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PubMed2001

A train of thoughts on gene mapping.

Complex traits, by definition, are the pheonotypic outcome from multiple interacting genes. The traditional analysis of association studies on complex traits is to test one locus at a time, but a better approach is to analyze all markers simultaneously. We previously proposed a two-stage approach, first selecting the influential markers and then modeling main and interaction effects of these markers. Here we introduce alternative approaches to marker selection and discuss issues regarding analytical tools for disease gene mapping, marker selection, and statistical modeling.

Analysis of Variance↗
PubMed1998

Multiple phenotype modeling in gene-mapping studies of quantitative traits: power advantages.

Genomewide searches for loci influencing complex human traits and diseases such as diabetes, hypertension, and obesity are often plagued by low power and interpretive difficulties. Attempts to remedy these difficulties have typically relied on, and have promoted the use of, novel subject-ascertainment schemes, larger sample sizes, a greater density of DNA markers, and more-sophisticated statistical modeling and analysis strategies. Many of these remedies can be costly to implement. We investigate the utility of a simple statistical model for the mapping of quantitative-trait loci that incorporates multiple phenotypic or diagnostic endpoints into a gene-mapping analysis. The approach considers finding a linear combination of multiple phenotypic values that maximizes the evidence for linkage to a locus. Our results suggest that substantial increases in the power to map loci can be obtained with the proposed technique, although the increase in power obtained is a function of the size and direction of the residual correlation among the phenotypes used in the analysis. Extensive simulation studies are described that justify these claims, for cases in which two phenotypic measures are analyzed. This approach can be easily extended to cover more-complex situations and may provide a basis for more insightful genetic-analysis paradigms.

Chromosome Mapping↗
PubMed2004

Quantitative trait loci controlling phenotypes related to the perennial versus annual habit in wild relatives of maize.

We used quantitative trait locus/loci (QTL) mapping to study the inheritance of traits associated with perennialism in a cross between an annual (Zea mays ssp. parviglumis) and a perennial (Z. diploperennis) species of teosinte. The most striking difference between these species is that Z. diploperennis forms rhizomes, whereas Z. mays ssp. parviglumis lacks these over-wintering underground stems. An F2 population of 425 individuals was genotyped at 95 restriction fragment length polymorphism marker loci and the association between phenotype and genotype was analyzed by composite interval mapping. We detected a total of 38 QTL for eight traits. The number of QTL found for each trait ranged from two for rhizome formation to nine for tillering. QTL for six of the traits mapped near each other on chromosome 2, and QTL for four traits mapped near each other on chromosome 6, suggesting that these regions play an important role in the evolution of the perennial habit in teosinte. Most of the 38 QTL had small effects, and no single QTL showed a strikingly large effect. The map positions that we determined for rhizome formation and other traits in teosinte may help to locate corresponding QTL in pasture and turf grasses used as forage for cattle and for erosion control in agro-ecosystems.

Chromosome Mapping↗
PubMed2001

[QTL mapping of the root traits in rice seedling].

Drought resistance is one of the most important traits in rice abiotic study. The report here analyzed several major root traits affecting drought resistance expression with the double haploid population (DH) from ZYQ8 (indica)/JX17 (japonica) containing 127 lines. After 10 days solution culturing, three rice root traits, Maximum Root Length (MRL), Dry Root Weight (DRW) and Root/Shoot Ratio of Dry Weight (RSR), were revealed existing significant difference among the DH lines. Using the constructed molecular linkage map from this segregating population, the QTL mapping was conducted among these three root parameters. MRL, DRW, and RSR were found being controlled by 2/1/2 QTLs respectively in JX17, 2/0/1 QTLs respectively in ZYQ8. Phenotype variance could be explained by 16.4% and 17.0% for MRL, 16.4% for DRW, 10.4% and 19.9% for RSR in JX17, 19.6% and 13.0% for MRL, 13.2% for RSR in ZYQ8. All these QTLs identified were distributed on rice chromosome 2, 3, 4, 5, 6, 9 and 10. Comparing with the other mapping results, one QTL for each trait (L169-CT106A for MRL, G45-G1314A for DRW, G62-G144 for RSR) was identical with the results reported previously.

