A locus on the X Chromosome is linked to body length in mice

Linkage between body length (anus to nose (AN) length) and three markers on the mouse X Chromosome was found in an interspecific backcross ((C57BL/6J×Mus spretus) F1 ×C57BL/6J), designated BSB. A cross of 409 mice were scored for 148 genetic markers distributed on all chromosomes except the Y Chromosome. Statistical analysis revealed highly significant linkage (LOD score 5.5) between body length and a locus in the middle portion of the X Chromosome, the nearest markers being the microsatellite marker DXMit73 and a farnesyl pyrophosphate locus (Fpsl9) 3.1 cM proximal to DXMit73. The locus explains 10% of the variance in AN length and affects both males and females to about the same extent. Received: 17 April 1995 / Accepted: 13 October 1995     

Unstable heart rate and temperature regulation predict mortality in AKR/J mice

Elderly populations face greater risks of mortality when exposed to changes in environmental stress. The purpose of the following study was to develop an age-dependent susceptibility model that achieved the following three goals: 1) to operationally define homeostasis by assessing the stability and periodicity in physical activity, heart rate (HR), and deep body temperature (T(db)), 2) to specify alterations in activity, HR, and T(db) regulation that signal imminent death, and 3) to test the hypothesis that the decay in homeostasis associated with imminent death incorporates the coincident disintegration of multiple physiological systems. To achieve these goals, the circadian regulation of activity, HR, and T(db) was assessed using radiotelemeters implanted in AKR/J (n = 17) inbred mice at approximately 190 days of age. During a 12:12-h light-dark cycle, weekly measurements were obtained at 30-min intervals for 48-h periods until each animal's natural death. The average (+/-SE) life span of surgically treated animals did not differ from untreated controls (319 +/- 12 vs. 319 +/- 14 days). Cardiac and thermal stability were characterized by a circadian periodicity, which oscillated around stable daily averages of 640 +/- 14 beats/min in HR and 36.6 +/- 0.1 degrees C in T(db). Stable HR and T(db) responses were compared with extreme conditions 3 days before death, during which a disintegration of circadian periodicity was coincident with a fall in the daily average HR and T(db) of approximately 29 and approximately 13% lower (i.e., 456 +/- 22 beats/min and 31.7 +/- 0.6 degrees C), respectively. The results further suggested that multiple predictors of cardiac and thermal instability in AK mice, including significant bradycardia, hypothermia, and a loss of circadian periodicity, forecast life span 5-6 wk before expiration.     

Gene-environment interaction: a significant diet-dependent obesity locus demonstrated in a congenic segment on mouse Chromosome 7

We have previously reported suggestive evidence for a locus on Chromosome (Chr) 7 that affects adiposity in F₂ mice from a CAST/Ei × C57BL/6J intercross fed a high-fat diet. Here we characterize the effect of a high-fat (32.6 Kcal% fat) diet on male and female congenic mice with a C57BL/6J background and a CAST/Ei-derived segment on Chr 7. Adiposity index (AI) and weights of certain fat pads were approximately 50% lower in both male and female congenic mice than in control C57BL/6J mice, and carcass fat content was significantly reduced. The reduction of fat depot weights was not seen, however, in congenic animals fed a low-fat chow diet (12 Kcal% fat). The congenic segment is approximately 25 cM in length, extending from D7Mit213 to D7Mit41, and includes the tub, Ucp2, and Ucp3, genes, all of which are candidate genes for this effect. Some polymorphisms have been found on comparing c-DNA sequences of the Ucp2 gene from C57BL/6J and CAST/Ei mice. These results suggest that one or more genes present in the congenic segment modulate the susceptibility to fat deposition on feeding a high-fat diet. We were unable to show any significant difference between the energy intakes of the congenic and the control C57BL/6J mice on the high-fat diet. Also, measurements of energy expenditure in male mice at 6 weeks of age, during the first 2 weeks of exposure to the high-fat diet, failed to show any differences between control and congenic animals. Received: 30 September 1998 / Accepted: 22 December 1998     

Diet-dependent obesity and hypercholesterolemia in the New Zealand obese mouse: identification of a quantitative trait locus for elevated serum cholesterol on the distal mouse chromosome 5

