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PubMed2005

Evaluation of linkage disequilibrium measures between multi-allelic markers as predictors of linkage disequilibrium between markers and QTL.

Effectiveness of marker-assisted selection (MAS) and quantitative trait loci (QTL) mapping using population-wide linkage disequilibrium (LD) between markers and QTL depends on the extent of LD and how it declines with distance in a population. Because marker-QTL LD cannot be observed directly, the objective of this study was to evaluate alternative measures of observable LD between multi-allelic markers as predictors of usable LD of multi-allelic markers with presumed biallelic QTL. Observable LD between marker pairs was evaluated using eight existing measures and one new measure. These consisted of two pooled and standardized measures of LD between pairs of alleles at two markers based on Lewontin's LD measure, two pooled measures of squared correlations between alleles, one standardized measure using Hardy-Weinberg heterozygosities, and four measures based on the chi-square statistic for testing for association between alleles at two loci. In simulated populations with a range of LD generated by drift and a range of marker polymorphism, marker-marker LD measured by a standardized chi-square statistic (denoted chi(2')) was found to be the best predictor of useable marker-QTL LD for a group of multi-allelic markers. Estimates of the level and decline of marker-marker LD with distance obtained from chi(2') were linearly and highly correlated with usable LD of those markers with QTL across population structures and marker polymorphism. Corresponding relationships were poorer for the other marker-marker LD measures. Therefore, when LD is generated by drift, chi(2') is recommended to quantify the amount and extent of usable LD in a population for QTL mapping and MAS based on multi-allelic markers.

Alleles↗
PubMed2005

A QTL analysis of female variation contributing to refractoriness and sperm competition in Drosophila melanogaster.

Sperm competition is an important fitness component in many animal groups. Drosophila melanogaster males exhibit substantial genetic variation for sperm competitive ability and females show considerable genetic variation for first versus second male sperm use. Currently, the forces responsible for maintaining genetic variation in sperm competition related phenotypes are receiving much attention. While several candidate genes contributing to the variation seen in male competitive ability are known, genes involved in female sperm use remain largely undiscovered. Without knowledge of the underlying genes, it will be difficult to distinguish between different models of sexual selection such as cryptic female choice and sexual conflict. We used quantitative trait locus (QTL) mapping to identify regions of the genome contributing to female propensity to use first or second male sperm, female refractoriness to re-mating, and early-life fertility. The most well supported markers influencing the phenotypes include 33F/34A (P2), 57B (refractoriness) and 23F/24A (fertility). Between 10% and 15% of the phenotypic variance observed in these recombinant inbred lines was explained by these individual QTLs. More detailed investigation of the regions detected in this experiment may lead to the identification of genes responsible for the QTLs identified here.

Animals↗
PubMed2002

Interacting QTLs for cholesterol gallstones and gallbladder mucin in AKR and SWR strains of mice.

We employed quantitative trait locus (QTL) mapping in a backcross between gallstone-susceptible SWR/J and gallstone-resistant AKR/J inbred mice to identify additional susceptibility loci for cholesterol gallstone formation. After 12 wk of feeding the mice a lithogenic diet, we phenotyped 330 backcross progeny for gallstones, gallbladder mucin accumulation, liver weight, and body weight. Marker-based regression analysis revealed significant single QTLs associated with gallstone formation on chromosome 9 and the liver weight/body weight ratio on chromosomes 5 and X. A search for gene pairs detected significant gene-gene interactions for mucin accumulation between loci on chromosomes 5 and 11 and suggestive gene-gene interactions linked to gallstone formation between the QTL on chromosome 9 and loci on chromosomes 6 and 15. These findings uncover new QTLs for cholesterol gallstones, reveal independent loci for mucin accumulation, and demonstrate the importance of considering gene-gene interactions in cholesterol cholelithiasis. According to standard nomenclature, the gallstone QTL on chromosome 9 is named Lith5.

Animals↗
PubMed2003

Molecular studies of identification of genes for osteoporosis: the 2002 update.

