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PubMed2006

A locus on mouse Chromosome 9 (Adip5) affects the relative weight of the gonadal but not retroperitoneal adipose depot.

To identify the gene or genes on mouse Chromosome 9 that contribute to strain differences in fatness, we conducted an expanded mapping analysis to better define the region where suggestive linkage was found, using the F(2 )generation of an intercross between the C57BL/6ByJ and 129P3/J mouse strains. Six traits were studied: the summed weight of two adipose depots, the weight of each depot, analyzed individually (the gonadal and retroperitoneal depot), and the weight of each depot (summed and individual) relative to body size. We found significant linkage (LOD = 4.6) that accounted for the relative weight of the summed adipose depots, and another for the relative weight of the gonadal (LOD = 5.3) but not retroperitoneal (LOD = 0.9) adipose depot. This linkage is near marker rs30280752 (61.1 Mb, Build 34) and probably is equivalent to the quantitative trait locus (QTL) Adip5. Because the causal gene is unknown, we identified and evaluated several candidates within the confidence interval with functional significance to the body fatness phenotype (Il18, Acat1, Cyp19a1, Crabp1, Man2c1, Neil1, Mpi1, Csk, Lsm16, Adpgk, Bbs4, Hexa, Thsd4, Dpp8, Anxa2, and Lipc). We conclude that the Adip5 locus is specific to the gonadal adipose depot and that a gene or genes near the linkage peak may account for this QTL.

Adipose Tissue↗
PubMed2006

Genetics of autoimmune diseases: a multistep process.

It has so far been difficult to identify genes behind polygenic autoimmune diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), and type I diabetes (T1D). With proper animal models, some of the complexity behind these diseases can be reduced. The use of linkage analysis and positional cloning of genes in animal models for RA resulted in the identification of one of the genes regulating severity of arthritis in rats and mice, the Ncf1 gene. The Ncf1 gene encodes for the Ncf1 protein that is involved in production of free oxygen radicals through the NADPH oxidase complex, which opens up a new pathway for therapeutic treatment of inflammatory diseases. In most cases, however, a quantitative trait locus (QTL) is the sum effect of several genes within and outside the QTL, which make positional cloning difficult. Here we will discuss the possibilities and difficulties of gene identification in animal models of autoimmune disorders.

Animals↗
PubMedDate not supplied

The contribution of epistatic pleiotropy to the genetic architecture of covariation among polygenic traits in mice.

The contribution that pleiotropic effects of individual loci make to covariation among traits is well understood theoretically and is becoming well documented empirically. However, little is known about the role of epistasis in determining patterns of covariation among traits. To address this problem we combine a quantitative trait locus (QTL) analysis with a two-locus model to assess the contribution of epistasis to the genetic architecture of variation and covariation of organ weights and limb bone lengths in a backcross population of mice created from the M16i and CAST/Ei strains. Significant epistasis was exhibited by 14 pairwise combinations of QTL for organ weights and 10 combinations of QTL for limb bone lengths, which contributed, on average, about 5% of the variation in organ weights and 8% in limb bone lengths beyond that of single-locus QTL effects. Epistatic pleiotropy was much more common in the limb bones (seven of 10 epistatic combinations affecting limb bone lengths were pleiotropic) than the organs (three of the 14 epistatic combinations affecting organ weights were pleiotropic). In both cases, epistatic pleiotropy was less common than single-locus pleiotropy. Epistatic pleiotropy accounted for an average of 6% of covariation among organ weights and 21% of covariation among limb bone lengths, which represented an average of one-fifth (for organ weights) and one-third (for limb bone lengths) of the total genetic covariance between traits. Thus, although epistatic pleiotropy made a smaller contribution than single-locus pleiotropy, it clearly made a significant contribution to the genetic architecture of variation/covariation.

Animals↗
PubMed2002

Characterisation of the mouse diabetes susceptibilty locus Nidd/SJL: islet cell destruction, interaction with the obesity QTL Nob1, and effect of dietary fat.

