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.     

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.     

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.     

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.     

Alcohol preference in AXB/BXA recombinant inbred mice: gender differences and gender-specific quantitative trait loci

The purpose of the present study was to characterize the C57BL/6J, A/J, and AXB/BXA Recombinant Inbred (RI) strains of mice for voluntary alcohol consumption. Quantitative Trait Locus (QTL) analysis was used to provide provisional location of QTLs for alcohol consumption. The inbred strains were screened for levels of alcohol intake (calculated as alcohol preference and absolute alcohol consumption) by receiving 4 days of forced exposure to a 10% (wt/vol) solution of alcohol, followed by 3 weeks of free choice between water and 10% alcohol. A wide and continuous distribution of values for alcohol consumption and preference was obtained in the AXB/BXA RI strains, confirming polygenic influences on alcohol-related behaviors. Significant gender differences were found for both alcohol preference [F_28,651= 2.12, p < 0.001] and absolute alcohol consumption [F_28,647= 2.57, p < 0.001]. In males, putative QTLs were mapped to chromosomes (Chrs) 2, 5, 7, 10, 11, and 16. Multiple regression analysis indicated that approximately 75% of the genetic variance in alcohol preference in males could be accounted for by three of the QTL regions. Several of the putative QTLs appeared to be male-specific (Tyr on Chr 7; D10Mit126 on Chr 10; D11Mit61 on Chr 11). In females, seven putative QTLs were mapped to Chrs 2, 4, 5, 7, 11, 16, and 19. Approximately 90% of the genetic variance in alcohol preference in females could be accounted for by four QTL regions, as determined by multiple regression. The QTL on Chr 11 near D11Mit35 appeared to be female-specific. This site was close to a female-specific QTL (Alcp2) previously mapped in C57BL/6J × DBA/2J backcrosses by Melo and coworkers (Nat Genet 13, 147, 1996). The QTLs mapped for alcohol preference in the present study must be considered suggestive at the present time, since only D2Mit74 met very strict statistical criteria for significance. However, the concordance across several studies for the loci on Chrs 2, 4, 7, 9, and 11 suggest that some common QTLs influencing alcohol preference have been identified. Confirmation of QTLs mapped in the present study is currently being conducted in a new series of recombinant congenic (RC) strains developed from reciprocal backcrosses between the A/J and C57BL/6J progenitors. The concomitant use of both RI and RC strains developed from the same progenitors should provide a powerful means of detecting, confirming, and mapping QTLs for alcohol-related traits. Received: 25 August 1998 / Accepted: 8 October 1998     

The mapping of quantitative trait loci underlying strain differences in locomotor activity between 129S6 and C57BL/6J mice

Performance in the open field and rotarod paradigms, two common assessments of locomotor function, have been demonstrated to be strain dependent in mice. In this study, eight significant quantitative trait loci (QTL) for behavior phenotypes in either the open field or rotarod paradigms were identified between the 129S6 (129/SvEvTac) and C57BL/6J strains. These strains were chosen for comparison because of their frequent use in the generation of mutant mice from gene-targeted, embryonic stem cells. Two of the QTLs for horizontal distance traveled are located on Chromosomes (Chrs) 1 and 12 and closely replicate the findings of other groups using different strains of mice. Rotarod performance was influenced in an oppositional manner by two separate QTLs on Chr 1 and 2. Additionally, examination of several different aspects of behavior in the open field revealed significant QTLs for average speed (Chr 12), duration (Chrs 2, 16, and 18), time spent in motion (Chr 16), vertical movements (rearing) (Chrs 6 and 12), and vertical time (rearing time) (Chrs 6 and 12). Our finding of independent QTLs for these topographic components of open field activity supports the idea that they are separate and distinct from total horizontal distance traveled and should be studied independently. The QTLs described in this study, in combination with our panel of polymorphic chromosomal markers for 129S6 and C57BL/6J strains, will be useful in assessing the potential epistatic effects of parental strain background on the phenotypes of genetically modified mice.     

