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PubMed2006

Genotyping pooled DNA using 100K SNP microarrays: a step towards genomewide association scans.

The identification of quantitative trait loci (QTLs) of small effect size that underlie complex traits poses a particular challenge for geneticists due to the large sample sizes and large numbers of genetic markers required for genomewide association scans. An efficient solution for screening purposes is to combine single nucleotide polymorphism (SNP) microarrays and DNA pooling (SNP-MaP), an approach that has been shown to be valid, reliable and accurate in deriving relative allele frequency estimates from pooled DNA for groups such as cases and controls for 10K SNP microarrays. However, in order to conduct a genomewide association study many more SNP markers are needed. To this end, we assessed the validity and reliability of the SNP-MaP method using Affymetrix GeneChip Mapping 100K Array set. Interpretable results emerged for 95% of the SNPs (nearly 110,000 SNPs). We found that SNP-MaP allele frequency estimates correlated 0.939 with allele frequencies for 97 605 SNPs that were genotyped individually in an independent population; the correlation was 0.971 for 26 SNPs that were genotyped individually for the 1028 individuals used to construct the DNA pools. We conclude that extending the SNP-MaP method to the Affymetrix GeneChip Mapping 100K Array set provides a useful screen of >100,000 SNP markers for QTL association scans.

DNA↗

PubMed2005

Genotyping DNA pools on microarrays: tackling the QTL problem of large samples and large numbers of SNPs.

BACKGROUND: Quantitative trait locus (QTL) theory predicts that genetic influence on complex traits involves multiple genes of small effect size. To detect QTL associations of small effect size, large samples and systematic screens of thousands of DNA markers are required. An efficient solution is to genotype case and control DNA pools using SNP microarrays. We demonstrate that this is practical using DNA pools of 100 individuals. RESULTS: Using standard microarray protocols for the Affymetrix GeneChip Mapping 10 K Array Xba 131, we show that relative allele signal (RAS) values provide a quantitative index of allele frequencies in pooled DNA that correlate 0.986 with allele frequencies for 104 SNPs that were genotyped individually for 100 individuals. The sensitivity of the assay was demonstrated empirically in a spiking experiment in which 15% and 20% of one individual's DNA was added to a DNA pool. CONCLUSION: We conclude that this approach, which we call SNP-MaP (SNP microarrays and pooling), is rapid, cost effective and promises to be a valuable initial screening method in the hunt for QTLs.

Alleles↗

PubMed2006

Power to detect higher-order epistatic interactions in a metabolic pathway using a new mapping strategy.

Epistatic interactions among quantitative trait loci (QTL) contribute substantially to the variation in complex traits. The main objectives of this study were to (i) compare three- vs. four-step genome scans to identify three-way epistatic interactions among QTL belonging to a metabolic pathway, (ii) investigate by computer simulations the power and proportion of false positives (PFP) for detecting three-way interactions among QTL in recombinant inbred line (RIL) populations derived from a nested mating design, and (iii) compare these estimates to those obtained for detecting three-way interactions among QTL in RIL populations derived from diallel and different partial diallel mating designs. The single-nucleotide polymorphism haplotype data of B73 and 25 diverse maize inbreds were used to simulate the production of various RIL populations. Compared to the three-step genome scan, the power to detect three-way interactions was higher with the four-step genome scan. Higher power to detect three-way interactions was observed for RILs derived from optimally allocated distance-based designs than from nested designs or diallel designs. The power and PFP to detect three-way interactions using a nested design with 5000 RILs were for both the 4-QTL and the 12-QTL scenario of a magnitude that seems promising for their identification.

Chromosome Mapping↗

PubMed1999

Mapping of a blood pressure quantitative trait locus to chromosome 15q in a Chinese population.

Blood pressure is a complex trait of pivotal biological importance, in which 20-50% of interindividual variation is genetically determined. Whereas genes have been identified in several rare Mendelian forms of hypertension, little progress has been made in understanding the genetics of blood pressure variation in the general population. Recently, we screened the human genome using rural Chinese sibling pairs with extreme blood pressure and identified suggestive linkage for two chromosomal regions. By refining the trait definition and genotyping additional markers, we detected significant linkage (maximum lod score = 3.77) near D15S203 in lower extreme diastolic blood pressure sibling pairs. Using a second independent data set from the same geographical area, we marginally replicated ( P = 0.05) this result, suggesting that this locus is very likely to be involved in the regulation of diastolic blood pressure.

