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.     

Genetic association of a GABAA receptor γ2 subunit variant with severity of acute physiological dependence on alcohol

The ultimate goal of quantitative trait locus (QTL) mapping is to identify the genes affecting complex traits. Using animal models, we recently identified QTLs on mouse Chromosomes (Chrs) 1, 4, and 11 affecting genetic predisposition to acute alcohol withdrawal. Among mice derived from the C57BL/6J (B6) and DBA/2J (D2) inbred strains, the locus identified on Chr 11 (∼20 cM) accounted for 12% of the genetic variability in withdrawal liability. Candidate genes in proximity to this QTL encode the γ₂, α₁, and α₆ subunits of GABA_A receptors. The present studies identify a polymorphism between the B6 and D2 strains in the γ₂ subunit gene, Gabrg2, and expand genotypic analysis to their BXD recombinant inbred strains. This polymorphism predicts a difference in amino acid sequence (Ala-11 vs. Thr-11) within the extracellular amino-terminal region of the γ₂ subunit. Analysis using BXD strain means for acute alcohol withdrawal severity suggests that the γ₂ subunit polymorphism is genetically correlated with alcohol withdrawal severity. This is the first report that QTL mapping for an alcohol-related trait has successfully led to the identification of a polymorphic candidate gene product that is genetically associated with the trait. Received: 15 September 1998 / Accepted: 8 October 1998     

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     

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     

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.     

Confirmation and dissection of QTL controlling resistanceto malaria in mice

We developed an F₁₁ AIL population from an F₁ cross of A/J (susceptible) and C57BL/6J (resistant) mouse strains. One thousand F₁₁ mice were challenged with P.c. chabaudi 54X, and 340 mice selected from the phenotypic extremes for susceptibility and resistance were genotyped for microsatellite markers on Chromosomes (Chrs) 5, 8, and 17. QTL originally detected in backcross and F₂ populations were confirmed on the three chromosomes within narrower genomic regions, by maximum likelihood and regression analyses. Each of the previously mapped QTL on Chrs 5 and 17 resolved into two linked QTLs. The distal and proximal QTLs on Chrs 5 and 17, respectively, map to the previously reported QTL.     

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.     

Influence of dent corn genetic backgrounds on QTL detection for plant-height traits and their relationships in high-oil maize

QTL mapping for plant-height traits has not been hitherto reported in high-oil maize. A high-oil maize inbred ‘GY220’ was crossed with two dent maize inbreds (‘8984’ and ‘8622’) to generate two connected F_2:3 populations. Four plant-height traits were evaluated in 284 and 265 F_2:3 families. Single-trait QTL mapping and multiple-trait joint QTL mapping was used to detect QTLs for the traits and the genetic relationship between plant height (PH) and two other plant-height traits. A total of 28 QTLs and 12 pairs of digenic interactions among detected QTLs for four traits were detected in the two F_2:3 families. Only one marker was shared between the two populations. Joint analysis of PH with ear height (EH) and PH with top height (TH) detected 32 additional QTLs. Our results showed that QTL detection for PH was dependent on the genetic background of dent corn inbreds. Multiple-trait joint QTL analysis could increase the number of detected QTLs.     

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     

Identification of novel non-insulin-dependent diabetes mellitus susceptibility loci in the Otsuka Long-Evans Tokushima Fatty rat by MQM-mapping method