Chromosome Mapping↗
PubMed2006

Confirmation and fine mapping of ethanol sensitivity quantitative trait loci, and candidate gene testing in the LXS recombinant inbred mice.

In previous studies, we have mapped quantitative trait loci (QTLs) for hypnotic sensitivity to ethanol using a small recombinant inbred (RI) panel and a large F(2) backcross. Alcohol sensitivity is a major predictor of long-term risk for alcoholism. We remapped hypnotic sensitivity using a new set of 75 RI strains, the LXS, derived from Inbred Long Sleep and Inbred Short Sleep strains. We expected to improve mapping resolution in the QTL regions and to identify novel QTLs for loss of the righting reflex due to ethanol. We used three common mapping algorithms (R/qtl, QTL Cartographer, and WebQTL) to map QTLs in the LXS, and we compared the results. Most mapping studies use only a single algorithm, an approach that may result in failure to identify minor QTLs. We confirmed most of our previously reported QTLs, although one major QTL from earlier work (Lore2) failed to replicate, possibly because it represented multiple linked genes separated by recombination in the RI strains. We also report narrowed confidence intervals, based on mapping with a new genetic resource of more than 4000 polymorphic single-nucleotide polymorphism markers. These narrowed confidence intervals will facilitate candidate gene identification and assessment of overlap with human regions specifying risk for alcoholism. Finally, we present an approach for using these RI strains to assess evidence for candidate genes in the narrowed intervals, and we apply this method to a strong candidate, the serotonin transporter.

Alcoholism↗
PubMed2001

[QTLs mapping of some agronomic traits of soybean].

A recombinant inbred population of soybean was developed from a intraspecies cross of Kefeng1 and Nannong 1138-2. A genetic linkage group of soybean genome was constructed, which composed of 22 linkage groups, included 302 loci, covered 2,363.8 cM. The interval mapping was used to identify quantitative trait loci (QLTs) associated with ten important agronomic traits in the RIL population. The results indicated that thirty-four QTLs were detected for the ten traits associated with yield and seed quality. We conclude that QTL analysis offers a useful tool for the genetic improvement of soybean cultivars.

Chromosome Mapping↗
PubMed2003

Mapping of genomic regions (quantitative trait loci) controlling production and quality in industrial cultures of the edible basidiomycete Pleurotus ostreatus.

Industrial production of the edible basidiomycete Pleurotus ostreatus (oyster mushroom) is based on a solid fermentation process in which a limited number of selected strains are used. Optimization of industrial mushroom production depends on improving the culture process and breeding new strains with higher yields and productivities. Traditionally, fungal breeding has been carried out by an empirical trial and error process. In this study, we used a different approach by mapping quantitative trait loci (QTLs) controlling culture production and quality within the framework of the genetic linkage map of P. ostreatus. Ten production traits and four quality traits were studied and mapped. The production QTLs identified explain nearly one-half of the production variation. More interestingly, a single QTL mapping to the highly polymorphic chromosome VII appears to be involved in control of all the productivity traits studied. Quality QTLs appear to be scattered across the genome and to have less effect on the variation of the corresponding traits. Moreover, some of the new hybrid strains constructed in the course of our experiments had production or quality values higher than those of the parents or other commercial strains. This approach opens the possibility of marker-assisted selection and breeding of new industrial strains of this fungus.

Chromosome Mapping↗
PubMed1999

Mapping and characterization of quantitative trait loci for non-insulin-dependent diabetes mellitus with an improved genetic map in the Otsuka Long-Evans Tokushima fatty rat.

