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PubMed2000

An integrated map of human 6q22.3-q24 including a 3-Mb high-resolution BAC/PAC contig encompassing a QTL for fetal hemoglobin.

Genetic studies have previously assigned a quantitative trait locus (QTL) for hemoglobin F and F cells to a region of approximately 4 Mb between the markers D6S408 and D6S292 on chromosome 6q23. An initial yeast artificial chromosome contig of 13 clones spanning this region was generated. Further linkage analysis of an extended kindred refined the candidate interval to 1-2 cM, and key recombination events now place the QTL within a region of <800 kb. We describe a high-resolution bacterial clone contig spanning 3 Mb covering this critical region. The map consists of 223 bacterial artificial chromosome (BAC) and 100 P1 artificial chromosome (PAC) clones ordered by sequence-tagged site (STS) content and restriction fragment fingerprinting with a minimum tiling path of 22 BACs and 1 PAC. A total of 194 STSs map to this interval of 3 Mb, giving an average marker resolution of approximately one per 15 kb. About half of the markers were novel and were isolated in the present study, including three CA repeats and 13 single nucleotide polymorphisms. Altogether 24 expressed sequence tags, 6 of which are unique genes, have been mapped to the contig.

Base Sequence↗
PubMed2005

Time-related mapping of quantitative trait loci controlling grain-filling in rice (Oryza sativa L.).

Grain-filling is a crucial process that determines final grain yield in rice (Oryza sativa L.). To understand the genetic basis of dynamics of grain-filling, quantitative trait locus (QTL) analysis was conducted using time-related phenotypic data on grain-filling collected from a population of 155 recombinant inbred lines (F12), derived from a cross between Milyang 23 and Akihikari. Two QTLs detected on chromosomes 8 and 12 were strongly associated with increased filling percentage per panicle. These QTLs were not linked with those controlling spikelet numbers per panicle. This result confers the possibility of improving grain-filling together with an enlargement of sink size. The QTL for filling percentage per panicle on chromosome 8 exactly overlapped that for non-structural carbohydrate (NSC) content in the culm and leaf sheaths during grain-filling, and the Milyang 23 allele associated with increased grain-filling percentage per panicle was associated with decreased NSC content. Therefore, this QTL may be directly involved in NSC translocation from the culm and leaf sheaths to panicle. In addition, the Milyang 23 alleles of QTLs associated with greater spikelet number per panicle on chromosomes 1 and 6 were also related with a reduction in NSC content in the culm and leaf sheaths during grain-filling. These results indicate that NSC dynamics during grain-filling is partly dependent on sink size. NSC accumulation in the culm and leaf sheaths at the heading stage was mainly controlled by different genetic regulations from NSC dynamics during grain-filling. Nitrogen dynamics during grain-filling may also be involved in carbohydrate dynamics.

Chromosome Mapping↗
PubMedDate not supplied

Hemochromatosis protein (HFE) and tumor necrosis factor receptor 2 (TNFR2) influence tissue iron levels: elements of a common gut pathway?

Quantitative genetic analysis of hepatic and splenic iron levels in recombinant inbred mice yielded a quantitative trait locus that was found to coincide with the genomic locale encompassing the tumor necrosis factor receptor 2 gene (Tnfr2). When fed an iron-enriched diet, mice nullizygous with respect to Tnfr2, but not the Tnfr1 gene, showed a significant increase in splenic non-heme iron levels. This result contrasted with mice deficient in the hemochromatosis protein, HFE, which demonstrated a significant increase in normally high hepatic iron levels, but no change in splenic iron, when fed an iron-enriched chow. Both Tnfr2 knockout and HFE knockout mice fed an iron-enriched diet failed to demonstrate intestinal epithelial cell iron following the application of the Perls' stain, as compared to both Tnfr1 knockout and normal control mice. Moreover, intestinal intraepithelial lymphocytes (IELs) isolated from HFE knockout mice did not show an increase in TNF expression following challenge with the iron-enriched diet, in contrast to normal controls. These results suggest that HFE and TNFR2 are both involved in regulating iron deposition in tissues and that the regulation occurs at the level of the intestine through IEL-orchestrated production of TNF following the binding to TNFR2. These data suggest that HFE and TNFR2 may contribute to a common pathway of the iron stores regulator insuring the controlled efflux of gut iron.

