The genetics of aryl hydrocarbon hydroxylase induction in mice: A single gene difference between C57BL/6J and DBA/2J

Twenty-one inbred strains of mice were surveyed for inducibility of hepatic aryl hydrocarbon hydroxylase (AHH) activity by the carcinogen 3-methylcholanthrene (MC). In 11 strains given MC, AHH activity increased 1.3- to 5-fold (inducible), whereas ten strains responded with a less than 0.5-fold increase (noninducible). Neither the inducible nor the noninducible class was homogeneous, and in each considerable variation was found in both the basal activity of AHH and the response to MC. Strains DBA/2J and C57BL/6J were chosen to represent the noninducible and inducible classes, respectively. In the crosses (C57BL/6 × DBA/2)F₁ × DBA/2 and (C57BL/6 × DBA/2)F₂, inducibility segregated as a single autosomal dominant gene. The gene symbols Ahh ⁱ and Ahh ⁿ are proposed for the alleles present in C57BL/6J and DBA/2J, respectively. No genetic linkage was found between the Ahh locus and the following loci: b, d, Es-1, Es-3, Gpd-1, Hbb, Id-1, Pgm-1, and sex. Some implications of this work in the study of mammalian enzyme induction and chemically induced carcinogenesis are discussed. There is a positive correlation between AHH inducibility and the development of an inflammatory response to the topical application of the carcinogen 7,12-dimethylbenzanthracene.     

Genetic resistance to diet-induced obesity in chromosome substitution strains of mice

Discovery of genes that confer resistance to diseases such as diet-induced obesity could have tremendous therapeutic impact. We previously demonstrated that the C57BL/6J-Chr^A/J/NaJ panel of chromosome substitution strains (CSSs) is a unique model for studying resistance to diet-induced obesity. In the present study, three replicate CSS surveys showed remarkable consistency, with 13 A/J-derived chromosomes reproducibly conferring resistance to high-fat-diet-induced obesity. Twenty CSS intercrosses, one derived from each of the 19 autosomes and chromosome X, were used to determine the number and location of quantitative trait loci (QTLs) on individual chromosomes and localized six QTLs. However, analyses of mean body weight in intercross progeny versus C57BL/6J provided strong evidence that many QTLs discovered in the CSS surveys eluded detection in these CSS intercrosses. Studies of the temporal effects of these QTLs suggest that obesity resistance was dynamic, with QTLs acting at different ages or after different durations of diet exposure. Thus, these studies provide insight into the genetic architecture of complex traits such as resistance to diet-induced obesity in the C57BL/6J-Chr^A/J/NaJ CSSs. Because some of the QTLs detected in the CSS intercrosses were not detected using a traditional C57BL/6J × A/J intercross, our results demonstrate that surveys of CSSs and congenic strains derived from them are useful complementary tools for analyzing complex traits.     

Allelic profile at 37 biochemical loci of two inbred strains of the house mouse derived from wild Mus musculus musculus

Two newly established inbred strains derived from Mus musculus musculus, designated PWD/Ph (F29) and PWK/Ph (F33), were examined for their alleles at 37 biochemical loci located on 12 different chromosomes. The allelic pattern showed characteristic differences from those observed in common inbred strains. The genetic distance D between PWK/Ph and PWD/Ph was 0.027, whereas the corresponding values for the genetic distances between PWK/Ph and C57BL/6J, DBA/2J, BALB/cJ and SWR/J were 0.777, 0.721, 0.721 and 0.838 respectively. New allozymes are described as being controlled by the loci Es-23, Pre-2 and Tam-1. The genetic relationship to M.m.molossinus is indicated by identical alleles at six other loci (Es-2, Es-9, Es-10, Es-11, Es-18 and Es-22).     

