Multiple obesity QTLs identified in an intercross between the NZO (New Zealand obese) and the SM (small) mouse strains

The inheritance of adiposity levels has been investigated in an intercross of the obese, diabetes-prone NZO and the small, lean SM mouse strains. Adiposity index (AI) was defined as the sum of four fat pad weights divided by body weight. DNA pools from fat and lean mice were analyzed with microsatellite variants to screen the genome for quantitative trait loci (QTLs) affecting AI. Ten significant QTLs affecting AI were identified on Chromosome (Chr) 1 (three loci), Chr 2, Chr 5 (two loci), Chr 6 (two loci), Chr 7, and Chr 17. Most of the QTLs appear to be novel. Several QTLs differentially affect specific fat depots. Thus, Chr 2 and Chr 7 QTLs affect gonadal more than inguinal fat, while the converse is true for the Chr 17 QTL. Gender influences the expression of several of the QTLs. For example, effects of the proximal Chr 1 QTL (Obq7) on AI appears to be primarily in males. The proximal AI QTL on Chr 6 (Obq13) maps near the neuropeptide Y (Npy) locus. Sequence analysis of the Npy gene revealed a 1-nucleotide deletion within a highly conserved portion of the 3′ untranslated region in strain NZO. However, the deletion is polymorphic among mouse strains. Furthermore, lack of association between this same variant and AI in previously analyzed crosses raises doubt that it is the basis of Obq13. The present cross is the fourth in a series of intercrosses among 10 inbred strains arranged such that each strain is crossed with each adjacent strain within a circle. This design affords multiple opportunities to analyze each segregating QTL. Received: 17 July 2000 / Accepted: 9 October 2000     

Quantitative trait loci influencing morphine antinociception in four mapping populations

Analgesia (pain reduction, or antinociception) is a classical and clinically important effect of morphine administration, and in rodent models sensitivity to morphine has been shown to be strongly influenced by genotype. For example, several studies have reported marked differences in morphine antinociception between the insensitive C57BL/6 (B6) and sensitive DBA/2 (D2) inbred mouse strains on the hot-plate assay. This prompted the present genome-wide search for quantitative trait loci (QTLs) that are chromosomal sites influencing the magnitude of antinociception, by using four mapping populations derived from the B6 and D2 progenitor inbred strains. These four were the BXD recombinant inbred (RI) strain set, an F2 (B6D2F2) population, short-term selective breeding for antinociception from a B6D2F2 founding population, and incipient or completed congenic strains. In the BXD RI set and in the B6D2F2, a genome-wide search identified 10-12 provisional QTLs at a nominal p <.05. The other populations were subsequently used as confirmation steps to test each of the provisional QTL regions. Based on all available mapping populations, four QTLs emerged as significant (p <.00005) on proximal Chromosome (Chr) 1 (females only), proximal Chr 9 (females only), mid Chr 9, and proximal Chr 10. The Chr 10 QTL comaps to the same region as the micro-opioid receptor gene (Oprm); this receptor is a known mediator of morphine's antinociceptive effects. The Chr 1 QTL was evident only in females and comapped with the kappa-opioid receptor gene, Oprk.     

Quantitative trait loci associated with blood pressure of metabolic syndrome in the progeny of NZO/HILtJ × C3H/HeJ intercrosses

