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Annotating the molecular basis of human disease remains an unsolved challenge, as 93% of disease loci are non-coding and gene-regulatory annotations are highly incomplete.sup.1-3. Here we present EpiMap, a compendium comprising 10,000 epigenomic maps across 800 samples, which we used to define chromatin states, high-resolution enhancers, enhancer modules, upstream regulators and downstream target genes. We used this resource to annotate 30,000 genetic loci that were associated with 540 traits.sup.4, predicting trait-relevant tissues, putative causal nucleotide variants in enriched tissue enhancers and candidate tissue-specific target genes for each. We partitioned multifactorial traits into tissue-specific contributing factors with distinct functional enrichments and disease comorbidity patterns, and revealed both single-factor monotropic and multifactor pleiotropic loci. Top-scoring loci frequently had multiple predicted driver variants, converging through multiple enhancers with a common target gene, multiple genes in common tissues, or multiple genes and multiple tissues, indicating extensive pleiotropy. Our results demonstrate the importance of dense, rich, high-resolution epigenomic annotations for the investigation of complex traits. The authors present EpiMap, a compendium that comprises 10,000 epigenomic maps across more than 800 biosamples for the annotation of genome-wide association study circuitry., Author(s): Carles A. Boix [sup.1] [sup.2] [sup.3] , Benjamin T. James [sup.1] [sup.2] , Yongjin P. Park [sup.1] [sup.2] [sup.4] , Wouter Meuleman [sup.5] , Manolis Kellis [sup.1] [sup.2] Author [...]

RNA extracted from skin biopsies of 53 psoriatic individuals and 57 healthy controls were used to identify 841 cis-acting expression quantitative trait locus (eQTL) and gain better insight into the role of genetic variants regulating cutaneous gene expression. The study provides a useful method to assess the overlap between various eQTL studies and a catalog of cis-eQTLs in skin that could be applied to better understand the functional impact of identified susceptibility variants on psoriasis and other skin traits.

Populations with low linkage disequilibrium (LD) offer unique opportunities to study functional variants influencing quantitative traits. We exploited the low LD in forest trees to identify functional polymorphisms in a Eucalyptus nitens COBRA-like gene (EniCOBL4A), whose Arabidopsis homolog has been implicated in cellulose deposition. Linkage analysis in a full-sib family revealed that EniCOBL4A is the most strongly associated marker in a quantitative trait locus (QTL) region for cellulose content. Analysis of LD by genotyping 11 common single-nucleotide polymorphisms (SNPs) and a simple sequence repeat (SSR) in an association population revealed that LD declines within the length of the gene. Using association studies we fine mapped the effect of the gene to SNP7, a synonymous SNP in exon 5, which occurs between two small haplotype blocks. We observed patterns of allelic expression imbalance (AEI) and differential binding of nuclear proteins to the SNP7 region that indicate that SNP7 is a cis-acting regulatory polymorphism affecting allelic expression. We also observed AEI in SNP7 heterozygotes in a full-sib family that is linked to heritable allele-specific methylation near SNP7. This study demonstrates the potential to reveal functional polymorphisms underlying quantitative traits in low LD populations.

The combination of QTL mapping studies of synthetic lines and association mapping studies of natural diversity represents an opportunity to throw light on the genetically based variation of quantitative traits. With the positional information provided through quantitative trait locus (QTL) mapping, which often leads to wide intervals encompassing numerous genes, it is now feasible to directly target candidate genes that are likely to be responsible for the observed variation in completely sequenced genomes and to test their effects through association genetics. This approach was performed in grape, a newly sequenced genome, to decipher the genetic architecture of anthocyanin content. Grapes may be either white or colored, ranging from the lightest pink to the darkest purple tones according to the amount of anthocyanin accumulated in the berry skin, which is a crucial trait for both wine quality and human nutrition. Although the determinism of the white phenotype has been fully identified, the genetic bases of the quantitative variation of anthocyanin content in berry skin remain unclear. A single QTL responsible for up to 62% of the variation in the anthocyanin content was mapped on a Syrah x Grenache [F.sub.1] pseudo-testcross. Among the 68 unigenes identified in the grape genome within the QTL interval, a cluster of four Myb-type genes was selected on the basis of physiological evidence (VvMybA1, VvMybA2, VvMybA3, and VvMybA4). From a core collection of natural resources (141 individuals), 32 polymorphisms revealed significant association, and extended linkage disequilibrium was observed. Using a multivariate regression method, we demonstrated that five polymorphisms in VvMybA genes except VvMybA4 (one retrotransposon, three single nucleotide polymorphisms and one 2-bp insertion/deletion) accounted for 84% of the observed variation. All these polymorphisms led to either structural changes in the MYB proteins or differences in the VvMybAs promoters. We concluded that the continuous variation in anthocyanin content in grape was explained mainly by a single gene cluster of three VvMybA genes. The use of natural diversity helped to reduce one QTL to a set of five quantitative trait nucleotides and gave a clear picture of how isogenes combined their effects to shape grape color. Such analysis also illustrates how isogenes combine their effect to shape a complex quantitative trait and enables the definition of markers directly targeted for upcoming breeding programs.