Esterase-6 (Es-6) in laboratory mice: Hormone-influenced expression and linkage relationship to oligosyndactylism (Os), esterase-1 (Es-1), and esterase-2 (Es-2) in chromosome 8

Allelic differences at an esterase locus designated Es-6 exist between mouse strain C57 BL/6J and a laboratory stock of M.m. molossinus. Strain C57BL/6J has been assigned the allele Es-6a and M. m. molossinus the alternate allele Es-6b. Kidney expression of the electrophoretic esterase band controlled by the Es-6 locus is sex influenced, with increased activity apparently induced by testosterone. A four-point test cross established the gene order Os-Es-1-Es-6-Es-2 within a 10-cM segment on chromosome 8.     

No recombinations between Tcra-V and Tcra-C gene segments in 669 backcross mice

Because T-cell receptor (Tcr) genes may possibly function as non-major histocompatibility complex (MHC) immune response genes or predispose for autoimmune diseases, it is important to know how these genes are inherited. We found that Bgl I-digested DNA of BALB/c, C3H, DBA/2, and C57BL/6 exhibited restriction enzyme fragment length polymorphisms (RFLPs) for the Tcra-V1, Tcra-V2, Tcra-V4, Tcra-V6, Tcra-V7, Tcra-V8, Tcra-V11, Tcra-122, Tcra-V13, and Tcra-C gene segments. Inheritance of these RFLPs in 669 offspring from (BALB/c × C57BL/6) × BALB/c, (BALB/c × C57BL/6) × C57BL/6, (C57BL/6 × DBA2) × DBA/2, and (C57BL/6 × C3H) × C3H backcrosses was studied. Since we did not find any recombinations in the offspring, Tcra-V and Tcra-C gene segments are tightly linked and inherited as a haplotype. A peculiar finding was that 22 out of 103 (BALB/c × C57BL/6) × BALB/c offspring, heterozygous for Tcra-C, had deleted a C57BL/6 Tcra-V1 band as well as Tcra-V2 and Tcra-V4 bands. As will be discussed, this deletion is probably caused by heterogeneity in the C57BL/6 breeding stock of a commercial supplier. In seven BXD and BXH recombinant inbred strains with known recombinations between the Tcra-C and Es-10 loci, all Tcra-V RFLPs cosegregated with the Tcra-C RFLP. This finding agrees with the conclusion from our backcross studies; namely that Tcra-V and Tcra-C gene segments are tightly linked.     

Genetic regulation of erythrocyte autoantibody production in New Zealand black mice

The incidences of positive anti-erythrocyte autoantibodies (AEA) in New Zealand Black (NZB), C57BL/6, their F₁, F₂ hybrid, and the F₁ × NZB backcross mice were 100, 0, 0, 17, and 51%, respectively. This finding is in keeping with the idea that a combined effect of one to three dominant predisposing NZB gene(s) and a single dominant modifying C57BL/6 gene regulates the AEA production. Studies suggested that the modifying locusAem-1 is loosely linked toMup-1 locus on chromosome 4, and the gene order isAem-1: Mup-1: Gpd-1. We analyzed the effects of theAem-1 locus on other autoimmune traits and found that the gene action ofAem-1 is unrelated to the spontaneous productions of dsDNA-specific antibodies, the retroviral gp70-anti-gp70 immune complexes and natural thymocytotoxic autoantibod ies and to the serum level of retroviral gp70. A significant association was observed between the negative AEA and the low (normal) serum IgM level in (C57BL/6 × NZB)F₁ × NZB backcross mice. It remains to be determined whether theAem-1 locus also controls the serum IgM level.Abbreviations used in this paper AEA anti-erythrocyte autoantibody - NTA natural thymocytotoxic autoantibody - gp70 major glycoprotein constituent of the murine C type retrovirus envelope - Mup-1 major urinary protein complex-1 - Gpd-1 glucose-6-phosphate dehydrogenase-1 - Akp-1 alkaline phosphatase-1 - Es-1 esterase-1 - Igh-1 immunoglobulin (IgG2a) heavy chain-1     

Susceptibility to Seizure-Induced Excitotoxic Cell Death Is Regulated by an Epistatic Interaction between Chr 18 (Sicd1) and Chr 15 (Sicd2) Loci in Mice