In a previous study in 15 inbred mouse strains, we found highest and lowest systolic blood pressures in NZO/HILtJ mice (metabolic syndrome) and C3H/HeJ mice (common lean strain), respectively. To identify the loci involved in hypertension in metabolic syndrome, we performed quantitative trait locus (QTL) analysis for blood pressure with direction of cross as a covariate in segregating F₂ males derived from NZO/HILtJ and C3H/HeJ mice. We detected three suggestive main-effect QTLs affecting systolic and diastolic blood pressures (SBP and DBP). We analyzed the first principle component (PC1) generated from SBP and DBP to investigate blood pressure. In addition to all the suggestive QTLs (Chrs 1, 3, and 8) in SBP and DBP, one suggestive QTL on Chr 4 was found in PC1 in the main scan. Simultaneous search identified two significant epistatic locus pairs (Chrs 1 and 4, Chrs 4 and 8) for PC1. Multiple regression analysis revealed three blood pressure QTLs (Bpq10, 100 cM on Chr 1; Bpq11, 6 cM on Chr 4; Bpq12, 29 cM on Chr 8) accounting for 29.4% of blood pressure variance. These were epistatic interaction QTLs constructing a small network centered on Chr 4, suggesting the importance of genetic interaction for development of hypertension. The blood pressure QTLs on Chrs 1, 4, and 8 were detected repeatedly in multiple studies using common inbred nonobese mouse strains, implying substantial QTL independent of development of obesity and insulin resistance. These results enhance our understanding of complicated genetic factors of hypertension in metabolic diseases. Eri Nishihara, Shirng-Wern Tsaih, Chieko Tsukahara and Sarah Langley contributed equally to this work.     

Identification of genetic determinants of IGF‐1 levels and longevity among mouse inbred strains

The IGF‐1 signaling pathway plays an important role in regulating longevity. To identify the genetic loci and genes that regulate plasma IGF‐1 levels, we intercrossed MRL/MpJ and SM/J, inbred mouse strains that differ in IGF‐1 levels. Quantitative trait loci (QTL) analysis of IGF‐1 levels of these F2 mice detected four QTL on chromosomes (Chrs) 9 (48 Mb), 10 (86 Mb), 15 (18 Mb), and 17 (85 Mb). Haplotype association mapping of IGF‐1 levels in 28 domesticated inbred strains identified three suggestive loci in females on Chrs 2 (13 Mb), 10 (88 Mb), and 17 (28 Mb) and in four males on Chrs 1 (159 Mb), 3 (52 and 58 Mb), and 16 (74 Mb). Except for the QTL on Chr 9 and 16, all loci co‐localized with IGF‐1 QTL previously identified in other mouse crosses. The most significant locus was the QTL on Chr 10, which contains the Igf1 gene and which had a LOD score of 31.8. Haplotype analysis among 28 domesticated inbred strains revealed a major QTL on Chr 10 overlapping with the QTL identified in the F2 mice. This locus showed three major haplotypes; strains with haplotype 1 had significantly lower plasma IGF‐1 and extended longevity (P < 0.05) than strains with haplotype 2 or 3. Bioinformatic analysis, combined with sequencing and expression studies, showed that Igf1 is the most likely QTL gene, but that other genes may also play a role in this strong QTL.     

Differences in DBA/1J and DBA/2J reveal lipid QTL genes

Recent advances in mouse genomics have revealed considerable variation in the form of single-nucleotide polymorphisms (SNPs) among common inbred strains. This has made it possible to characterize closely related strains and to identify genes that differ; such genes may be causal for quantitative phenotypes. The mouse strains DBA/1J and DBA/2J differ by just 5.6% at the SNP level. These strains exhibit differences in a number of metabolic and lipid phenotypes, such as plasma levels of triglycerides (TGs) and HDL. A cross between these strains revealed multiple quantitative trait loci (QTLs) in 294 progeny. We identified significant TG QTLs on chromosomes (Chrs) 1, 2, 3, 4, 8, 9, 10, 11, 12, 13, 14, 16, and 19, and significant HDL QTLs on Chrs 3, 9, and 16. Some QTLs mapped to chromosomes with limited variability between the two strains, thus facilitating the identification of candidate genes. We suggest that Tshr is the QTL gene for Chr 12 TG and HDL levels and that Ihh may account for the TG QTL on Chr 1. This cross highlights the advantage of crossing closely related strains for subsequent identification of QTL genes.     