Animals↗
PubMed2007

Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass.

UNLABELLED: Several genome-wide scans have been performed to detect loci that regulate BMD, but these have yielded inconsistent results, with limited replication of linkage peaks in different studies. In an effort to improve statistical power for detection of these loci, we performed a meta-analysis of genome-wide scans in which spine or hip BMD were studied. Evidence was gained to suggest that several chromosomal loci regulate BMD in a site-specific and sex-specific manner. INTRODUCTION: BMD is a heritable trait and an important predictor of osteoporotic fracture risk. Several genome-wide scans have been performed in an attempt to detect loci that regulate BMD, but there has been limited replication of linkage peaks between studies. In an attempt to resolve these inconsistencies, we conducted a collaborative meta-analysis of genome-wide linkage scans in which femoral neck BMD (FN-BMD) or lumbar spine BMD (LS-BMD) had been studied. MATERIALS AND METHODS: Data were accumulated from nine genome-wide scans involving 11,842 subjects. Data were analyzed separately for LS-BMD and FN-BMD and by sex. For each study, genomic bins of 30 cM were defined and ranked according to the maximum LOD score they contained. While various densitometers were used in different studies, the ranking approach that we used means that the results are not confounded by the fact that different measurement devices were used. Significance for high average rank and heterogeneity was obtained through Monte Carlo testing. RESULTS: For LS-BMD, the quantitative trait locus (QTL) with greatest significance was on chromosome 1p13.3-q23.3 (p = 0.004), but this exhibited high heterogeneity and the effect was specific for women. Other significant LS-BMD QTLs were on chromosomes 12q24.31-qter, 3p25.3-p22.1, 11p12-q13.3, and 1q32-q42.3, including one on 18p11-q12.3 that had not been detected by individual studies. For FN-BMD, the strongest QTL was on chromosome 9q31.1-q33.3 (p = 0.002). Other significant QTLs were identified on chromosomes 17p12-q21.33, 14q13.1-q24.1, 9q21.32-q31.1, and 5q14.3-q23.2. There was no correlation in average ranks of bins between men and women and the loci that regulated BMD in men and women and at different sites were largely distinct. CONCLUSIONS: This large-scale meta-analysis provided evidence for replication of several QTLs identified in previous studies and also identified a QTL on chromosome 18p11-q12.3, which had not been detected by individual studies. However, despite the large sample size, none of the individual loci identified reached genome-wide significance.

Bone Density↗
PubMedDate not supplied

Mapping QTLs associated with drought resistance in sorghum (Sorghum bicolor L. Moench).

Drought is a major abiotic stress factor limiting crop production. Identification of genetic factors involved in plant responses to drought stress will provide a solid foundation to improve drought resistance. Sorghum is well adapted to hot dry environments and regarded as a model for studying drought resistance among the grasses. Significant progress in genome mapping of this crop has also been made. In sorghum, rapid premature leaf death generally occurs when water is limited during the grain filling period. Premature leaf senescence, in turn, leads to charcoal rot, stalk lodging, and significant yield loss. More than 80% of commercial sorghum hybrids in the United States are grown under non-irrigated conditions and although most of them have pre-flowering drought resistance, many do not have any significant post-flowering drought resistance. Stay-green is one form of drought resistance mechanism, which gives sorghum resistance to premature senescence under soil moisture stress during the post-flowering period. Quantitative trait locus (QTL) studies with recombinant inbred lines (RILs) and near-isogenic lines (NILs) identified several genomic regions associated with resistance to pre-flowering and post-flowering drought stress. We have identified four genomic regions associated with the stay-green trait using a RIL population developed from B35 x Tx7000. These four major stay-green QTLs were consistently identified in all field trials and accounted for 53.5% of the phenotypic variance. We review the progress in mapping stay-green QTLs as a component of drought resistance in sorghum. The molecular genetic dissection of the QTLs affecting stay-green will provide further opportunities to elucidate the underlying physiological mechanisms involved in drought resistance in sorghum and other grasses.