Bruchids (Coleoptera: Bruchidae) can cause serious damage to mungbean and several other leguminous crops and there is a strong association between small seed size and bruchid resistance. In investigating the feasibility of breeding large-seeded cultivars with high levels of bruchid resistance, we studied the relationship between these two traits by QTL analysis. A major locus conferring resistance to Callosobruchus chinensis was identified from a wild mungbean genotype, 'ACC41' (belonging to Vigna radiata var. sublobata), collected in Australia. The proportion of the C. chinensis resistance response that could be attributed to this single QTL varied among four different resistance assays. The highest value reached was 98.5%, suggesting that bruchid resistance in this genotype is likely conditioned by this single locus. The QTL was robust and its detection was not affected by the use of different sources of the insect, different lengths and conditions of seed storage, or different bruchid resistance assay methods. This bruchid resistance QTL was coincident with one of the loci conferring seed mass detected from the three seed sources produced in Australia. However, such a co-location was not detected for the seed source produced in China. Covariance analysis revealed a complex relationship between seed mass and bruchid resistance. Nevertheless, the effect of the bruchid resistance QTL remained highly significant for all four assays after the effect of seed mass was accounted for. These results, together with the relationship between the bruchid resistance QTL identified in this study and a second one detected previously in a wild mungbean genotype from Madagascar, are discussed. Key words: bruchids, Callosobruchus, seed-feeding weevils, seed mass, mungbean. Les bruchides (Coleoptera : Bruchidae) peuvent causer des dommages importants chez le haricot mungo et plusieurs autres ldgumineuses cultivars. De plus, il y a une association etroite entre la petite taille des graines et la resistance aux bruchides. En investiguant la possibilite de selectionner des cultivars a grosses graines avec une forte resistance aux bruchides, les auteurs ont etudie les relations entre ces deux caracteres par analyse QTL. Un locus majeur conferant la resistance an Callosobruchus chinensis a ete identifiee chez le genotype sauvage 'ACC41' du haricot mungo (appartenant an V. radiata var. sublobata) obtenu en Australie. La proportion de la resistance an C. chinensis attribuable a un unique QTL variait selon les quatre evaluations de la resistance. La plus haute valeur enregistree etait 98,5 %, ce qui suggere que la resistance aux bruchides chez ce genotype est vraisemblablement contrelee par un seul locus. Ce QTL etait robuste et sa detection n'etait pas affectee par l'emploi d'insectes provenant de diffdrentes sources, par la durde et les conditions d'entreposage des grains on par la methode d'evaluation de la resistance aux bruchides. Ce QTL coincidait avec un des locus controlant la taille des graines, lequel avait ete detecte chez trois sources de graines produites en Australie. Une telle co-localisation n'a cependant pas ete observee chez une source provenant de la Chine. Une analyse de covariance a revele une relation complexe entre la taille des graines et la resistance aux bruchides. Neanmoins, l'effet de ce QTL de resistance aux bruchides est demeure hautement significatif pour l'ensemble des quatre evaluations apres avoir tenu compte de l'effet de la taille des graines. Les auteurs discutent ces resultats ainsi que les relations entre le QTL identifie ici et un autre detecte anterieurement chez un genotype sauvage provenant de Madagascar. Mots-cles : bruchides, Callosobruchus, charanrcons de la graine, poids des graines, haricot mungo. [Traduit par la Redaction], Introduction Bruchids (Coleoptera: Bruchidae) are seed-feeding weevil-like insects. They can cause serious damage to several leguminous crops including cultivated Vigna species such as mungbean, cowpea, and adzuki bean (Singh et [...]