QTL and systems genetics analysis of mouse grooming and behavioral responses to novelty in an open field

The open field is a classic test used to assess exploratory behavior, anxiety and locomotor activity in rodents. Here, we mapped quantitative trait loci (QTLs) underlying behaviors displayed in an open field, using a panel of 53 BXD recombinant inbred mouse strains with deep replication (10 per strain and sex). The use of these strains permits the integration and comparison of data obtained in different laboratories, and also offers the possibility to study trait covariance by exploiting powerful bioinformatics tools and resources. We quantified behavioral traits during 20‐min test sessions including (1) percent time spent and distance traveled near the wall (thigmotaxis), (2) leaning against the wall, (3) rearing, (4) jumping, (5) grooming duration, (6) grooming frequency, (7) locomotion and (8) defecation. All traits exhibit moderate heritability making them amenable to genetic analysis. We identified a significant QTL on chromosome M.m. 4 at approximately 104 Mb that modulates grooming duration in both males and females (likelihood ratio statistic values of approximately 18, explaining 25% and 14% of the variance, respectively) and a suggestive QTL modulating locomotion that maps to the same locus. Bioinformatic analysis indicates Disabled 1 (Dab1, a key protein in the reelin signaling pathway) as a particularly strong candidate gene modulating these behaviors. We also found 2 highly suggestive QTLs for a sex by strain interaction for grooming duration on chromosomes 13 and 17. In addition, we identified a pairwise epistatic interaction between loci on chromosomes 12 at 36–37 Mb and 14 at 34–36 Mb that influences rearing frequency in males.     

QTL for body composition on chromosome 7 detected using a chromosome substitution mouse strain

Objective: Previous studies in mice have detected quantitative trait loci (QTLs) on chromosome 7 that affect body composition. As a step toward identifying the responsible genes, we compared a chromosome 7 substitution strain C57BL/6J‐Chr7^129S1/SvImJ/Na (CSS‐7) to its host (C57BL/6J) strain. Methods and Procedures: Fourteen‐week‐old mice were measured for body size (weight, length), organ weight (brain, heart, liver, kidneys, and spleen), body and bone composition (fat and lean weight; bone area, mineral content, and density), and individual adipose depot weights (gonadal, retroperitoneal, mesenteric, inguinal, and subscapular). Differences between the CSS‐7 strain and the host strain were interpreted as evidence for the presence of one or more QTLs on chromosome 7. Results: Using this criterion, we detected QTLs for body weight, bone area, bone mineral content, brain, and heart weight, most adipose depot weights and some indices of fatness. A few strain differences were more pronounced in males (e.g., most adiposity measures) and others were more pronounced in females (e.g., bone area). QTLs for body length, lean weight, bone mineral density, and kidney, spleen, and liver weight were not detected. Discussion: This study found several associations that suggest one or more QTLs specific to the weight of select tissues and organs exist on mouse chromosome 7. Because these loci are detectable on a fixed and uniform genetic background, they are reasonable targets for high‐resolution mapping and gene identification using a congenic approach.     

Mapping genetic loci that regulate lipid levels in a NZB/B1NJxRF/J intercross and a combined intercross involving NZB/B1NJ, RF/J, MRL/MpJ, and SJL/J mouse strains

The NZB/B1NJ (NZB) mouse strain exhibits high cholesterol and HDL levels in blood compared with several other strains of mice. To study the genetic regulation of blood lipid levels, we performed a genome-wide linkage analysis in 542 chow-fed F2 female mice from an NZBxRF/J (RF) intercross and in a combined data set that included NZBxRF and MRL/MpJxSJL/J intercrosses. In the NZBxRF F2 mice, the cholesterol and HDL concentrations were influenced by quantitative trait loci (QTL) on chromosome (Chr) 5 [logarithm of odds (LOD) 17-19; D5Mit10] that was in the region identified earlier in crosses involving NZB mice, but two QTLs on Chr 12 (LOD 4.7; D12Mit182) and Chr 19 (LOD 5.7; D19Mit1) were specific to the NZBxRF intercross. Triglyceride levels were affected by two novel QTLs at D12Mit182 (LOD 8.7) and D15Mit13 (LOD 3.5). The combined-cross linkage analysis (1,054 mice, 231 markers) 1) identified four shared QTLs (Chrs 5, 7, 14, and 17) that were not detected in one of the parental crosses and 2) improved the resolution of two shared QTLs. In summary, we report additional loci regulating lipid levels in NZB mice that had not been identified earlier in crosses involving the NZB strain of mice. The identification of shared loci from multiple crosses increases confidence toward finding the QTL gene.     

