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PubMed1999

Utilization of gene mapping information in livestock animals.

A number of recent advances in genomic research will change and improve livestock production in the near future. Genetic linkage maps have been developed for a number of livestock species including cattle, sheep, and pigs. These maps allow scientists to identify chromosomal regions that influence traits of economic importance. This information will lead to improved genetic selection practices by identifying animals with superior copies of the chromosomal regions that affect the selected trait. This mapping information will also be used to identify the genes controlling the trait. A number of genomic regions or loci have already been reported that affect production, carcass or disease traits, and in a few cases, a specific gene has been identified. Production of transgenic animals with sequence changes in these genes may be beneficial for evaluating the effect of the gene upon the selected trait and more specifically the effect of certain polymorphisms (mutations) within the gene.

Animals↗
PubMed2005

Atherosclerosis quantitative trait loci are sex- and lineage-dependent in an intercross of C57BL/6 and FVB/N low-density lipoprotein receptor-/- mice.

Atherosclerosis is a complex disease that is affected by environmental as well as genetic factors. The aim of the present study was to identify loci of atherosclerosis susceptibility in a cross of atherosclerosis-susceptible C57BL/6 and atherosclerosis-resistant FVB/N mice on the low-density lipoprotein (LDL) receptor (LDLR)-deficient background (LDLR(-/-)) and to test whether these loci are affected by lineage. A total of 459 F(2)s were generated in two ways: In cross "mB6xfFVB," male B6.LDLR(-/-) mice were crossed to female FVB.LDLR(-/-) mice to generate 107 female and 112 male F(2)s. In cross "mFVBxfB6," male FVB.LDLR(-/-) mice were crossed to female B6.LDLR(-/-) mice to generate 120 female and 120 male F(2)s. Animals were phenotyped for cross-sectional atherosclerotic lesion area at the aortic root, and a genome scan was carried out with 192 microsatellite markers. Quantitative trait locus mapping revealed significant loci of atherosclerosis susceptibility on chromosomes 3, 10, and 12. On chromosome 10 maximal logarithm of odds (LOD) scores of 13.1 (D10Mit16, 16 cM) and 5.7 (D10Mit168, 9 cM) were found in female and male mice, respectively. On chromosome 3, a maximal LOD score of 5.1 (D3Mit45, 79 cM) was detected only in females. On proximal chromosome 12 significant LOD scores were lineage-dependent, with maximal LOD scores of 3.9 (D12Mit82, 3 cM) and 4.8 (D12Mit189, 24 cM) present only in female mice of cross mB6xfFVB and male mice of cross mFVBxfB6, respectively. We conclude that, in this intercross, loci of atherosclerosis susceptibility are in part sex- and lineage-dependent. Awareness of these complexities may have major consequences for the identification of atherosclerosis susceptibility genes by quantitative trait locus mapping.

Animals↗
PubMed2005

Strategies for mapping and cloning quantitative trait genes in rodents.

Over the past 15 years, more than 2,000 quantitative trait loci (QTLs) have been identified in crosses between inbred strains of mice and rats, but less than 1% have been characterized at a molecular level. However, new resources, such as chromosome substitution strains and the proposed Collaborative Cross, together with new analytical tools, including probabilistic ancestral haplotype reconstruction in outbred mice, Yin-Yang crosses and in silico analysis of sequence variants in many inbred strains, could make QTL cloning tractable. We review the potential of these strategies to identify genes that underlie QTLs in rodents.

Animals↗
PubMed2005

Linkage mapping of a complex trait in the New York population of the GAW14 simulated dataset: a multivariate phenotype approach.

Multivariate phenotypes underlie complex traits. Thus, instead of using the end-point trait, it may be statistically more powerful to use a multivariate phenotype correlated to the end-point trait for detecting linkage. In this study, we develop a reverse regression method to analyze linkage of Kofendrerd Personality Disorder affection status in the New York population of the Genetic Analysis Workshop 14 (GAW14) simulated dataset. When we used the multivariate phenotype, we obtained significant evidence of linkage near four of the six putative loci in at least 25% of the replicates. On the other hand, the linkage analysis based on Kofendrerd Personality Disorder status as a phenotype produced significant findings only near two of the loci and in a smaller proportion of replicates.

Chromosome Mapping↗
PubMed2000

Least squares estimation of variance components for linkage.

