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     

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 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.     

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.     

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.     

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.     

Quantitative trait locus analysis of abnormal circadian period in CS mice

CS mice show a free-running period (κ) longer than 24 h and rhythm splitting in constant darkness (DD). These features in behavioral circadian rhythms are distinctive as compared with other inbred strains of mice, which exhibit robust free-running rhythms with κ shorter than 24 h. To identify the genes affecting κ, quantitative trait locus (QTL) analysis was initially conducted by using 289 F₂ mice derived from a cross between CS and C57BL/6J strain. A suggestive QTL (LOD = 3.71) with CS allele increasing κ was detected on the distal region of Chromosome (Chr) 19. Next, using 192 F₂ mice from a cross between CS and MSM strain, the presence of the QTL on Chr 19 was examined, and we confirmed the QTL at the genome-wide significant level (LOD = 4.61 with 10.4% of the total variance explained). This QTL was named long free-running period (Lfp). Three other suggestive QTLs (LOD = 3.24–4.28) were mapped to the midportion of Chr 12 in (CS×C57BL/6J)F₂ mice, and to the proximal and middle region of Chr 19 in (CS×MSM)F₂ mice, respectively, of which, CS alleles for two QTLs on Chr 19 have the effect of lengthening κ. None of these QTLs were mapped to the chromosomal regions of previously described QTLs for κ and known clock genes (Clock, mPer1, Bmal1, mCry1, mCry2, mTim, and Csnk1e). Received: 5 July 2000 / Accepted: 5 December 2000     

Genetic dissection of ``OLETF', a rat model for non-insulin-dependent diabetes mellitus

To elucidate the genetic factors underlying non-insulin-dependent diabetes mellitus (NIDDM), we performed genome-wide quantitative trait locus (QTL) analysis, using the Otsuka Long-Evans Tokushima Fatty (OLETF) rat. The OLETF rat is an excellent animal model of NIDDM because the features of the disease closely resemble human NIDDM. Genetic dissection with two kinds of F2 intercross progeny, from matings between the OLETF rat and non-diabetic control rats F344 or BN, allowed us to identify on Chromosome (Chr) 1 a major QTL associated with features of NIDDM that was common to both crosses. We also mapped two additional significant loci, on Chrs 7 and 14, in the (OLETF × F344)F₂ cross alone, and designated these three loci as Diabetes mellitus, OLETF type Dmo 1, Dmo2 and Dmo3 respectively. With regard to suggestive QTLs, we found loci on Chrs 10, 11, and 16 that were common to both crosses, as well as loci on Chrs 5 and 12 in the (OLETF × F344)F₂ cross and on Chrs 4 and 13 in the (OLETF × BN)F₂ cross. Our results showed that NIDDM in the OLETF rat is polygenic and demonstrated that different genetic backgrounds could affect ``fitness' for QTLs and produce different phenotypic effects from the same locus. Received: 9 October 1997 / Accepted: 29 January 1998     

Quantitative trait locus analysis of unsaturated fatty acids in a recombinant inbred population of soybean

Soybean [Glycine max (L.) Merr.] is an important oilseed crop which produces about 30 % of the world’s edible vegetable oil. The quality of soybean oil is determined by its fatty acid composition. Soybean oil high in oleic and low in linolenic fatty acids is desirable for human consumption and other uses. The objectives of this study were to identify quantitative trait loci (QTLs) for unsaturated fatty acids and to evaluate the genetic effects of single QTL and QTL combinations in soybean. A population of recombinant inbred lines derived from the cross of SD02-4-59 × A02-381100 was evaluated for fatty acid content in seven environments. In total, 516 polymorphic single nucleotide polymorphism markers, 477 polymorphic simple sequence repeat markers and three GmFAD3 genes were used to genotype the mapping population. By using the composite interval mapping and/or the interval mapping method, a total of 15 QTLs for the three unsaturated fatty acids were detected in more than two environments. Two QTLs for oleic acid on linkage groups G [chromosome (Chr) 18] (qOLE-G) and J (Chr 16) (qOLE-J), three QTLs for linoleic acid on linkage groups A1 (Chr 5) (qLLE-A1) and G (Chr 18) (qLLE-G-1 and qLLE-G-2), and five QTLs for linolenic acid on linkage groups C2 (Chr 6), D1a (Chr 1), D1b (Chr 2), F (Chr 13) and G (Chr 18) were consistently detected in at least three individual environments and the average data over all environments. Significant QTL × QTL interactions were not detected. However, significant QTL × environment interactions were detected for all the QTLs which were repeatedly detected. Some QTLs reported previously were confirmed, and seven new QTLs (two for oleic acid, two for linoleic acid and three for linolenic acid) were identified in this study. Comparisons of two-locus and three-locus combinations indicated that cumulative effects of QTLs were significant for all the three unsaturated fatty acids. QTL pyramiding by molecular marker-assisted breeding would be an appropriate strategy for the improvement of unsaturated fatty acids in soybean.     