AIMS: New Zealand obese (NZO) mice exhibit a polygenic syndrome of obesity, insulin resistance, and hypercholesterolemia that resembles the human metabolic syndrome. This study was performed in order to locate genes responsible for elevated serum cholesterol and to compare their effects under a standard and high fat diet.METHODS: A backcross population of NZO with SJL mice (NZO x F1(SJL x NZO)) was generated. Mice were raised on a normal or high fat diet and were monitored for 22 weeks (body weight, serum cholesterol, and blood glucose). A genome-wide scan was performed by genotyping of approximately 200 polymorphic microsatellite markers by PCR and linkage analysis was performed with the MAPMAKER program.RESULTS: In the genome-wide scan, a single susceptibility locus for hypercholesterolemia (Chol1/NZO, maximum LOD score 14.5 in a combined population of 523 backcross mice) was identified on chromosome 5. Cholesterol levels were significantly elevated in both male and female homozygous carriers of the Chol1/NZO allele. The locus maps 40cM distal of the previously described obesity locus Nob1 in the vicinity of the marker D5Mit244 and in the vicinity of hypercholesterolemia QTL previously identified in the NZB, CAST, and C57BL/6J strains. Chol1/NZO was not associated with elevated body weight, serum insulin, or hyperglycemia. The high fat diet significantly increased serum cholesterol levels, but the fat content of the diet did not alter the absolute effect of Chol1/NZO.Conclusions: Chol1/NZO is a major susceptibility locus on the distal mouse chromosome 5, which produces gender-independent hypercholesterolemia in NZO mice. The effect of Chol1/NZO was independent of the dietary fat content and was not associated with the other traits of the metabolic syndrome. Thus, it is suggested that the responsible gene might be involved in cholesterol metabolism.     

Maternally transmitted resistance to lymphoma development in mice of reciprocal crosses of the RF/J and AKR/J strains

Females but not males of the low-lymphoma RF/J strain transmit a non-Mendelian factor which suppresses the development of lymphoma in F1 crosses with mice of the high-lymphoma AKR/J strain. Suppression of lymphoma was also evident in the first backcross generation to the parental AKR strain, but only when (RF female x AKR male)F1 mice had been the female parent. This "maternal resistance factor" was transmitted independently of the dominant, lymphoma-suppressing Fv-1n allele transmitted by both males and females of the RF strain, but the suppressive capacities of the two factors appeared to be additive. In this cross, F1 progeny of RF females also showed marked suppression of ecotropic murine leukemia virus expression by comparison with mice of the reciprocal F1 cross, but this suppression of virus expression was not detected in the lymphoma-suppressed AKR backcross population. The observation of lymphoma suppression in the absence of ectropic virus suppression in mice of the (RF X AKR)F1 female x AKR male backross generation indicates a qualitative or quantitative difference in the determination of these two effects.     

Emv-13 (Akv-3): a noninducible endogenous ecotropic provirus of AKR/J mice

All AKR/J mice carry at least three endogenous ecotropic viral loci which have been designated Emv-11 (Akv-1), Emv-13 (Akv-3), and Emv-14 (Akv-4) (Jenkins et al., J. Virol. 43:26-36, 1982.) Using two independent AKR/J-derived sets of recombinant inbred mouse strains, AKXL (AKR/J x C57L/J) and AKXD (AKR/J x DBA/2J), as well as the HP/EiTy strain (an Emv-13-carrying inbred strain partially related to AKR/J mice) (Taylor et al., J. Virol. 23:106-109, 1977), we have examined the association of these endogenous viral loci with virus expression. Strains which transmit Emv-11 or Emv-14 or both were found to produce virus spontaneously, whereas strains that transmit Emv-13 alone were negative for virus expression. Restriction endonuclease digestion and hybridization with an ecotropic virus-specific hybridization probe of DNAs from strains which transmit only Emv-13 yielded enzyme cleavage patterns identical to those observed with DNAs from strains transmitting Emv-11 or Emv-14 or both. These findings indicate the absence of any gross rearrangement of Emv-13 proviral sequences. Cell cultures derived from recombinant inbred strains that carry only Emv-13 failed to express detectable infectious virus, viral proteins, or cytoplasmic ecotropic virus-specific RNA even after treatment with 5-iodo-2-deoxyuridine or 5-azacytidine, an inhibitor of DNA methylation. Our results indicate that a mechanism(s) other than methylation of Emv-13 proviral DNA is responsible for inhibition of Emv-13 expression.     