Seizure-induced cell death is believed to be regulated by multiple genetic components in addition to numerous external factors. We previously defined quantitative trait loci that control susceptibility to seizure-induced cell death in FVB/NJ (susceptible) and C57BL/6J (resistant) mice. Two of these quantitative trait loci assigned to chromosomes 18 (Sicd1) and 15 (Sicd2), control seizure-induced cell death resistance. In this study, through the use of a series of novel congenic strains containing the Sicd1 and Sicd2 congenic strains and different combinations of the Sicd1 or Sicd2 sub region(s), respectively, we defined these genetic interactions. We generated a double congenic strain, which contains the two C57BL/6J differential segments from chromosome 18 and 15, to determine how these two segments interact with one another. Phenotypic comparison between FVB-like littermates and the double congenic FVB.B6-Sicd1/Sicd2 strain identified an additive effect with respect to resistance to seizure-induced excitotoxic cell death. It thus appears that C57BL/6J alleles located on chromosomes 18 and 15 interact epistatically in an additive manner to control the extent of seizure-induced excitotoxic cell death. Three interval-specific congenic lines were developed, in which either segments of C57BL/6J Chr 18 or C57BL/6J Chr 15 were introduced in the FVB/NJ genetic background, and progeny were treated with kainate and examined for the extent of seizure-induced cell death. All of the interval-specific congenic lines exhibited reduced cell death in both area CA3 and the dentate hilus, associated with the C57BL/6J phenotype. These experiments demonstrate functional interactions between Sicd1 and Sicd2 that improve resistance to seizure-induced excitotoxic cell death, validating the critical role played by gene-gene interactions in excitotoxic cell death.     

Genetic Analysis of Ligation-Induced Neointima Formation in an F2 Intercross of C57BL/6 and FVB/N Inbred Mouse Strains

Objective

Proliferation and migration of vascular smooth muscle cells (SMCs) are central for arterial diseases including atherosclerosis and restenosis. We hypothesized that the underlying mechanisms may be modeled by carotid ligation in mice. In FVB/N inbred mice, ligation leads to abundant neointima formation with proliferating media-derived SMCs, whereas in C57BL/6 mice hardly any neointima is formed. In the present study, we aimed to identify the chromosomal location of the causative gene variants in an F2 intercross between these two mouse strains.

Methods and Results

The neointimal cross-sectional area was significantly different between FVB/N, C57BL/6 and F1 female mice 4 weeks after ligation. Carotid artery ligation and a genome scan using 800 informative SNP markers were then performed in 157 female F2 mice. Using quantitative trait loci (QTL) analysis, we identified suggestive, but no genome-wide significant, QTLs on chromosomes 7 and 12 for neointimal cross-sectional area and on chromosome 14 for media area. Further analysis of the cross revealed 4 QTLs for plasma cholesterol, which combined explained 69% of the variation among F2 mice.

Conclusions

We identified suggestive QTLs for neointima and media area after carotid ligation in an intercross of FVB/N and C57BL/6 mice, but none that reached genome-wide significance indicating a complex genetic architecture of the traits. Genome-wide significant QTLs for total cholesterol levels were identified on chromosomes 1, 3, 9, and 12.     

Hybrid breakdown caused by substitution of the X chromosome between two mouse subspecies

Hybrid breakdown is a type of reproductive failure that appears after the F2 generation of crosses between different species or subspecies. It is caused by incompatibility between interacting genes. Genetic analysis of hybrid breakdown, particularly in higher animals, has been hampered by its complex nature (i.e., it involves more than two genes, and the phenotype is recessive). We studied hybrid breakdown using a new consomic strain, C57BL/6J-X(MSM), in which the X chromosome of C57BL/6J (derived mostly from Mus musculus domesticus) is substituted by the X chromosome of the MSM/Ms strain (M. m. molossinus). Males of this consomic strain are sterile, whereas F1 hybrids between C57BL/6J and MSM/Ms are completely fertile. The C57BL/6J-X(MSM) males showed reduced testis weight with variable defects in spermatogenesis and abnormal sperm head morphology. We conducted quantitative trait locus (QTL) analysis for these traits to map the X-linked genetic factors responsible for the sterility. This analysis successfully detected at least three distinct loci for the sperm head morphology and one for the testis weight. This study revealed that incompatibility of interactions of X-linked gene(s) with autosomal and/or Y-linked gene(s) causes the hybrid breakdown between the genetically distant C57BL/6J and MSM/Ms strains.     