Dissecting the genes involved in complex traits can be confounded by multiple factors, including extensive epistatic interactions among genes, the involvement of epigenetic regulators, and the variable expressivity of traits. Although quantitative trait locus (QTL) analysis has been a powerful tool for localizing the chromosomal regions underlying complex traits, systematically identifying the causal genes remains challenging. Here, through its application to plasma levels of high-density lipoprotein cholesterol (HDL) in mice, we demonstrate a strategy for narrowing QTL that utilizes comparative genomics and bioinformatics techniques. We show how QTL detected in multiple crosses are subjected to both combined cross analysis and haplotype block analysis; how QTL from one species are mapped to the concordant regions in another species; and how genomewide scans associating haplotype groups with their phenotypes can be used to prioritize the narrowed regions. Then we illustrate how these individual methods for narrowing QTL can be systematically integrated for mouse chromosomes 12 and 15, resulting in a significantly reduced number of candidate genes, often from hundreds to

The genetic architecture of plant defense against microbial pathogens may be influenced by pathogen lifestyle. While plant interactions with biotrophic pathogens are frequently controlled by the action of large-effect resistance genes that follow classic Mendelian inheritance, our study suggests that plant defense against the necrotrophic pathogen Botrytis cinerea is primarily quantitative and genetically complex. Few studies of quantitative resistance to necrotrophic pathogens have used large plant mapping populations to dissect the genetic structure of resistance. Using a large structured mapping population of Arabidopsis thaliana, we identified quantitative trait loci influencing plant response to B. cinerea, measured as expansion of necrotic lesions on leaves and accumulation of the antimicrobial compound camalexin. Testing multiple B. cinerea isolates, we identified 23 separate QTL in this population, ranging in isolate-specificity from being identified with a single isolate to controlling resistance against all isolates tested. We identified a set of QTL controlling accumulation of camalexin in response to pathogen infection that largely colocalized with lesion QTL. The identified resistance QTL appear to function in epistatic networks involving three or more loci. Detection of multilocus connections suggests that natural variation in specific signaling or response networks may control A. thaliana-B, cinerea interaction in this population.

In genomewide mapping of expression quantitative trait loci (eQTL), it is widely believed that thousands of genes are trans-regulated by a small number of genomic regions called 'regulatory hotspots,' resulting in 'trans-regulatory bands' in an eQTL map. As several recent studies have demonstrated, technical confounding factors such as batch effects can complicate eQTL analysis by causing many spurious associations including spurious regulatory hotspots. Yet little is understood about how these technical confounding factors affect eQTL analyses and how to correct for these factors. Our analysis of data sets with biological replicates suggests that it is this intersample correlation structure inherent in expression data that leads to spurious associations between genetic loci and a large number of transcripts inducing spurious regulatory hotspots. We propose a statistical method that corrects for the spurious associations caused by complex intersample correlation of expression measurements in eQTL mapping. Applying our intersample correlation emended (ICE) eQTL mapping method to mouse, yeast, and human identifies many more cis associations while eliminating most of the spurious trans associations. The concordances of cis and trans associations have consistently increased between different replicates, tissues, and populations, demonstrating the higher accuracy of our method to identify real genetic effects.

The pediatric bipolar disorder profile of the Child Behavior checklist is used to differentiate patterns of comorbidity and to search for quantitative trait loci in multiple affected ADHD sibling pairs. The CBCL-PBD profiling identified 8 percent of individuals with severe psychopathology and increased rates of oppositional defiant, conduct and anxiety disorders in clinical samples.

Genome-wide linkage analyses are performed in the Dutch subsample of the International Multi-Center ADHD Genetics (IMAGE) study. During the study it is observed that endophenotypes approaches increase the power to detect susceptibility loci in ADHD and in other complex disorders.

The Bayesian meta-analysis approach is employed to analyze the different genetic effects on quantitative traits or complex-disease risk with several distinct set of markers. The method has shown to be extremely advantageous, as it is not completely dependent on the typing of the single nucleotide polymorphisms (SNPs).