We aim to give a comprehensive review, updated to 2002, of the most important and representative molecular genetic studies, performed mainly within the past decade, that aimed to identify the gene(s) involved in osteoporosis. Early reviews were largely confined to association studies in humans, but we review here, separately, the results of both association and linkage studies in humans, and quantitative trait locus (QTL) mapping in animal models. The main results of all the studies are tabulated for comparison and ease of reference, and to provide a comprehensive retrospective view of molecular genetics studies of osteoporosis. The most striking findings and the most representative studies are singled out for comment regarding the immediacy of their influence on present understanding of the genetics of osteoporosis and on the current status of genetic research in osteoporosis. This is particularly relevant for studies on the association of the vitamin D receptor (VDR) gene, for which there has been a large body of studies and reviews published. The format adopted by this review should be ideal for accommodating future new advances and studies in a fairly young field that is still developing rapidly.

Animals↗
PubMed2002

Identification and mapping of the QTL for aluminum tolerance introgressed from the new source, Oryza Rufipogon Griff., into indica rice (Oryza sativa L.).

This study was conducted to identify and map the quantitative trait locus (QTL) controlling Al tolerance in rice using molecular markers. A population of 171 F(6) recombinant inbred lines (RILs) derived from the cross of Oryza sativa (IR64), the Al susceptible parent, and Oryza rufipogon, the Al tolerant parent, was evaluated for Al tolerance using a nutrient solution with and without 40 ppm of active Al(+3). A genetic map, consisting of 151 molecular markers covering 1,755 cM with an average distance of 11.6 cM between loci, was constructed. Nine QTLs were dentified including one for root length under non-stress conditions (CRL), three for root length under Al stress (SRL) and five for relative root length (RRL). O. rufipogon contributed favorable alleles for each of the five QTLs for RRL, which is a primary parameter for Al tolerance, and individually they explained 9.0-24.9% of the phenotypic variation. Epistatic analysis revealed that CRL was conditioned by an epistatic effect, whereas SRL and RRL were controlled by additive effects. Comparative genetic analysis showed that QTLs for RRL, which mapped on chromosomes 1 and 9, appear to be consistent among different rice populations. Interestingly, a major QTL for RRL, which explained 24.9% of the phenotypic variation, was found on chromosome 3 of rice, which is conserved across cereal species. These results indicate the possibilities to use marker-assisted selection and pyramiding QTLs for enhancing Al tolerance in rice. Positional cloning of such QTLs introgressed from O. rufipogon will provide a better understanding of the Al tolerance mechanism in rice and the evolutionary genetics of plant adaptation to acid-soil conditions across cereal species.

Alleles↗
PubMed1997

Quantitative trait loci differentiating the outbreeding Mimulus guttatus from the inbreeding M. platycalyx.

Theoretical predictions about the evolution of selfing depend on the genetic architecture of loci controlling selfing (monogenic vs. polygenic determination, large vs. small effect of alleles, dominance vs. recessiveness), and studies of such architecture are lacking. We inferred the genetic basis of mating system differences between the outbreeding Mimulus guttatus and the inbreeding M. platycalyx by quantitative trait locus (QTL) mapping using random amplified polymorphic DNA and isozyme markers. One to three QTL were detected for each of five mating system characters, and each QTL explained 7.6-28.6% of the phenotypic variance. Taken together, QTL accounted for up to 38% of the variation in mating system characters, and a large proportion of variation was unaccounted for. Inferred QTL often affected more than one trait, contributing to the genetic correlation between those traits. These results are consistent with the hypothesis that quantitative variation in plant mating system characters is primarily controlled by loci with small effect.

Chromosome Mapping↗
PubMed2005

An expectation-maximization-likelihood-ratio test for handling missing data: application in experimental crosses.

The mapping of quantitative trait loci (QTL) is an important research question in animal and human studies. Missing data are common in such study settings, and ignoring such missing data may result in biased estimates of the genotypic effect and thus may eventually lead to errant results and incorrect inferences. In this article, we developed an expectation-maximization (EM)-likelihood-ratio test (LRT) in QTL mapping. Simulation studies based on two different types of phylogenetic models revealed that the EM-LRT, a statistical technique that uses EM-based parameter estimates in the presence of missing data, offers a greater statistical power compared with the ordinary analysis-of-variance (ANOVA)-based test, which discards incomplete data. We applied both the EM-LRT and the ANOVA-based test in a real data set collected from F2 intercross studies of inbred mouse strains. It was found that the EM-LRT makes an optimal use of the observed data and its advantages over the ANOVA F-test are more pronounced when more missing data are present. The EM-LRT method may have important implications in QTL mapping in experimental crosses.