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese-type, non-insulin-dependent diabetes mellitus (NIDDM) in humans. We have previously reported four quantitative trait loci (QTLs) responsible for NIDDM on Chromosomes (Chrs) 7, 14, 8, and 11 (Nidd1-4/of for Non-insulin-dependent diabetes1-4/oletf) by a whole-genome search in 160 F2 progenies obtained by mating the OLETF and the Fischer-344 (F344) rats. Our present investigation was designed to identify and characterize novel QTLs affecting NIDDM by performing a genome-wide linkage analysis of genes for glucose levels and body weight and analysis for gene-to-gene and gene-to-body-weight interactions on an improved genetic map with a set of 382 informative markers in the 160 F2 progenies. We have identified seven novel QTLs on rat Chrs 1 (Nidd5 and 6/of), 5 (Nidd7/of), 9 (Nidd8/of), 12 (Nidd9/of), 14 (Nidd10/of) and 16 (Nidd11/of) which, together with the Nidd1-4/of, account for a total of approximately 60% and approximately 75% of the genetic variance of the fasting and postprandial glucose levels, respectively, in the F2. While the OLETF allele corresponds with increased glucose levels as expected for the novel QTLs except Nidd8 and 9/of, the Nidd8 and 9/of exhibit heterosis: heterozygotes showing significantly higher glucose levels than OLETF or F344 homozygotes. There are epistatic interactions between Nidd1 and 10/of and between Nidd2 and 8/of. Additionally, our results indicated that the Nidd6 and 11/of could also contribute to an increase of body weight, and that the other five QTLs could show no linkage with body weight, but Nidd8,9, and 10/of have an interaction with body weight.

Animals↗
PubMed2001

Genome partitioning and whole-genome analysis.

Standard DNA marker-based approaches to mapping genes that influence complex traits typically consider a limited number of hypotheses. Most of these hypotheses concentrate on the effect of a single individual locus (or relatively few loci) on the trait of interest. Although of tremendous importance scientifically, such hypotheses do not accommodate the full range of genetic phenomena that may contribute to phenotypic expression. We present novel approaches to complex trait analysis that make as complete use of marker information as is possible. The proposed methodologies can be used to entertain a wide variety of hypotheses, including those that engage, for example, the contribution of a particular chromosome, genome-wide heterozygosity, and multiple genomic regions, to phenotypic expression. We consider a number of possible extensions of the proposed methods as well as their limitations. Although we discuss many methodological details in the context of quantitative trait locus mapping involving sampling units such as human pedigrees and hybrids resulting from crosses between inbred strains of model organisms, our procedures can be easily adapted to standard sibpair and other sampling unit-based designs. Ultimately, the proposed approaches not only have the potential to increase power to identify individual loci that harbor trait-influencing genes, but also present a framework for testing a number of hypotheses about the nature of the genetic determinants of phenotypes in general.

Alleles↗
PubMed2003

Quantitative trait loci analysis of nitrogen use efficiency in Arabidopsis.

Improving plant nitrogen (N) use efficiency or controlling soil N requires a better knowledge of the regulation of plant N metabolism. This could be achieved using Arabidopsis as a model genetic system, taking advantage of the natural variation available among ecotypes. Here, we describe an extensive study of N metabolism variation in the Bay-0 x Shahdara recombinant inbred line population, using quantitative trait locus (QTL) mapping. We mapped QTL for traits such as shoot growth, total N, nitrate, and free-amino acid contents, measured in two contrasting N environments (contrasting nitrate availability in the soil), in controlled conditions. Genetic variation and transgression were observed for all traits, and most of the genetic variation was identified through QTL and QTL x QTL epistatic interactions. The 48 significant QTL represent at least 18 loci that are polymorphic between parents; some may correspond to known genes from the N metabolic pathway, but others represent new genes controlling or interacting with N physiology. The correlations between traits are dissected through QTL colocalizations: The identification of the individual factors contributing to the regulation of different traits sheds new light on the relations among these characters. We also point out that the regulation of our traits is mostly specific to the N environment (N availability). Finally, we describe four interesting loci at which positional cloning is feasible.

Amino Acids↗
PubMed2005

Using cDNA and genomic sequences as tools to develop SNP strategies in cassava (Manihot esculenta Crantz).