Characterization of epistasis influencing complex spontaneous obesity in the BSB model

There is growing awareness that complex interactions among multiple genes and environmental factors play an important role in controlling obesity traits. The BSB mouse, which is produced by the backcross of (lean C57BL/6J x lean Mus spretus) x C57BL/6J, provides an excellent model of epistatic obesity. To evaluate potential epistatic interactions among six chromosomal regions previously determined to influence obesity phenotypes, we performed novel Bayesian analyses on the basis of both epistatic and nonepistatic models for four obesity traits: percentage of body fat, adiposity index, total fat mass, and body weight, and also for plasma total cholesterol. The epistatic analysis detected at least one more QTL than the nonepistatic analysis did for all obesity traits. These obesity traits were variously influenced by QTL on chromosomes 2, 7, 12, 15, and 16. Interaction between genes on chromosomes 2 and 12 was present for all obesity traits, accounting for 3-4.8% of the phenotypic variation. Chromosome 12 was found to have weak main effects on all obesity traits. Several different epistatic interactions were also detected for percentage of body fat, adiposity index, and total fat mass. Chromosomes 6 and 12 have not only main effects but also strong epistatic effects on plasma total cholesterol. Our results emphasize the importance of modeling epistasis for discovery of obesity genes.     

Influence of the maternal effect on allogenic inhibition of hematopoietic stem cells]

Bone marrow cells (0,5-10(6)) of female mice of CBA or C57BL strains were injected intravenously to lethally irradiated CBA, C57BL/6, (femaleCBA X maleC57BL/6)F1 and (femaleC57BL/6 X maleCBA)F1 mice. Spleen of recipients as assayed for colony count on the 9th day after bone marrow transplantation by the method of Till and McCullouch. Stem cells of CBA mice demonstrated failure of allogenic inhibition in (CBA X C57BL/6)F1 hybrid mice and formed the same number of colonies as in the spleen of syngenic recipients. The level of allogenic inhibition of CBA stem cells transplanted to (C57BL/6 X X CBA)F1 hybrid mice was 50%. Bone marrow cells of C57BL/6 mice formed colonies in spleen of (CBA X C57BL/6)F1 mice at least in 20 times less than in syngenic combination. In the transplantation of bone marrow from C57BL/6 mice to (C57BL/6 X CBA)F1 hybrid mice the allogenic inhibition was less pronounced (77-85%) as compared with the transfer of cells to (CBA X C57BL/6)F1 hybrid mice (95%). The sex of a recipient did not influence the number of formed colonies. The different level of allogenic inhibition of parental stem cells can not be explained by the effect of linkage with sex as the female of reciprocal hybrid mice have identical structure of sex chromosomes (X(CBA)XC57BL/6). The data obtained indicate that the maternal effect affects allogenic inhibition of stem cells in parent--F1 system. It is possible that the maternal influence may be determined by cytoplasmic factors of inheritance which affect the expressivity of recessive genes Hh, controlling the inheritance of specific haematopoietic cell antigens.     