Detection of quantitative trait loci for body weight at 10 weeks from Philippine wild mice

A genome-wide scan for quantitative trait loci (QTLs) controlling body weight at 10 weeks after birth was carried out in a population of 387 intersubspecific backcross mice derived from a cross between C57BL/6J inbred mice (Mus musculus domesticus) and wild mice (M. m. castaneus) captured in the Philippines, in order to discover novel QTLs from the wild mice that have about 60% lower body weight than C57BL/6J. By interval mapping, we detected four QTLs: a highly significant QTL on Chromosome (Chr) 2, which was common in both sexes; two significant QTLs on Chr 13, one male-specific and the other female-specific; and a suggestive male-specific QTL on X Chr. By composite interval mapping, we confirmed the presence of the three QTLs on Chrs 2 and 13, but not of the male-specific X-linked QTL. The composite interval mapping analysis newly identified three QTLs: a significant male-specific QTL on Chr 11 and two highly significant female-specific QTLs on Chrs 9 and X. Individual QTLs explained 3.8–11.6% of the phenotypic variance, and all the QTL alleles derived from the wild mice decreased body weight. A two-way analysis of variance revealed a significant epistatic interaction between the Chr 2 QTL and the background marker locus D12Mit4 on Chr 12 only in males. The interaction effect unexpectedly increased body weight. The chromosomal region containing the Chr 2 QTL did not coincide with those of growth or fatness QTLs mapped in previous studies. These results suggest that a population of wild mice may play an important role as new sources of valuable QTLs. Received: 14 January 2000 / Accepted: 14 April 2000     

The genetic basis of adrenal gland weight and structure in BXD recombinant inbred mice

Adrenal gland function is mediated through secreted hormones, which play a vital role in the autonomic and hypothalamic-pituitary-adrenal (HPA)-axis-mediated stress response. The genetic underpinnings of the stress response can be approached using a quantitative trait locus (QTL) analysis. This method has been used to investigate genomic regions associated with variation in complex phenotypes, but it has not been used to explore the structure of the adrenal. We used QTL analyses to identify candidate genes underlying adrenal weight and adrenal cortical zone and medulla widths. We used 64 BXD recombinant inbred (RI) strains of mice (n?=?528) and 2 parental strains (C57BL/6J and DBA/2J; n?=?20) to measure adrenal weights and adrenal zone widths. For adrenal weight, we found significant QTLs on chromosome 3 for females (Fawq1) and Chr 4 for males (Mawq1) and suggestive QTLs on Chrs 1, 3, 10, and 14 for females and Chrs 2, 4, 10, 17, and X for males. We identified a significant QTL on Chr 10 (Mawdq1) and a suggestive QTL on Chr 13 for male adrenal total width. For male adrenal medulla width, we found a significant QTL on Chr 5 (Mmwdq1) and a suggestive QTL on Chr 1. We also identified significant QTLs on Chrs 10 (Mxwdq1) and 14 (Mxwdq2) for male X-zone width. There are 113 genes that mapped within the significant QTL intervals, and we identified 4 candidate genes associated with adrenal structure and/or function. In summary, this study is an important first step for detecting genetic factors influencing the structure of the adrenal component of the HPA axis using QTL analyses, which may relate to adrenal function and provide further insights into elucidating genes critical for stress-related phenotypes.     

Detection of quantitative trait loci for meat quality in a commercial slaughter pig cross

The primary goal of this study was to localize quantitative trait loci (QTL) affecting meat quality traits in swine. In total, 42 traits were scored on 305 F₂ individuals from a commercial slaughter pig cross in Norway. F₁ and F₂ individuals were genotyped for 29 markers on Chromosomes (Chrs) 4, 6, and 7, since previous studies had revealed QTL affecting meat quality traits on these chromosomes. The most evident result was detection of a QTL affecting amount of intramuscular fat on Chr 6. The QTL might also influence tenderness, whereas no effect was observed for back-fat thickness. Additionally, suggestive evidence for QTL affecting other meat quality traits was found on Chr 4 and Chr 7. Received: 16 June 2000 / Accepted: 5 December 2000     

Distribution of body weight, blood insulin and lipid levels in the SMXA recombinant inbred strains and the QTL analysis.