Adaptation, Physiological↗
PubMed2003

Effects of marker-assisted selection under different initial frequency of QTL favorable allele.

A ten-generation continuous selection experiment on a single trait in a closed population was carried out by stochastic simulation. It assumed that the trait was controlled by polygenes and a single autosomal bi-allelic marked quantitative trait locus (QTL). Individual breeding values were estimated through animal model marker-assisted best linear unbiased prediction (MB-LUP), and breeding animals were selected according to their breeding values. The effects of three levels initial frequencies of QTL favorable allele on marker-assisted selection (MAS) were studied. The results showed that it would gain higher genetic response when implementing MAS on those traits with lower initial frequency of QTL favorable allele. When the initial frequency of QTL favorable allele was low, although the generation number required for fixing QTL favorable allele in the population would be lengthened, its frequency would be increased faster. However, the initial frequency of QTL favorable allele had little effects on the inbreeding rates.

Algorithms↗
PubMed2003

Genotype-environment interactions at quantitative trait loci affecting inflorescence development in Arabidopsis thaliana.

Phenotypic plasticity and genotype-environment interactions (GEI) play a prominent role in plant morphological diversity and in the potential functional capacities of plant life-history traits. The genetic basis of plasticity and GEI, however, is poorly understood in most organisms. In this report, inflorescence development patterns in Arabidopsis thaliana were examined under different, ecologically relevant photoperiod environments for two recombinant inbred mapping populations (Ler x Col and Cvi x Ler) using a combination of quantitative genetics and quantitative trait locus (QTL) mapping. Plasticity and GEI were regularly observed for the majority of 13 inflorescence traits. These observations can be attributable (at least partly) to variable effects of specific QTL. Pooled across traits, 12/44 (27.3%) and 32/62 (51.6%) of QTL exhibited significant QTL x environment interactions in the Ler x Col and Cvi x Ler lines, respectively. These interactions were attributable to changes in magnitude of effect of QTL more often than to changes in rank order (sign) of effect. Multiple QTL x environment interactions (in Cvi x Ler) clustered in two genomic regions on chromosomes 1 and 5, indicating a disproportionate contribution of these regions to the phenotypic patterns observed. High-resolution mapping will be necessary to distinguish between the alternative explanations of pleiotropy and tight linkage among multiple genes.

Arabidopsis↗
PubMed2004

Quantitative trait loci that determine lipoprotein cholesterol levels in an intercross of 129S1/SvImJ and CAST/Ei inbred mice.

To identify genetic determinants of lipoprotein levels, we are performing quantitative trait locus (QTL) analysis on a series of mouse intercrosses in a "daisy chain" experimental design, to increase the power of detecting QTL and to identify common variants that should segregate in multiple intercrosses. In this study, we intercrossed strains CAST/Ei and 129S1/SvImJ, determined HDL, total, and non-HDL cholesterol levels, and performed QTL mapping using Pseudomarker software. For HDL cholesterol, we identified two significant QTL on chromosome (Chr) 1 (Hdlq5, 82 cM, 60-100 cM) and Chr 4 (Hdlq10, 20 cM, 10-30 cM). For total cholesterol, we identified three significant QTL on Chr 1 (Chol7, 74 cM, 65-80 cM), Chr 4 (Chol8, 12 cM, 0-30 cM), and Chr 17 (Chol9, 54 cM, 20-60 cM). For non-HDL cholesterol, we identified significant QTL on Chr 8 (Nhdlq1, 34 cM, 20-60 cM) and Chr X (Nhdlq2, 6 cM, 0-18 cM). Hdlq10 was the only QTL detected in two intercrosses involving strain CAST/Ei. Hdlq5, Hdlq10, Nhdlq1, and two suggestive QTL at D7Mit246 and D15Mit115 coincided with orthologous human lipoprotein QTL. Our analysis furthers the knowledge of the genetic control of lipoprotein levels and points to the importance of Hdlq10, which was detected repeatedly in multiple studies.

ATP Binding Cassette Transporter 1↗
PubMed1999

Testing the correspondence between map positions of quantitative trait loci.