Adult↗

PubMed2001

Power and robustness of a score test for linkage analysis of quantitative traits using identity by descent data on sib pairs.

Identification of genes involved in complex traits by traditional (lod score) linkage analysis is difficult due to many complicating factors. An unfortunate drawback of non-parametric procedures in general, though, is their low power to detect genetic effects. Recently, Dudoit and Speed [2000] proposed using a (likelihood-based) score test for detecting linkage with IBD data on sib pairs. This method uses the likelihood for theta, the recombination fraction between a trait locus and a marker locus, conditional on the phenotypes of the two sibs to test the null hypothesis of no linkage (theta = (1/2)). Although a genetic model must be specified, the approach offers several advantages. This paper presents results of simulation studies characterizing the power and robustness properties of this score test for linkage, and compares the power of the test to the Haseman-Elston and modified Haseman-Elston tests. The score test is seen to have impressively high power across a broad range of true and assumed models, particularly under multiple ascertainment. Assuming an additive model with a moderate allele frequency, in the range of p = 0.2 to 0.5, along with heritability H = 0.3 and a moderate residual correlation rho = 0.2 resulted in a very good overall performance across a wide range of trait-generating models. Generally, our results indicate that this score test for linkage offers a high degree of protection against wrong assumptions due to its strong robustness when used with the recommended additive model.

Computer Simulation↗

PubMed1995

Complete multipoint sib-pair analysis of qualitative and quantitative traits.

Sib-pair analysis is an increasingly important tool for genetic dissection of complex traits. Current methods for sib-pair analysis are primarily based on studying individual genetic markers one at a time and thus fail to use the full inheritance information provided by multipoint linkage analysis. In this paper, we describe how to extract the complete multipoint inheritance information for each sib pair. We then describe methods that use this information to map loci affecting traits, thereby providing a unified approach to both qualitative and quantitative traits. Specifically, complete multipoint approaches are presented for (1) exclusion mapping of qualitative traits; (2) maximum-likelihood mapping of qualitative traits; (3) information-content mapping, showing the extent to which all inheritance information has been extracted at each location in the genome; and (4) quantitative-trait mapping, by two parametric methods and one nonparametric method. In addition, we explore the effects of marker density, marker polymorphism, and availability of parents on the information content of a study. We have implemented the analysis methods in a new computer package, MAPMAKER/SIBS. With this computer package, complete multipoint analysis with dozens of markers in hundreds of sib pairs can be carried out in minutes.

Chromosome Mapping↗

PubMed2000

Bayesian mapping of quantitative trait loci under the identity-by-descent-based variance component model.

Variance component analysis of quantitative trait loci (QTL) is an important strategy of genetic mapping for complex traits in humans. The method is robust because it can handle an arbitrary number of alleles with arbitrary modes of gene actions. The variance component method is usually implemented using the proportion of alleles with identity-by-descent (IBD) shared by relatives. As a result, information about marker linkage phases in the parents is not required. The method has been studied extensively under either the maximum-likelihood framework or the sib-pair regression paradigm. However, virtually all investigations are limited to normally distributed traits under a single QTL model. In this study, we develop a Bayes method to map multiple QTL. We also extend the Bayesian mapping procedure to identify QTL responsible for the variation of complex binary diseases in humans under a threshold model. The method can also treat the number of QTL as a parameter and infer its posterior distribution. We use the reversible jump Markov chain Monte Carlo method to infer the posterior distributions of parameters of interest. The Bayesian mapping procedure ends with an estimation of the joint posterior distribution of the number of QTL and the locations and variances of the identified QTL. Utilities of the method are demonstrated using a simulated population consisting of multiple full-sib families.

Alleles↗

PubMed2005

Development of a genomic library of near isogenic lines (NILs) in melon (Cucumis melo L.) from the exotic accession PI161375.