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese-type, non-insulin-dependent diabetes mellitus (NIDDM) in humans. We have previously identified 11 quantitative trait loci (QTLs) responsible for NIDDM susceptibility on Chromosomes (Chrs) 1, 5, 7, 8, 9, 11, 12, 14, and 16 (Nidd1–11/of for Non-insulin-dependent diabetes1–11/oletf) by using the interval mapping method in 160 F₂ progenies obtained by mating the OLETF and the Fischer-344 (F344) rats. MQM-mapping, which was applied for QTL analysis based on multiple-QTL models, is reported to be more powerful than interval mapping, because in the process of mapping one QTL the genetic background, which contains the other QTLs, is controlled. Application of MQM-mapping in the F₂ intercrosses has led to a revelation of three novel QTLs on rat Chrs 5 (Nidd12/of), 7 (Nidd13/of), and 17 (Nidd14/of), in addition to Nidd1–11/of loci. The three QTLs, together with the Nidd1–11/of, account for a total of ∼70% and ∼85% of the genetic variance of the fasting and postprandial glucose levels, respectively, in the F₂. While the OLETF allele corresponds with increased glucose levels as expected for Nidd12 and 14/of, the Nidd13/of exhibits heterosis: heterozygotes showing significantly higher glucose levels than OLETF or F344 homozygotes. There is epistatic interaction between Nidd2 and 14/of. Additionally, our results indicated that the novel QTLs could show no linkage with body weight, but Nidd12/of has an interaction with body weight. Received: 23 February 1999 / Accepted: 3 August 1999     

Chromosomal loci influencing chronic alcohol withdrawal severity

Ethanol (alcohol) withdrawal-induced convulsions are a key index of physical dependence on ethanol and a clinically important consequence of alcohol abuse in humans. In rodent models, severity of withdrawal is strongly influenced by genotype. For example, many studies have reported marked differences in withdrawal severity between the WSR (Withdrawal Seizure Resistant) and WSP (Withdrawal Seizure Prone) mouse strains selectively bred for over 25 generations to differ in chronic withdrawal severity. Therefore, we used an F₂ intercross between the inbred WSP and WSR strains for a genome-wide search for quantitative trait loci (QTLs), which are chromosomal sites containing genes influencing the magnitude of withdrawal. We also used the recently developed HW, RHW (high withdrawal) and LW, RLW (low withdrawal) lines selectively bred for the same trait and in the same manner as the WSP, WSR lines. QTL analysis was then used to dissect the continuous trait distribution of withdrawal severity into component loci, and to map them to broad chromosomal regions by using the Pseudomarker 0.9 and Map Manager QT29b programs. This genome-wide search identified five significant QTLs influencing chronic withdrawal severity on Chromosomes (Chrs) 1 (proximal), 4 (mid), 8 (mid), 11 (proximal), and 14 (mid), plus significant interactions (epistasis) between loci on Chr 11 with 13, 4 with 8, and 8 with 14.     

QTL identification of flowering time at three different latitudes reveals homeologous genomic regions that control flowering in soybean

Since the genetic control of flowering time is very important in photoperiod-sensitive soybean (Glycine max (L.) Merr.), genes affecting flowering under different environment conditions have been identified and described. The objectives were to identify quantitative trait loci (QTLs) for flowering time in different latitudinal and climatic regions, and to understand how chromosomal rearrangement and genome organization contribute to flowering time in soybean. Recombinant inbred lines from a cross between late-flowering ‘Jinpumkong 2’ and early-flowering ‘SS2-2’ were used to evaluate the phenotypic data for days to flowering (DF) collected from Kamphaeng Saen, Thailand (14°01′N), Suwon, Korea (37°15′N), and Longjing, China (42°46′N). A weakly positive phenotypic correlation (r = 0.36) was found between DF in Korea and Thailand; however, a strong correlation (r = 0.74) was shown between Korea and China. After 178 simple sequence repeat (SSR) markers were placed on a genetic map spanning 2,551.7 cM, four independent DF QTLs were identified on different chromosomes (Chrs). Among them, three QTLs on Chrs 9, 13 and 16 were either Thailand- or Korea-specific. The DF QTL on Chr 6 was identified in both Korea and China, suggesting it is less environment-sensitive. Comparative analysis of four DF QTL regions revealed a syntenic relationship between two QTLs on Chrs 6 and 13. All five duplicated gene pairs clustered in the homeologous genomic regions were found to be involved in the flowering. Identification and comparative analysis of multiple DF QTLs from different environments will facilitate the significant improvement in soybean breeding programs with respect to control of flowering time.     