Algorithms↗
PubMed2002

RFLP genetic linkage maps from four F(2.3) populations and a joinmap of Gossypium hirsutum L.

An RFLP genetic linkage joinmap was constructed from four different mapping populations of cotton ( Gossypium hirsutum L.). Genetic maps from two of the four populations have been previously reported. The third genetic map was constructed from 199 bulk-sampled plots of an F(2.3) (HQ95-6x'MD51ne') population. The map comprises 83 loci mapped to 24 linkage groups with an average distance between markers of 10.0 centiMorgan (cM), covering 830.1 cM or approximately 18% of the genome. The fourth genetic map was developed from 155 bulk-sampled plots of an F(2.3) (119- 5 sub-okrax'MD51ne') population. This map comprises 56 loci mapped to 16 linkage groups with an average distance between markers of 9.3 cM, covering 520.4 cM or approximately 11% of the cotton genome. A core of 104 cDNA probes was shared between populations, yielding 111 RFLP loci. The constructed genetic linkage joinmap from the above four populations comprises 284 loci mapped to 47 linkage groups with the average distance between markers of 5.3 cM, covering 1,502.6 cM or approximately 31% of the total recombinational length of the cotton genome. The linkage groups contained from 2 to 54 loci each and ranged in distance from 1.0 to 142.6 cM. The joinmap provided further knowledge of competitive chromosome arrangement, parental relationships, gene order, and increased the potential to map genes for the improvement of the cotton crop. This is the first genetic linkage joinmap assembled in G. hirsutum with a core of RFLP markers assayed on different genetic backgrounds of cotton populations (Acala, Delta, and Texas plain). Research is ongoing for the identification of quantitative trait loci for agronomic, physiological and fiber quality traits on these maps, and the identification of RFLP loci lineage for G. hirsutum from its diploid progenitors (the A and D genomes).

Journal Article↗
PubMed2006

QTL identification for early blight resistance (Alternaria solani) in a Solanum lycopersicum x S. arcanum cross.

Alternaria solani (Ellis and Martin) Sorauer, the causal agent of early blight (EB) disease, infects aerial parts of tomato at both seedling and adult plant stages. Resistant cultivars would facilitate a sustainable EB management. EB resistance is a quantitatively expressed character, a fact that has hampered effective breeding. In order to identify and estimate the effect of genes conditioning resistance to EB, a quantitative trait loci (QTL) mapping study was performed in F2 and F3 populations derived from the cross between the susceptible Solanum lycopersicum (syn. Lycopersicon esculentum) cv. 'Solentos' and the resistant Solanum arcanum (syn. Lycopersicon peruvianum) LA2157 and genotyped with AFLP, microsatellite and SNP markers. Two evaluation criteria of resistance were used: measurements of EB lesion growth on the F2 plants in glasshouse tests and visual ratings of EB severity on foliage of the F3 lines in a field test. A total of six QTL regions were mapped on chromosomes 1, 2, 5-7, and 9 with LOD scores ranging from 3.4 to 17.5. Three EB QTL also confer resistance to stem lesions in the field, which has not been reported before. All QTL displayed significant additive gene action; in some cases a dominance effect was found. Additive x additive epistatic interactions were detected between one pair of QTL. For two QTL, the susceptible parent contributed resistance alleles to both EB and stem lesion resistance. Three of the QTL showed an effect in all tests despite methodological and environmental differences.

Alternaria↗
PubMed2003

Genetic complementation in female (BXSB x NZW)F2 mice.

