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PubMed2005

Regression-based quantitative trait loci mapping: robust, efficient and effective.

Regression has always been an important tool for quantitative geneticists. The use of maximum likelihood (ML) has been advocated for the detection of quantitative trait loci (QTL) through linkage with molecular markers, and this approach can be very effective. However, linear regression models have also been proposed which perform similarly to ML, while retaining the many beneficial features of regression and, hence, can be more tractable and versatile than ML in some circumstances. Here, the use of linear regression to detect QTL in structured outbred populations is reviewed and its perceived shortfalls are revisited. It is argued that the approach is valuable now and will remain so in the future.

Genetics, Population↗
PubMed2003

The structure of linkage disequilibrium at the DBH locus strongly influences the magnitude of association between diallelic markers and plasma dopamine beta-hydroxylase activity.

There is currently a great deal of interest in using linkage disequilibrium (LD) mapping to locate both disease and quantitative-trait loci on a genomewide scale. Recent findings suggest that much of the human genome is organized in discrete "blocks" of low haplotype diversity, but the utility of such blocks in identifying genes influencing complex traits is not yet known and must ultimately be tested empirically through use of real data. We recently identified a putative functional polymorphism (-1021C-->T) in the 5' upstream region of the DBH gene that accounted for 35%-52% of the total phenotypic variance in plasma dopamine beta-hydroxylase (DBH) activity in samples from three distinct populations. In the present study, we genotyped 11 diallelic markers at the DBH locus surrounding -1021C-->T in 386 unrelated individuals of European origin. We identified a single 10-kb block containing -1021C-->T, in which four haplotypes comprised 93% of the observed chromosomes. Only markers within the block were highly associated with phenotype (P< or =2.2 x 10(-10)), with one exception. In general, association with phenotype was strongly correlated with the degree of LD between each marker and -1021C-->T. Of four LD measures assessed, d(2) was the best predictor of this relationship. Had one attempted to map quantitative-trait loci for plasma DBH activity on a genomewide basis without prior knowledge of candidate regions and not included (by chance) markers within this haplotype block, the DBH locus might have been missed entirely. These results provide a direct example of the potential value of constructing a haplotype map of the human genome prior to embarking on large-scale association studies.

Adult↗
PubMed1993

[Genetic polymorphism of haptoglobin and quantitative changes in its levels during exposure to asbestos].

The polymorphism and serum levels of haptoglobin were studied in asbestosis patients, in the control and the workers exposed to asbest. Hp1-1 has the highest, Hp2-2--the lowest and Hp2-1 has the intermediate concentration of this protein. In the course of contact with asbest, and especially in asbestosis patients, the haptoglobin levels are higher (for all phenotypes). The standard deviation from the Hp concentration in asbestosis patients was significantly higher. The phenotypes Hp1-1 were found more often in asbestosis patients than among asbest-exposed workers.

Asbestos↗
PubMed2003

Expression of additive genetic variances and covariances for wild radish floral traits: comparison between field and greenhouse environments.

Measurements of the genetic variation and covariation underlying quantitative traits are crucial to our understanding of current evolutionary change and the mechanisms causing this evolution. This fact has spurred a large number of studies estimating heritabilities and genetic correlations in a variety of organisms. Most of these studies have been done in laboratory or greenhouse settings, but it is not well known how accurately these measurements estimate genetic variance and covariance expressed in the field. We conducted a quantitative genetic half-sibling analysis on six floral traits in wild radish. Plants were grown from seed in the field and were exposed to natural environmental variation throughout their lives, including herbivory and intra- and interspecific competition. The estimates of heritabilities and the additive genetic variance-covariance matrix (G) obtained from this analysis were then compared to previous greenhouse estimates of the same floral traits from the same natural population. Heritabilities were much lower in the field for all traits, and this was due to both large increases in environmental variance and decreases in additive genetic variance. Additive genetic covariance expressed was also much lower in the field. These differences resulted in highly significant differences in the G matrix between the greenhouse and field environments using two complementary testing methods. Although the G matrices shared some principal components in common, they were not simply proportional to each other. Therefore, the greenhouse results did not accurately depict how the floral traits would respond to natural selection in the field.