Isozymes of NADP-dependent isocitrate dehydrogenase in normal and tumor tissues of various mouse strains and their hybrids

Normal tissues of DBA, CBA, CC57W, C3H, Balb/c, SHR mice and F1 hybrids CC57W/DBA appeared to differ in the ratios of mitochondrial and supernatant NADP-dependent isocitrate dehydrogenase (IDH). Tested inbred mice strains CC57W, C3H, SHR, Balb/c contain allelic form Idh-1a of supernatant IDH gene Idh-1, whereas allelic form Idh-1b is characteristic of mice strains DBA and CBA. In tumors IDH isozymes have the same mobility as do isozymes of homologous normal tissues; but their activity is lower. A high variability of each isozyme activity in the isozyme spectrum is revealed in various tissues of F1 hybrids CC57W/DBA. Allelic forms of gene Idh-1 were used as markers of normal and tumor cells for the experimental model: transplantation of sarcoma 37 (Idh-1a/Idh-1a) to subcutaneous tissue of the mouse strain DBA (Idh-1b/Idh-1b). It enables us to reveal isozymes of stromal cell in tumor IDH isozyme spectrum. The results indicate that the relation of normal and tumor isozymes vary in different tumors.     

Esterase-8 (Es-8): Characterization,polymorphism, and linkage of an erythrocyte esterase locus on chromosome 7 of Mus musculus

An electrophoretic polymorphism of an erythrocyte esterase, esterase-8, specific for the substrates α- and β-naphthyl acetate has been observed in the Asian house mouse, Mus musculus castaneus. M. m. castaneus is interfertile with inbred strains of mice, and F₁ hybrids (C57BL/6J × castaneus)F₁ and (SWR/J × castaneus)F₁ show a double-banded phenotype similar to a mixture of parental forms. This pattern suggests codominant expression of a structural gene difference. In backcrosses, ES-8 segregated as a single autosomal gene, designated Es-8, linked to Gpi-1 on chromosome 7. A gene order of Es-8, Gpi-1, c, Mod-2, and Hbb was determined from a series of crosses.     

Quantitative trait locus analysis of circulating adhesion molecules in hyperlipidemic apolipoprotein E-deficient mice

Circulating soluble adhesion molecules have been suggested as useful markers to predict several clinical conditions such as atherosclerosis, type 2 diabetes, obesity, and hypertension. To determine genetic factors influencing plasma levels of soluble vascular cell adhesion molecule-1 (VCAM-1) and P-selectin, quantitative trait locus (QTL) analysis was performed on an intercross between C57BL/6J (B6) and C3H/HeJ (C3H) mouse strains deficient in apolipoprotein E-deficient (apoE^−/−). Female F₂ mice were fed a western diet for 12 weeks. One significant QTL, named sVcam1 (71 cM, LOD 3.9), on chromosome 9 and three suggestive QTLs on chromosomes 5, 13 and 15 were identified to affect soluble VCAM-1 levels. Soluble P-selectin levels were controlled by one significant QTL, named sSelp1 (8.5 cM, LOD 3.4), on chromosome 16 and two suggestive QTLs on chromosomes 10 and 13. Both adhesion molecules showed significant or an apparent trend of correlations with body weight, total cholesterol, and LDL/VLDL cholesterol levels in the F₂ population. These results indicate that plasma VCAM-1 and P-selectin levels are complex traits regulated by multiple genes, and this regulation is conferred, at least partially, by acting on body weight and lipid metabolism in hyperlipidemic apoE^−/− mice. Zuobiao Yuan and Zhiguang Su contributed equally.     

Exacerbated susceptibility to infection-stimulated immunopathology in CD1d-deficient mice