Genetic studies of B-lymphocyte deficiency and mastocytosis in strain A/WySnJ mice

The A/WySnJ mouse, but not the related A/J strain, has peripheral B-lymphocyte deficiency and mastocytosis. Minimally, two quantitative trait loci (QTLs) control the B-cell deficiency in (A/WySnJ x CAST/Ei)F2 intercross mice; one of them, Bcmd-1, mapped to Chromosome (Chr) 15. Several QTLs controlled the mastocytosis in this intercross, and it was not possible to determine whether any of them co-segregated with Bcmd-1. We have now mapped a second QTL controlling the B-cell deficiency, Bcmd-2, to Chr 4. Furthermore, we narrowed the map position of Bcmd-1 to <2.0 cM. Both QTLs have been confirmed through the construction of AW. Bcmd-1(c), AW. Bcmd-2(c), and AW. Bcmd-1(c)Bcmd-2(c) recombinant congenic strains. The Bcmd-1 locus is the major regulator of B-cell homeostasis, while Bcmd-2 is the minor regulator, and their effects are additive, as shown by splenic B-cells analysis in these congenic strains. In addition, Bcmd-2 or a linked locus controls mastocytosis, while Bcmd-1 does not, as indicated by splenic mast cell analysis in the congenic strains. Thus, the major genetic controls on B-cell homeostasis and mast cell homeostasis in A/WySnJ mice are asserted by distinct genes.     

A congenic mouse and candidate gene at the Chromosome 13 locus regulating bone density

Previously, we identified two significant quantitative trait loci (QTLs) specifying the peak relative bone mass (bone mass corrected for bone size) on chromosomes (Chrs) 11 and 13 by interval mapping in two mouse strains, SAMP2 and SAMP6. The latter strain is an established murine model of senile osteoporosis and exhibits a significantly lower peak relative bone mass than SAMP2 mice. We recently designated the Chr 13 locus as Pbd2 (Peak bone density 2) and constructed a congenic strain, P6.P2-Pbd2(b), which carried a single genomic interval from the Chr 13 of SAMP2 on a SAMP6-derived osteoporotic background. In this study, we have constructed a congenic strain, P2.P6-Pbd2(a), carrying a SAMP6-derived susceptible interval on a SAMP2-derived resistance background. This congenic strain had a lower bone density than the background strain, SAMP2, based on three measurement methods, each utilizing a different principle for evaluating bone density: MD, DXA, and pQCT. Next, a candidate gene approach was used to find polymorphisms of Bmp6 (bone morphogenetic protein 6). The CAG trinucleotide repeat numbers in exon 1 of this gene differ among SAM strains. We found an association of CAG repeat length with relative peak bone mass in mice.     

A novel strategy for genetic dissection of complex traits: the population of specific chromosome substitution strains from laboratory and wild mice

The mouse is an irreplaceable model for understanding the precise genetic mechanisms of mammalian physiological pathways. Thousands of quantitative trait loci (QTLs) have been mapped onto the mouse genome during the last two decades. However, only a few genes’ underlying complex traits have been successfully identified, and rapid fine mapping of QTL genes still remains a challenge for mouse geneticists. Currently, the Collaborative Cross (CC) has proceeded to the goal of establishing more than 1,000 recombinant inbred strains for the sub-centimorgan mapping resolution of QTL loci. In this article, a novel complementary strategy, designated as population of specific chromosome substitution strains or PSCSS, is proposed for rapid fine mapping of QTLs on the substituted chromosome. One specific chromosome (Chr 1) of recipient mouse strain C57BL/6 J has been substituted by homologous counterparts from five different inbred strains (C3H/He, FVB/N, AKR, NOD/LtJ, NZW/LacJ), an outbred line Kunmin mouse in China, and 23 wild mice captured in different localities. The primary genetic studies on the structure of these wild donor chromosomes (Chr 1) show that these donor chromosomes harbor extensive genetic polymorphisms, with a high density of SNP distribution, abundant variations of STR alleles, and a high level of historical recombination accumulation. These specific chromosome substitution strains eventually form a special population that has the identical genetic background of the recipient strain and differs only in the donor chromosomes. With simple association studies, known QTLs on the donor chromosome can be rapidly mapped in high resolution without requirement of further crosses. This approach, taking advantage of the extensive genetic polymorphisms of wild resources and chromosome substitution strategy, brings a new outlook for genetic dissection of complex traits.     