Complete genome searches for quantitative trait loci controlling blood pressure and related traits in four segregating populations derived from Dahl hypertensive rats

The Dahl salt-sensitive rat is one of the principal animal models of hereditary hypertension. Genome-wide searches were undertaken to detect quantitative trait loci (QTLs) that influence blood pressure, cardiac mass, and body weight in four F₂ populations derived from Dahl salt-sensitive rats and different inbred normotensive control strains of rat. We detected three QTLs associated with one or more of the phenotypes, using a stringent statistical criterion for linkage (p < 0.00003). These included a novel QTL linked to blood pressure on rat Chromosome (Chr) 12, and another QTL on rat Chr 3 linked to body weight. A QTL on rat Chr 10 for which linkage to blood pressure has been described in other crosses was found to be a principal determinant of blood pressure and cardiac mass in some but not all of the crosses examined here. Three other regions showed evidence of linkage to these phenotypes with a less stringent statistical criterion of linkage at QTLs previously reported in other studies. As part of our study, microsatellite markers have been developed for three candidate genes for investigation in hypertension, and the genes have been localized by linkage mapping. These are: the rat Gs alpha subunit (Gnas) gene, the alpha-1B adrenergic receptor (Adra1b), and the Na⁺, K⁺-ATPase beta2 subunit (Atp1b2) gene. Received: 29 June 1998 / Accepted: 30 October 1998     

Cold Tolerance of the Photosynthetic Apparatus: Pleiotropic Relationship between Photosynthetic Performance and Specific Leaf Area of Maize Seedlings

The objective of this study was to elucidate the genetic relationship between the specific leaf area (SLA) and the photosynthetic performance of maize (Zea mays L.) as dependent on growth temperature. Three sets of genotypes: (i) 19 S₅ inbred lines, divergently selected for high or low operating efficiency of photosystem II (Φ_PSII) at low temperature, (ii) a population of 226 F_2:3 families from the cross of ETH-DL3 × ETH-DH7, and (iii) a population of 168 F_2:4 families from the cross of Lo964 × Lo1016 were tested at low (15/13 °C day/night) or at optimal (25/22 °C day/night) temperature. The latter cross was originally developed to study QTLs for root traits. At 15/13 °C the groups of S₅ inbred lines selected for high or low Φ_PSII differed significantly for all the measured traits, while at optimal temperature the groups differed only with regard to leaf greenness (SPAD). At low temperature, the SLA of these inbred lines was negatively correlated with Φ_PSII (r = − 0.56, p < 0.05) and SPAD (r = − 0.80, p < 0.001). This negative relationship was confirmed by mapping quantitative trait loci (QTL) in the two mapping populations. A co-location of three QTLs for SLA with QTLs for photosynthesis-related traits was detected in both populations at 15/13 °C, while co-location was not detected at 25/22 °C. The co-selection of SLA and Φ_PSII in the inbred lines and the co-location of QTL for SLA, SPAD, and Φ_PSII at 15/13 °C in the QTL populations strongly supports pleiotropy. There was no evidence that selecting for high Φ_PSII at low temperature leads to a constitutively altered SLA.     

A large QTL for fear and anxiety mapped using an F2 cross can be dissected into multiple smaller QTLs

Using chromosome substitution strains (CSS), we previously identified a large quantitative trait locus (QTL) for conditioned fear (CF) on mouse chromosome 10. Here, we used an F₂ cross between CSS‐10 and C57BL/6J (B6) to localize that QTL to distal chromosome 10. That QTL accounted for all the difference between CSS‐10 and B6. We then produced congenic strains to fine‐map that interval. We identified two congenic strains that captured some or all the QTL. The larger congenic strain (Line 1: 122.387121–129.068 Mb; build 37) appeared to account for all the difference between CSS‐10 and B6. The smaller congenic strain (Line 2: 127.277–129.068 Mb) was intermediate between CSS‐10 and B6. We used haplotype mapping followed by quantitative polymerase chain reaction to identify one gene that was differentially expressed in both lines relative to B6 (Rnf41) and one that was differentially expressed between only Line 1 and B6 (Shmt2). These cis‐eQTLs may cause the behavioral QTLs; however, further studies are required to validate these candidate genes. More generally, our observation that a large QTL mapped using CSS and F₂ crosses can be dissected into multiple smaller QTLs shows a weaknesses of two‐stage approaches that seek to use coarse mapping to identify large regions followed by fine‐mapping. Indeed, additional dissection of these congenic strains might result in further subdivision of these QTL regions. Despite these limitations, we have successfully fine‐mapped two QTLs to small regions and identified putative candidate genes, showing that the congenic approach can be effective for fine‐mapping QTLs .     