Mice lacking functional CD1d genes were used to study mechanisms of resistance to the protozoan parasite Toxoplasma gondii. Wild-type (WT) BALB/c mice, CD1d-deficient BALB/c mice, and WT C57BL/6 mice all survived an acute oral infection with a low dose of mildly virulent strain ME49 T. gondii cysts. In contrast, most CD1d-deficient C57BL/6 mice died within 2 wk of infection. Despite having parasite burdens that were only slightly higher than WT mice, CD1d-deficient C57BL/6 mice displayed greater weight loss and intestinal pathology. In C57BL/6 mice, CD4(+) cells can cause intestinal pathology during T. gondii infection. Compared with WT mice, infected CD1d-deficient C57BL/6 mice had higher frequencies and numbers of activated (CD44(high)) CD4(+) cells in mesenteric lymph nodes. Depletion of CD4(+) cells from CD1d-deficient mice reduced weight loss and prolonged survival, demonstrating a functional role for CD4(+) cells in their increased susceptibility to T. gondii infection. CD1d-deficient mice are deficient in Valpha14(+) T cells, a major population of NKT cells. Involvement of these cells in resistance to T. gondii was investigated using gene-targeted Jalpha18-deficient C57BL/6 mice, which are deficient in Valpha14(+) T cells. These mice did not succumb to acute infection, but experienced greater weight loss and more deaths than B6 mice during chronic infection, indicating that Valpha14(+) cells contribute to resistance to T. gondii. The data identify CD4(+) cells as a significant component of the marked susceptibility to T. gondii infection observed in CD1d-deficient C57BL/6 mice, and establish T. gondii as a valuable tool for deciphering CD1d-dependent protective mechanisms.     

Interacting quantitative trait loci control loss of peripheral tolerance and susceptibility to autoimmune ovarian dysgenesis after day 3 thymectomy in mice

Day 3 thymectomy (D3Tx) results in a loss of peripheral tolerance mediated by CD4(+)CD25(+) T cells and the development of autoimmune ovarian dysgenesis (AOD) in A/J and (C57BL/6J x A/J)F(1) (B6AF(1)) hybrids but not in C57BL/6J mice. Quantitative trait loci (QTL) linkage analysis using a B6AF(1) x C57BL/6J backcross population verified Aod1 and Aod2 that were previously mapped as qualitative traits. Additionally, three new QTL intervals, Aod3, Aod4, and Aod5, on chromosomes 1, 2, and 7, respectively, influencing specific subphenotypes of AOD were identified. QTL linkage analysis using the A x B and B x A recombinant inbred lines verified Aod3 and confirmed linkage to H2. Aod5 colocalized with Mater, an ovarian-specific autoantigen recognized by anti-ovarian autoantibodies in the sera of D3Tx mice. Sequence analysis of Mater identified allelic, strain-specific splice variants between A/J and C57BL/6J mice making it an attractive candidate gene for Aod5. Interaction analysis revealed significant epistatic effects between Aod1-5 and Gasa2, a locus associated with susceptibility to D3Tx-induced autoimmune gastritis, as well as with H2. These results indicate that the QTL controlling D3Tx-induced autoimmune phenomenon are both organ specific and more generalized in their effects with respect to the genesis and activity of the immunoregulatory mechanisms maintaining peripheral tolerance.     

Genetic polymorphism of the sixth component of complement (C6) in mice

Immunofixation after isoelectric focusing revealed two forms of mouse C6, C6A and C6M, both of which consist of two major protein bands and one or more acidic minor bands. They were distinguishable by their different isoelectric point (pI) ranges: C6M has more acidic pI ranges (pH < 6.2) than C6A (pH < 6.3). C6A was found in common inbred mice of Mus musculus domesticus, while C6M was found in inbred and wild mice of M. m. molossinus (Japanese wild mice, an Asian subspecies). Breeding experiments showed that these two forms of C6 were controlled by a single codominant autosomal locus. We propose the designation C-6 for this locus with two alleles, C-6 ^a and C-6 ^m , which encode for C6A and C6M, respectively. Linkage analysis indicated that the locus is not closely linked to the following loci: Idh-1, agouti, Amy-1, brown, Gpd-1, Mup-1, Pgm-2, Pgm-1, albino, Hbb, Es-1, Mod-1, Sep-1, Es-3, Igh-1, beige, Es-10, Sod-1, and C-3.     

Genetic influences on oestrous cyclicity in mice: evidence that cycle length and frequency are differentially regulated.