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     

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     

Congenic strain confirms putative quantitative trait locus for body weight in the rat

Quantitative trait loci (QTLs) affecting body weight were investigated in the backcross population derived from nondiabetic BB/OK and spontaneously hypertensive rat (SHR) strains. The F₁ hybrids were backcrossed onto SHR rats, and QTL analysis was performed separately with the resulting backcross populations for each sex on Chromosomes (Chrs) 1, 3, 4, 10, 13, and 18. The body weight was determined at the age of 14 weeks, and the statistical analysis was performed with MAPMAKER/QTL 1.1b computer program. According to the stringent threshold for a lod score of 3.0, markers on Chr 1 were found to be linked with body weight. The QTL with a peak lod score (5.1) on Chr 1 for a male population was located within markers Igf2 and D1Mgh12. In contrast, in the female population the body weight affecting QTL (lod = 5.7) on Chr 1 was located between the D1Mit3 and Lsn markers. The existence of QTLs on Chr 1 affecting body weight in the male population was confirmed by congenic BB.Sa rats, carrying chromosomal region of SHR (Sa-Igf2) on the genetic background of BB rat. Received: 14 July 1997 / Accepted: 22 December 1997     

Mapping quantitative trait loci mediating sensitivity to etomidate

Long- and Short-Sleep (LS and SS) mice were selectively bred for differences in ethanol-induced loss of the righting reflex (LORR) and have been found to differ in LORR induced by various anesthetic agents. We used a two-stage mapping strategy to identify quantitative trait loci (QTLs) affecting duration of LORR caused by the general anesthetic etomidate and brain levels of etomidate (BEL) following regain of the righting reflex. Analysis of recombinant-inbred strains derived from a cross between LS and SS mice (LSXSS) yielded a heritability estimate of 0.23 for etomidate-induced LORR and identified one marker that showed suggestive linkage for a QTL, on mouse Chromosome (chr) 12. Mapping in an F(2) population derived from a cross between inbred LS and SS (ILS and ISS) revealed a significant QTL for etomidate-induced LORR on Chr 12, and two significant QTLs mediating BEL on Chrs 6 and 12. Several QTLs showing suggestive linkage for etomidate-induced LORR and BEL were also identified in the F(2) population. Brain levels of etomidate in the RI and F(2) mice suggested that differences in LORR were due to differential central nervous system sensitivity, rather than differential etomidate metabolism. Interestingly, the region on Chr 7 has also been identified as a region influencing ethanol-induced LORR, suggesting the possibility of a common genetic mechanism mediating etomidate and ethanol sensitivity. These QTL regions need to be further narrowed before the testing of candidate genes is feasible.     

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     

Identifying Quantitative Trait Loci Affecting Resistance to Congenital Hypothyroidism in 129+Ter/SvJcl Strain Mice