Environment↗
PubMed2006

Mapping quantitative trait loci by an extension of the Haley-Knott regression method using estimating equations.

The Haley-Knott (HK) regression method continues to be a popular approximation to standard interval mapping (IM) of quantitative trait loci (QTL) in experimental crosses. The HK method is favored for its dramatic reduction in computation time compared to the IM method, something that is particularly important in simultaneous searches for multiple interacting QTL. While the HK method often approximates the IM method well in estimating QTL effects and in power to detect QTL, it may perform poorly if, for example, there is strong epistasis between QTL or if QTL are linked. Also, it is well known that the estimation of the residual variance by the HK method is biased. Here, we present an extension of the HK method that uses estimating equations based on both means and variances. For normally distributed phenotypes this estimating equation (EE) method is more efficient than the HK method. Furthermore, computer simulations show that the EE method performs well for very different genetic models and data set structures, including nonnormal phenotype distributions, nonrandom missing data patterns, varying degrees of epistasis, and varying degrees of linkage between QTL. The EE method retains key qualities of the HK method such as computational speed and robustness against nonnormal phenotype distributions, while approximating the IM method better in terms of accuracy and precision of parameter estimates and power to detect QTL.

Chromosome Mapping↗
PubMed2000

Genotype-environment interaction for quantitative trait loci affecting life span in Drosophila melanogaster.

The nature of genetic variation for Drosophila longevity in a population of recombinant inbred lines was investigated by estimating quantitative genetic parameters and mapping quantitative trait loci (QTL) for adult life span in five environments: standard culture conditions, high and low temperature, and heat-shock and starvation stress. There was highly significant genetic variation for life span within each sex and environment. In the analysis of variance of life span pooled over sexes and environments, however, the significant genetic variation appeared in the genotype x sex and genotype x environment interaction terms. The genetic correlation of longevity across the sexes and environments was not significantly different from zero in these lines. We estimated map positions and effects of QTL affecting life span by linkage to highly polymorphic roo transposable element markers, using a multiple-trait composite interval mapping procedure. A minimum of 17 QTL were detected; all were sex and/or environment-specific. Ten of the QTL had sexually antagonistic or antagonistic pleiotropic effects in different environments. These data provide support for the pleiotropy theory of senescence and the hypothesis that variation for longevity might be maintained by opposing selection pressures in males and females and variable environments. Further work is necessary to assess the generality of these results, using different strains, to determine heterozygous effects and to map the life span QTL to the level of genetic loci.

Animals↗
PubMed2001

Use of weighted p-values in regional inference procedures.

Our previous studies have demonstrated that the power to detect linkage was improved by calculating a moving average of consecutive p-values in a small region as compared with testing all single p-values. The goal of this study was to test whether the power can be improved further with an alternative method whereby the middle p-values in the sequence were given more weight than the others. We also wanted to compare the moving average tests with multipoint linkage tests. The simulated extended pedigree data from the general population was analyzed to identify two major genes (MG1 and MG5) underlying two quantitative traits (Q1 and Q5). We used the variance components method implemented in the GENEHUNTER program to test for linkage of 14-marker regions each on chromosome 19 and chromosome 1 to the adjusted quantitative traits Q1 and Q5, respectively, in all 50 replicates. As before, we found that the moving average test was more powerful than a test based on single p-values. In some cases, the weighting procedure increased the power further and was similar to that of multipoint analysis, but this was not consistently found. In addition, all methods had low power and it is not possible to make a general conclusion that some weighting schemes are better than others.

Chromosome Mapping↗
PubMed2006

A simplified QTL mapping approach for screening and mapping of novel AFLP markers associated with beef marbling.