Studies in C57BL/6J, DBA/2J and C3H/HeJ mice and in two F1 hybrid strains (B6D2F1 and B6C3HF1) 2-5 months old revealed marked genotypic differences among inbred strains. C57 mice had three times as many regular (3-6 days) cycles as DBA and C3H mice, due largely to fewer pseudopregnant-like (7-14 day) cycles. C57 had longer regular cycles than DBA and C3H mice. Although the frequencies of regular cycles of DBA and C3H mice were similar, the cycles of C3H mice were shorter than those of DBA mice. The results indicated that the genetic determinants of the frequency of regular cycles differ from those specifying cycle length. Frequency of regular cycles of F1 hybrids was either intermediate between the parent strains (B6D2F1) or similar to the C57 strain (B6C3HF1), suggesting that regular cycle frequency shows additive genetic variation in the former crosses, but mostly dominant variance in the latter background. Regular cycles were either shorter than in both parent strains (B6D2F1) or similar to one of them (B6C3HF1), indicating heterosis and dominance for genes specifying short cycles. Although the lack of reciprocal crosses meant that maternal effects and possible genomic imprinting effects could not be assessed, these results reveal marked genetic influences on cycle length and frequency and suggest that some of the genes specifying these two traits differ.     

Body Composition QTLs Identified in Intercross Populations Are Reproducible in Consomic Mouse Strains

Genetic variation contributes to individual differences in obesity, but defining the exact relationships between naturally occurring genotypes and their effects on fatness remains elusive. As a step toward positional cloning of previously identified body composition quantitative trait loci (QTLs) from F₂ crosses of mice from the C57BL/6ByJ and 129P3/J inbred strains, we sought to recapture them on a homogenous genetic background of consomic (chromosome substitution) strains. Male and female mice from reciprocal consomic strains originating from the C57BL/6ByJ and 129P3/J strains were bred and measured for body weight, length, and adiposity. Chromosomes 2, 7, and 9 were selected for substitution because previous F₂ intercross studies revealed body composition QTLs on these chromosomes. We considered a QTL confirmed if one or both sexes of one or both reciprocal consomic strains differed significantly from the host strain in the expected direction after correction for multiple testing. Using these criteria, we confirmed two of two QTLs for body weight (Bwq5-6), three of three QTLs for body length (Bdln3-5), and three of three QTLs for adiposity (Adip20, Adip26 and Adip27). Overall, this study shows that despite the biological complexity of body size and composition, most QTLs for these traits are preserved when transferred to consomic strains; in addition, studying reciprocal consomic strains of both sexes is useful in assessing the robustness of a particular QTL.     

A growth QTL (<Emphasis Type="Italic">Pbwg1</Emphasis>) region of mouse chromosome 2 contains closely linked loci affecting growth and body composition

Previous QTL studies have identified 24 QTLs for body weight and growth from 3 to 10 weeks after birth in an intersubspecific backcross mouse population between C57BL/6J and wild Mus musculus castaneus that has 60% of the body size of C57BL/6J. The castaneus allele at the most potent QTL (Pbwg1) on proximal chromosome 2 retards growth. In this study we have developed a congenic strain with a 44.1-Mb interval containing the castaneus allele at Pbwg1 by recurrent backcrossing to C57BL/6J. The congenic mouse developed was characterized by significantly higher body weight gain between 1 and 3 weeks of age and lower weight of white fat pads at 10 weeks of age than C57BL/6J. However, no clear difference in body weight at 1–10 weeks of age was observed between congenic and C57BL/6J strains. QTL analysis with 269 F₂ mice between the two strains did not identify any QTLs for body weight at 1, 3, 6, and 10 weeks of age, but it discovered eight closely linked QTLs affecting body weight gain from 1 to 3 weeks of age, lean body weight, weight of white fat pads, and body length within the Pbwg1 region. The castaneus alleles at all fat pad QTLs reduced the phenotypes, whereas at the remaining growth and body composition QTLs, they increased the trait values. These results illustrate that Pbwg1, which initially appeared to be a single locus, was resolved into several loci with opposite effects on the composition traits of overall body weight. This gives a reason for the loss of the Pbwg1 effect found in the original backcross population. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.