Single nucleotide polymorphisms (SNP) are the most abundant type of DNA polymorphism found in animal and plant genomes. They provide an important new source of molecular markers that are useful in genetic mapping, map-based positional cloning, quantitative trait locus mapping and the assessment of genetic distances between individuals. Very little is known on the frequency of SNPs in cassava. We have exploited the recently-developed collection of cassava expressed sequence tags (ESTs) to detect SNPs in the five cultivars of cassava used to generate the sequences. The frequency of intra-cultivar and inter-cultivar SNPs after analysis of 111 contigs was one polymorphism per 905 and one per 1,032 bp, respectively; totaling 1 each 509 bp. We have obtained further information on the frequency of SNPs in six cassava cultivars by analysis of 33 amplicons obtained from 3' EST and BAC end sequences. Overall, about 11 kb of DNA sequence was obtained for each cultivar. A total of 186 SNPs (136 and 50 from ESTs and BAC ends, respectively) were identified. Among these, 146 were intra-cultivar polymorphisms, while 80 were inter-cultivar polymorphisms. Thus the total frequency of SNPs was one per 62 bp. This information will help to develop new strategies for EST mapping as well as their association with phenotypic characteristics.

Computational Biology↗
PubMed2006

Modeling segregation distortion for viability selection. I. Reconstruction of linkage maps with distorted markers.

Molecular markers have been widely used to map quantitative trait loci (QTL). The QTL mapping partly relies on accurate linkage maps. The non-Mendelian segregation of markers, which affects not only the estimation of genetic distance between two markers but also the order of markers on a same linkage group, is usually observed in QTL analysis. However, these distorted markers are often ignored in the real data analysis of QTL mapping so that some important information may be lost. In this paper, we developed a multipoint approach via Hidden Markov chain model to reconstruct the linkage maps given a specified gene order while simultaneously making use of distorted, dominant and missing markers in an F(2) population. The new method was compared with the methods in the MapManager and Mapmaker programs, respectively, and verified by a series of Monte Carlo simulation experiments along with a working example. Results showed that the adjusted linkage maps can be used for further QTL or segregation distortion locus (SDL) analysis unless there are strong evidences to prove that all markers show normal Mendelian segregation.

Chromosome Mapping↗
PubMed1999

Construction of an AFLP genetic map with nearly complete genome coverage in Pinus taeda.

De novo construction of complete genetic linkage maps requires large mapping populations, large numbers of genetic markers, and efficient algorithms for ordering markers and evaluating order confidence. We constructed a complete genetic map of an individual loblolly pine (Pinus taeda L.) using amplified fragment length polymorphism (AFLP) markers segregating in haploid megagametophytes and PGRI mapping software. We generated 521 polymorphic fragments from 21 AFLP primer pairs. A total of 508 fragments mapped to 12 linkage groups, which is equal to the Pinus haploid chromosome number. Bootstrap locus order matrices and recombination matrices generated by PGRI were used to select 184 framework markers that could be ordered confidently. Order support was also evaluated using log likelihood criteria in MAPMAKER. Optimal marker orders from PGRI and MAPMAKER were identical, but the implied reliability of orders differed greatly. The framework map provides nearly complete coverage of the genome, estimated at approximately 1700 cM in length using a modified estimator. This map should provide a useful framework for merging existing loblolly pine maps and adding multiallelic markers as they become available. Map coverage with dominant markers in both linkage phases will make the map useful for subsequent quantitative trait locus mapping in families derived by self-pollination.

Chromosome Mapping↗
PubMed2004

Comparative recombination rates in the rat, mouse, and human genomes.

Levels of recombination vary among species, among chromosomes within species, and among regions within chromosomes in mammals. This heterogeneity may affect levels of diversity, efficiency of selection, and genome composition, as well as have practical consequences for the genetic mapping of traits. We compared the genetic maps to the genome sequence assemblies of rat, mouse, and human to estimate local recombination rates across these genomes. Humans have greater overall levels of recombination, as well as greater variance. In rat and mouse, the size of the chromosome and proximity to telomere have less effect on local recombination rate than in human. At the chromosome level, rat and mouse X chromosomes have the lowest recombination rates, whereas human chromosome X does not show the same pattern. In all species, local recombination rate is significantly correlated with several sequence variables, including GC%, CpG density, repetitive elements, and the neutral mutation rate, with some pronounced differences between species. Recombination rate in one species is not strongly correlated with the rate in another, when comparing homologous syntenic blocks of the genome. This comparative approach provides additional insight into the causes and consequences of genomic heterogeneity in recombination.