QTL consistency and meta-analysis for grain yield components in three generations in maize

Grain yield is the most important and complex trait in maize. In this study, a total of 258 F₉ recombinant inbred lines (RIL), derived from a cross between dent corn inbred Dan232 and popcorn inbred N04, were evaluated for eight grain yield components under four environments. Quantitative trait loci (QTL) and their epistatic interactions were detected for all traits under each environment and in combined analysis. Meta-analysis was used to integrate genetic maps and detected QTL across three generations (RIL, F_2:3 and BC₂F₂) derived from the same cross. In total, 103 QTL, 42 pairs of epistatic interactions and 16 meta-QTL (mQTL) were detected. Twelve out of 13 QTL with contributions (R ²) over 15% were consistently detected in 3–4 environments (or in combined analysis) and integrated in mQTL. Only q100GW-7-1 was detected in all four environments and in combined analysis. 100qGW-1-1 had the largest R ² (19.3–24.6%) in three environments and in combined analysis. In contrast, 35 QTL for 6 grain yield components were detected in the BC₂F₂ and F_2:3 generations, no common QTL across three generations were located in the same marker intervals. Only 100 grain weight (100GW) QTL on chromosome 5 were located in adjacent marker intervals. Four common QTL were detected across the RIL and F_2:3 generations, and two between the RIL and BC₂F₂ generations. Each of five important mQTL (mQTL7-1, mQTL10-2, mQTL4-1, mQTL5-1 and mQTL1-3) included 7–12 QTL associated with 2–6 traits. In conclusion, we found evidence of strong influence of genetic structure and environment on QTL detection, high consistency of major QTL across environments and generations, and remarkable QTL co-location for grain yield components. Fine mapping for five major QTL (q100GW-1-1, q100GW-7-1, qGWP-4-1, qERN-4-1 and qKR-4-1) and construction of single chromosome segment lines for genetic regions of five mQTL merit further studies and could be put into use in marker-assisted breeding.     

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.     

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     

Identification of genetic loci affecting the establishment and development of Echinococcus multilocularis larvae in mice

Alveolar echinococcosis (AE) is a severe hepatic disorder caused by larval infection by the fox tapeworm Echinococcus multilocularis. The course of parasitic development and host reactions are known to vary significantly among host species, and even among different inbred strains of mice. As reported previously, after oral administration of parasite eggs, DBA/2 (D2) mice showed a higher rate of cyst establishment and more advanced protoscolex development in the liver than C57BL/6 (B6) mice. These findings strongly suggest that the outcome of AE is affected by host genetic factor(s). In the present study, the genetic basis of such strain-specific differences in susceptibility/resistance to AE in murine models was studied by whole-genome scanning for quantitative trait loci (QTLs) using a backcross of (B6 × D2)F₁ and D2 mice with varying susceptibility to E. multilocularis infection. For cyst establishment, genome linkage analysis identified one suggestive and one significant QTL on chromosomes (Chrs.) 9 and 6, respectively, whereas for protoscolex development, two suggestive and one highly significant QTLs were detected on Chrs. 6, 17 and 1, respectively. Our QTL analyses using murine AE models revealed that multiple genetic factors regulated host susceptibility/resistance to E. multilocularis infection. Moreover, our findings show that establishment of the parasite cysts in the liver is affected by QTLs that are distinct from those associated with the subsequent protoscolex development of the parasite, indicating that different host factors are involved in the host–parasite interplay at each developmental stage of the larval parasite. Further identification of responsible genes located on the identified QTLs could lead to the development of effective disease prevention and control strategies, including an intensive screening and clinical follow-up of genetically high-risk groups for AE infection.