There are several instances in which quantitative trait locus (QTL) mapping experiments have been independently carried out for similar traits in different laboratories. We develop a permutation test of the correspondence between the test statistics obtained from genome-wide QTL scans in two such experiments to test whether the same QTLs are segregating in the experimental pair. In simulations, we show that the permutation test has the desired properties if chromosomes are of equal length, but bias can occur if chromosomes are of unequal length, a problem connected with autocorrelation of test statistic values. We apply the test to data from three recent mouse body weight QTL mapping experiments. The results from the test are non-significant, and imply a lack of overall concordance between the QTLs that were segregating in these experiments.

Animals↗
PubMed2003

Multivariate mixed inheritance models for QTL detection on porcine chromosome 6.

A series of multivariate mixed-inheritance models is fitted to the data from an outbred-line pig cross commercially used in Norway. Each model accommodates information on polygenic (co)variances between F2 individuals and their F1 parents across the five traits through incorporation of a random animal effect. Considered traits relate to meat quality and are chosen following up the results from a previous evaluation, in which a putative quantitative trait locus (QTL) was identified on chromosome six that affects the amount of intramuscular fat (IMF), meat percentage, meat tenderness and smell intensity (Grindflek et al., 2001). An additional trait included in the model, based on results of other studies, is the backfat thickness. The analysed material comprises data scored for 305 F2 individuals, whereas marker information is available for F1 and F2 generations. Based on the results of the multivariate analysis with the mixed-inheritance model, it was possible to conclude that the evidence for QTLs for meat percentage, meat tenderness and smell intensity in the study of Grindflek et al. (2001) do not represent separate QTLs, but is caused by the fact that the applied pre-adjustment of trait values for polygenic effects failed properly to remove the polygenic variation. The QTL effect on IMF on chromosome six was confirmed.

Animals↗
PubMed2003

Molecular cloning and endometrial expression of porcine amphiregulin.

The porcine amphiregulin gene was previously reported to be within the quantitative trait locus (QTL) for uterine capacity on chromosome 8. Because amphiregulin stimulates cell proliferation, the amphiregulin gene might be responsible for this QTL. The objectives of this study were to clone amphiregulin cDNA and compare endometrial expression of its mRNA in pregnant Meishan (M) and White composite (WC) pigs. We obtained two amphiregulin cDNAs, one with 1,221 bp and another with 1,109 bp. The 112 bp difference corresponded to exon 5 of the human amphiregulin gene, which codes for the cytoplasmic domain. Endometrial mRNA expression of amphiregulin was significantly lower in M pigs than in WC pigs during early pregnancy (day 15 - 40 of gestation). Amphiregulin mRNA expression in the endometrium of both M and WC pigs increased (P < 0.01) from days 15 to 20, decreased (P = 0.01) from days 20 to 30, and did not change between days 30 and 40. This may result in reduced amphiregulin protein production leading to the slower development of M conceptuses, contributing to greater uterine capacity and litter size in prolific Chinese M pigs. Porcine genomic sequences isolated from a bacterial artificial chromosome genomic library contained exon 5, suggesting that the deletion of exon 5 in the mRNA may be due to differential splicing. The amphiregulin gene consisted of six exons and five introns spanning 10.3 kb. Mol.

Amino Acid Sequence↗
PubMed2000

Genetic dissection of the syndrome X in the rat.

In 1988, Reaven used the term syndrome X to describe a relation between several disorders including hypertension, dyslipidemia, impaired glucose tolerance, obesity, and coronary heart disease. Despite a number of studies dealing with syndrome X, its genetic basis remains poorly understood. Regarding the complexity of this syndrome, it is important to use animal models developing the traits of the disease. Here we show a genetic dissection of syndrome X in the WOKW rat, an animal model of genetically determined syndrome X. We found a major quantitative trait locus (QTL) for glucose metabolism on chromosome 3 and further QTLs influencing obesity and body weight on chromosomes 1 and 5. Genetic determinants of dyslipidemia were mapped to chromosomes 4 and 17. In addition, suggestive linkage for serum insulin was found on chromosome 1 to the region previously shown to be associated with type-1 diabetes mellitus. This is the first study demonstrating independent genetic factors influencing traits of the syndrome X in the rat as well as a possible genetic relationships between syndrome X and diabetes mellitus. Moreover, regarding the close similarities between WOKW rat and human syndrome X, the study could help in a search of genetic factors involved in this complex metabolic disorder in human.