Animals↗
PubMed2004

A microsatellite linkage map of Drosophila mojavensis.

BACKGROUND: Drosophila mojavensis has been a model system for genetic studies of ecological adaptation and speciation. However, despite its use for over half a century, no linkage map has been produced for this species or its close relatives. RESULTS: We have developed and mapped 90 microsatellites in D. mojavensis, and we present a detailed recombinational linkage map of 34 of these microsatellites. A slight excess of repetitive sequence was observed on the X-chromosome relative to the autosomes, and the linkage groups have a greater recombinational length than the homologous D. melanogaster chromosome arms. We also confirmed the conservation of Muller's elements in 23 sequences between D. melanogaster and D. mojavensis. CONCLUSIONS: The microsatellite primer sequences and localizations are presented here and made available to the public. This map will facilitate future quantitative trait locus mapping studies of phenotypes involved in adaptation or reproductive isolation using this species.

Animals↗
PubMed2004

QTL mapping of economically important traits in silkworm (Bombyx mori).

A backcrossed population (BC1) was derived from a cross between C100 and Dazao. AFLP technique was employed for mapping the QTLs. The QTLs for the whole cocoon weight, cocoon shell weight, ratio of cocoon shell, weight of pupae etc. were analyzed and 11 QTLs were detected based on the constructed linkage map. Two QTLs for whole cocoon weight were localized on linkage group 6 and 19; three QTLs for cocoon shell weight were localized on linkage group 3, 14 and 19; three QTLs for ratio of cocoon shell were localized on the linkage group 2, 11 and 15, and three QTLs for the weight of pupae were localized on linkage 2, 14 and 19. All these have laid an important base for the marker assisted breeding of the silkworm.

Animals↗
PubMed2005

Linkage mapping bovine EST-based SNP.

BACKGROUND: Existing linkage maps of the bovine genome primarily contain anonymous microsatellite markers. These maps have proved valuable for mapping quantitative trait loci (QTL) to broad regions of the genome, but more closely spaced markers are needed to fine-map QTL, and markers associated with genes and annotated sequence are needed to identify genes and sequence variation that may explain QTL. RESULTS: Bovine expressed sequence tag (EST) and bacterial artificial chromosome (BAC)sequence data were used to develop 918 single nucleotide polymorphism (SNP) markers to map genes on the bovine linkage map. DNA of sires from the MARC reference population was used to detect SNPs, and progeny and mates of heterozygous sires were genotyped. Chromosome assignments for 861 SNPs were determined by twopoint analysis, and positions for 735 SNPs were established by multipoint analyses. Linkage maps of bovine autosomes with these SNPs represent 4585 markers in 2475 positions spanning 3058 cM. Markers include 3612 microsatellites, 913 SNPs and 60 other markers. Mean separation between marker positions is 1.2 cM. New SNP markers appear in 511 positions, with mean separation of 4.7 cM. Multi-allelic markers, mostly microsatellites, had a mean (maximum) of 216 (366) informative meioses, and a mean 3-lod confidence interval of 3.6 cM Bi-allelic markers, including SNP and other marker types, had a mean (maximum) of 55 (191) informative meioses, and were placed within a mean 8.5 cM 3-lod confidence interval. Homologous human sequences were identified for 1159 markers, including 582 newly developed and mapped SNP. CONCLUSION: Addition of these EST- and BAC-based SNPs to the bovine linkage map not only increases marker density, but provides connections to gene-rich physical maps, including annotated human sequence. The map provides a resource for fine-mapping quantitative trait loci and identification of positional candidate genes, and can be integrated with other data to guide and refine assembly of bovine genome sequence. Even after the bovine genome is completely sequenced, the map will continue to be a useful tool to link observable phenotypes and animal genotypes to underlying genes and molecular mechanisms influencing economically important beef and dairy traits.

Alleles↗