AIMS/HYPOTHESIS: The diabetes susceptibility locus Nidd/SJL was identified in an outcross of New Zealand obese (NZO) and lean Swiss/Jackson Laboratory mouse strain (SJL) mice. Here we characterise its effects in a NZO x F1(SJLxNZO) backcross population raised on high-fat or standard diet, and describe its interaction with the obesity quantitative trait locus (QTL) Nob1. METHODS: NZO x F1(SJLxNZO) backcross mice were raised on a normal or high fat diet and were monitored (body weight, blood glucose, serum insulin) for 22 weeks. Genotypes of polymorphic markers were determined by PCR, and linkage analysis was done. Pancreas morphology was assessed by conventional staining and immunohistochemistry of insulin. RESULTS: In backcross mice raised on a high-fat diet, Nidd/SJL produced hyperglycaemia (maximum likelihood of the odds (LOD) score 9.9), hypoinsulinaemia, reduction of islet-cell volume, and loss of beta cells. No effect was observed on body weight and serum insulin concentrations before the onset of hyperglycaemia. The development of diabetes in carriers of Nidd/SJL was markedly accelerated and aggravated by the obesity/hyperinsulinaemia QTL Nob1; together, these loci were responsible for approximately 90% of the diabetes observed in the backcross population. When raised on a standard diet, Nidd/SJL carriers exhibited a fivefold higher prevalence of diabetes, but Nob1 failed to enhance the effect of Nidd/SJL. CONCLUSION/INTERPRETATION: Diabetes in this obese mouse model is the result of an interaction of genes responsible for obesity/insulin resistance (e.g. Nob1) and islet cell failure ( Nidd/SJL). The combined diabetogenic effects of Nidd/SJL and Nob1 were markedly enhanced by a high-fat diet, whereas that of Nidd/SJL alone was independent of the dietary fat content.

Animals↗
PubMed2004

Mapping of quantitative trait loci (QTLs) affecting autumn freezing resistance and phenology in Salix.

Quantitative trait locus (QTL) analysis was performed at different time points during cold-acclimation of a tetraploid F(2 ) Salix pedigree. The pedigree ( n=92) was derived from a cross between a frost-susceptible diploid female clone 'Jorunn' ( Salix viminalis) and a frost resistant hexaploid male clone 'SW901290' ( Salix dasyclados). Freezing resistance, height growth increment and number of new leaves were assessed at days 0, 12, 20, 24, 31 and 42 of a short day-low temperature (SD-LT) hardening regime, while the initiation of shoot tip abscission and shoot tip abscission were measured daily. Height increment, dry-to-fresh weight ratio and number of new leaves were also measured in a replicated field trial. Freezing resistance was determined from electrolyte leakage of leaf tissues and from visual injuries on stem segments, after exposure to a predetermined freeze-thaw stress. Using a genetic map of the F(2) composed of 432 single-dose AFLP markers, a total of 19 genomic regions controlling freezing resistance (10) and phenological traits (9) before and during cold-acclimation (SD-LT) were identified. The magnitude of the phenotypic variation explained by each freezing resistance locus varied over acclimation time (0-45%), and there was no time point at which all the QTLs could be detected. The single QTL detected for non-acclimated freezing resistance did not reach significance at any time point during cold-acclimation, suggesting an independent genetic relationship between non-acclimated and acclimated resistance to freezing in Salix. Five of the loci associated with freezing resistance shared common intervals with loci controlling phenological traits. Of the 14 QTLs controlling autumn freezing resistance and/or phenological traits in the indoors experiment, six (43%) were associated with autumn phenology-related traits, i.e. height increment, dry-to-fresh weight ratio and number of new leaves, measured in the field. A major locus with multi-trait association in both indoor and outdoor experiments was detected.

Acclimatization↗
PubMed1998

New genetic concepts in hypertensive cardiovascular disease.

Hypertension is a complex quantitative trait under polygenic control. The identification of genes responsible for high blood pressure is of major importance, because it provides a mechanistic classification of the common phenotype and guide therapy tailored to the underlying primary abnormality. Experimental studies have identified several quantitative trait loci for blood pressure and other cardiovascular phenotypes. Further strategies that include congenic and subcongenic lines should ultimately lead to positional cloning of the causative genes, but this final step remains elusive at present. Human studies have focused on the rare Mendelian forms of human hypertension or candidate gene studies. Moreover, two recent examples show direct translation of a candidate gene and a quantitative trait locus from the experimental setting to human investigation. These strategies, together with new molecular genetic tools, will ultimately result in the identification of major genes contributing to human essential hypertension.

Animals↗
PubMed2003

Parametric and nonparametric genome scan analyses for human handedness.

We have performed a genome scan using 25 nuclear families consisting of right-handed parents with at least two left-handed children. Handedness was assessed as a qualitative trait using a laterality quotient. Laterality quotients indicate the direction of handedness, which is hand preference for performing unimanual tasks. Both parametric and nonparametric linkage analyses were applied. The parametric analysis using the single-locus genetic model of Klar resulted in four different regions with LOD scores higher than 1. The region on chromosome 10q26 gave a suggestive LOD score of 2.02 at a recombination fraction of 0.05. Nonparametric analysis gave an NPL score for this region of 2.16. However, further fine mapping of the region on chromosome 10q26 failed to obtain a higher LOD score. These results suggest that handedness is a human quantitative trait locus and that the proposed non-Mendelian monogenic models are incorrect.