F(1) hybrids among New Zealand Black (NZB), New Zealand White (NZW), and BXSB lupus-prone strains develop accelerated autoimmunity in both sexes regardless of the specific combination. To identify BXSB susceptibility loci in the absence of the Y chromosome accelerator of autoimmunity (Yaa) and to study the genetics of this complementation, genome-wide quantitative trait locus (QTL) mapping was performed on female (BXSB x NZW)F(2) mice. Six QTL were identified on chromosomes 1, 4, 5, 6, 7, and 17. Survival mapped to chromosomes 5 and 17, anti-chromatin Ab to chromosomes 4 and 17, glomerulonephritis to chromosomes 6 and 17, and splenomegaly to chromosomes 1, 7, and 17. QTL on chromosomes 4 and 6 were new and designated as Lxw1 and -2, respectively. Two non-MHC QTL (chromosomes 1 and 4) were inherited from the BXSB and the rest were NZW-derived, including two similar to previously defined loci. Only two of 11 previously defined non-MHC BXSB QTL using male (Yaa(+)) crosses were implicated, suggesting that some male-defined BXSB QTL may require coexpression of the Yaa. Findings from this and other studies indicate that BXSB and NZB backgrounds contribute completely different sets of genes to complement NZW mice. Identification of susceptibility genes and complementing genes in several lupus-prone strain combinations will be important for defining the epistatic effects and background influences on the heterogeneous genetic factors responsible for lupus induction.

Animals↗
PubMed1993

Karyotype-phenotype correlations in autosomal chromosomal aberrations.

Karyotype phenotype correlation studies on the basis of clinical findings released the following consistent results. 1. Monosomy for an autosomal segment causes more and more severe alterations to the phenotype and restricts survival more than does trisomy for the same segment. The clinical pictures of monosomy versus trisomy for the same segment do not go into an opposite direction (the type-contratype approach). 2. For trisomy versus tetrasomy of a given autosomal segment, clinical pictures are principally similar, but tetrasomy leads to more severe alterations of the phenotype and to more restricted survival. Therefore, tetrasomy seems to allow for survival in only few segments, and often only in mosaic state. 3. Mapping of specific traits to the aneuploid segment of a specific chromosome region is partially successful. 3.1. For certain patterns of minor anomalies, the aneuploid segment can be narrowed down to a very short region. Both in trisomy and monosomy, these regions tend to be closer to the telomere. 3.2. Deletion mapping has allowed the mapping of a number of autosomal dominant gene mutations to small segments of a chromosome and hereby often gave the first hint towards the fine localization and cloning of these genes. Both deletion and duplication mapping have also shown associations of some congenital anomalies, mostly rarer malformations, to the aneuploid state of a small chromosome segment. The approach, however, has not been successful for most of the malformations frequent in many autosomal chromosome aberrations. 4. Comparison of congenital anomalies in monozygotic twins with autosomal chromosome aberrations revealed the following. 4.1. Monozygotic twins are highly concordant for patterns or minor anomalies. 4.2. Monozygotic twins tend to be concordant for rare congenital defects and malformations, but they are predominantly discordant for more common major malformations; the more undergrown twin is usually more severely affected. The latter finding might be explained by differences in placental blood supply between the twins during early embryogenesis, either due to different placental nutrition in general or to differences in secondary mutations in the placentas allowing for a better embryonic blood supply during organogenesis. 5. The data are in accordance with a multifactorial model for frequent congenital malformations in which placental function is the modifying environmental influence besides the action of more than one gene in aneuploid state.

Animals↗
PubMed2001

Genetic architecture of adiposity in the cross of LG/J and SM/J inbred mice.

The genetic basis of variation in obesity in human populations is thought to be owing to many genes of relatively small effect and their interactions. The LG/J by SM/J intercross of mouse inbred strains provides an excellent model system in which to investigate multigenic obesity. We previously mapped a large number of quantitative trait loci (QTLs) affecting adult body weight in this cross. We map body composition traits, adiposity, and skeletal size, in a replicate F2 intercross of the same two strains containing 510 individuals. Using interval-mapping methods, we located eight QTLs affecting adiposity (Adip1-8). Two of these adiposity loci also affected tail length (Adip4 and Adip6) along with seven additional tail length QTLs (Skl1-7). A further four QTLs (Wt1-4) affect adult weight but not body composition. These QTLs have relatively small effects, typically about 0.2-0.4 standard deviation units, and account for between 3% and 10% of the variance in individual characters. All QTLs participated in epistatic interactions with other QTLs. Most of these interactions were due to additive-by-additive epistasis, which can nullify the apparent effects of single loci in our population. Adip8 interacts with all the other adiposity QTLs and seems to play a central role in the genetic system affecting obesity in this cross. Only two adiposity QTLs, Adip4 and Adip6, also affect tail length, indicating largely separate genetic control of variation in adiposity and skeletal size. Body size and obesity QTLs in the same locations as those discovered here are commonly found in mapping experiments with other mouse strains.