Identification of quantitative trait loci that regulate obesity and serum lipid levels in MRL/MpJ x SJL/J inbred mice

The total body fat mass and serum concentration of total cholesterol, HDL cholesterol, and triglyceride (TG) differ between standard diet-fed female inbred mouse strains MRL/MpJ (MRL) and SJL/J (SJL) by 38-120% (P < 0.01). To investigate genetic regulation of obesity and serum lipid levels, we performed a genome-wide linkage analysis in 621 MRLx SJL F2 female mice. Fat mass was affected by two significant loci, D11Mit36 [43.7 cM, logarithm of the odds ratio (LOD) 11.2] and D16Mit51 (50.3 cM, LOD 3.9), and one suggestive locus at D7Mit44 (50 cM, LOD 2.4). TG levels were affected by two novel loci at D1Mit43 (76 cM, LOD 3.8) and D12Mit201 (26 cM, LOD 4.1), and two suggestive loci on chromosomes 5 and 17. HDL and cholesterol concentrations were influenced by significant loci on chromosomes 1, 3, 5, 7, and 17 that were in the regions identified earlier for other strains of mice, except for a suggestive locus on chromosome 14 that was specific to the MRL x SJL cross. In summary, linkage analysis in MRL x SJL F2 mice disclosed novel loci affecting TG, HDL, and fat mass, a measure of obesity. Knowledge of the genes in these quantitative trait loci will enhance our understanding of obesity and lipid metabolism.     

Cytological identification of the lymphocytes in highly leukemic AKR/J mice in ontogenesis. Effect of somatotropin on the cellular composition of the lymphoid organs]

In AKR/J mice lymphocytes of thymus, spleen and lymph nodes can be classified according to their morphology as revealed by the Stockinger and Kellner staining: I--basophilic cytoplasm, 1--3 large basophilic nucleoli (blast cells), II--basophilic cytoplasm, 1--4 small clearly visible nucleoli (T-lymphocytes), III-weakly basophilic cytoplasm, 1-4 small fairly visible nucleoli (B-lymphocytes). The number of cells of types I and II increases with the progressing of leucaemia. After the administration of somatotrophic hormone the number of cells of types I and II increases only in the lymphoid organs of 5 months old AKR/J mice.     

Autologous immune responses to the major oncornavirus polypeptides in unmanipulated AKR/J mice.

The autologous immune response of AKR/J mice to the structural proteins of murine leukemia virus (MuLV) was examined. Immunoglobulins from the renal glomeruli were chemically eluted, separated from antigens, recovered, and tested for immunological reactivity against MuLV structural proteins. Analyzing immune precipitates obtained after mixing radiolabeled Tween-disrupted MuLV preparations with eluates from AKR/J mice on sodium dodecyl sulfategel electrophoresis, we found evidence of antibodies to the major classes of MuLV structural components: gp70, gp45, p30, and one or more proteins in the 10,000- to 15,000-dalton class. Using rate zonal centrifugation we confirmed that the eluates from AKR/J glomeruli contained antibody(s) that bound specifically to p30. These results indicate that AKR/J mice spontaneously mount immune responses against the major oncornavirus polypeptide antigens.     

Quantitative trait loci for body weight in the intercross between SM/J and A/J mice.

We performed a genome-wide quantitative trait locus (QTL) analysis of body weight at 10 weeks of age in a population of 321 intercross offspring from SM/J and A/J mice, progenitor strains of SMXA recombinant inbred strains. Interval mapping revealed two significant QTLs, Bwq3 (body weight QTL3) and Bwq4, on Chromosomes (Chrs) 8 and 18 respectively, and five suggestive QTLs on Chrs 2, 6, 7, 15 and 19. Bwq3 and Bwq4 explained 6% of the phenotypic variance. The SM/J alleles at both QTLs increased body weight, though the SM/J mouse was smaller than the A/J mouse. On the other hand, four of the five suggestive QTLs detected had male-specific effects on body weight and the remainder was female-specific. These suggestive QTLs explained 5-6% of the phenotypic variance and all the SM/J alleles decreased body weight.     

Quantitative trait locus analysis of serum insulin, triglyceride, total cholesterol and phospholipid levels in the (SM/J x A/J)F2 mice.

