2 in controlling growth., (Copyright 2001 Academic Press.)

The mouse high growth (hg) gene was identified in a selection experiment for rapid growth. It produces a 30-50% increase in weight gain of homozygous individuals without resulting in obesity. Recently, hg was mapped to a deletion around marker D10Mit69. Here we report a map of yeast artificial chromosome and bacterial artificial chromosome clones spanning the entire region deleted in high-growth mice. The size of the deletion estimated from the clone lengths is approximately 500 kb. Using exon trapping, the murine Raidd/Cradd gene was identified in the hg region, and its cDNA sequence and expression pattern were determined. The human RAIDD/CRADD was mapped using radiation hybrid mapping to human chromosome 12, 2.9 cR distal to marker AFMB311WC5. The identified Raidd/Cradd gene, which is deleted in high-growth mice, presents a potential candidate for hg., (Copyright 1998 Academic Press.)

Effects of a recessive gene causing high growth (hg) were studied on two major components of the growth axis in mice. Plasma and pituitary levels of growth hormone and plasma levels of insulin-like growth factor I (IGF-I) were measured in three lines homozygous for hg, each compared with a control line of alike genetic background but wild type for the hg locus (Hg). Line Gh (hghg) and line GH (HgHg) are from a line which had undergone long-term selection for high postweaning weight gain; line Ch (hghg) and line CH (HgHg) were extracted from the second backcross of Gh to C57BL/6J; line L54 (hghg) was from the sixth backcross to C57BL/6J (B6) (HgHg). Pituitary GH levels and plasma IGF-I levels were measured in both sexes at 3, 4.5, 6 and 9 wk of age. Plasma growth hormone was measured in 8- to 12-wk-old males at hourly intervals from 08.00 to 17.00. Body weight in lines homozygous for hg at 6 and 9 wk of age was 10-30% greater than in control lines. The ontogeny of this increased growth depended on genetic background. Pituitary growth hormone content was 52% lower in the two hghg lines measured (lines Ch and Gh) than in control lines at 4.5, 6 and 9 wk. Plasma growth hormone levels were also much lower in hg mice, with values only 20-30% of those in their respective controls. hg lines showed consistently low plasma growth hormone levels throughout the 9 hr sampling period, while control lines expressed the characteristic pulsatile hormone secretion.(ABSTRACT TRUNCATED AT 250 WORDS)