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PubMed2004

A genetic analysis of relative growth rate and underlying components in Hordeum spontaneum.

Species from productive and unproductive habitats differ inherently in their relative growth rate (RGR) and a wide range of correlated quantitative traits. We investigated the genetic basis of this trait complex, and specifically assessed whether it is under the control of just one or a few genes that can act as 'master switches' by simultaneously affecting a range of traits in the complex. To address this problem, we crossed two Hordeum spontaneum lines originating from two habitats that differ in productivity. The F3 offspring, in which parental alleles are present in different combinations due to recombination and segregation, was analysed for RGR and its underlying components (leaf area ratio, unit leaf rate, photosynthesis, respiration), as well as a number of other physiological and morphological parameters. For this intra-specific comparison, we found a complex of positively and negatively correlated traits, which was quite similar to what is generally observed across species. A quantitative trait loci (QTL) analysis showed three major and one minor QTL for RGR. Most other variables of the growth-trait complex showed fewer QTLs that were typically scattered over various locations on the genome. Thus, at least in H. spontaneum, we found no evidence for regulation of the trait complex by one or two master switches.

Crosses, Genetic↗
PubMed2006

Detection of SNP epistasis effects of quantitative traits using an extended Kempthorne model.

Epistasis effects (gene interactions) have been increasingly recognized as important genetic factors underlying complex traits. The existence of a large number of single nucleotide polymorphisms (SNPs) provides opportunities and challenges to screen DNA variations affecting complex traits using a candidate gene analysis. In this article, four types of epistasis effects of two candidate gene SNPs with Hardy-Weinberg disequilibrium (HWD) and linkage disequilibrium (LD) are considered: additive x additive, additive x dominance, dominance x additive, and dominance x dominance. The Kempthorne genetic model was chosen for its appealing genetic interpretations of the epistasis effects. The method in this study consists of extension of Kempthorne's definitions of 35 individual genetic effects to allow HWD and LD, genetic contrasts of the 35 extended individual genetic effects to define the 4 epistasis effects, and a linear model method for testing epistasis effects. Formulas to predict statistical power (as a function of contrast heritability, sample size, and type I error) and sample size (as a function of contrast heritability, type I error, and type II error) for detecting each epistasis effect were derived, and the theoretical predictions agreed well with simulation studies. The accuracy in estimating each epistasis effect and rates of false positives in the absence of all or three epistasis effects were evaluated using simulations. The method for epistasis testing can be a useful tool to understand the exact mode of epistasis, to assemble genome-wide SNPs into an epistasis network, and to assemble all SNP effects affecting a phenotype using pairwise epistasis tests.

Computer Simulation↗
PubMed2006

Statistical methods for expression quantitative trait loci (eQTL) mapping.

Traditional genetic mapping has largely focused on the identification of loci affecting one, or at most a few, complex traits. Microarrays allow for measurement of thousands of gene expression abundances, themselves complex traits, and a number of recent investigations have considered these measurements as phenotypes in mapping studies. Combining traditional quantitative trait loci (QTL) mapping methods with microarray data is a powerful approach with demonstrated utility in a number of recent biological investigations. These expression quantitative trait loci (eQTL) studies are similar to traditional QTL studies, as a main goal is to identify the genomic locations to which the expression traits are linked. However, eQTL studies probe thousands of expression transcripts; and as a result, standard multi-trait QTL mapping methods, designed to handle at most tens of traits, do not directly apply. One possible approach is to use single-trait QTL mapping methods to analyze each transcript separately. This leads to an increased number of false discoveries, as corrections for multiple tests across transcripts are not made. Similarly, the repeated application, at each marker, of methods for identifying differentially expressed transcripts suffers from multiple tests across markers. Here, we demonstrate the deficiencies of these approaches and propose a mixture over markers (MOM) model that shares information across both markers and transcripts. The utility of all methods is evaluated using simulated data as well as data from an F(2) mouse cross in a study of diabetes. Results from simulation studies indicate that the MOM model is best at controlling false discoveries, without sacrificing power. The MOM model is also the only one capable of finding two genome regions previously shown to be involved in diabetes.

Animals↗
PubMed2003

The extent and distribution of linkage disequilibrium in a multi-hierarchic outbred canine pedigree.