A doubled haploid line (DHL) population of melon derived from a cross between the Korean cultivar "Songwhan Charmi" accession PI161375 (SC), included in the horticultural group conomon, and the Spanish cultivar "Piel de Sapo" (PS), included in the horticultural group inodorus, was used to develop a collection of near isogenic lines (NILs). These parental lines represent very different melon cultivar groups, with important differences at fruit, plant, disease response and molecular level. This cross is one of the most polymorphic ones within melon germplasm. Selected DHLs were backcrossed to PS and further backcrossing and selfing was performed, monitoring introgressions from SC using molecular markers covering the melon genetic map. A final collection of 57 NILs was obtained, containing a unique independent introgression from SC in the PS genetic background. The introgressions within the collection cover at least 85% of the SC genome with an average introgression size of 41 cM, corresponding to 3.4% of the SC genome. The average resolution for mapping genes or quantitative trait loci is 18.90 cM. This set of NILs is a potentially powerful tool for the study of quantitative trait locus involved in melon fruit quality and other important complex traits, and the introduction of new genetic variability in modern cultivars from exotic sources. The NILs can also be used as pre-competitive breeding lines in melon breeding projects.

Breeding↗

PubMed1998

Genetic association of a GABA(A) receptor gamma2 subunit variant with severity of acute physiological dependence on alcohol.

The ultimate goal of quantitative trait locus (QTL) mapping is to identify the genes affecting complex traits. Using animal models, we recently identified QTLs on mouse Chromosomes (Chrs) 1, 4, and 11 affecting genetic predisposition to acute alcohol withdrawal. Among mice derived from the C57BL/6J (B6) and DBA/2J (D2) inbred strains, the locus identified on Chr 11 ( approximately 20 cM) accounted for 12% of the genetic variability in withdrawal liability. Candidate genes in proximity to this QTL encode the gamma2, alpha1, and alpha6 subunits of GABAA receptors. The present studies identify a polymorphism between the B6 and D2 strains in the gamma2 subunit gene, Gabrg2, and expand genotypic analysis to their BXD recombinant inbred strains. This polymorphism predicts a difference in amino acid sequence (Ala-11 vs. Thr-11) within the extracellular amino-terminal region of the gamma2 subunit. Analysis using BXD strain means for acute alcohol withdrawal severity suggests that the gamma2 subunit polymorphism is genetically correlated with alcohol withdrawal severity. This is the first report that QTL mapping for an alcohol-related trait has successfully led to the identification of a polymorphic candidate gene product that is genetically associated with the trait.

Animals↗

PubMed2005

SNPs, microarrays and pooled DNA: identification of four loci associated with mild mental impairment in a sample of 6000 children.

Mild mental impairment (MMI) represents the low extreme of the quantitative trait of general intelligence and is highly heritable. Quantitative trait loci (QTLs) conferring susceptibility to MMI, as for most complex traits, are likely to be of small effect size. Using a novel approach we call SNP-MaP (SNP Microarrays and Pooling), we have identified four loci associated with MMI. These four loci have been replicated in two SNP-MaP studies and verified by individual genotyping. The two SNP-MaP studies conducted were a case versus control comparison (n = 515 and n = 1028, respectively) and a low versus high general intelligence extremes group comparison (n = 503 and n = 505, respectively). Each of the four groups consisted of five independent 'subpools', with each subpool assayed on a separate microarray. Twelve loci showing the largest significant differences in both SNP-MaP studies were individually genotyped on 6154 children. Of the four loci positively associated with MMI, the minor allele of each conferred the greater risk for MMI. Two of the loci are close to known genes and may be in linkage disequilibrium with them. One of the loci is between the candidate genes KLF7 and CREB1, but given possible long-range effects on expression and the unknown importance of untranslated elements such as micro-RNAs, all four loci deserve attention as candidates. Although each SNP accounts for a small amount of variance, their effects are additive and they can be combined in a 'SNP set' that can be used as a genetic risk index for MMI in behavioral genomic analyses.

Child↗

PubMed2005

Identification of quantitative trait loci that regulate Arabidopsis root system size and plasticity.

Root system size (RSS) is a complex trait that is greatly influenced by environmental cues. Hence, both intrinsic developmental pathways and environmental-response pathways contribute to RSS. To assess the natural variation in both types of pathways, we examined the root systems of the closely related Arabidopsis ecotypes Landsberg erecta (Ler) and Columbia (Col) grown under mild osmotic stress conditions. We found that Ler initiates more lateral root primordia, produces lateral roots from a higher percentage of these primordia, and has an overall larger root system than Col under these conditions. Furthermore, although each of these parameters is reduced by osmotic stress in both ecotypes, Ler shows a decreased sensitivity to osmotica. To understand the genetic basis for these differences, QTL for RSS under mild osmotic stress were mapped in a Ler x Col recombinant inbred population. Two robust quantitative trait loci (QTL) were identified and confirmed in near-isogenic lines (NILs). The NILs also allowed us to define distinct physiological roles for the gene(s) at each locus. This study provides insight into the genetic and physiological complexity that determines RSS and begins to dissect the molecular basis for naturally occurring differences in morphology and developmental plasticity in the root system.

