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PubMed2005

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

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

Adiposity↗
PubMedDate not supplied

Identification of quantitative trait loci for non-insulin-dependent diabetes mellitus that interact with body weight in the Otsuka Long-Evans Tokushima Fatty rat.

Non-insulin-dependent diabetes mellitus (NIDDM) is a prototypical multifactorial disease. Genetic predisposition and obesity are major risk factors for NIDDM development and the interactions between these factors are likely to be important in the etiology of this disease. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is one of the best animal models of NIDDM, since the OLETF rat develops NIDDM with mild obesity that is very similar to human NIDDM. Therefore, the OLETF rat is a powerful model for investigating the interaction between genetic susceptibility to NIDDM and obesity. In this study, our goal was to clarify the relationship between an individual NIDDM susceptibility locus and obesity in the OLETF using a molecular genetics approach. We identified four novel quantitative trait loci (QTLs) that contribute to the susceptibility to NIDDM, none of which shows significant linkage with body weight. However, Nidd1/of on chromosome 7 and Nidd2/of on chromosome 14 have an interaction with body weight. In contrast, one locus was mapped to chromosome 10 for body weight, but not to fasting or postprandial glucose levels. These data illustrate that NIDDM and body weight are under separate genetic control in the OLETF yet interact to yield the final disease phenotype in the two Nidd/of loci. In addition, body weight could be used in place of body mass index as an indicator of obesity in our experimental system of genetic study. This study will facilitate the understanding of the complex interaction between genetic susceptibility to NIDDM and obesity.

Animals↗
PubMed1998

Quantitative trait loci for blood glucose confirm diabetes predisposing and protective genes, Iddm4 and Iddm5r, in the spontaneously diabetic BB/OK rat.

Several crossing studies using diabetic BB/OK and diabetes-resistant rat strains have clearly shown that the MHC class-II-genes of the RT1u haplotype (Iddm1) and the lymphopenia (Iddm2) are essential but not sufficient for type 1 diabetes development. The search for additional diabetogenic genes revealed predisposing non-MHC genes, Iddm3 and Iddm4, and a diabetes protective gene, Iddm5r, cosegregating with diabetes in the BB/OK rat subline. These findings were based on cosegregation studies comparing allele frequencies between diabetic and non-diabetic cross hybrids. Since, type 1 diabetes is characterised by hyperglycaemia we analysed 22 diabetic and 43 non-diabetic [(BB x SHR)FI x BB] backcross hybrids (28M:37F) which were already homozygous for Iddml and Iddm2 to search for quantitative trait loci (QTLs) affecting blood glucose in BB/OK rats. The QTL analysis using 117 microsatellite markers located on 19 autosomal chromosomes and the X chromosome, revealed suggestive linkage for blood glucose at the same position for diabetics (lod score 3.1) and non-diabetics at an age of 16 weeks at locus D6Mgh2 on chromosome 6 (lod score 1.9). In contrast, the peak for nondiabetics at an age of 28 weeks (lod score 3.1) was located in the region on chromosome 1 flanked by D1Mgh12 and D1Mit14, whereas the peak for diabetics (lod score 1.9) was found between Sa and Igf2. The distance between two peaks is ca. 50 cM. These findings are consistent with previously described results and provide strong evidence on the relevance of the described region for the development of diabetes not only in the rat, but, regarding the chromosomal homology also in human.

Animals↗
PubMed2002

Provisional mapping of quantitative trait loci modulating the acoustic startle response and prepulse inhibition of acoustic startle.

Prepulse inhibition (PPI) of the acoustic startle response (ASR) is a form of sensorimotor gating, defined as an inhibition of the startle response when a low intensity stimulus, the prepulse, precedes the startling stimulus. Deficits in PPI have been reported in schizophrenia and other psychiatric/neurological disorders, and correlate with symptom severity in schizophrenia, suggesting that deficient PPI per se or abnormalities in neural circuits regulating PPI may cause some symptoms of schizophrenia. If so, then genes conferring reduced PPI may contribute toward genetic vulnerability to schizophrenia. Studies with selectively bred rodent strains indicate that PPI is under genetic control; however, the identity of the relevant genes is unknown. The current study used recombinant congenic mouse strains derived from C57BL/6J and A/J parents to assess genetic variability in PPI and in ASR and to identify provisional quantitative trait loci (QTLs) modulating these phenotypes. Significant between-strain differences in ASR and in PPI at each of several prepulse intensities (75, 80, 85, 90, 95 dB) were found. Correlations between PPI at the various prepulse intensities were highly significant, suggesting appreciable overlap in genetic regulation of PPI across prepulse intensities. Five QTLs (chromosomes 3, 5, 7, 16) associated with PPI across all prepulse intensities, but not with ASR, were identified. Two additional QTLs (chromosomes 2, 11) associated with both PPI and ASR were found. Fifteen QTLs were associated with ASR alone. Data on genotypes of informative congenic strains were used to support probable involvement of loci modulating PPI and to narrow the probable chromosomal location of QTLs. If confirmed, these QTLs may suggest candidate genes directing novel mechanisms for regulation of PPI