Quantitative trait locus (QTL) analysis of serum insulin, triglyceride, total cholesterol and phospholipid levels at 10 weeks of age was performed in 321 F2 offspring from SM/J and A/J mice. Interval mapping revealed a total of 22 suggestive QTLs affecting the four traits: two insulin QTLs on Chromosomes (Chrs) 6 and 8; six triglyceride QTLs on Chrs 4, 8, 9, 11, 12 and 19; six total-cholesterol QTLs on Chrs 1, 3, 4, 14, 17 and 19; and eight phospholipid QTLs on Chrs 2, 3, 4, 6, 8, 10 and 19. Gender influenced the expression of eight of the suggestive QTLs. The total-cholesterol QTLs on Chrs 4, 14 and 17, the triglyceride QTL on Chr 9 and the phospholipid QTL on Chr 4 were specific to females. The phospholipid QTLs on Chrs 2 and 6 and the insulin QTL on Chr 8 were specific to males. In addition, common QTLs involved in the regulation of some of the traits were identified. The female-specific QTL on Chr 4 appeared to be involved in the regulation of total cholesterol and phospholipid levels. The QTL on Chr 8 affected insulin and phospholipid levels, whereas the Chr 19 QTL was common to the three lipid parameters.     

Quantitative trait loci affecting the behavior of A/J and CBA/J intercross mice in the elevated plus maze

How allelic diversity affects neural mechanisms to produce behavioral variation is largely unknown. The elevated plus maze, consisting of open and closed arms, has been used as a model of behavioral variation in rodent exploration. Under dim illumination the nature of the sensory stimuli that influence arm choice is uncertain. Two inbred mouse strains, A/J (Tyr ^c /Tyr ^c , the albino phenotype, mutation in tyrosinase) with a strong preference for closed arm entry, and CBA/J (Pdeb ^rdl /Pdeb ^rdl , the retinal degeneration phenotype, mutation in the β-subunit of rod cGMP phosphodiesterase), with a weak preference for open arm entry, were studied under varying light. Because behavioral differences persist under red light, variation in light perception is not likely to fully account for variation in arm choice. To identify genetic factors influencing arm choice (100 × Open arm entries/Total arm entries) quantitative trait loci analyses (QTL) were performed on (A/J × CBA/J)F₂ mice. Two QTLs, one of which includes PDEB, were identified on Chr 5 (LOD > 10) and account for > 30% of the behavioral variation in arm preference. Tyr (Chr 7, 44 cM) was linked to closed arm entries but not arm preference, and is unlikely to be acting through a direct effect on light perception, because A/J arm entries were not affected by red light and there was no interaction with PDEB in the (A/J × CBA/J)F₂ mice. Whether the candidate QTLs on Chr 5 affect arm choice through an effect on light perception is unknown, but phenotypic differences between F₂ mice with retinal degeneration and CBA/J mice and F₂ mice with albinism and A/J mice suggest that factors other than light sensitivity contribute to arm preference in these two strains. Received: 11 January 2001 / Accepted: 22 March 2001     

Quantitative trait loci that determine plasma lipids and obesity in C57BL/6J and 129S1/SvImJ inbred mice

The plasma lipid concentrations and obesity of C57BL/6J (B6) and 129S1/SvImJ (129) inbred mouse strains fed a high-fat diet containing 15% dairy fat, 1% cholesterol, and 0.5% cholic acid differ markedly. To identify the loci controlling these traits, we conducted a quantitative trait loci (QTL) analysis of 294 (B6 x 129) F(2) females fed a high-fat diet for 14 weeks. Non-HDL cholesterol concentrations were affected by five significant loci: Nhdlq1 [chromosome 8, peak centimorgan (cM) 38, logarithm of odds [LOD] 4.4); Nhdlq4 (chromosome 10, cM 70, LOD 4.0); Nhdlq5 (chromosome 6, cM 0) interacting with Nhdlq4; Nhdlq6 (chromosome 7, cM 10) interacting with Nhdlq1; and Nhdlq7 (chromosome 15, cM 0) interacting with Nhdlq4. Triglyceride (TG) concentrations were affected by three significant loci: Tgq1 (chromosome 18, cM 42, LOD 3.2) and Tgq2 (chromosome 9, cM 66) interacting with Tgq3 (chromosome 4, cM 58). Obesity measured by percentage of body fat mass and body mass index was affected by two significant loci: Obq16 (chromosome 8, cM 48, LOD 10.0) interacting with Obq18 (chromosome 9, cM 65). Knowing the genes for these QTL will enhance our understanding of obesity and lipid metabolism.     