A canine integrated linkage-radiation map has been recently constructed by using microsatellite markers. This map, with a good coverage of the canine genome, allows for a genome-wide search for the extent and distribution of linkage disequilibrium derived from linkage and evolutionary forces. In this study, we genotyped an outbred pedigree between Labrador retriever and Greyhound breeds with a set of microsatellite markers (240) from the canine linkage map. Linkage disequilibrium was measured between all syntenic and nonsyntenic marker pairs. Analysis of syntenic pairs revealed a significant correlation (-0.229, P < 0.001) between linkage disequilibrium and genetic distance (log transformed). Significant linkage disequilibria were observed more frequently between syntenic pairs spaced <40 cM than those paced >40 cM. There is a clear trend for linkage disequilibrium to decline with marker distance. From our results, a genome-wide screen with markers at low to moderate density (1-2 per 10 cM) should take full advantage of linkage disequilibrium for quantitative trait locus mapping in dogs. This study supports the appropriateness of linkage disequilibrium analysis to detect and map quantitative trait loci underlying complex traits in dogs.

Animals↗
PubMed2005

Exploiting naturally occurring DNA variation and molecular profiling data to dissect disease and drug response traits.

Identifying the key drivers of common human diseases and associated signaling pathways remains one of the primary objectives in the biomedical and life sciences. In this respect, common inbred strains of mice have played a crucial role, and recent advances in the development of genomics and bioinformatics tools have significantly enhanced their utility for this purpose. These advances have enabled a more holistic, network-oriented view of biological systems that facilitates elucidation of the underlying causes of disease and the best ways to target them. Success in reconstructing gene networks underlying disease traits (or other complex traits like drug response) and identifying the key drivers of these traits now largely rests on integrative approaches that combine data from multiple different sources. Such integrative genomics approaches that take into account genotypic, molecular profiling and clinical data in segregating mouse populations have recently been developed. Key to this integration has been the development and application of sophisticated algorithms to mine the diversity of data.

Algorithms↗
PubMed2004

The human genome project and the discovery of genetic determinants of cancer susceptibility.

The Human Genome Project has recently provided a great deal of information on the sequence that comprises the human genome. We are now in the process of structuring and deciphering the 3 x 10(9) base sequence in order to gain insights into its functional role. Several efforts are focusing on the search for DNA sequence variations underlying common/complex diseases that constitute a real burden in terms of public health measures. As expected, the genetic architecture of these complex traits, shows tremendous complexity, and the discovery and characterisation of susceptibility alleles constitute a real challenge for the geneticist. Conceptual and experimental genetic approaches aimed at dissecting the molecular features of susceptibility genes, in particular those predisposing to cancer, are outlined and discussed in this review.

Animals↗
PubMed2001

Nonsyndromic cleft lip and palate: complex genetics and environmental effects.

Nonsyndromic cleft lip and palate (CL/P) is a common craniofacial malformation with a complex genetic component. Attempts at identifying susceptibility loci via family and case-control studies have proved inconsistent. It is likely that initial predictions of the complex interactions involved in facial development were underestimated. The candidate gene list for CL/P is getting longer and the need for an impartial, systematic screening technique, to implicate or refute the inclusion of particular loci, is apparent. Large-scale multi-centre collaborations will also be necessary if we are to pursue the avenues of gene-environment interactions, which have opened up over recent years. So we are faced with the question 'Can this complex trait be too complex?'

Animals↗
PubMed2004

Regulation of human p53 activity and cell localization by alternative splicing.

The development of cancer is a multistep process involving mutations in proto-oncogenes, tumor suppressor genes, and other genes which control cell proliferation, telomere stability, angiogenesis, and other complex traits. Despite this complexity, the cellular pathways controlled by the p53 tumor suppressor protein are compromised in most, if not all, cancers. In normal cells, p53 controls cell proliferation, senescence, and/or mediates apoptosis in response to stress, cell damage, or ectopic oncogene expression, properties which make p53 the prototype tumor suppressor gene. Defining the mechanisms of regulation of p53 activity in normal and tumor cells has therefore been a major priority in cell biology and cancer research. The present study reveals a novel and potent mechanism of p53 regulation originating through alternative splicing of the human p53 gene resulting in the expression of a novel p53 mRNA. This novel p53 mRNA encodes an N-terminally deleted isoform of p53 termed p47. As demonstrated within, p47 was able to effectively suppress p53-mediated transcriptional activity and impair p53-mediated growth suppression. It was possible to select for p53-null cells expressing p47 alone or coexpressing p53 in the presence of p47 but not cells expressing p53 alone. This showed that p47 itself does not suppress cell viability but could control p53-mediated growth suppression. Interestingly, p47 was monoubiquitinated in an Mdm2-independent manner, and this was associated with its export out of the nucleus. In the presence of p47, there was a reduction in Mdm2-mediated polyubiquitination and degradation of p53, and this was also associated with increased monoubiquitination and nuclear export of p53. The expression of p47 through alternative splicing of the p53 gene thus has a major influence over p53 activity at least in part through controlling p53 ubiquitination and cell localization.