Adult↗
PubMed2005

Loci controlling partial resistance to rice blast do not show marked QTL x environment interaction when plant nitrogen status alters disease severity.

Plant disease susceptibility is often increased by nitrogen (N) application. Therefore, it is important to know if resistance loci are effective in different plant N environments. One-hundred lines of the Bala x Azucena rice (Oryza sativa) mapping population were grown in two N treatments and tested for partial resistance to blast (Magnaporthe grisea) isolate CD100. Disease severity (DS), the number and size of lesions and plant N and C concentrations were measured and the results subject to quantitative trait loci (QTL) and QTL x environment analysis. There was a 66% higher plant N concentration in the high N treatment and DS increased significantly, mostly as a result of increased numbers of lesions. Nine regions contained QTL for disease traits but only one showed evidence of statistically significant QTL x treatment interaction. This was a large effect quantitative trait locus at marker R1933 on chromosome 12 which was less effective at high N. Apparently, blast disease is increased by higher plant N, but the efficacy of partial resistance genes is not greatly affected by N application.

Chromosome Mapping↗
PubMed2006

PolymiRTS Database: linking polymorphisms in microRNA target sites with complex traits.

Polymorphism in microRNA Target Site (PolymiRTS) database is a collection of naturally occurring DNA variations in putative microRNA target sites. PolymiRTSs may affect gene expression and cause variations in complex phenotypes. The database integrates sequence polymorphism, phenotype and expression microarray data, and characterizes PolymiRTSs as potential candidates responsible for the quantitative trait locus (QTL) effects. It is a resource for studying PolymiRTSs and their implications in phenotypic variations. PolymiRTS database can be accessed at http://compbio.utmem.edu/miRSNP/.

Animals↗
PubMed2000

Fine mapping and characterization of candidate lung tumor resistance genes for the Par2 locus on mouse chromosome 18.

In a number of recent studies, a lung tumor resistance locus designated either Par2 or Pas7 was mapped to distal chromosome 18 in crosses between susceptible A/J and more resistant BALB/c mice. This locus is important in that it accounts for as much as 60% of the difference in lung tumor susceptibility between the A/J and BALB/c mice, both of which contain the susceptible allele of Kras2, a marker and strong candidate for the major lung tumor susceptibility gene on mouse chromosome 6. We have now fine-mapped the Par2 locus by using congenic mice that were constructed by placing part of chromosome 18 from the susceptible A/J onto the genetic background of lung tumor-resistant BALB/c mice. After 7 generations of backcrossing, N7 mice that carried 28 cM of the A/J quantitative trait locus (QTL) region were crossed to the BALB/c to generate the N8 generation. Congenic strains (N8) that contain various QTL regions were generated. N9 mice, generated from N8 males x 3 BALB/c females, were genotyped in the region of the Par2 locus and treated with an initiating dose of urethane and allowed to form lung tumors over 6 months. The mice were killed and the lung tumors counted. With this cross the Par2 locus was narrowed to a 6-cM region. Potential candidate genes in this region include Smad4, Smad2, and Dcc. Previously, we excluded Smad4 and Smad2 as candidates for Par2 based on the lack of functional polymorphism(s) and differential expression in lungs from A/J and BALB/c mice. In this study, no polymorphism of the coding sequence of Dcc was observed between A/J and BALB/c mice. Further fine mapping and positional cloning are required for the identification of the Par2 gene.

Adenoma↗
PubMed2002

Erythrocyte sodium-lithium countertransport and blood pressure: a genome-wide linkage study.

Increased activity of erythrocyte sodium-lithium countertransport is associated with essential hypertension. Sodium-lithium countertransport is highly heritable, but no single gene product mediating the exchange or explaining the association of increased sodium-lithium countertransport activity and hypertension has been identified. We performed a linkage study by using erythrocyte sodium-lithium countertransport as a quantitative phenotype and genome-wide markers at an average resolution of approximately 10 cM to identify quantitative trait loci explaining sodium-lithium countertransport activity. A peak LOD score of 2.83 was detected on chromosome 15q at D15S642, a marker previously shown to be linked to blood pressure. Several genes mapped to this region are possible candidates for factors affecting erythrocyte sodium-lithium countertransport and/or blood pressure. Further studies confirming the presence of a quantitative trait locus in this region and evaluating these candidate genes may help explain the association of elevated sodium-lithium countertransport and hypertension.