Genome screening of quantitative trait loci (QTL) for a complex trait is usually costly and highly laborious, as it requires a large number of markers spanning the whole genome. Here we present a simplified approach for screening and mapping of QTL-linked markers for beef marbling using a WagyuxLimousin F(2) reference population. This simplified approach involves integration of the amplified fragment length polymorphism (AFLP) with DNA pooling and selective genotyping and comparative bioinformatics tools. AFLP analysis on two high and two low marbling DNA pools yielded ten visually different markers. Among them, four were confirmed based on individual AFLP validation. Sequencing and in silico characterization assigned two of these AFLP markers to bovine chromosomes 1 (BTA1) and 13 (BTA13), which are orthologous to human chromosomes HSA21q22.2 and HSA10p11.23 with both regions harboring QTL for obesity-related phenotypes. Both AFLP markers showed significantly large additive genetic effects (0.28+/-0.11 on BTA1 and 0.54+/-0.21 on BTA13) on beef-marbling score (BMS) (P<0.05). Overall, this approach is less time consuming, inexpensive and in particular, suitable for screening and mapping QTL-linked markers when targeting one or a few complex traits.

Animals↗
PubMed2000

More about quantitative trait locus mapping with diallel designs.

We present a general regression-based method for mapping quantitative trait loci (QTL) by combining different populations derived from diallel designs. The model expresses, at any map position, the phenotypic value of each individual as a function of the specific-mean of the population to which the individual belongs, the additive and dominance effects of the alleles carried by the parents of that population and the probabilities of QTL genotypes conditional on those of neighbouring markers. Standard linear model procedures (ordinary or iteratively reweighted least-squares) are used for estimation and test of the parameters.

Alleles↗
PubMed1998

A nonparametric bootstrap method for testing close linkage vs. pleiotropy of coincident quantitative trait loci.

A novel method using the nonparametric bootstrap is proposed for testing whether a quantitative trait locus (QTL) at one chromosomal position could explain effects on two separate traits. If the single-QTL hypothesis is accepted, pleiotropy could explain the effect on two traits. If it is rejected, then the effects on two traits are due to linked QTLs. The method can be used in conjunction with several QTL mapping methods as long as they provide a straightforward estimate of the number of QTLs detectable from the data set. A selection step was introduced in the bootstrap procedure to reduce the conservativeness of the test of close linkage vs. pleiotropy, so that the erroneous rejection of the null hypothesis of pleiotropy only happens at a frequency equal to the nominal type I error risk specified by the user. The approach was assessed using computer simulations and proved to be relatively unbiased and robust over the range of genetic situations tested. An example of its application on a real data set from a saline stress experiment performed on a recombinant population of wheat (Triticum aestivum L. ) doubled haploid lines is also provided.

Computer Simulation↗
PubMed2003

Genome-wide linkage analysis of blood pressure under locus heterogeneity.

We describe a method for mapping quantitative trait loci that allows for locus heterogeneity. A genome-wide linkage analysis of blood pressure was performed using sib-pair data from the Framingham Heart Study. Evidence of linkage was found on four markers (GATA89G08, GATA23D06, GATA14E09, and 049xd2) at a significance level of 0.01. Two of them (GATA14E09 and 049xd2) seem to overlap with linkage signals reported previously, while the other two are not linked to any known signals.

Adult Children↗
PubMed2005

Transformation of maize with the p1 transcription factor directs production of silk maysin, a corn earworm resistance factor, in concordance with a hierarchy of floral organ pigmentation.