Alternative Splicing↗
PubMed2003

Genetics of cleft lip and palate revisited.

Cleft lip with or without cleft palate (CL/CP) is one of the most common structural birth defects with treatment including multiple surgeries speech therapy, and dental and orthodontic treatments over the first 18 years of life. Providing care for these patients and families includes educating patients and parents about the genetics of CL/CP, as well as meeting the immediate medical needs. Attempts at identifying susceptibility loci via family and case-control studies have proved inconsistent. It is likely that initial predictions of the complex interactions involved in facial development were underestimated. The candidate gene list for CL/P is getting longer and the need for an impartial systematic screening technique, to implicate or refute the inclusion of particular loci, is apparent. So we are faced with the question "Can this complex trait be too complex?" The aim of this review is to make the dentist aware of the differences between syndromic and non-syndromic cleft as well as understanding the etiological variation in cleft lip with and without cleft palate. This will aid the dentist in diagnosis and give proper genetic counseling to parents and patients of cleft lip and palate.

Adolescent↗
PubMed1999

Allele dose analysis in recombinant inbred strains: a tool for multiple phenotype analysis with implications for quantitative trait loci mapping.

A considerable investment in genetic mapping is necessary to confirm linkages of quantitative trait loci for complex traits such as ethanol sensitivity, a significant predictor of alcoholism. Before embarking on such intensive mapping efforts in large intercrosses, we suggest an approach based on genetic marker data in recombinant strains that yield a rationale for selecting a battery of related phenotypes for confirmation studies of quantitative trait loci action. Using this approach with selected strains of mice, we retrospectively consider the relationship between ethanol sensitivity and neurotensin levels in several mammalian brain regions.

Alcoholism↗
PubMed1997

Epistasis for three grain yield components in rice (Oryza sativa L.).

The genetic basis for three grain yield components of rice, 1000 kernel weight (KW), grain number per panicle (GN), and grain weight per panicle (GWP), was investigated using restriction fragment length polymorphism markers and F4 progency testing from a cross between rice subspecies japonica (cultivar Lemont from USA) and indica (cv. Tequing from China). Following identification of 19 QTL affecting these traits, we investigated the role of epistasis in genetic control of these phenotypes. Among 63 markers distributed throughout the genome that appeared to be involved in 79 highly significant (P < 0.001) interactions, most (46 or 73%) did not appear to have "main" effects on the relevant traits, but influenced the trait(s) predominantly through interactions. These results indicate that epistasis is an important genetic basis for complex traits such as yield components, especially traits of low heritability such as GN and GWP. The identification of epistatic loci is an important step toward resolution of discrepancies between quantitative trait loci mapping and classical genetic dogma, contributes to better understanding of the persistence of quantitative genetic variation in populations, and impels reconsideration of optimal mapping methodology and marker-assisted breeding strategies for improvement of complex traits.

Adaptation, Physiological↗
PubMed2006

Genetics of divergence in male wing pigmentation and courtship behavior between Drosophila elegans and D. gunungcola.

Many sex-specific traits involved in mating consist of functionally coordinated morphologies and behaviors. How the components of these complex traits evolve and become coordinated during evolution is unknown. In order to understand how such trait complexes evolve and diversify, we must decipher the genetic underpinnings of their components. In this study, we begin to elucidate the genetic architecture underlying differences in functionally related male pigmentation and behavior between two Asian Drosophila melanogaster group species, D. elegans and D. gunungcola. D. elegans possesses a male-specific wing melanin spot and a stereotypical wing display element in male courtship, whereas D. gunungcola lacks both of these traits. Using reciprocal F1 male hybrids, we demonstrate that the X-chromosome contains a major locus or loci required for wing spot formation and that autosomal loci largely determine the male courtship display. Using phenotypic and genetic analysis of backcross progeny, we further demonstrate that both the wing spot and courtship differences between the two species are polygenic and both depend at least in small part on genetic factors on both the X and the autosomes. Finally, we find that male wing spot size and courtship wing display are highly correlated in backcross progeny, suggesting that linkage or pleiotropy may have been involved in their coordinated evolution.

Animals↗
PubMed1988

Genetics: quantitative versus qualitative characters.

Some of the main topics regarding the inheritance of a complex trait are discussed and the relative procedure of genetic analysis described. In particular, two complementary approaches to the study of an inherited trait in humans are outlined: the biometrical approach and the proposed methodology of dissection of the complex trait into its components. Some aspects relating to the genetics of essential hypertension are used as examples.