Adult↗
PubMed1997

[Preparation of new microsatellite markers of rat chromosome 10 in the region, containing genes regulating blood pressure level].

Primer walking is a simple and efficient technique to find new microsatellites in the regions adjacent to known sequences. The method was applied to obtaining new microsatellite markers for rat chromosome 10 in the region of a blood pressure quantitative trait locus. Eight microsatellites were found, five of them were polymorphic in at least one population used for mapping. Improved genetic maps of this region for F2(SxMNS) and F2(SxLEW) populatons were constructed.

Animals↗
PubMed2006

A resistance-like gene identified by EST mapping and its association with a QTL controlling Fusarium head blight infection on wheat chromosome 3BS.

Fusarium head blight (FHB) is a major disease in the wheat growing regions of the world. A quantitative trait locus (QTL) on the short arm of chromosome 3B controls much of the variation for resistance. The cloning of candidate disease-resistance genes for FHB QTLs on chromosome 3B can provide further elucidation of the mechanisms that control resistance. However, rearrangements and divergence during plant genome evolution often hampers the identification of sequences with similarity to known disease-resistance genes. This study focuses on the use of wheat expressed sequence tags (ESTs) that map to the region on chromosome 3B containing the QTL for FHB resistance and low-stringency BLAST searching to identify sequences with similarity to known disease-resistance genes. One EST rich with leucine repeats and low similarity to a protein kinase domain of the barley Rpg1 gene was identified. Genetic mapping using a Ning894037 x Alondra recombinant inbred (RI) population showed that this EST mapped to the QTL on the short arm of chromosome 3B and may represent a portion of a newly diverged gene contributing to FHB resistance. The EST is a new marker suitable for marker-assisted selection and provides a starting point to begin map-based cloning for chromosome walking and investigate new diverged genes at this locus.

Amino Acid Sequence↗
PubMed2004

A genomewide search using an original pairwise sampling approach for large genealogies identifies a new locus for total and low-density lipoprotein cholesterol in two genetically differentiated isolates of Sardinia.

A powerful approach to mapping the genes for complex traits is to study isolated founder populations, in which genetic heterogeneity and environmental noise are likely to be reduced and in which extended genealogical data are often available. Using graph theory, we applied an approach that involved sampling from the large number of pairwise relationships present in an extended genealogy to reconstruct sets of subpedigrees that maximize the useful information for linkage mapping while minimizing calculation burden. We investigated, through simulation, the properties of the different sets in terms of bias in identity-by-descent (IBD) estimation and power decrease under various genetic models. We applied this approach to a small isolated population from Sardinia, the village of Talana, consisting of a unique large and complex pedigree, and performed a genomewide search through variance-components linkage analysis for serum lipid levels. We identified a region of significant linkage on chromosome 2 for total serum cholesterol and low-density lipoprotein (LDL) cholesterol. Through higher-density mapping, we obtained an increased linkage for both traits on 2q21.2-q24.1, with a LOD score of 4.3 for total serum cholesterol and of 3.9 for LDL cholesterol. A replication study was performed in an independent and larger set from a genetically differentiated isolated population of the same region of Sardinia, the village of Perdasdefogu. We obtained consistent linkage to the region for total serum cholesterol (LOD score 1.4) and LDL cholesterol (LOD score 2.2), with a level of concordance uncommon for complex traits, and refined the location of the quantitative-trait locus. Interestingly, the 2q21.1-22 region has also been linked to premature coronary heart disease in Finns, and, in the adjacent 2q14 region, significant linkage with triglycerides has been reported in Hutterites.

Cholesterol↗
PubMed2005

Marker-assisted selection to introgress rice QTLs controlling root traits into an Indian upland rice variety.

A marker-assisted back-crossing (MABC) breeding programme was conducted to improve the root morphological traits, and thereby drought tolerance, of the Indian upland rice variety, Kalinga III. This variety, the recurrent parent in the MABC, had not previously been used for quantitative trait locus (QTL) mapping. The donor parent was Azucena, an upland japonica variety from Philippines. Five segments on different chromosomes were targeted for introgression; four segments carried QTLs for improved root morphological traits (root length and thickness) and the fifth carried a recessive QTL for aroma. Some selection was made at non-target regions for recurrent parent alleles. We describe the selection made in three backcross (BC) generations and two further crosses between BC3 lines to pyramid (stack) all five target segments. Pyramids with four root QTLs were obtained in eight generations, completed in 6 years using 3,000 marker assays in a total of 323 lines. Twenty-two near-isogenic lines (NILs) were evaluated for root traits in five field experiments in Bangalore, India. The target segment on chromosome 9 (RM242-RM201) significantly increased root length under both irrigated and drought stress treatments, confirming that this root length QTL from Azucena functions in a novel genetic background. No significant effects on root length were found at the other four targets. Azucena alleles at the locus RM248 (below the target root QTL on chromosome 7) delayed flowering. Selection for the recurrent parent allele at this locus produced early-flowering NILs that were suited for upland environments in eastern India.