In the SMXA recombinant inbred (RI) strains, we measured body weight, blood insulin and lipid (triglyceride, total cholesterol and phospholipid) levels in each strain. In the five traits, mean values of substrains varied remarkably and showed a continuous spectrum of distribution, suggesting control by multiple genes at distinct loci for each trait. We also screened for quantitative trait loci (QTLs) involved in the five traits. Suggestive QTLs for body weight (Chromosomes 1 and 6), insulin (Chromosomes 1, 3, 10 and 17), triglyceride (Chromosomes 4 and 11) and phospholipid (Chromosome 18) levels were detected. The SMXA RI strains are unique tools for analyzing genetic factors that influence body weight, blood insulin and lipids levels.     

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.     

QTL mapping for genetic determinants of lipoprotein cholesterol levels in combined crosses of inbred mouse strains

To identify additional loci that influence lipoprotein cholesterol levels, we performed quantitative trait locus (QTL) mapping in offspring of PERA/EiJxI/LnJ and PERA/EiJxDBA/2J intercrosses and in a combined data set from both crosses after 8 weeks of consumption of a high fat-diet. Most QTLs identified were concordant with homologous chromosomal regions that were associated with lipoprotein levels in human studies. We detected significant new loci for HDL cholesterol levels on chromosome (Chr) 5 (Hdlq34) and for non-HDL cholesterol levels on Chrs 15 (Nhdlq9) and 16 (Nhdlq10). In addition, the analysis of combined data sets identified a QTL for HDL cholesterol on Chr 17 that was shared between both crosses; lower HDL cholesterol levels were conferred by strain PERA. This QTL colocalized with a shared QTL for cholesterol gallstone formation detected in the same crosses. Haplotype analysis narrowed this QTL, and sequencing of the candidate genes Abcg5 and Abcg8 confirmed shared alleles in strains I/LnJ and DBA/2J that differed from the alleles in strain PERA/EiJ. In conclusion, our analysis furthers the knowledge of genetic determinants of lipoprotein cholesterol levels in inbred mice and substantiates the hypothesis that polymorphisms of Abcg5/Abcg8 contribute to individual variation in both plasma HDL cholesterol levels and susceptibility to cholesterol gallstone formation.     

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.     

Quantitative Trait Locus Analysis of Plasma Cholesterol and Triglyceride Levels in KK × RR F2 Mice

A previous quantitative trait locus (QTL) study on hyperlipidemia in C57BL/6J x KK-Ay/a F2 mice identified three significant cholesterol QTLs (Cq1 and Cq2 on chromosome 1, and Cq3 on chromosome 3), and a suggestive triglyceride QTL on chromosome 9. An alternative analysis of this study identified a novel cholesterol QTL on chromosome 9 (Cq4), and a significant triglyceride QTL on chromosome 9 (Tgq1). In the present study, QTL analysis was performed on KK x RR F2 mice. A significant cholesterol QTL (Cq5, lod score 5.6) was identified on chromosome 9, and a significant triglyceride QTL (Tgq2, lod score 4.7) was identified on chromosome 8. The Cq5 locus was mapped to a region similar to the Cq4 locus. On the other hand, the Tgq2 locus overlapped with the QTL region responsible for glucose intolerance (Giq1) that was identified in a previous study. The results suggest that a different combination of QTLs is involved in the trait when a different counterpart strain is used. Identification of distinct, but related traits in an identical chromosomal region will facilitate revealing the responsible gene.     