Adipose Tissue↗
PubMed1999

A scan for linkage disequilibrium across the human genome.

Linkage disequilibrium (LD), the tendency for alleles of linked loci to co-occur nonrandomly on chromosomal haplotypes, is an increasingly useful phenomenon for (1) revealing historic perturbation of populations including founder effects, admixture, or incomplete selective sweeps; (2) estimating elapsed time since such events based on time-dependent decay of LD; and (3) disease and phenotype mapping, particularly for traits not amenable to traditional pedigree analysis. Because few descriptions of LD for most regions of the human genome exist, we searched the human genome for the amount and extent of LD among 5048 autosomal short tandem repeat polymorphism (STRP) loci ascertained as specific haplotypes in the European CEPH mapping families. Evidence is presented indicating that approximately 4% of STRP loci separated by <4.0 cM are in LD. The fraction of locus pairs within these intervals that display small Fisher's exact test (FET) probabilities is directly proportional to the inverse of recombination distance between them (1/cM). The distribution of LD is nonuniform on a chromosomal scale and in a marker density-independent fashion, with chromosomes 2, 15, and 18 being significantly different from the genome average. Furthermore, a stepwise (locus-by-locus) 5-cM sliding-window analysis across 22 autosomes revealed nine genomic regions (2.2-6.4 cM), where the frequency of small FET probabilities among loci was greater than or equal to that presented by the HLA on chromosome 6, a region known to have extensive LD. Although the spatial heterogeneity of LD we detect in Europeans is consistent with the operation of natural selection, absence of a formal test for such genomic scale data prevents eliminating neutral processes as the evolutionary origin of the LD.

Alleles↗
PubMed2001

Genetic loci determining bone density in mice with diet-induced atherosclerosis.

This study investigates the phenotypic and genetic relationships among bone-density-related traits and those of adipose tissue and plasma lipids in mice with diet-induced atherosclerosis. Sixteen-month-old female F2 progeny of a C57BL/6J and DBA/2J intercross, which had received an atherogenic diet for 4 mo, were examined for multiple measures of femoral bone mass, density, and biomechanical properties using both computerized tomographic and radiographic methods. In addition, body weight and length, adipose tissue mass, plasma lipids and insulin, and aortic fatty lesions were assessed. Bone mass was inversely correlated with extent of atherosclerosis and with a prooxidant lipid profile and directly correlated with body weight, length, and, most strongly, adipose tissue mass. Quantitative trait locus (QTL) analysis, using composite interval mapping (CIM) and multi-trait analysis, identified six loci with multi-trait CIM LOD scores > 5. Three of these coincided with loci linked with adipose tissue and plasma high-density lipoprotein. Application of statistical tests for distinguishing close linkage vs. pleiotropy supported the presence of a potential pleiotropic effect of two of the loci on these traits. This study shows that bone mass in older female mice with atherosclerosis has multiple genetic determinants and provides phenotypic and genetic evidence linking the regulation of bone density with adipose tissue and plasma lipids.

Adipose Tissue↗
PubMed2001

Genetic identification of a locus, Mot1, that affects renal tumor size in the rat.

Prognosis and treatment of solid tumors are directly dependent on the stage of disease. For any type of cancer, tumor characteristics such as size, multiplicity, and metastatic potential are highly heterogeneous among patients. Our understanding of the genetic determinants of tumor burden is rudimentary. Here, rats carrying a germline mutation of the gene Tsc2 were found to develop variable size and number of renal tumors. We hypothesize that "modifier" genes unlinked to Tsc2 affect its expressivity. Using a backcross (BC) analysis between the two strains that showed the greatest difference in tumor size (Fischer344 and Brown Norway), we mapped a quantitative trait locus based on tumor volume to rat chromosome 3q, lying in the interval between D3Mit3 and D3Rat17, with a maximum lod score of 4.4. This locus, Mot1 (modifier of Tsc2 1), accounts for approximately 35% of the genetic variation in tumor size between the two strains. No significant difference in tumor multiplicity was noted between Brown Norway and Fischer344 rats. This suggests that Mot1 modulates the rate of disease progression and not tumor initiation. Candidate genes on rat chromosome 3 included Tsc1, whose product interacts biochemically with the TSC2 protein, but it was excluded on the basis of linkage analysis (LOD=0.01). Comparative genomics suggest that the Mot1 region is represented by human chromosomes 15q and 20pq. Our results provide the first evidence of a modifier gene affecting the Tsc2 pathway in the progression of renal tumorigenesis.

