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At least 649 records · Page 36Linked to original sources
PubMed2003

A haplotype-based algorithm for multilocus linkage disequilibrium mapping of quantitative trait loci with epistasis.

For tightly linked loci, cosegregation may lead to nonrandom associations between alleles in a population. Because of its evolutionary relationship with linkage, this phenomenon is called linkage disequilibrium. Today, linkage disequilibrium-based mapping has become a major focus of recent genome research into mapping complex traits. In this article, we present a new statistical method for mapping quantitative trait loci (QTL) of additive, dominant, and epistatic effects in equilibrium natural populations. Our method is based on haplotype analysis of multilocus linkage disequilibrium and exhibits two significant advantages over current disequilibrium mapping methods. First, we have derived closed-form solutions for estimating the marker-QTL haplotype frequencies within the maximum-likelihood framework implemented by the EM algorithm. The allele frequencies of putative QTL and their linkage disequilibria with the markers are estimated by solving a system of regular equations. This procedure has significantly improved the computational efficiency and the precision of parameter estimation. Second, our method can detect marker-QTL disequilibria of different orders and QTL epistatic interactions of various kinds on the basis of a multilocus analysis. This can not only enhance the precision of parameter estimation, but also make it possible to perform whole-genome association studies. We carried out extensive simulation studies to examine the robustness and statistical performance of our method. The application of the new method was validated using a case study from humans, in which we successfully detected significant QTL affecting human body heights. Finally, we discuss the implications of our method for genome projects and its extension to a broader circumstance. The computer program for the method proposed in this article is available at the webpage http://www.ifasstat.ufl.edu/genome/~LD.

Algorithms↗
PubMed2003

Congenic mapping and candidate sequencing of susceptibility genes for Type 1 diabetes in the NOD mouse.

Inheritance of type 1 diabetes is polygenic with a major susceptibility gene located in the major histocompatibility complex (MHC). In addition to MHC-linked susceptibility, a number of susceptibility genes have been mapped outside the MHC in both humans and animal models. In order to localize and identify susceptibility genes for type 1 diabetes, we have developed a series of congenic strains in which either susceptibility intervals from the NOD mouse, a mouse model of type 1 diabetes, were introgressed onto control background genes or protective intervals from control strains were introgressed onto NOD background genes. NOD. CTS-H-2 congenic mice, which possess recombinant MHC with NOD alleles at class II A and E genes, which are candidates for Idd1, revealed that Idd1 consists of multiple components, one in class II (Idd1) and the other adjacent to, but distinct from, Idd1 (Idd16). Phenotypes of NOD. IIS-Idd3 congenic mice, which share the same alleles at both Il2 and Il21 as the NOD mouse, were indistinguishable from the NOD parental strain, indicating that both Il2 and Il21 are candidates for Idd3. In contrast, NOD. IIS-Idd10 congenic mice, which share the same alleles at Fcgr1, a previous candidate for Idd10, as the NOD mouse, were protected from type 1 diabetes, suggesting that Fcgr1 may not be responsible for the Idd10 effect. These data suggest that the use of strain colony closely related to a disease model to find the same candidate mutation on different haplotypes and make congenic strains with this recombinant chromosome, termed ancestral haplotype congenic mapping, is an effective strategy for fine mapping and identification of genes responsible for complex traits.

Animals↗
PubMed2006

Poorly known relatives of Arabidopsis thaliana.

Non-model Arabidopsis species have been widely used as outgroup taxa in studies of molecular evolution. In Arabidopsis lyrata, Arabidopsis halleri and Arabidopsis arenosa, traits pertaining to self-incompatibility, heavy metal tolerance and inter-specific hybridization have been subjected to detailed genetic analysis. However, the full potential for exploring the causes and consequences of natural variation in complex traits within the genus Arabidopsis has not been widely appreciated or realized. Here, we draw on broadly dispersed information to characterize the basic biology, ecology, population genetics and molecular evolution for these three non-model Arabidopsis species. We illustrate how the wealth of functional and genomic tools pioneered in A. thaliana can be applied to gain insights into adaptive evolution of ecologically important traits and genome-wide processes, such as polyploidy, speciation and reticulate evolution, within and among Arabidopsis species.