Arabidopsis↗

PubMed2003

Human chromosome 17 in essential hypertension.

Hypertension affects up to 30% of the adult population in Western societies and is a major risk factor for kidney disease, stroke and coronary heart disease. It is a complex trait thought to be influenced by a number of genes and environmental factors, although the precise aetiology remains unknown at this time. A number of methods have been successfully used to identify mutations that cause Mendelian traits and these are now being applied to the investigation of complex diseases. This review summarises the data gathered, using such approaches, that suggest there is a gene or genes on chromosome 17 causing human essential hypertension. Studies in rodent models are discussed first, followed by studies of human hypertension that include the investigation of pseudohypoaldosteronism type II, a monogenic trait that manifests with hypertension alongside other phenotypic variables. In addition, candidate gene studies, genome screens and linkage studies based on comparative mapping are outlined. To date no gene has been identified on human chromosome 17 that influences blood pressure and causes human essential hypertension. However, results of ongoing fine mapping and candidate gene studies in both rodents and man are eagerly awaited.

Animals↗

PubMed2002

Mapping quantitative trait loci with epistatic effects.

Epistatic variance can be an important source of variation for complex traits. However, detecting epistatic effects is difficult primarily due to insufficient sample sizes and lack of robust statistical methods. In this paper, we develop a Bayesian method to map multiple quantitative trait loci (QTLs) with epistatic effects. The method can map QTLs in complicated mating designs derived from the cross of two inbred lines. In addition to mapping QTLs for quantitative traits, the proposed method can even map genes underlying binary traits such as disease susceptibility using the threshold model. The parameters of interest are various QTL effects, including additive, dominance and epistatic effects of QTLs, the locations of identified QTLs and even the number of QTLs. When the number of QTLs is treated as an unknown parameter, the dimension of the model becomes a variable. This requires the reversible jump Markov chain Monte Carlo algorithm. The utility of the proposed method is demonstrated through analysis of simulation data.

Algorithms↗

PubMed2000

Parametric and nonparametric multipoint linkage analysis with imprinting and two-locus-trait models: application to mite sensitization.

We present two extensions to linkage analysis for genetically complex traits. The first extension allows investigators to perform parametric (LOD-score) analysis of traits caused by imprinted genes-that is, of traits showing a parent-of-origin effect. By specification of two heterozygote penetrance parameters, paternal and maternal origin of the mutation can be treated differently in terms of probability of expression of the trait. Therefore, a single-disease-locus-imprinting model includes four penetrances instead of only three. In the second extension, parametric and nonparametric linkage analysis with two trait loci is formulated for a multimarker setting, optionally taking imprinting into account. We have implemented both methods into the program GENEHUNTER. The new tools, GENEHUNTER-IMPRINTING and GENEHUNTER-TWOLOCUS, were applied to human family data for sensitization to mite allergens. The data set comprises pedigrees from England, Germany, Italy, and Portugal. With single-disease-locus-imprinting MOD-score analysis, we find several regions that show at least suggestive evidence for linkage. Most prominently, a maximum LOD score of 4.76 is obtained near D8S511, for the English population, when a model that implies complete maternal imprinting is used. Parametric two-trait-locus analysis yields a maximum LOD score of 6.09 for the German population, occurring exactly at D4S430 and D18S452. The heterogeneity model specified for analysis alludes to complete maternal imprinting at both disease loci. Altogether, our results suggest that the two novel formulations of linkage analysis provide valuable tools for genetic mapping of multifactorial traits.

Allergens↗

PubMed2006

Localization of two new X-linked quantitative trait loci controlling corpus callosum size in the mouse.

Corpus callosum (CC) size is a complex trait, characterized by a gradation of values within a normal range, as well as abnormalities that include a small or totally absent CC. Among inbred mouse strains with defects of the CC, BTBR T(+)tf/J (BTBR) mice have the most extreme phenotype; all animals show total absence of the CC and severe reduction of the hippocampal commissure (HC). In contrast, the BALB/cByJ (BALB) strain has a low frequency of small CC and consistently normal HC. Reciprocal F(1) crosses between BTBR and BALB suggest the presence of X-linked quantitative trait loci (QTLs) affecting CC size. Through linkage analysis of backcross male progeny, we have localized two regions on the X chromosome, having peaks at 68.5 Mb (approximately 29.5 cM) and at 134.5 Mb (approximately 60.5 cM) that are largely responsible for the reciprocal differences, with the BTBR allele showing X-linked dominant inheritance associated with CC defects.