Comparative mapping of mouse Chromosome 4 and human Chromosome 9: Lv,Orm, and Hxb are closely linked on mouse Chromosome 4

The genes for orosomucoid (ORM-1 and ORM-2), delta-aminolevulinate dehydratase (ALAD), and hexabrachion or tenascin (HXB) all map to the q31-qter region of human Chromosome (Chr) 9. The mouse homolog of each of these genes has been mapped to Chr 4, but hexabrachion has not previously been mapped by linkage analysis. We have now ordered Orm-1, Lv (the mouse homolog of ALAD), and Hxb in an interspecific backcross panel, by use of tyrosinase related protein-1, Tyrp-1, whose human homolog maps to 9p13-pter (Abbott et al., Genomics 1991) as a reference locus. No recombinants were identified in 124 animals between Lv and Orm-1. Hxb was found to be 1.6 cM distal to Lv and Orm-1, and 4.8 cM proximal to Tyrp-1, or b. These data therefore contribute to our knowledge of the conserved synteny between HSA 9q and MMU 4.     

Identification of a new quantitative trait locus on Chromosome 7 controlling disease severity of collagen-induced arthritis in rats

 Autoimmune diseases, such as rheumatoid arthritis, Crohn's disease, and multiple sclerosis, are regulated by multiple genes. Major histocompatibility complex (MHC) genes have the strongest effects, but non-MHC genes also contribute to disease susceptibility/severity. In this paper, we describe a new non-MHC quantitative trait locus, Cia8, on rat Chromosome (Chr) 7 that controls collagen-induced arthritis severity in F2 progeny of DA and F344 inbred rats, and present an updated localization of Cia4 on the same chromosome. We also describe the location of mouse and human genes, orthologous to the genes in the genomic intervals containing Cia4 and Cia8, and provide evidence that the segment of rat Chr 7 containing Cia4 and Cia8 is homologous to segments of mouse Chr 10 and 15 and human Chr 8, 12, and 19. Received: 1 November 1998 / Revised: 24 January 1999     

Lymphoma development of simultaneously combined exposure to two radiofrequency signals in AKR/J mice

There are public concerns regarding possible carcinogenic or cancer-promoting effects of radiofrequency electromagnetic fields (RF-EMFs) because of the extensive use of wireless mobile phones and other telecommunication devices in daily life. However, so far it is unclear if non-thermal exposure of single EMF exposure in animal studies has a direct influence on carcinogenesis. Here, carcinogenic effects of combined signal RF-EMFs on AKR/J mice, which were used for the lymphoma animal model, were investigated. Six-week-old AKR/J mice were simultaneously exposed to two types of RF signals: single code division multiple access (CDMA) and wideband code division multiple access (WCDMA). AKR/J mice were exposed to combined RF-EMFs for 45 min/day, 5 days/week, for a total of 42 weeks. The whole-body average specific absorption rate (SAR) of CDMA and WCDMA fields was 2.0 W/kg each, 4.0 W/kg in total. When we examined final survival, lymphoma incidence, and splenomegaly incidence, no differences were found between sham- and RF-exposed mice. However, occurrence of metastasis infiltration to the brain in lymphoma-bearing mice was significantly different in RF-exposed mice when compared to sham-exposed mice, even though no consistent correlation (increase or decrease) was observed between male and female mice. However, infiltration occurrence to liver, lung, and spleen was not different between the groups. From the results, we suggested that simultaneous exposure to CDMA and WCDMA RF-EMFs did not affect lymphoma development in AKR/J mice.     

Development of donor-derived thymic lymphomas after allogeneic bone marrow transplantation in AKR/J mice

The transplantation of bone marrow cells from BALB/c (but not C57BL/6 and C3H/HeN) mice was observed to lead to the development of thymic lymphomas (leukemias) in AKR/J mice. Two leukemic cell lines, CAK1.3 and CAK4.4, were established from the primary culture of two thymic lymphoma, and surface phenotypes of these cell lines found to be H-2d and Thy-1.2+, indicating that these lymphoma cells are derived from BALB/c donor bone marrow cells. Further analyses of surface markers revealed that CAK1.3 is L3T4+ Lyt2+ IL2R-, whereas CAK4.4 is L3T4- Lyt2- IL2R+. Both CAK1.3 and CAK4.4 were transplantable into BALB/c but not AKR/J mice, further indicating that these cells are of BALB/c bone marrow donor origin. The cells were found to produce XC+-ecotropic viruses, but xenotropic and mink cell focus-forming viruses were undetectable. Inasmuch as thymic lymphomas are derived from bone marrow cells of leukemia-resistant BALB/c strain of mice under the allogeneic environment of leukemia-prone AKR/J mice, this animal model may serve as a useful tool not only for the analysis of leukemic relapse after bone marrow transplantation but also for elucidation of the mechanism of leukemogenesis.