Integration of QTL and bioinformatic tools to identify candidate genes for triglycerides in mice

To identify genetic loci influencing lipid levels, we performed quantitative trait loci (QTL) analysis between inbred mouse strains MRL/MpJ and SM/J, measuring triglyceride levels at 8 weeks of age in F2 mice fed a chow diet. We identified one significant QTL on chromosome (Chr) 15 and three suggestive QTL on Chrs 2, 7, and 17. We also carried out microarray analysis on the livers of parental strains of 282 F2 mice and used these data to find cis-regulated expression QTL. We then narrowed the list of candidate genes under significant QTL using a "toolbox" of bioinformatic resources, including haplotype analysis; parental strain comparison for gene expression differences and nonsynonymous coding single nucleotide polymorphisms (SNP); cis-regulated eQTL in livers of F2 mice; correlation between gene expression and phenotype; and conditioning of expression on the phenotype. We suggest Slc25a7 as a candidate gene for the Chr 7 QTL and, based on expression differences, five genes (Polr3 h, Cyp2d22, Cyp2d26, Tspo, and Ttll12) as candidate genes for Chr 15 QTL. This study shows how bioinformatics can be used effectively to reduce candidate gene lists for QTL related to complex traits.     

Quantitative trait loci for bone density in C57BL/6J and CAST/EiJ inbred mice

Genetic analyses for loci regulating bone mineral density have been conducted in a cohort of F₂ mice derived from intercross matings of (C57BL/6J × CAST/EiJ)F₁ parents. Femurs were isolated from 714 4-month-old females when peak adult bone density had been achieved. Bone mineral density (BMD) data were obtained by peripheral quantitative computed tomography (pQCT), and genotype data were obtained by Polymerase Chain Reaction (PCR) assays for polymorphic markers carried in genomic DNA of each mouse. Genome-wide scans for co-segregation of genetic marker data with high or low BMD revealed loci on eight different chromosomes, four of which (Chrs 1, 5, 13, and 15) achieved conservative statistical criteria for suggestive, significant, or highly significant linkage with BMD. These four quantitative trait loci (QTLs) were confirmed by a linear regression model developed to describe the main effects; none of the loci exhibited significant interaction effects by ANOVA. The four QTLs have been named Bmd1 (Chr 1), Bmd2 (Chr 5), Bmd3 (Chr 13), and Bmd4 (Chr 15). Additive effects were observed for Bmd1, recessive for Bmd3, and dominant effects for Bmd2 and Bmd4. The current large size of the QTL regions (6→31 cM) renders premature any discussion of candidate genes at this time. Fine mapping of these QTLs is in progress to refine their genetic positions and to evaluate human homologies. Received: 5 May 1999 / Accepted: 22 June 1999     

Further studies on using multiple-cross mapping (MCM) to map quantitative trait loci

We have completed whole-genome scans for quantitative trait loci (QTLs) associated with acute ethanol-induced activation in the six F₂ intercrosses that can be formed from the C57BL/6J (B6), DBA/2J (D2) , BALB/cJ (C), and LP/J (LP) inbred strains. The goal was to test the hypothesis that given the relatively simple structure of the laboratory mouse genome, the same QTLs will be detected in multiple crosses which in turn will provide support for the strategy of multiple-cross mapping (MCM). QTLs with LOD scores greater than 4 were detected on Chrs 1, 2, 3, 8, 9, 13, 14, and 16. Only for the QTL on distal Chr 1 was there convincing evidence that the same or at least a very similar QTL was detected in multiple crosses. We also mapped the Chr 2 QTL directly in heterogeneous stock (HS) animals derived from the four inbred strains. At G₁₉ the QTL was mapped to an approximately 3-Mbp interval and this interval was associated with a haplotype block with a largely biallelic structure: B6-L:C-D2. We conclude that mapping in HS animals not only provides significantly greater QTL resolution, at least in some cases it provides significantly more information about the QTL haplotype structure.     