Chromosomes, Plant↗
PubMed2005

Genetic mapping of a cross between Gossypium hirsutum (cotton) and the Hawaiian endemic, Gossypium tomentosum.

The existence of five tetraploid species that derive from a common polyploidization event about 1 million years ago makes Gossypium (cotton) an attractive genus in which to study polyploid evolution and offers opportunities for crop improvement through introgression. To date, only crosses (HB) between the cultivated tetraploid cottons Gossypium hirsutum and G. barbadense have been genetically mapped. Genetic analysis of a cross (HT) between G. hirsutum and the Hawaiian endemic G. tomentosum is reported here. Overall, chromosomal lengths are closely correlated between the HB and HT maps, although there is generally more recombination in HT, consistent with a closer relationship between the two species. Interspecific differences in local recombination rates are observed, perhaps involving a number of possible factors. Our data corroborate cytogenetic evidence that chromosome arm translocations have not played a role in the divergence of polyploid cottons. However, one terminal inversion on chromosome (chr.) 3 does appear to differentiate G. tomentosum from G. barbadense; a few other apparent differences in marker order fall near gaps in the HT map and/or lack the suppression of recombination expected of inversions, and thus remain uncertain. Genetic analysis of a discrete trait that is characteristic of G. tomentosum, nectarilessness, mapped not to the classically reported location on chr. 12 but to the homoeologous location on chr. 26. We propose some hypotheses for further study to explore this incongruity. Preliminary quantitative trait locus (QTL) analysis of this small population, albeit with a high probability of false negatives, suggests a different genetic control of leaf morphology in HT than in HB, which also warrants further investigation.

Chromosome Mapping↗
PubMed2001

Cost of linkage versus association methods.

Identifying genetic factors that influence disease risk is a major goal in genetic epidemiology. In the past, for disease with relatively simple etiology, genetic linkage methods have been highly effective for this purpose. However, as we begin to study more complex diseases and disorders for which each specific genetic factor may play a minor role in causation, the relative values of genetic linkage methods that do not require linkage disequilibrium versus association-based methods that do require linkage disequilibrium must be evaluated. Here, we compare the cost-effectiveness of linkage and association methods for identifying genetic factors for a quantitative trait locus that explains 10% of interindividual variability. We find that the choice of analytical scheme depends upon the degree of disequilibrium in the population. Because this parameter has not been adequately assessed, planning association studies is currently difficult.

Analysis of Variance↗
PubMed2025

Association of AGER genetic variants with chronic obstructive pulmonary disease susceptibility in Southern Chinese Han populations.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) remains a leading cause of disability and mortality among elderly populations. Studies indicate that AGER plays a critical regulatory role in the pathogenesis of respiratory disorders. However, the genetic variations in AGER to COPD susceptibility remain incompletely understood. This study employs a case-control design to investigate associations between AGER genetic variants and COPD risk in the Southern Chinese Han population. METHODS: This study enrolled 270 COPD patients and 271 healthy controls. AGER single-nucleotide polymorphisms (SNPs) were analysed using the MassARRAY iPLEX platform. Logistic regression models evaluated associations between AGER polymorphisms and COPD susceptibility, with false discovery rate (FDR) correction applied to mitigate multiple testing errors. SNP-SNP interactions were investigated through multifactor dimensionality reduction (MDR) analysis. Expression quantitative trait locus (eQTL) data from the GTEx database were further analysed to assess regulatory relationships between SNPs and AGER gene expression levels. RESULTS: This study showed that rs3134941 (G allele, OR = 0.21, 95% CI = 0.10-0.41, p (FDR) = 0.001) and rs3131300 (G allele, OR = 0.32, 95% CI = 0.20-0.49, p (FDR) = 0.0001) were significantly associated with a reduced susceptibility to COPD. MDR indicated that rs3131300 was the optimal predictive model for COPD risk. Additionally, initial mechanistic investigations utilizing the GTEx database identify rs3134941 (C > G) and rs3131300 (A > G) as significant expression quantitative trait loci for AGER mRNA in cell-cultured fibroblasts and whole blood. CONCLUSION: Our study demonstrated that AGER genetic variants might play a protective role in the progression of COPD.

Aged↗