Acoustic Stimulation↗
PubMed2003

Mapping quantitative trait loci that influence serum insulin-like growth factor binding protein-5 levels in F2 mice (MRL/MpJ X SJL/J).

Recent studies using twins and inbred strains of mice reveal evidence for genetic mechanisms contributing to variation in circulating levels of IGF-I, IGF-II, and IGF binding protein (IGFBP)-3. To examine the hypothesis that serum IGFBP-5 levels have a strong heritable component, we intercrossed two inbred strains of mice, MRL/MpJ and SJL, which exhibit 79% difference in serum IGFBP-5 levels (554 +/- 68 vs. 309 +/- 51 ng/ml respectively, P < 0.001). A genome-wide scan was carried out using 137 polymorphic markers in 633 F2 female mice. Serum IGFBP-5 levels in the F2 progeny showed a normal distribution with an estimated heritability of 74%. Whole genome-wide scans for cosegregation of genetic marker data with high or low serum IGFBP-5 levels revealed six different quantitative trait loci (QTL) in chromosomes 1, 9 (two), 10, and 11 (two), which together explained 24% of F2 variance. Chromosome 11 QTL exhibited the highest LOD score (7.5). Based on the past findings that IGFBP-5 is an important bone formation stimulator, we predicted IGFBP-5 to contribute to bone mineral density variation in F2 mice. Accordingly, we found two of the six IGFBP-5 QTLs (Chrs 1 and 11) identified for serum IGFBP-5 phenotype also showed significant association with total body bone mineral density phenotype (measured by dual energy x-ray absorptiometry) in the F2 mice.

Absorptiometry, Photon↗
PubMed1999

Smoking behavior is under the influence of a major quantitative trait locus on human chromosome 5q.

Despite some evidence that smoking behavior is influenced by both genetic and environmental factors, efforts at identifying specific genes that influence smoking are extremely limited. Using information on smoking behavior history for 973 individuals distributed across 105 COGA families and a multipoint variance components method, we tested for linkage between smoking behavior (as defined by number of cigarette packs per day for 1 year) and chromosomal locations across the genome using information from 296 markers. We found strong evidence (lod = 3.2) for linkage of smoking behavior to a genetic location on chromosome 5q (D5S1354). Weaker evidence was found for linkage of smoking behavior to genetic locations on chromosomes 4 (between markers D4S244 and D4S2393), 15 (D15S642), and 17 (GATA193). Oligogenic linkage analyses suggest the putative locus on chromosome 5q is the primary determinant of genetic variation in smoking. Although the magnitude of the lod score is compelling, the large gap between the markers D5S1456 and D5S1354 (which is also at the end of chromosome 5q) in the COGA data set reduces the enthusiasm for this putative quantitative trait locus. However, typing of additional markers in this region may provide greater support for the localization of a susceptibility locus at this chromosomal location, which is not far from the DRD1 (D1 dopamine receptor gene) locus.

Chromosomes, Human, Pair 5↗
PubMed2006

A quantitative trait locus on chromosome 18q for physical activity and dietary intake in Hispanic children.