The maize p1 gene encodes an R2R3-MYB transcription factor that controls the biosynthesis of red flavonoid pigments in floral tissues of the maize plant. Genetic and quantitative trait locus analyses have also associated the p1 gene with the synthesis of maysin, a flavone glycoside from maize silks that confers natural resistance to corn earworm. Here, we show directly that the p1 gene induces maysin accumulation in silk tissues. Transformation of maize plants that had low or no silk maysin with p1 transgenes elevated silk maysin concentrations to levels sufficient for corn earworm abiosis. The p1 transgenes also conferred red pigment to pericarp, cob, husk and tassel tissues, as expected; however, different subsets of these tissues were pigmented within individual transgenic plants. Statistical analysis shows that the pigmentation patterns observed amongst the p1 transgenic plants conform to a hierarchy that is similar to the temporal ordering of floral organ initiation. We propose that the observed hierarchy of pigmentation patterns is conferred by variation due to epigenetic control of the p1 transgenes. The production of plants with improved traits through genetic engineering can depend in large part on the achievement of tight organ-specific expression of the introduced transgenes. Our results demonstrate that the production of transgenic plants using a promoter with well-defined tissue specificity, such as the p1 promoter, can result in unexpected variation in tissue specificity amongst the resulting transgenic plants.

Journal Article↗
PubMed2002

Relationship between microsatellite marker alleles on chromosomes 1-5 originating from the Rhode Island Red and Green-legged Partrigenous breeds and egg production and quality traits in F(2) mapping population.

The objective of this study was to determine the relationship between the origin of marker alleles from the Rhode Island Red (RIR) and Green-legged Partrigenous (GlP) breeds and chosen egg production and quality traits in F(2) generation consisting of 10 full-sib families. Polymorphism analysis of 23 microsatellite markers within the mapping population (519 F(2)) was made. In parental generation 17 alleles were identified as specific for the GlP and 23 for the RIR. The least squares method was used to evaluate the significance of effects of genotype (GlP/GlP, RIR/RIR, GlP/RIR) on the analysed quantitative traits. Thirty traits of egg production and quality were measured during the laying period. It was shown that the effects of the genotype (GlP/GlP, RIR/RIR, GlP/RIR) at the loci on analysed traits of F(2) animals were diversified. Significant effects were found for 16 traits. These results confirm that the analysed microsatellite loci may be linked to the genes affecting egg production and quality traits. The loci examined and the experimental population constitutes a valuable material for QTL mapping (linkage analysis).

Alleles↗
PubMed2004

Score test for detecting linkage to complex traits in selected samples.

We present a unified approach to selection and linkage analysis of selected samples, for both quantitative and dichotomous complex traits. It is based on the score test for the variance attributable to the trait locus and applies to general pedigrees. The method is equivalent to regressing excess IBD sharing on a function of the traits. It is shown that when population parameters for the trait are known, such inversion does not entail any loss of information. For dichotomous traits, pairs of pedigree members of different phenotypic nature (e.g., affected sib pairs and discordant sib pairs) can easily be combined as well as populations with different trait prevalences.

Analysis of Variance↗
PubMed2005

Mapping quantitative trait loci using linkage disequilibrium: marker- versus trait-based methods.

Two approaches for mapping quantitative trait loci (QTL) using linkage disequilibrium at the population level were investigated. In the trait-based (TB) approach, the frequencies of marker alleles (or genotypes) are compared in individuals selected from the two tails of the trait distribution. The TB approach uses phenotypic information only in the selection step. In the marker-based (MB) approach, the quantitative trait values for the marker genotypes in the selected individuals are compared. The MB approach uses both the difference in marker allele (or genotype) frequencies and the phenotypic values of each marker genotype in the selected samples. We quantify the power of each approach and show that the power of the MB approach is greater than or equal to that of the TB approach. The advantage of the former is expected to increase with increasing number of traits phenotyped. Our accurate predictions obviate the need for elaborate simulation studies.