Tyrosylprotein sulfotransferase 2 (TPST2) is one of the enzymes responsible for tyrosine O-sulfation and catalyzes the sulfation of the specific tyrosine residue of thyroid stimulating hormone receptor (TSHR). Since this modification is indispensable for the activation of TSH signaling, a non-functional TPST2 mutation (Tpst2^grt) in DW/J-grt mice leads to congenital hypothyroidism (CH) characterized by severe thyroid hypoplasia and dwarfism related to TSH hyporesponsiveness. Previous studies indicated that the genetic background of the 129^+Ter/SvJcl (129) mouse strain ameliorates Tpst2^grt-induced CH. To identify loci responsible for CH resistance in 129 mice, we performed quantitative trait locus (QTL) analysis using backcross progenies from susceptible DW/J and resistant 129 mice. We used the first principal component calculated from body weights at 5, 8 and 10 weeks as an indicator of CH, and QTL analysis mapped a major QTL showing a highly significant linkage to the distal portion of chromosome (Chr) 2; between D2Mit62 and D2Mit304, particularly close to D2Mit255. In addition, two male-specific QTLs showing statistically suggestive linkage were also detected on Chrs 4 and 18, respectively. All QTL alleles derived from the 129 strain increased resistance to growth retardation. There was also a positive correlation between recovery from thyroid hypoplasia and the presence of the 129 allele at D2Mit255 in male progenies. These results suggested that the major QTL on Chr 2 is involved in thyroid development. Moreover, since DW/J congenic strain mice carrying both a Tpst2^grt mutation and 129 alleles in the major QTL show resistance to dwarfism and thyroid hypoplasia, we confirmed the presence of the resistant gene in this region, and that it is involved in thyroid development. Further genetical analysis should lead to identification of genes for CH tolerance and, from a better understanding of thyroid organogenesis and function, the subsequent development of new treatments for thyroid disorders.     

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.     

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     

Genetic and Molecular Analysis of Wild-Derived Arrhythmic Mice

A new circadian variant was isolated by screening the intercross offspring of wild-caught mice (Mus musculus castaneus). This variant was characterized by an initial maintenance of damped oscillations and subsequent loss of rhythmicity after being transferred from light-dark (LD) cycles to constant darkness (DD). To map the genes responsible for the persistence of rhythmicity (circadian ratio) and the length of free-running period (τ), quantitative trait locus (QTL) analysis was performed using F₂ mice obtained from an F₁ cross between the circadian variant and C57BL/6J mice. As a result, a significant QTL with a main effect for circadian ratio (Arrhythmicity; Arrh-1) was mapped on Chromosome (Chr) 8. For τ, four significant QTLs, Short free-running period (Sfp-1) (Chr 1), Sfp-2 (Chr 6), Sfp-3 (Chr 8), Sfp-4 (Chr 11) were determined. An epistatic interaction was detected between Chr 3 (Arrh-2) and Chr 5 (Arrh-3). An in situ hybridization study of clock genes and mouse Period1::luciferase (mPer1::luc) real-time monitoring analysis in the suprachiasmatic nucleus (SCN) suggested that arrhythmicity in this variant might not be attributed to core circadian mechanisms in the SCN neurons. Our strategy using wild-derived variant mice may provide a novel opportunity to evaluate circadian and its related disorders in human that arise from the interaction between multiple variant genes.     

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     

Genomic screen for QTLs underlying alcohol consumption in the P and NP rat lines

Selective breeding for voluntary alcohol consumption was utilized to establish the alcohol-preferring (P) and alcohol-nonpreferring (NP) rat lines. Inbreeding was initiated after 30 generations of selection and, after 19 generations of inbreeding, 384 F₂ intercross progeny were created to identify quantitative trait loci (QTLs) influencing alcohol consumption. We had reported previously a QTL on Chromosome (Chr) 4; additional markers genotyped on Chr 4 have increased the maximum lod score from 8.6 to 9.2. This QTL acts in an additive fashion and continues to account for approximately 11% of the phenotypic variability. The 95% confidence interval is 12.5 cM and includes the candidate gene, neuropeptide Y. Subsequent to the identification of the QTL on Chr 4, a genome scan was completed to identify additional QTLs influencing alcohol consumption. A lod score of 2.5 was obtained on Chr 3, syntenic to a region previously reported for alcohol preference in mice. Analysis of Chr 8 produced a lod score of 2.2 near the dopamine D2 and serotonin 1b receptors, which have been previously reported as candidate genes for alcohol preference. Evidence for linkage to alcohol consumption was not found on any other chromosome. It therefore appears likely that, in addition to the QTL on Chr 4, multiple loci of small to moderate effect, such as those on Chrs 3 and 8, underlie the difference in alcohol consumption in the P/NP lines. Received: 15 September 1998 / Accepted: 8 October 1998