OBJECTIVE: Genetic components of energy homeostasis contributing to childhood obesity are poorly understood. Genome scans were performed to identify chromosomal regions contributing to physical activity and dietary intake traits in Hispanic children participating in the VIVA LA FAMILIA Study. RESEARCH METHODS AND PROCEDURES: We report linkage findings on chromosome 18 for physical activity and dietary intake in 1030 siblings from 319 Hispanic families. Measurements entailed physical activity by accelerometry, dietary intake by two 24-hour recalls, and genetic linkage analyses using SOLAR software. RESULTS: Significant heritabilities were seen for physical activity and dietary intake, ranging from 0.46 to 0.69, except for vigorous activity (h2 = 0.18). Percentage time in sedentary activity mapped to markers D18S1102-D18S64 on chromosome 18 [logarithm of the odds (LOD) score = 4.07], where melanocortin 4 receptor gene (MC4R) resides. Quantitative trait loci (QTLs) for total activity counts, percentage time in light or in moderate activity, and carbohydrate intake and percentage of energy intake from carbohydrates were detected in the same region (LOD = 2.28, 2.79, 2.2, 1.84, and 1.51, respectively). A novel loss of function mutation in MC4R (G55V) was detected in six obese relatives, but not in the rest of the cohort. Removal of these MC4R-deficient subjects from the analysis reduced the LOD score for sedentary activity to 3.94. DISCUSSION: Given its role in the regulation of food intake and energy expenditure, MC4R is a strong positional candidate gene for the QTL on chromosome 18 detected for physical activity and dietary intake in Hispanic children.

Adolescent↗
PubMed2003

Large changes in the structure of the major histone H1 subtype result in small effects on quantitative traits in legumes.

Electrophoretic analysis of the most abundant subtype of histone H1 (H1-1) of 301 accessions of grasspea (Lathyrus sativus) and 575 accessions of lentil (Lens culinaris) revealed allelic variants which most probably arose due to recent mutations. In each species, a single heterozygote for a mutation was taken for construction of isogenic lines carrying different H1-1 variants. Sequencing of alleles encoding H1-1 in lentil, grasspea, pea and Lathyrus aphaca showed the presence of an extended region in C-terminal tail which we termed 'regular zone' (RZ). It consists of 14 6-amino-acid units of which 12 (pea and Lathyrus species) or 13 (lentil) are represented by an AKPAAK sequence. The structure of the hypervariable unit 8 is species-specific. At the DNA level most AKPAAK units differ in the third codon positions, implying the action of natural selection preserving the RZ organization. In lentil, the fast variant lost two units (including unit 8), while one AKPAAK repeat of the slow variant is transformed into an anomalous SMPAAK. The mutant variant of the grasspea H1-1 differs from the standard one by duplication of an 11-amino-acid segment in N-terminal tail. The isogenic lines of lentil and grasspea were compared for a number of quantitative traits, some of them showing small (1-8%) significant differences.

Alleles↗
PubMed2003

Linkage disequilibrium mapping of a Verticillium dahliae resistance quantitative trait locus in tetraploid potato ( Solanum tuberosum) through a candidate gene approach.

We have used the linkage disequilibrium mapping method to test for an association between a candidate gene marker and resistance to Verticillium dahliae in tetraploid potato. A probe derived from the tomato Verticillium resistance gene ( Ve1) identified homologous sequences ( StVe1) in potato, which in a diploid population map to chromosome 9, in a position analogous to that of the tomato resistance gene. When a molecular marker closely linked (1.5 cM) to the homologues was used as a candidate gene marker on 137 tetraploid potato genotypes (mostly North American cultivars), the association between the marker and resistance was confirmed ( P<0.001). The amount of phenotypic variation in resistance explained by the allele of the STM1051 marker was greater than 10% and 25% in two subpopulations that were inferred from coancestry data matrix. Cloning of homologues from the highly resistant potato cv. Reddale indicates that the resistance quantitative trait locus (QTL) comprises at least an eleven-member family, encoding plant-specific leucine-rich repeat proteins highly similar to the tomato Ve genes. The sequence analysis shows that all homologues are uninterrupted open reading frames and thus represent putative functional resistance genes. This is the first time that the linkage disequilibrium method has been used to find an association between a resistance gene and a candidate gene marker in tetraploid potato. We have shown that it is possible to map QTL directly on already available potato cultivars, without developing a new mapping population.

Chromosome Mapping↗
PubMed2003

alpha-Synuclein maps to a quantitative trait locus for alcohol preference and is differentially expressed in alcohol-preferring and -nonpreferring rats.

Total gene expression analysis (TOGA) was used to identify genes that are differentially expressed in brain regions between the alcohol-naive, inbred alcohol-preferring (iP), and -nonpreferring (iNP) rats. alpha-Synuclein, expressed at >2-fold higher levels in the hippocampus of the iP than the iNP rat, was prioritized for further study. In situ hybridization was used to determine specific brain regions and cells expressing alpha-synuclein in the iP and iNP rats. Similar to alpha-synuclein mRNA levels, protein levels in the hippocampus were higher in iP rats than iNP rats. Higher protein levels were also observed in the caudate putamen of iP rats compared with iNP rats. Sequence analysis identified two single nucleotide polymorphisms in the 3' UTR of the cDNA. The polymorphism was used to map the gene, by using recombination-based methods, to chromosome 4, within a quantitative trait locus for alcohol consumption that was identified in the iP and iNP rats. A nucleotide exchange in the iNP 3' UTR reduced expression of the luciferase reporter gene in SK-N-SH neuroblastoma cells. These results suggest that differential expression of the alpha-synuclein gene may contribute to alcohol preference in the iP rats.