Contrasting epistatic interactions between rat quantitative trait loci controlling mammary cancer development

We previously defined quantitative trait loci (QTLs) that control susceptibility to 7,12-dimethylbenz(α)anthracene-induced mammary carcinoma in SPRD-Cu3 (susceptible) and WKY (resistant) rats. Two of these QTLs, assigned to chromosomes (Chr) 10 and 18, control tumor growth rate and invasiveness. In this study we characterized a congenic strain in which a large segment of WKY Chr 10 was introduced in the SPRD-Cu3 genetic background and demonstrated that this chromosome segment controls this tumor trait. The WKY allele at this QTL (Mcsta1) reduces the growth rate of the fastest growing tumors by 26%. We also previously showed that two SPRD-Cu3-WKY congenic strains containing a WKY chromosome segment derived either from Chr 5 or from Chr 18 exhibit a reduction in tumor multiplicity (QTLs Msctm1 and Mcstm2, respectively) (with no reduction in tumor growth rate in the Chr 18 congenic). In this study we generated a double congenic strain, which contains the two WKY differential segments from Chr 5 and 18, to determine how these two segments interact with one another. Interestingly, two types of epistatic interactions were found: no additive effect was seen with respect to tumor multiplicity, while a reduction in tumor growth rate was observed. It thus appears that WKY alleles located on Chr 5 and Chr 8 interact epistatically in a contrasting manner to modulate tumor multiplicity (in a nonadditive manner) and growth rate (in a synergic manner). Tumor growth rate is thus influenced by two QTLs, on Chr 10 (Mcsta1) and on Chr 18 (Mcsta2), the action of the latter being dependent on the presence of the Chr5 QTL (Mcstm1). The expression level of positional and functional candidate genes was also analyzed. On Chr 5, Pla2g2a is subject to a syntenic control while expression of the Tp53 (Chr 10) and Pmai1/Noxa (Chr 18) genes appears to be controlled by several mammary cancer resistance QTLs.     

Genetic loci affecting body weight and fatness in a C57BL/6J × PWK/PhJ mouse intercross

To determine the genetic variation that contributes to body composition in the mouse, we interbred a wild-derived strain (PWK/PhJ; PWK) with a common laboratory strain (C57BL/6J; B6). The parental, F₁, and F₂ mice were phenotyped at 18 weeks old for body weight and composition using dual-energy X-ray absorptiometry (DEXA). A total of 479 (244 male and 235 female) F₂ mice were genotyped for 117 polymorphic markers spanning the autosomes. Twenty-eight suggestive or significant linkages for four traits (body weight, adjusted lean and fat weight, and percent fat) were detected. Of these, three QTLs were novel: one on the proximal portion of Chr 5 for body weight (Bwq8; LOD = 4.7), one on Chr 3 for lean weight (Bwtq13; LOD = 3.6), and one on Chr 11 for percent fat (Adip19; LOD = 5.8). The remaining QTLs overlapped previously identified linkages, e.g., Adip5 on Chr 9. One QTL was sex-specific (present in males only) and seven were sex-biased (more prominent in one sex than the other). Most alleles that increased body weight were contributed by the B6 strain, and most alleles that increased percent fat were contributed by the PWK strain. Eight pairs of interacting loci were identified, none of which exactly overlapped the main-effect QTLs. Many of the QTLs found in the B6 × PWK cross map to the location of previously reported linkages, suggesting that some QTLs are common to many strains (consensus QTLs), but three new QTLs appear to be particular to the PWK strain. The location and type of QTLs detected in this new cross will assist in future efforts to identify the genetic variation that determines the ratio of lean to fat weight as well as body size in mice.     