Animals↗
PubMed2003

New quantitative trait loci that contribute to cholesterol gallstone formation detected in an intercross of CAST/Ei and 129S1/SvImJ inbred mice.

Cholesterol gallstone formation is a response to interactions between multiple genes and environmental stimuli. To determine the subset of cholesterol gallstone susceptibility (Lith) genes possessed by strains CAST/Ei (susceptible) and 129S1/SvImJ (resistant), we conducted quantitative trait locus (QTL) analyses of an intercross between these strains. Parental strains and F(1) mice of both genders were evaluated for gallstone formation after consumption of a lithogenic diet for 8 wk. Gallstone susceptibility of strain CAST was predominantly due to cholesterol hypersecretion. Male intercross offspring were genotyped and phenotyped for cholesterol gallstone formation after consumption of the lithogenic diet for 10 wk. Linkage analysis was performed using PSEUDOMARKER software. One significant, new QTL was detected and named Lith13 [chromosome (Chr) 5, 30 cM]. Statistical analyses and QTL fine mapping suggest this QTL may comprise two closely linked loci. We confirmed the presence of Lith6 (Chr 6). Suggestive QTL were detected on Chrs 1, 2, 5, 14, and 16. The QTL on Chrs 2 and 16 confirmed previously identified, suggestive QTL. Therefore, they were named Lith12 (101 cM) and Lith14 (42 cM), respectively. We identified candidate genes based on known function and location and performed mRNA expression analyses using both parental strains and intercross progeny for preliminary evaluation of their contributions to gallstone formation. Cebpb (Lith12), Pparg (Lith6), and Slc21a1 (Lith6) displayed expression differences. Our work continues to demonstrate the genetic complexity and to elucidate the pathophysiology of cholesterol gallstone formation. It should facilitate the development of new approaches for treating this common human disorder.

Alleles↗
PubMed2003

Intersection tests for single marker QTL analysis can be more powerful than two marker QTL analysis.

BACKGROUND: It has been reported in the quantitative trait locus (QTL) literature that when testing for QTL location and effect, the statistical power supporting methodologies based on two markers and their estimated genetic map is higher than for the genetic map independent methodologies known as single marker analyses. Close examination of these reports reveals that the two marker approaches are more powerful than single marker analyses only in certain cases. Simulation studies are a commonly used tool to determine the behavior of test statistics under known conditions. We conducted a simulation study to assess the general behavior of an intersection test and a two marker test under a variety of conditions. The study was designed to reveal whether two marker tests are always more powerful than intersection tests, or whether there are cases when an intersection test may outperform the two marker approach.We present a reanalysis of a data set from a QTL study of ovariole number in Drosophila melanogaster. RESULTS: Our simulation study results show that there are situations where the single marker intersection test equals or outperforms the two marker test. The intersection test and the two marker test identify overlapping regions in the reanalysis of the Drosophila melanogaster data. The region identified is consistent with a regression based interval mapping analysis. CONCLUSION: We find that the intersection test is appropriate for analysis of QTL data. This approach has the advantage of simplicity and for certain situations supplies equivalent or more powerful results than a comparable two marker test.

Animals↗
PubMed2006

Heritability and genetic loci of fatty liver in familial combined hyperlipidemia.

VLDL overproduction, a process that is driven by an excess amount of hepatic fat, is a well-documented feature of familial combined hyperlipidemia (FCHL). The aims of this study were to investigate whether fatty liver, measured with ultrasound and as plasma alanine aminotransferase (ALT) levels, develops against a genetic background in FCHL and to identify chromosomal loci that are linked to these traits. In total, 157 FCHL family members and 20 spouses participated in this study. Radiological evidence of fatty liver was more prevalent not only in FCHL probands (40%) but also in their relatives (35%) compared with spouses (15%) (P < 0.05). Heritability calculations revealed that 20-36% of the variability in ALT levels could be attributed to genetic factors. Nonparametric quantitative trait locus (QTL) analysis revealed three significant (P < 0.001) loci with either the ultrasound or the ALT trait in the male sample: 1q42.3, 7p12-21, and 22p13-q11; none was found in the female sample or the entire group. Of these QTLs, the 7p region was consistent over time, because reanalysis with ALT levels that were determined during a visit 5 years earlier yielded similar results. This study shows that fatty liver is a heritable aspect of FCHL. Replication of particularly the 7p region is awaited.