We develop least squares (LS) procedures for variance components estimation in genetic linkage studies. The LS procedure is expressed by simple expressions, and does not require inversion of large matrices. Simulations comparing LS with maximum likelihood (ML) procedures for normal data show that both yield unbiased estimators, but the efficiency of the LS procedure was less than 50% of the ML procedure. For bivariate normal data, the efficiency of the LS procedure relative to the ML method was better, generally over 60%. For skewed data, the LS method was markedly more efficient than ML for parameter estimation. The LS method was computationally rapid, over 4,000 times faster than ML estimation for bivariate data. Because ML estimation is time consuming, LS methods are suggested for initial interval mapping with multivariate data.

Computer Simulation↗
PubMed1997

Cost-effective sib-pair designs in the mapping of quantitative-trait loci.

The extreme discordant-sib-pair design has been found to be the most powerful, across most genetic models. In this paper, we address two of the most frequently asked questions related to this design. First, under the extreme discordant-sib-pair design, a large number of people have to be screened for the phenotype of interest, before the desired number of discordant sibs can be collected for genotyping and linkage analysis. When the phenotyping cost is not negligible compared with the genotyping cost, such methods might not be cost effective. The second question is how sensitive the cost is to the genetic model and allele frequency. In this paper, we compare the cost under different sampling strategies, different genetic models, and different phenotyping:genotyping cost ratios. Because our knowledge of the underlying genetic model for a trait is limited, the discordant-sib-pair design proves to be the most robust. When the cost for screening probands is not included, the design that genotypes sibs with one sib in the top 10% and the other sib in the bottom 30% of the population with respect to the trait of interest is, across most models studied, the optimum among the designs considered in this paper. The cost under this design, across different genetic models, appears to be relatively robust to allele frequency and model type, whether additive or dominant. If probands initially must be screened as well, then 25% appears to be the optimal portions of the upper and lower distributions to be studied.

Chromosome Mapping↗
PubMed2006

Refined association mapping for a quantitative trait: weight in the H19-IGF2-INS-TH region.

Previous analyses have provided evidence for one or more loci affecting body weight in the H19-IGF2-INS-TH region on chromosome 11p15. To identify the location of a possible causal locus or loci we applied association analysis by composite likelihood to a large cohort under the Malecot model for body weight. A random sample of 2731 men in the UK were typed for eleven single nucleotide polymorphisms (SNPs) in IGF2, two SNPs in H19, one SNP in INS and one microsatellite marker in the TH genes. Using F tests appropriate to small marker sets, the superiority of regression over correlation was confirmed. All the evidence for association came from IGF2, with P= 0.007 for height-adjusted weight and P= 0.019 for weight additionally adjusted for smoking and alcohol drinking. Although the estimated point location for the suspected causal variant was close to IGF2 ApaI, the 95% confidence and support intervals covered most of IGF2 but none of the other loci. Identification of the causal SNP or SNPs within IGF2 will require typing of more variants in this region.

Body Mass Index↗
PubMed2004

Quantitative trait loci affecting health traits in Swedish dairy cattle.

The purpose of this study was to map quantitative trait loci (QTL) affecting health traits in Swedish dairy cattle. A genome scan covering 17 chromosomes was performed. Ten grandsire families were used in a granddaughter design. Nine of the families belonged to the Swedish Red and White breed, which is related to other Nordic Ayrshire breeds, and one family was of the Swedish Holstein breed. A total of 417 bulls were genotyped for 116 microsatellite markers distributed over 17 chromosomes. Daughter yield deviations for clinical mastitis, somatic cell count (SCC), and other diseases (OD) were included in the analysis. Least squares interval mapping using putative QTL as cofactors was applied both within and across grandsire families. Significance thresholds were set by permutation tests. In the across-family analysis, we detected 8 suggestive QTL and 3 QTL significant at the genome level. The QTL affecting clinical mastitis were found on 3 chromosomes (9, 11, and 25), 4 QTL for SCC were found (on chromosomes 5, 9, 11, and 23), and we detected 4 QTL for OD (on chromosomes 9, 11, 15, and 25). In addition, we found several QTL that segregated within single families but where the QTL effect was not significant in the across-family analysis. In conclusion, we were able to locate QTL for all 3 analyzed traits, and overlapping QTL for several traits were observed.

Animals↗
PubMed2003

Summary report: Missing data and pedigree and genotyping errors.