Congenic strains provide evidence that a mapped locus on chromosome 15 influences excitotoxic cell death

Inbred strains of mice differ in their susceptibility to excitotoxin‐induced cell death, but the genetic basis of individual variation is unknown. Prior studies with crosses of the FVB/NJ (seizure‐induced cell death susceptible) mouse and the seizure‐induced cell death resistant mouse, C57BL/6J, showed the presence of three quantitative trait loci (QTLs), named seizure‐induced cell death 1 (Sicd1) to Sicd3. To better localize and characterize the Sicd2 locus, two reciprocal congenic mouse strains were created. While the B6.FVB‐Sicd2 congenic mouse was without effect on modifying susceptibility to seizure‐induced excitotoxic cell death, the FVB.B6‐Sicd2 congenic mouse, in which the chromosome (Chr) 15 region of C57BL/6J was introgressed into FVB/NJ, showed reduced seizure‐induced excitotoxic cell death following kainate administration. Phenotypic comparison between FVB and the congenic FVB.B6‐Sicd2 strain confirmed that the Sicd2 interval harbors gene(s) conferring strong protection against seizure‐induced excitotoxic cell death. Interval‐specific congenic lines (ISCLs) that encompass Sicd2 on Chr 15 were generated and were used to fine‐map this QTL. Resultant progeny were treated with kainate and examined for the extent of seizure‐induced cell death in order to deduce the Sicd2 genotypes of the recombinants through linkage analysis. All of the ISCLs exhibited reduced cell death associated with the C57BL/6J phenotype; however, ISCL‐2 showed the most dramatic reduction in seizure‐induced cell death in both area CA3 and in the dentate hilus. These findings confirm the existence of polymorphic loci within the reduced critical region of Sicd2 that regulate the severity of seizure‐induced cell death.     

Quantitative trait Loci for glomerulosclerosis, kidney weight and body weight in the focal glomerulosclerosis mouse model.

In 183 male progeny derived from a backcross between the FGS/Kist strain, a new mouse model for focal glomerulosclerosis (FGS) in humans, and the standard normal strain, C57BL/6J, we performed a genome-wide scan for quantitative trait loci (QTLs) affecting the glomerulosclerosis index (GSI) based on histological observation as well as kidney and body weights. Two QTLs for GSI (Gsi1-2) located on chromosomes (Chrs) 8 and 10, a kidney weight QTL (Kdw1) on Chr 19, and a body weight QTL (Bdw1) on Chr 13 were detected at the genome-wide 5% or less level. The allele derived from FGS/Kist increased GSI at Gsi1, but decreased it at Gsi2. The mice homozygous for the FGS/Kist allele decreased body and kidney weights. The identified QTLs accounted for 5-8% of the phenotypic variance.     

Genetic Analysis of a New Mouse Model for Non-Insulin-Dependent Diabetes

The TallyHo (TH) mouse strain is a newly established model for non-insulin-dependent diabetes mellitus (NIDDM). TH mice show obesity, hyperinsulinemia, hyperlipidemia, and male-limited hyperglycemia. A genetic dissection of the diabetes syndrome has been carried out using male backcross 1 progeny obtained from crosses between (C57BL/6J x TH)F1 and TH mice or (CAST/Ei x TH)F1 and TH mice. A genome-wide scan reveals three quantitative trait loci (QTLs), Tanidd1-3 (TH-associated NIDDM) linked to hyperglycemia. The major QTL (common in both crosses), Tanidd1, maps to chromosome (Chr) 19. Additionally, gene-gene interactions contributing to hyperglycemia have been observed between Tanidd1 and a locus on Chr 18 as well as between Tanidd2 and a locus on Chr 16. The overt hyperglycemia in TH mice is, therefore, likely due to a mutation in a major diabetes susceptibility locus on Chr 19, which interacts with additional genes to lead to an observable phenotype.     