Establishment of consomic strains derived from A/J and SM/J mice for genetic analysis of complex traits

Consomic strains, in which one chromosome is derived from a donor strain and the other chromosomes are derived from the recipient strain, provide a powerful tool for the dissection of complex genetic traits. In this study we established ten consomic strains (A-2^SM, A-6^SM, A-11^SM, A-12^SM, A-13^SM, A-15^SM, A-17^SM, A-18^SM, A-19^SM, A-Y^SM) using the SM/J strain as the donor and the A/J strain as the recipient; these are the parental strains of a set of SMXA recombinant inbred (RI) strains that we had developed previously. We analyzed body weights and blood lipid levels in the consomic and parental strains. The mean values for each trait showed a continuous range of variation in the consomic strains suggesting that they are controlled by multiple genes. We previously identified suggestive QTLs for body weight on chromosome 6 in SMXA RI strains and (SM/J?×?A/J)F₂ mice. The observation that the A-6^SM consomic strain had a significantly lower mean body weight than the A/J strain supports the presence of this QTL on chromosome 6. Similarly, the higher blood triglyceride level in the A-11^SM strain shows the existence of a previously mapped QTL on chromosome 11, and the A-12^SM strain provides evidence of a QTL for blood total cholesterol level on chromosome 12. These consomic strains, along with the previously developed set of SMXA RI strains from A/J and SM/J mice, offer an invaluable and powerful resource for the analysis of complex genetic traits in mice.     

Genes on mouse Chromosomes 2 and 9 determine variation in ethanol consumption

Quantitative trait locus (QTL) mapping efforts in alcohol (ethanol) research are beginning to generate promising data that may ultimately lead to the identification of genes influencing alcohol addiction. Rodents have been extensively utilized to study ethanol's rewarding and aversive effects, and to demonstrate the existence of genetic influences on traits such as free-choice ethanol-consumption, ethanol-conditioned place preference and ethanol-conditioned taste aversion. The purpose of the current investigation was to verify or eliminate from further consideration putative QTLs for free-choice ethanol consumption originally identified in BXD Recombinant Inbred (RI) strains and other informative genetic crosses. B6D2F₂ mice were utilized in a verification testing strategy to evaluate the viability of putative ethanol consumption QTLs. When data were combined from BXD RI, B6D2F₂ and short-term selected line (STSL) mapping studies, verification was obtained for two QTLs, one on Chromosome (Chr) 9 (proximal-mid) and another on Chr 2 (distal), and suggestive verification was obtained for QTLs on Chrs 2 (proximal), 3, 4, 7, and 15. In addition, the possible genetic association of ethanol consumption with conditioned place preference was evaluated. Genetic correlations were estimated from BXD RI strain means, and QTL maps for these traits were compared to evaluate the possibility of a genetic association. The correlational analysis yielded a trend (r = 0.34, p = 0.09), but no statistically significant results. However, comparisons of QTL mapping results between phenotypes suggested some possible genetic overlap for these traits, both putative measures of ethanol reward. These data suggest that the determinants of these two measures are genetically diverse, but may share some common genetic elements. Received: 15 September 1998 / Accepted: 8 October 1998     

Four additional mouse crosses improve the lipid QTL landscape and identify Lipg as a QTL gene

To identify genes controlling plasma HDL and triglyceride levels, quantitative trait locus (QTL) analysis was performed in one backcross, (NZO/H1Lt × NON/LtJ) × NON/LtJ, and three intercrosses, C57BL/6J × DBA/2J, C57BL/6J × C3H/HeJ, and NZB/B1NJ × NZW/LacJ. HDL concentrations were affected by 25 QTL distributed on most chromosomes (Chrs); those on Chrs 1, 8, 12, and 16 were newly identified, and the remainder were replications of previously identified QTL. Triglyceride concentrations were controlled by nine loci; those on Chrs 1, 2, 3, 7, 16, and 18 were newly identified QTL, and the remainder were replications. Combining mouse crosses with haplotype analysis for the HDL QTL on Chr 18 reduced the list of candidates to six genes. Further expression analysis, sequencing, and quantitative complementation testing of these six genes identified Lipg as the HDL QTL gene on distal Chr 18. The data from these crosses further increase the ability to perform haplotype analyses that can lead to the identification of causal lipid genes.