Blood Pressure↗
PubMed2026

Pervasive context-dependent effects in the genetic architecture of complex and quantitative traits revealed by a powerful multiparent mapping population in yeast.

The genetic dissection of complex traits remains a major challenge in basic and biomedical research, but is essential for understanding the molecular pathways that shape phenotypic variation and for developing predictive models of trait and disease susceptibility. Here, we leverage a novel multiparent mapping population of budding yeast, CYClones, comprising 9,344 haploid strains derived from eight genetically diverse founders (~270,000 SNVs,&#x2009;~&#x2009;1 per 44 bp, capturing 56% of common variants and 32% of all variants with a minor allele frequency greater than 0.005 in the global population), to identify quantitative trait loci (QTL) and systematically investigate the genetic architecture of growth rates across ten environmental conditions. In total, we identified 349 QTL (ranging from 18 to 49 QTL per growth condition) that explained between 60% and 100% of narrow sense heritability across traits. The high power and resolution of CYClones revealed that growth traits exhibited distinct, condition-specific genetic architectures with extensive allelic heterogeneity, where a QTL was the result of multiple tightly linked causal variants. We also observed pleiotropy among QTL with complex, trait-dependent allele effects that are also consistent with allelic heterogeneity. Genetic complexity varied widely, with some traits showing nearly Mendelian architectures, while others were highly polygenic. Introgressed loci played a prominent role in the landscape of growth rate QTL, including a QTL localized to a 2.4 kb interval in the PCA1 cadmium transporter that explains 72% of variation in cadmium resistance and is largely driven by an introgression, and a non-additive interaction between the GAL3 regulator and introgressed GAL1/7/10 alleles, extending a previously described three-locus GAL-pathway incompatibility to a four-locus interaction. In both cadmium and galactose conditions, we show that allelic variation at a small number of loci stratifies the population into regulatory or physiological subgroups, each with distinct genetic architectures, a specific manifestation of epistasis we term allele-dependent stratification. Collectively, our results provide novel insights into the genetics of growth rates in budding yeast, the architectural features of genetic complexity, and demonstrate that CYClones is a powerful platform for revealing the molecular basis of complex trait variation.

Quantitative Trait Loci↗
PubMed2026

A novel reusable transcriptome-wide association study workflow used to map key genes linked to important cattle traits.

Transcriptome-wide association studies (TWAS) are a powerful approach for studying the genes underlying complex traits by directly integrating GWAS and gene expression datasets. In cattle, they have been previously applied to identify genes driving fertility, milk production, and health. However, these studies have also highlighted several challenges, from difficulties in reproducing these complex analyses to limitations from poor genotype calls, especially when called directly from RNA sequencing data. To address these and other challenges, for the H2020 BovReg Project, we have developed a streamlined, species-agnostic, and reusable Nextflow TWAS workflow to integrate transcriptomic and GWAS summary statistic datasets. Our workflow first generates accurate genotype calls and gene expression prediction models from transcriptomic datasets and then applies these tools to impute gene expression levels into GWAS cohorts, enabling the association of genes with traits of interest. We explore optimal strategies for calling genetic variants directly from transcriptomic data and illustrate that using imputation approaches specifically designed for low-pass sequencing data can improve variant calling over previously adopted methods. We demonstrate the utility of our TWAS workflow by applying it to both novel and publicly available GWAS cohorts for cattle, detecting novel gene-trait associations for complex traits. Using a new transcriptome annotation of the cattle genome generated for the BovReg project we also illustrate how previously un-assayable associations can be detected. The results and the workflow we present, provide a new resource for the community and contribute to a better understanding of the molecular drivers of complex traits in cattle with the goal of eventually leveraging this information in future breeding decisions.

Animals↗
PubMed2006

Introduction to the special issue: human linkage studies for behavioral traits.

In the post Genome era, the aim of behavior genetics has shifted from estimating the relative contributions of genes and environmental factors to (co-)variation in human complex traits, to localization of genes and identification of functional genetic variants. This special issue reflects this transition and presents fifteen papers that report on genome-wide linkage scans for complex traits in humans and on methodological tools and innovations. Six papers focus on cognition and report overlapping linkage peaks on chromosomes 6p and 14p. Papers on addictive behavior, i.e. smoking and alcohol dependence and its endophenotypes, find moderate LOD scores on chromosomes 6p, 5q, 4p and 7q, respectively. Three papers concentrate on emotionality, depression and loneliness and examine chromosomes 2q and 12q. The papers in this issue represent a summary of the first large scale linkage enterprises of human behavioral traits.

Genetic Linkage↗