Adult↗
PubMed2005

Power of in silico QTL mapping from phenotypic, pedigree, and marker data in a hybrid breeding program.

Most quantitative trait locus (QTL) mapping studies in plants have used designed mapping populations. As an alternative to traditional QTL mapping, in silico mapping via a mixed-model approach simultaneously exploits phenotypic, genotypic, and pedigree data already available in breeding programs. The statistical power of this in silico mapping method, however, remains unknown. Our objective was to evaluate the power of in silico mapping via a mixed-model approach in hybrid crops. We used maize (Zea mays L.) as a model species to study, by computer simulation, the influence of number of QTLs (20 or 80), heritability (0.40 or 0.70), number of markers (200 or 400), and sample size (600 or 2,400 hybrids). We found that the average power to detect QTLs ranged from 0.11 to 0.59 for a significance level of alpha=0.01, and from 0.01 to 0.47 for alpha=0.0001. The false discovery rate ranged from 0.22 to 0.74 for alpha=0.01, and from 0.05 to 0.46 for alpha=0.0001. As with designed mapping experiments, a large sample size, high marker density, high heritability, and small number of QTLs led to the highest power for in silico mapping via a mixed-model approach. The power to detect QTLs with large effects was greater than the power to detect QTL with small effects. We conclude that gene discovery in hybrid crops can be initiated by in silico mapping. Finding an acceptable compromise, however, between the power to detect QTL and the proportion of false QTL would be necessary.

Breeding↗
PubMed2003

Genetic analysis for diabetes in a new rat model of nonobese type 2 diabetes, Spontaneously Diabetic Torii rat.

The Spontaneously Diabetic Torii (SDT) rat has recently been established as a new rat model of nonobese type 2 diabetes. In this study, we characterized diabetic features in SDT rats, and performed quantitative trait locus (QTL) analysis for glucose intolerance using 319 male (BNxSDT)xSDT backcrosses. Male SDT rats exhibited glucose intolerance at 20 weeks, and spontaneously developed diabetes with the incidence of 100% at 38 weeks, and glucose intolerance is well associated with the development of diabetes. The QTL analysis identified three highly significant QTLs (Gisdt1, Gisdt2, and Gisdt3) for glucose intolerance on rat chromosomes 1, 2, and X, respectively. The SDT allele for these QTLs significantly exacerbated glucose intolerance. Furthermore, synergistic interactions among these QTLs were detected. These findings indicate that diabetic features in SDT rats are inherited as polygenic traits and that SDT rats would provide insights into genetics of human type 2 diabetes.

Age of Onset↗
PubMed2004

The effect of an imprecise map on interval mapping QTLs.

The statistical analysis of quantitative trait locus (QTL) experiments relies on the use of a linkage map of the markers genotyped. Such a map is, at best, a good estimate of the true map. Resources might be diverted into developing better marker maps or improved maps become available after the analysis, raising concerns over the original analysis. It is therefore important to understand the sensitivity of QTL analysis to map inaccuracy. We have used simulation methods to investigate the consequences of an incorrect map on the results of a QTL analysis using interval mapping. Backcross data sets were generated with a particular map and then analysed with both the correct map and incorrect maps. If the incorrect maps maintained the true linkage groups (i.e. no markers were incorrectly assigned to another linkage group), the accuracy of the map had little or no impact on the ability to detect QTLs, the true significance levels of the tests or the relative placement of QTLs. When a marker was incorrectly placed on another linkage group, there was a small increase in the level of the test. After adjusting for this increase, there was a decrease in power to detect a QTL near the misplaced marker. This decrease was of a similar magnitude to that found when using a single-marker analysis compared with interval mapping. These results mean that QTL analyses can proceed without the need for very accurate marker maps, and that estimated QTL positions can be translated onto updated maps without the need for reanalysis.

Chromosome Mapping↗