The purpose of the research presented here was to explore the genetic basis of cotton (Gossypium hirsutum L) fiber quality traits through quantitative trait locus (QTL) analysis and epistasis effects dissection, and further discuss the mechanism of heterosis. An immortalized [F.sub.2] population was developed by intercrossing Xiangzamian 2-derived recombinant inbred lines (RILs) (XZM2). Fiber quality traits were investigated in [F.sub.1] and [F.sub.2] generations of hybrid XZM2, its two parents, and the immortalized [F.sub.2] population in multiple environments in China. The low level of heterosis in XZM2 and in the immortalized [F.sub.2] population suggested a lack of dominant and dominant x dominant interaction. In general, the low correlations of genotypic heterozygosity with trait performance and mid-parent heterosis showed that heterozygosity was not always advantageous for performance, and they excluded overdominance as a major genetic basis of heterosis. A total of 50 QTLs for fiber quality were identified by single-locus QTL analysis. Although partial dominance and overdominance were detected, additive genetic variance was predominant. Common QTLs were detected both in the homozygous RILs and in the heterozygous immortalized [F.sub.2] populations. Additionally, single-locus heterotic effects and epistasis effects at the two-locus level were detected. Our results indicated that additive gene action was the primary mechanism responsible for genetic variability in fiber quality traits, Additionally, we found that single-locus heterotic effects and epistasis effects contributed to heterosis of fiber quality traits in XZM2.

Recently, reniform nematode (Rotylenchulus reniformis Linford and Oliveira) has been recognized to be a major problem on soybean [Glycine max (L.) Merr.] in the southern USA. Planting reniform nematode-resistant soybean cultivars is the most cost effective control method. With restriction fragment length polymorphism (RFLP) markers, Pioneer Hi-Bred International, Inc. had previously identified quantitative trait loci (QTL) on linkage group B1 (LG-B1) and another on LG-L associated with reniform nematode resistance in a cross between 'BSR101' and PI 437654. In this study, we refined the QTL locations and identified additional QTL conditioning resistance to reniform nematode in a population of 228 recombinant inbred lines (RILs) from a cross of BSR101 x PI 437654. A QTL ([R.sup.2] = 21%) conditioning reniform reproductive index (RI) was found on LG-L and was flanked by Sat 184 and Satt513. Two other QTL were identified, one on LG-B1 ([R.sup.2] = 16%) and the other on LG-G ([R.sup.2] = 8%). These two QTL acted in an epistatic manner with lines homozygous for PI 437654 alleles at both QTL providing the lowest reniform RI. The 31 RILs from BSR101 x PI 437654 that were homozygous for the PI 437654 alleles at Satt513, Satt359, and Sat_168 averaged 1077 reniform eggs and juveniles (RI = 0.63), while the 33 RILs homozygous for the BSR101 alleles averaged 10606 (RI = 6.24). By screening the RILs population of 'Prichard' x 'Anand' we confirmed that the QTL on LG-G and-B1 conditioned reniform RI.

Pearl millet marker-assisted selection (MAS) programs targeting adaptation to variable postflowering moisture environments would benefit from quantitative trait loci (QTLs) that improve grain yield across the full range of postflowering moisture conditions, rather than just in drought-stressed environments. This research was undertaken to identify such QTLs from an extensive (12-environment) phenotyping data set that included both stressed and unstressed postflowering environments. Genetic materials were test crosses of 79 [F.sub.2]-derived [F.sub.4] progenies from a mapping population based on a widely adapted maintainer line (ICMB 841) x a postflowering drought-tolerant maintainer (863B). Three QTLs (on linkage group [LG] 2, LG 3, and LG 4) were identified as primary candidates for MAS for improved grain yield across variable postflowering moisture environments. The QTLs on LG 2 and LG 3 (the most promising) explained a useful proportion (13-25%) of phenotypic variance for grain yield across environments. They also co-mapped with QTLs for harvest index across environments, and with QTLs for both grain number and individual grain mass under severe terminal stress. Neither had a significant QTL x environment interaction, indicating that their predicted effects should occur across a broad range of available moisture environments. We have estimated the benefits in grain yield and accompanying changes in yield components and partitioning indices that would be expected as a result of incorporating these QTLs into other genetic backgrounds by MAS.