3' Untranslated Regions↗
PubMed2001

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

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

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1996

Quantitative trait loci and metabolic pathways: genetic control of the concentration of maysin, a corn earworm resistance factor, in maize silks.

Interpretation of quantitative trait locus (QTL) studies of agronomic traits is limited by lack of knowledge of biochemical pathways leading to trait expression. To more fully elucidate the biological significance of detected QTL, we chose a trait that is the product of a well-characterized pathway, namely the concentration of maysin, a C-glycosyl flavone, in silks of maize, Zea mays L. Maysin is a host-plant resistance factor against the corn earworm, Helicoverpa zea (Boddie). We determined silk maysin concentrations and restriction fragment length polymorphism genotypes at flavonoid pathway loci or linked markers for 285 F2 plants derived from the cross of lines GT114 and GT119. Single-factor analysis of variance indicated that the p1 region on chromosome 1 accounted for 58.0% of the phenotypic variance and showed additive gene action. The p1 locus is a transcription activator for portions of the flavonoid pathway. A second QTL, represented by marker umc 105a near the brown pericarp1 locus on chromosome 9, accounted for 10.8% of the variance. Gene action of this region was dominant for low maysin, but was only expressed in the presence of a functional p1 allele. The model explaining the greatest proportion of phenotypic variance (75.9%) included p1, umc105a, umc166b (chromosome 1), r1 (chromosome 10), and two epistatic interaction terms, p1 x umc105a and p1 x r1. Our results provide evidence that regulatory loci have a central role and that there is a complex interplay among different branches of the flavonoid pathway in the expression of this trait.

Journal Article↗
PubMed1973

The analysis of quantitative traits for simple genetic models from parental, F 1 and backcross data.

THE FOLLOWING MODELS ARE CONSIDERED FOR THE GENETIC DETERMINATION OF QUANTITATIVE TRAITS: segregation at one locus, at two linked loci, at any number of equal and additive unlinked loci, and at one major locus and an indefinite number of equal and additive loci. In each case an appropriate likelihood is given for data on parental, F(1) and backcross individuals, assuming that the environmental variation is normally distributed. Methods of testing and comparing the various models are presented, and methods are suggested for the simultaneous analysis of two or more traits.

Biometry↗
PubMed1995

Extreme discordant sib pairs for mapping quantitative trait loci in humans.

Analysis of differences between siblings (sib pair analysis) is a standard method of genetic linkage analysis for mapping quantitative trait loci, such as those contributing to hypertension and obesity, in humans. In traditional designs, pairs are selected at random or with one sib having an extreme trait value. The majority of such pairs provide little power to detect linkage; only pairs that are concordant for high values, low values, or extremely discordant pairs (for example, one in the top 10 percent and the other in the bottom 10 percent of the distribution) provide substantial power. Focus on discordant pairs can reduce the amount of genotyping necessary over conventional designs by 10- to 40-fold.

Alleles↗
PubMed2004

A family-based association test for repeatedly measured quantitative traits adjusting for unknown environmental and/or polygenic effects.

We propose a family-based association test, FBAT-PC, for studies with quantitative traits that are measured repeatedly. The traits may be influenced by partially or completely unknown factors that may vary for each measurement. Using generalized principal component analysis, FBAT-PC amplifies the genetic effects of each measurement by constructing an overall phenotype with maximal heritability. Analytically, and in the simulation studies, we compare FBAT-PC with standard methodology and assess both the heritability of the overall phenotype and the power of FBAT-PC. Compared to univariate analysis, FBAT-PC achieves power gains of up to 200%. Applications of FBAT-PC to an osteoporosis study and to an asthma study show the practical relevance of FBAT-PC. FBAT-PC has been implemented in the software package PBAT and is freely available at http://www.biostat.harvard.edu/~clange/default.htm.

Journal Article↗
PubMed2005

Quantitative trait loci governing carotenoid concentration and weight in seeds of chickpea (Cicer arietinum L.).