Animals↗
PubMed2001

A dominant modifier of transgene methylation is mapped by QTL analysis to mouse chromosome 13.

The single-copy hepatitis B virus transgene in the E36 transgenic mouse strain undergoes methylation changes in a parent-of-origin, tissue, and strain-specific fashion. In a C57BL/6 background, the paternally transmitted transgene is methylated in 30% of cells, whereas it is methylated in more than 80% of cells in (BALB/c x C57BL/6) F1 mice. We established previously that several genetic factors were likely to contribute to the transgene methylation profile, some with demethylating and some with de novo methylating activities. Using quantitative trait loci (QTL) mapping, we have now localized one major modifier locus on chromosome 13 (Mod13), which explains a 30% increase in the methylation level of this transgene with no effect on the flanking endogenous sequences. No other QTL could be identified, except for a demethylating activity of low significance located on chromosome 12. Recombinant inbred mice containing a BALB/c allele of Mod13 were then used to show that the presence of Mod13 is sufficient to induce de novo methylation. A segregation between de novo methylation and repression of transgene expression was uncovered, suggesting that this genetic system is also useful for the identification of factors that interpret methylation patterns in the genome.

Animals↗
PubMed2006

Replication of small effect quantitative trait loci for behavioral traits facilitated by estimation of effect size from independent cohorts.

Quantitative trait locus (QTL) mapping is often done in a single segregating population, such as a backcross or an intercross. Both QTL location and effect size are then estimated from the same dataset. This approach results in an over-estimate of effect size for two reasons: (1) LOD scores, which are maximized over numerous point-wise tests, are correlated with estimated effect size and (2) small effect QTLs are often undetected in underpowered experiments, yielding inflated effect sizes for detected QTLs (the Beavis effect). When it is impractical to maintain or generate large population sizes, an alternative is to use two populations, one for initial detection and localization and a second for a locus-matched estimate of effect size, not conditioned on significance. Recombinant inbred (RI) panels are eminently suitable for this approach, as each strain genotype can be sampled repeatedly. We present mapping results from the LXS RI panel for two behavioral phenotypes relating to ethanol response: low-dose ethanol activation and loss of righting following high-dose injection. Both the phenotypes were measured in two or three independent cohorts, which were then used to re-estimate effect size. Many small-effect QTLs replicated using this approach, but in all cases, effect size, in the replicate cohorts, was reduced from the initial estimate, often substantially. Such a reduction will have important consequences for power analyses in which sample sizes are determined for subsequent confirmation studies.

Alcoholism↗
PubMed2005

Haplotype sharing analysis using mantel statistics.

OBJECTIVE: The potential value of haplotypes has attracted widespread interest in the mapping of complex traits. Haplotype sharing methods take the linkage disequilibrium information between multiple markers into account, and may have good power to detect predisposing genes. We present a new approach based on Mantel statistics for spacetime clustering, which is developed in order to improve the power of haplotype sharing analysis for gene mapping in complex disease. METHODS: The new statistic correlates genetic similarity and phenotypic similarity across pairs of haplotypes for case-only and case-control studies. The genetic similarity is measured as the shared length between haplotypes around a putative disease locus. The phenotypic similarity is measured as the mean-corrected cross-product based on the respective phenotypes. We analyzed two tests for statistical significance with respect to type I error: (1) assuming asymptotic normality, and (2) using a Monte Carlo permutation procedure. The results were compared to the chi(2) test for association based on 3-marker haplotypes. RESULTS: The results of the type I error rates for the Mantel statistics using the permutational procedure yielded pointwise valid tests. The approach based on the assumption of asymptotic normality was seriously liberal. CONCLUSION: Power comparisons showed that the Mantel statistics were better than or equal to the chi(2) test for all simulated disease models.

Case-Control Studies↗