Quantitative trait locus and haplotype mapping in closely related inbred strains identifies a locus for open field behavior

Quantitative trait locus (QTL) mapping in the mouse typically utilizes inbred strains that exhibit significant genetic and phenotypic diversity. The development of dense SNP panels in a large number of inbred strains has eliminated the need to maximize genetic diversity in QTL studies as plenty of SNP markers are now available for almost any combination of strains. We conducted a QTL mapping experiment using both a backcross (N₂) and an intercross (F₂) between two genetically similar inbred mouse strains: C57BL/6J (B6) and C57L/J (C57). A set of additive QTLs for activity behaviors was identified on Chrs 1, 9, 13, and 15. We also identified additive QTLs for anxiety-related behaviors on Chrs 7, 9, and 16. A QTL on Chr 11 is sex-specific, and we revealed pairwise interactions between QTLs on Chrs 1 and 13 and Chrs 10 and 18. The Chr 9 activity QTL accounts for the largest amount of phenotypic variance and was not present in our recent analysis of a B6 × C58/J (C58) intercross (Bailey et al. in Genes Brain Behav 7:761–769, 2008). To narrow this QTL interval, we used a dense SNP haplotype map with over 7 million real and imputed SNP markers across 74 inbred mouse strains (Szatkiewicz et al. in Mamm Genome 19(3):199–208, 2008). Evaluation of shared and divergent haplotype blocks among B6, C57, and C58 strains narrowed the Chr 9 QTL interval considerably and highlights the utility of QTL mapping in closely related inbred strains.     

Detection of Obesity QTLs on Mouse Chromosomes 1 and 7 by Selective DNA Pooling

The inheritance of obesity has been analyzed in an intercross between the lean 129/Sv mouse strain and the obesity-prone EL/Suz mouse strain. The weights of three major fat pads were determined on 4-month-old mice, and the sum of these weights, divided by body weight, was used as an adiposity index. The strategy of selective DNA pooling was used as a primary screen to identify putative quantitative trait loci (QTLs) affecting adiposity index. DNA pools representing the leanest 15% and fattest 15% of the F2 progeny were compared for differential allelic enrichment using widely dispersed microsatellite variants. To evaluate putative QTLs, individual genotyping and interval mapping were employed to estimate QTL effects and assess statistical significance. One QTL affecting adiposity index, which accounted for 12.3% of phenotypic variance in gender-merged data, was mapped to the central region of Chromosome (Chr) 7. The QTL allele inherited from EL conferred increased adiposity. A second QTL that accounts for 6.3% of phenotypic variance was identified on Chr 1 nearD1Mit211.At both QTLs, the data are consistent with dominant inheritance of the allele contributing to obesity. The possible relationships between these QTLs and previously described obesity QTLs, major obesity mutations, and candidate genes are discussed.     

Phenotyping mouse chromosome substitution strains reveal multiple QTLs for febrile seizure susceptibility

Febrile seizures (FS) are the most common seizure type in children and recurrent FS are a risk factor for developing temporal lobe epilepsy. Although the mechanisms underlying FS are largely unknown, recent family, twin and animal studies indicate that genetics are important in FS susceptibility. Here, a forward genetic strategy was used employing mouse chromosome substitution strains (CSS) to identify novel FS susceptibility quantitative trait loci (QTLs). FS were induced by exposure to warm air at postnatal day 14. Video electroencephalogram monitoring identified tonic–clonic convulsion onset, defined as febrile seizure latency (FSL), as a reliable phenotypic parameter to determine FS susceptibility. FSL was determined in both sexes of the host strain (C57BL/6J), the donor strain (A/J) and CSS. C57BL/6J mice were more susceptible to FS than A/J mice. Phenotypic screening of the CSS panel identified six strains (CSS1, -2, -6 -10, -13 and -X) carrying QTLs for FS susceptibility. CSS1, -10 and -13 were less susceptible (protective QTLs), whereas CSS2, -6 and -X were more susceptible (susceptibility QTLs) to FS than the C57BL/6J strain. Our data show that mouse FS susceptibility is determined by complex genetics, which is distinct from that for chemically induced seizures. This is the first data set using CSS to screen for a seizure trait in mouse pups. It provides evidence for common FS susceptibility QTLs that serve as starting points to fine map FS susceptibility QTLs and to identify FS susceptibility genes. This will increase our understanding of human FS, working toward the identification of new therapeutic targets.