White mold caused by Sclerotinia sclerotiorum (Lib.) de Bary is a major disease limiting dry bean (Phaseolus vulgaris L.) production. Genetic resistance provides some control but is difficult to breed for because of low heritability. We sought to determine if marker-assisted selection for quantitative trait loci (QTL) conferring partial resistance could facilitate breeding for resistance to white mold in dry bean. The Phs marker linked with a QTL derived from landrace G122 on linkage group B7 was back-crossed into 'Winchester' pinto, forming two B[C.sub.3][F.sub.4:6] inbred line populations. The AW9.1200 and SS18.1650 markers linked with a QTL from snap bean breeding line NY6020-4 on B8 were backcrossed into 'Maverick' pinto and 'Matterhorn' great northern, forming B[C.sub.2][F.sub.4:6] inbred line populations. The B7 QTL in the B[C.sub.3][F.sub.4:6] populations on average explained 52% of the phenotypic variation for disease reaction in the greenhouse test and 10% across four field tests. The B8 QTL explained 30% in the greenhouse and 10% in the field. Averaged across tests and populations the B7 and B8 QTL conditioned 15 and 17% reduction in disease severity score, respectively. Linkage drag from selection of the B7 QTL was observed for yield. MAS for the B7 and B8 QTL was an effective breeding tool for introgressing partial resistance to white mold into susceptible pinto and great northern dry bean market classes, but further selection for agronomic performance may be required to obtain lines worthy of commercial production.

Available approaches for controlling stratification by use of substructure-informative loci is not able to resolve the population stratification in case-control studies of disease-marker association hence, a new two-step procedure is proposed to address the issue. This two-step procedure approach yields a more appropriate correction for stratification than the principal components or genomic control.

A genomewide linkage screen of simple heavy-smoking quantitative trait is conducted using two independent samples. The study found significant evidence of linkage to chromosome 20 in the Finnish sample.

The doubled-haploid (DH) barley population (Harrington x TR306) developed by the North American Barley Genome Mapping Project (NABGMP) for QTL mapping consisted of 145 lines and 127 markers covering a total genome length of 1270 cM. These DH lines were evaluated in ~25 environments for seven quantitative traits: heading, height, kernel weight, lodging, maturity, test weight, and yield. We applied an empirical Bayes method that simultaneously estimates 127 main effects for all markers and 127(127 - 1)/2 = 8001 interaction effects for all marker pairs in a single model. We found that the largest main-effect QTL (single marker) and the largest epistatic effect (single pair of markers) explained ~18 and 2.6% of the phenotypic variance, respectively. On average, the sum of all significant main effects and the sum of all significant epistatic effects contributed 35 and 6% of the total phenotypic variance, respectively. Epistasis seems to be negligible for all the seven traits. We also found that whether two loci interact does not depend on whether or not the loci have individual main effects. This invalidates the common practice of epistatic analysis in which epistatic effects are estimated only for pairs of loci of which both have main effects.

Genetic control of yield under reproductive-stage drought stress was studied in a population of 436 random [F.sub.3]-derived lines from a cross between the upland rice (Oryza sativa L.) cultivars Vandana and Way Rarem. Screening was conducted under upland conditions at IRRI during the dry seasons of 2005 and 2006. Lines were evaluated in drought stress and nonstress trials in both years to identify QTL contributing to drought resistance. For QTL detection, a set of random lines and the highest and lowest-yielding lines under both stress and nonstress conditions were genotyped by 126 SSR markers. A QTL (qtl12.1) with a large effect on grain yield under stress was detected on Chromosome 12 in both years. The whole population was genotyped for additional markers on Chromosome 12, allowing QTL localization to a 10.2 cM region between SSR markers RM28048 and RM511. Under stress conditions, the locus also increased harvest index, biomass yield, and plant height while reducing the number of days to flowering. Under nonstress conditions, qtl12.1 did not significantly affect any trait. The additive effect of this QTL on grain yield under stress was 172 kg [ha.sup.-1] per year over the 2 yr of testing, representing 47% of the average yield under stress and explaining 51% of the genetic variance. The yield-increasing allele was derived from the susceptible parent, Way Rarem, suggesting an epistatic effect. This is the first QTL reported in rice having a large and repeatable effect on grain yield under severe drought stress in the field.