Genetic epidemiology is faced with mapping complex traits to genes with relatively small effects whose phenotypes may be modulated by temporal factors. To do this, detailed and accurate data must be available on families, perhaps collected over time. The Framingham Heart Study data supplied to Genetic Analysis Workshop 13 (GAW13), along with its simulated counterpart, contain longitudinal measurements and genomic scan data on 2,885 individuals in 330 families, and offer an opportunity to examine data quality and completeness issues as they affect analytical conclusions. Six GAW13 contributions applied methods to deal with missing data, both phenotypic and genotypic, at a single time point and longitudinally, and with possible errors in pedigree structure and genotypes. The methods included missing phenotypic data imputation by Markov chain Monte Carlo sampling, propensity scoring, regression, and adjusted mean values, as well as the assessment of transmission-disequilibrium tests when missing marker data may be allele-specific. Pedigree structural errors were found by genome-wide allele-sharing probabilities, while Mendelian consistent genotype errors were evaluated through likelihoods of double-recombination events. Each of the methods reviewed here offered insights into how to better take advantage of large, time-dependent, familial data sets. However, no one of them dealt with the longitudinal and familial aspects simultaneously. Overall, more consideration needs to be given to the effects that missing data and data errors have on our ability to map complex traits efficiently and accurately.

Cardiovascular Diseases↗
PubMed1996

Using discordant sib pairs to map loci for qualitative traits with high sibling recurrence risk.

A common approach for detecting genetic linkage using siblings is to collect affected sib pairs (ASPs) and to identify markers where allele sharing exceeds expectation. Alternatively, markers can be analyzed in discordant sib pairs (DSPs) for allele sharing below expectation. Relative to the ASP approach, according to Risch, the power of the DSP approach increases with sibling recurrence risk, the two approaches being equally effective at 50% recurrence risk. However, with many diseases associated with more moderate sibling recurrence risk, less emphasis has been placed on the use of DSPs and the development of the underlying theory. In this paper, we expand the work of Risch to provide a more general foundation for DSP studies, since power can be quite high under the appropriate conditions. For example, in some highly affected populations, such as the diabetes-prone Pima Indians, sibling recurrence risk can be very large and, thus, DSPs ideal. Similarly, as we show through simulation, DSPs are preferable for diabetic nephropathy due to a 70% recurrence rate among siblings with insulin-dependent diabetes mellitus. Following the diabetic nephropathy example, we consider more systematically the situations in which DSPs can provide an efficient alternative to ASPs.

Alleles↗
PubMed2006

A quantitative trait loci analysis to map genes involved in lipopolysaccharide-induced inflammatory response: identification of macrophage scavenger receptor 1 as a candidate gene.

Septic shock, which is a major complication observed after trauma and other human diseases, is likely the product of a prolonged and poorly controlled systemic inflammatory response. Symptoms of sepsis can be partially reproduced by injection of bacterial LPS in mice. Differences in mortality between C57BL/6J(high) and A/J(low) mice after LPS injection have been previously observed and correlated with differences in the inflammatory response between these two inbred strains. In the present study, we have mapped four loci responsible for differences in levels of LPS-induced IL-10, named modifier of IL-10, between the two strains. A locus within mouse chromosome 8 was confirmed using chromosome 8 consomic mice. This locus was further reduced in size by haplotype analysis and evaluated by the presence of potential candidate genes. The macrophage scavenger receptor 1 (Msr1) within this locus emerged as a candidate gene based on differences at the expression and structural levels between C57BL/6J and A/J mice. In comparison with wild-type (C57BL/6J) mice, Msr1 knockout mice displayed reduced levels of LPS-induced IL-10, but not of TNF-alpha or IL-6, confirming a specific role for this gene in the regulation of IL-10. These results suggest that Msr1 is involved in the regulation of the anti-inflammatory process, thus offering a new perspective on the molecular mechanisms involved in endotoxemia and sepsis.

Animals↗
PubMed2005

Genetic mapping of QTLs controlling horticultural traits in diploid roses.