Agenesis of Corpus Callosum↗

PubMed2005

A male-specific quantitative trait locus on 1p21 controlling human stature.

BACKGROUND: Many genome-wide scans aimed at complex traits have been statistically underpowered due to small sample size. Combining data from several genome-wide screens with comparable quantitative phenotype data should improve statistical power for the localisation of genomic regions contributing to these traits. OBJECTIVE: To perform a genome-wide screen for loci affecting adult stature by combined analysis of four previously performed genome-wide scans. METHODS: We developed a web based computer tool, Cartographer, for combining genetic marker maps which positions genetic markers accurately using the July 2003 release of the human genome sequence and the deCODE genetic map. Using Cartographer, we combined the primary genotype data from four genome-wide scans and performed variance components (VC) linkage analyses for human stature on the pooled dataset of 1417 individuals from 277 families and performed VC analyses for males and females separately. RESULTS: We found significant linkage to stature on 1p21 (multipoint LOD score 4.25) and suggestive linkages on 9p24 and 18q21 (multipoint LOD scores 2.57 and 2.39, respectively) in males-only analyses. We also found suggestive linkage to 4q35 and 22q13 (multipoint LOD scores 2.18 and 2.85, respectively) when we analysed both females and males and to 13q12 (multipoint LOD score 2.66) in females-only analyses. CONCLUSIONS: We strengthened the evidence for linkage to previously reported quantitative trait loci (QTL) for stature and also found significant evidence of a novel male-specific QTL on 1p21. Further investigation of several interesting candidate genes in this region will help towards characterisation of this first sex-specific locus affecting human stature.

Adult↗

PubMed2001

Genetic control of the mouse cerebellum: identification of quantitative trait loci modulating size and architecture.

To discover genes influencing cerebellum development, we conducted a complex trait analysis of variation in the size of the adult mouse cerebellum. We analyzed two sets of recombinant inbred BXD strains and an F2 intercross of the common inbred strains, C57BL/6J and DBA/2J. We measured cerebellar size as the weight or volume of fixed or histologically processed tissue. Among BXD recombinant inbred strains, the cerebellum averages 52 mg (12.4% of the brain) and ranges 18 mg in size. In F2 mice, the cerebellum averages 62 mg (12.9% of the brain) and ranges approximately 20 mg in size. Five quantitative trait loci (QTLs) that significantly control variation in cerebellar size were mapped to chromosomes 1 (Cbs1a), 8 (Cbs8a), 14 (Cbs14a), and 19 (Cbs19a, Cbs19b). In combination, these QTLs can shift cerebellar size an appreciable 35% of the observed range. To assess regional genetic control of the cerebellum, we also measured the volume of the cell-rich, internal granule layer (IGL) in a set of BXD strains. The IGL ranges from 34 to 43% of total cerebellar volume. The QTL Cbs8a is significantly linked to variation in IGL volume and is suggestively linked to variation in the number of cerebellar folia. The QTLs we have discovered are among the first loci shown to modulate the size and architecture of the adult mouse cerebellum.

Animals↗

PubMed2026

CYClones: a highly powered, fully genotyped, eight-parent yeast mapping population.

The budding yeast Saccharomyces cerevisiae is a remarkably adaptable organism that thrives in diverse environments. Global sequencing of natural isolates has revealed extensive genetic diversity within the species. Here, we describe the construction and characterization of CYClones (Collaborative Yeast Cross clones), a library of 11,392 segregants generated from a multiparent funnel cross of eight genetically diverse parental strains. To enable the genetic dissection of complex traits, we imputed whole-genome sequences for all segregants and show that CYClones captures a substantial fraction of the global genetic diversity of S. cerevisiae. Haplotype representation is well maintained, with each parental haplotype present at >5% frequency across >95% of the genome. Simulations demonstrate that CYClones has ≥95% power to detect variants with heritability as low as 0.36%, with mapping resolution often finer than the length of a single gene. In summary, CYClones is a powerful community resource for dissecting the genetic architecture of complex and quantitative traits, uncovering context-dependent mutational effects, and identifying causal variants underlying phenotypic diversity.

Saccharomyces cerevisiae↗