Chickpea is a staple protein source in many Asian and Middle Eastern countries. The seeds contain carotenoids such as beta-carotene, cryptoxanthin, lutein and zeaxanthin in amounts above the engineered beta-carotene-containing "golden rice" level. Thus, breeding for high carotenoid concentration in seeds is of nutritional, socio-economic, and economic importance. To study the genetics governing seed carotenoids in chickpea, we studied the relationship between seed weight and concentrations of beta-carotene and lutein by means of high-performance liquid chromatography in segregating progeny from a cross between an Israeli cultivar and wild Cicer reticulatum Ladiz. Seeds of the cross progeny varied with respect to their carotenoid concentration (heritability estimates ranged from 0.5 to 0.9), and a negative genetic correlation was found between mean seed weight and carotenoid concentration in the F(3). To determine the loci responsible for the genetic variation observed, the population was genotyped using 91 sequence tagged microsatellite site markers and two CytP450 markers to generate a genetic map consisting of nine linkage groups and a total length of 344.6 cM. Using quantitative data collected for beta-carotene and lutein concentration and seed weight of the seeds of the F(2) population, we were able to identify quantitative trait loci (QTLs) by interval mapping. At a LOD score of 2, four QTLs for beta-carotene concentration, a single QTL for lutein concentration and three QTLs for seed weight were detected. The results of this investigation may assist in improving the nutritional quality of chickpea.

Carotenoids↗
PubMed2005

Construction of two BAC libraries from cucumber (Cucumis sativus L.) and identification of clones linked to yield component quantitative trait loci.

Two bacterial artificial chromosome (BAC) libraries were constructed from an inbred line derived from a cultivar of cucumber (Cucumis sativus L.). Intact nuclei were isolated and embedded in agarose plugs, and high-molecular-weight DNA was subsequently partially digested with BamHI or EcoRI. Ligation of double size-selected DNA fragments with the pECBAC1 vector yielded two libraries containing 23,040 BamHI and 18,432 EcoRI clones. The average BamHI and EcoRI insert sizes were estimated to be 107.0 kb and 100.8 kb, respectively, and BAC clones lacking inserts were 1.3% and 14.5% in the BamHI and EcoRI libraries, respectively. The two libraries together represent approximately 10.8 haploid cucumber genomes. Hybridization with a C(0)t-1 DNA probe revealed that approximately 36% of BAC clones likely carried repetitive sequence-enriched DNA. The frequencies of BAC clones that carry chloroplast or mitochondrial DNA range from 0.20% to 0.47%. Four sequence-characterized amplified region (SCAR), four simple sequence repeat, and an randomly amplified polymorphic DNA marker linked with yield component quantitative trait loci were used either as probes to hybridize high-density colony filters prepared from both libraries or as primers to screen an ordered array of pooled BAC DNA prepared from the BamHI library. Positive BAC clones were identified in predicted numbers, as screening by polymerase chain reaction amplification effectively overcame the problems associated with an overabundance of positives from hybridization with two SCAR markers. The BAC clones identified herein that are linked to the de (determinate habit) and F (gynoecy) locus will be useful for positional cloning of these economically important genes. These BAC libraries will also facilitate physical mapping of the cucumber genome and comparative genome analyses with other plant species.

Chromosomes, Artificial, Bacterial↗
PubMed2005

Identification of quantitative trait loci that regulate Arabidopsis root system size and plasticity.

Root system size (RSS) is a complex trait that is greatly influenced by environmental cues. Hence, both intrinsic developmental pathways and environmental-response pathways contribute to RSS. To assess the natural variation in both types of pathways, we examined the root systems of the closely related Arabidopsis ecotypes Landsberg erecta (Ler) and Columbia (Col) grown under mild osmotic stress conditions. We found that Ler initiates more lateral root primordia, produces lateral roots from a higher percentage of these primordia, and has an overall larger root system than Col under these conditions. Furthermore, although each of these parameters is reduced by osmotic stress in both ecotypes, Ler shows a decreased sensitivity to osmotica. To understand the genetic basis for these differences, QTL for RSS under mild osmotic stress were mapped in a Ler x Col recombinant inbred population. Two robust quantitative trait loci (QTL) were identified and confirmed in near-isogenic lines (NILs). The NILs also allowed us to define distinct physiological roles for the gene(s) at each locus. This study provides insight into the genetic and physiological complexity that determines RSS and begins to dissect the molecular basis for naturally occurring differences in morphology and developmental plasticity in the root system.

Arabidopsis↗