A segregating progeny set of 96 F1 diploid hybrids (2n = 2x = 14) between "Blush Noisette" (D10), one of the first seedlings from the original "Champneys' Pink Cluster", and Rosa wichurana (E15), was used to construct a genetic linkage map of the rose genome following a "pseudo-testcross" mapping strategy. A total of 133 markers (130 RAPD, one morphological and two microsatellites) were located on the 14 linkage groups (LGs) of the D10 and E15 maps, covering total map lengths of 388 and 260 cM, respectively. Due to the presence of common biparental markers the homology of four LGs between parental maps (D10-1/E15-1 to D10-4/E15-4) could be inferred. Four horticulturally interesting quantitative traits, flower size (FS), days to flowering (DF), leaf size (LS), and resistance to powdery mildew (PM) were analysed in the progeny in order to map quantitative trait loci (QTLs) controlling these traits. A total of 13 putative QTLs (LOD > 3.0) were identified, four for FS, two for flowering time, five for LS, and two for resistance to PM. Possible homologies between QTLs detected in the D10 and E15 maps could be established between Fs1 and Fs3, Fs2 and Fs4, and Ls1 and Ls3. Screening for pairwise epistatic interactions between loci revealed additional, epistatic QTLs (EQTLs) for DF and LS that were not detected in the original QTL analysis. The genetic maps developed in this study will be useful to add new markers and locate genes for important traits in the genus providing a practical resource for marker-assisted selection programs in roses.

Chromosome Mapping↗
PubMed2004

Mapping of a quantitative trait locus for morphine withdrawal severity.

Chronic morphine exposure results in physical dependence, manifested by physical symptoms during naloxone-precipitated withdrawal. Jumping frequency is widely considered the most sensitive and reliable index of withdrawal intensity in mice. Inbred mouse strains surveyed for naloxone-precipitated withdrawal display large and significant strain differences in jumping frequency, including an approximately tenfold difference between C57BL/6 and 129P3 mice. In the present study, (B6 x 129)F2 hybrid mice were given daily morphine injections for four days using an escalating dosing schedule, and naloxone-precipitated withdrawal on day 5 was measured. A full-genome scan for linkage to phenotypic data was performed using polymorphic microsatellite markers. Significant linkage was observed between withdrawal jumping frequencies and a 28 cM-wide region of Chromosome 1 (32-60 cM; peak at 51 cM), accounting for 20% of the overall phenotypic variance. Two other suggestive QTLs were found, on Chromosomes 5 and 10, and an additive model fitting all three loci accounted for 43% of the total variance. F2 mice were also assessed for changes in morphine analgesic potency using the tail-withdrawal test in dose-response studies on days 1 and 4. No linkage was observed between Chromosomes 1, 5, and 10 and morphine analgesic tolerance, suggestive of genetic dissociation of naloxone-precipitated withdrawal from morphine and chronic morphine intake per se. The significant quantitative trait locus for naloxone-precipitated withdrawal severity in morphine-dependent mice, which we name Depmq1, may prove to be of considerable heuristic value once the underlying gene or genes are identified.

Analgesics, Opioid↗
PubMed2006

Improved power offered by a score test for linkage disequilibrium mapping of quantitative-trait loci by selective genotyping.

Selective genotyping is used to increase efficiency in genetic association studies of quantitative traits by genotyping only those individuals who deviate from the population mean. However, selection distorts the conditional distribution of the trait given genotype, and such data sets are usually analyzed using case-control methods, quantitative analysis within selected groups, or a combination of both. We show that Hotelling's T(2) test, recently proposed for association studies of one or several tagging single-nucleotide polymorphisms in a prospective (i.e., trait given genotype) design, can also be applied to the retrospective (i.e., genotype given trait) selective-genotyping design, and we use simulation to demonstrate its improved power over existing methods.

Data Interpretation, Statistical↗
PubMed2001

Modeling linkage disequilibrium between a polymorphic marker locus and a locus affecting complex dichotomous traits in natural populations.

Linkage disequilibrium is an important topic in evolutionary and population genetics. An issue yet to be settled is the theory required to extend the linkage disequilibrium analysis to complex traits. In this study, we present theoretical analysis and methods for detecting or estimating linkage disequilibrium (LD) between a polymorphic marker locus and any one of the loci affecting a complex dichotomous trait on the basis of samples randomly or selectively collected from natural populations. Statistical properties of these methods were investigated and their powers were compared analytically or by use of Monte Carlo simulations. The results show that the disequilibrium may be detected with a power of 80% by using phenotypic records and marker genotype when both the trait and marker variants are common (30%) and the LD is relatively high (40-100% of the theoretical maximum). The maximum-likelihood approach provides accurate estimates of the model parameters as well as detection of linkage disequilibrium. The likelihood method is preferred for its higher power and reliability in parameter estimation. The approaches developed in this article are also compared to those for analyzing a continuously distributed quantitative trait. It is shown that a larger sample size is required for the dichotomous trait model to obtain the same level of power in detecting linkage disequilibrium as the continuous trait analysis. Potential use of these estimates in mapping the trait locus is also discussed.