Humans↗
PubMed2004

Quantitative analysis of SMN1 gene and estimation of SMN1 deletion carrier frequency in Korean population based on real-time PCR.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder, caused by homozygous absence of the survival motor neuron gene (SMN1) in approximately 94% of patients. Since most carriers have only one SMN1 gene copy, several SMN1 quantitative analyses have been used for the SMA carrier detection. We developed a reliable quantitative real-time PCR with SYBR Green I dye and studied 13 patients with SMA and their 24 parents, as well as 326 healthy normal individuals. The copy number of the SMN1 gene was determined by the comparative threshold cycle (Ct) method and albumin was used as a reference gene. The homozygous SMN1 deletion ratio of patients was 0.00 and the hemizygous SMN1 deletion ratio of parents ranged from 0.39 to 0.59. The deltadelta Ct ratios of 7 persons among 326 normal individuals were within the carrier range, 0.41-0.57. According to these data, we estimated the carrier and disease prevalence of SMA at 1/47 and 1/8,496 in Korean population, respectively. These data indicated that there would be no much difference in disease prevalence of SMA compared with western countries. Since the prevalence of SMA is higher than other autosomal recessive disorders, the carrier detection method using real-time PCR could be a useful tool for genetic counseling.

Adult↗
PubMed2001

Complex trait analysis of the mouse striatum: independent QTLs modulate volume and neuron number.

BACKGROUND: The striatum plays a pivotal role in modulating motor activity and higher cognitive function. We analyzed variation in striatal volume and neuron number in mice and initiated a complex trait analysis to discover polymorphic genes that modulate the structure of the basal ganglia. RESULTS: Brain weight, brain and striatal volume, neuron-packing density and number were estimated bilaterally using unbiased stereological procedures in five inbred strains (A/J, C57BL/6J, DBA/2J, BALB/cJ, and BXD5) and an F2 intercross between A/J and BXD5. Striatal volume ranged from 20 to 37 mm3. Neuron-packing density ranged from approximately 50,000 to 100,000 neurons/mm3, and the striatal neuron population ranged from 1.4 to 2.5 million. Inbred animals with larger brains had larger striata but lower neuron-packing density resulting in a narrow range of average neuron populations. In contrast, there was a strong positive correlation between volume and neuron number among intercross progeny. We mapped two quantitative trait loci (QTLs) with selective effects on striatal architecture. Bsc10a maps to the central region of Chr 10 (LRS of 17.5 near D10Mit186) and has intense effects on striatal volume and moderate effects on brain volume. Stnn19a maps to distal Chr 19 (LRS of 15 at D19Mit123) and is associated with differences of up to 400,000 neurons among animals. CONCLUSION: We have discovered remarkable numerical and volumetric variation in the mouse striatum, and we have been able to map two QTLs that modulate independent anatomic parameters.

Animals↗
PubMed2002

Association of a lysine-232/alanine polymorphism in a bovine gene encoding acyl-CoA:diacylglycerol acyltransferase (DGAT1) with variation at a quantitative trait locus for milk fat content.

DGAT1 encodes diacylglycerol O-acyltransferase (EC ), a microsomal enzyme that catalyzes the final step of triglyceride synthesis. It became a functional candidate gene for lactation traits after studies indicated that mice lacking both copies of DGAT1 are completely devoid of milk secretion, most likely because of deficient triglyceride synthesis in the mammary gland. Our mapping studies placed DGAT1 close to the region of a quantitative trait locus (QTL) on bovine chromosome 14 for variation in fat content of milk. Sequencing of DGAT1 from pooled DNA revealed significant frequency shifts at several variable positions between groups of animals with high and low breeding values for milk fat content in different breeds (Holstein-Friesian, Fleckvieh, and Braunvieh). Among the variants was a nonconservative substitution of lysine by alanine (K232A), with the lysine-encoding allele being associated with higher milk fat content. Haplotype analysis indicated the lysine variant to be ancestral. Two animals that were typed heterozygous (Qq) at the QTL based on marker-assisted QTL-genotyping were heterozygous for the K232A substitution, whereas 14 animals that are most likely qq at the QTL were homozygous for the alanine-encoding allele. An independent association study in Fleckvieh animals confirmed the positive effect of the lysine variant on milk fat content. We consider the nonconservative K232A substitution to be directly responsible for the QTL variation, although our genetic studies cannot provide formal proof.

Acyltransferases↗