Alleles↗
PubMed2003

Construction of a linkage map and QTL analysis of horticultural traits for watermelon [Citrullus lanatus (THUNB.) MATSUM & NAKAI] using RAPD, RFLP and ISSR markers.

We have been constructing linkage maps for watermelon ( Citrullus lanatus) on the basis of random amplified polymorphic DNA (RAPD), restriction fragment length polymorphism (RFLP), inter-simple sequence repeats (ISSRs) and isozymes using an F(2) population derived from a crossing between a cultivated inbred line (H-7; C. lanatus) and an African wild form (SA-1; C. lanatus). A total of 120 F(2) plants was used for construction of a linkage map using 477 RAPDs, 53 RFLPs, 23 ISSRs and one isozyme markers. Linkage analysis revealed that 554 loci could be mapped to 11 linkage groups that extended for 2,384 centimorgans (cM). While a BC(1) population [(H-7 x SA-1) x H-7] consisting of 60 individuals was grown and scored for quantitative traits. Another linkage map with a total length of 1,729 cM was constructed in the BC(1) using genetic markers found to segregate in the F(2) population. A QTL analysis was applied by means of interval mapping for locating such agronomic traits as hardness of rind, Brix of flesh juice, flesh color (red and yellow) and rind color. The relative order of markers in the BC(1) map was essentially the same as that on the linkage map in the F(2). A total of five QTLs for four agronomic traits was detected. The QTL for hardness of rind was mapped on group 4. The linkage group 8 contained the QTL for sugar content of the flesh as expressed in Brix of the juice. The QTL for red flesh color was detected on groups 2 and 8. The QTL for rind color mapped on the group 3. The present map and QTL analysis may provide a useful tool for breeders by introducing valuable wild watermelon genes to cultivars.

Chromosome Mapping↗
PubMed2007

Analysis of an introgressed Nicotiana tomentosa genomic region affecting leaf number and correlated traits in Nicotiana tabacum.

Germplasm from closely related diploid relatives of tobacco (Nicotiana tabacum L.) could be of value for continued genetic modification of this species and for mapping quantitative trait loci (QTLs). We examined near isogenic tobacco lines and hybrids differing for an introgressed genomic region from N. tomentosa Ruiz and Pavon designated as Many Leaves that exhibits a large influence on leaf number and correlated traits. Within a 'Red Russian' genetic background, the region acted in an additive to partially dominant fashion to delay flowering time, and increase leaf number, plant height, and green leaf yield. Evidence of epistasis was observed as the region affected these traits to varying degrees in diverse near isogenic hybrids. Fifteen amplified fragment length polymorphism (AFLP) markers of N. tomentosa origin were mapped within a single linkage group of 34.5 cM using a population of 207 BC(1)F(1) individuals segregating for Many Leaves. Composite interval mapping produced 2-LOD confidence intervals for likely QTL positions influencing leaf number (3.1 cM region), plant height (2.9 cM region), and days to flowering (3.3 cM region). These intervals were overlapping. Results demonstrate that genomic regions with large genetic effects can be transferred to tobacco from closely related diploid relatives, and that sufficient recombination within these regions may permit mapping of genes controlling quantitative traits. Materials and results described here may be useful in future research to gain insight on the genetic control of the transition from vegetative to reproductive development in Nicotiana.

Amplified Fragment Length Polymorphism Analysis↗
PubMed2003

Linkage map of Cucumis melo including phenotypic traits and sequence-characterized genes.

A new linkage map of Cucumis melo, derived from the F2 progeny of a cross between PI 414723 and C. melo 'TopMark' is presented. The map spans a total of 1421 cM and includes 179 points consisting of random amplified polymorphic DNA (RAPD), amplified fragment length polymorphism (AFLP), inter-simple sequence repeats (ISSRs), simple sequence repeats (SSRs), and restriction fragment length polymorphism (RFLP) markers. The map also includes an aphid resistance trait (Vat) and the sex type gene, andromonoecious (a), the two of which are important in resistance breeding and the control of hybrid seed production, as well as a seed-color gene, Wt-2. Most RFLPs represent sequence-characterized cDNA probes from C. melo and Cucumis sativus. These include resistance gene homologues and genes involved in various aspects of plant development and metabolism. A sub-set of our SSR and RFLP markers were also mapped, as part of this study, on additional mapping populations that were published for this species. This provides important reference points ("anchors"), enabling us to identify several linkage groups with respect to other melon maps.

Chromosome Mapping↗