Arabidopsis↗
PubMed2003

A general statistical framework for mapping quantitative trait loci in nonmodel systems: issue for characterizing linkage phases.

Because of uncertainty about linkage phases of founders, linkage mapping in nonmodel, outcrossing systems using molecular markers presents one of the major statistical challenges in genetic research. In this article, we devise a statistical method for mapping QTL affecting a complex trait by incorporating all possible QTL-marker linkage phases within a mapping framework. The advantage of this model is the simultaneous estimation of linkage phases and QTL location and effect parameters. These estimates are obtained through maximum-likelihood methods implemented with the EM algorithm. Extensive simulation studies are performed to investigate the statistical properties of our model. In a case study from a forest tree, this model has successfully identified a significant QTL affecting wood density. Also, the probability of the linkage phase between this QTL and its flanking markers is estimated. The implications of our model and its extension to more general circumstances are discussed.

Chromosome Mapping↗
PubMed2026

Kv11.1 (hERG) Protein Interaction Networks Connect Endocytic Trafficking to Polygenic Influences on Cardiac Repolarization.

Polygenic scores (PGS) capture the combined effect of many common genetic variants on quantitative traits and disease risk, yet their functional consequences at the protein level remain poorly defined. Here, we integrated quantitative and interaction proteomics to resolve how polygenic liability for cardiac repolarization manifests in human cells. We studied human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from donors with extreme PGS for QT interval duration, a clinically relevant electrophysiologic trait associated with arrhythmia risk. Global quantitative proteomics revealed increased abundance of mitochondrial proteins in high-PGS cardiomyocytes. To define protein network-level effects on a key repolarizing ion channel, we performed multiplexed affinity purification-mass spectrometry (AP-MS) of Kv11.1. While mitochondrial changes did not directly explain Kv11.1-associated complexes, interactome analysis revealed increased association of Kv11.1 with myosin motor proteins and endosomal recycling machinery in high-PGS cells. These findings suggest altered channel trafficking dynamics of Kv11.1, distinct from the trafficking defects observed in monogenic Kv11.1 variants. Together, these data show that integrating global and interaction proteomics can resolve how polygenic variation reshapes protein networks. Future work using these methods could connect genomic risk to subcellular remodeling and our work provides a generalizable framework to probe the proteomic basis of complex traits. SIGNIFICANCE STATEMENT: Polygenic scores (PGS) predict disease risk, but how biological pathways are influenced by these common variants remains difficult to define. We generated human induced pluripotent stem cells from individuals with extreme high- and low- PGS for QT interval, a key electrocardiographic measure linked to arrhythmia risk. By combining global proteomics and interactomics for a common ion channel involved in regulating the QT interval (Kv11.1) we found potential mechanisms that are influenced by common genetic traits in patients. Our work provides an approach to connect polygenic scores to pathway-level molecular mechanisms in human cells and a general framework for uncovering how complex genetic architecture drives disease-relevant biology.

AP-MS↗
PubMed2002

The nature of robustness in development.

A trait is robust to a genetic or environmental variable if its variation is weakly correlated with variation in that variable. The source of robustness lies in the fact that the developmental processes that give rise to complex traits are nonlinear. A consequence of this nonlinearity is that not all genes are equally correlated with the trait whose ontogeny they control. Here we explore how developmental mechanisms determine and alter the correlation structure between genes and the traits that they control. A formula is developed by which the correlation of a gene or environmental variable with a trait can be calculated if the mechanism that gives rise to the trait is known. The nature of robustness and the ways in which robustness can evolve are discussed in the context of the problems that arise in the analysis of inherently nonlinear systems.

Alleles↗
PubMed2001

Quantitative trait loci (QTLs) associated with resistance/susceptibility to infectious pancreatic necrosis virus (IPNV) in rainbow trout (Oncorhynchus mykiss).

Infectious pancreatic necrosis (IPN) is a well-known acute viral disease of salmonid species. We have identified quantitative trait loci (QTLs) associated with resistance to this disease in rainbow trout. We searched for linkage among 51 microsatellite markers used to construct a framework linkage map in backcross families of rainbow trout (Oncorhynchus mykiss), produced by crossing IPN-resistant (YN-RT201) and -susceptible (YK-RT101) strains. Two putative QTLs affecting disease resistance were detected on chromosomes A (IPN R S-1) and C (IPN R/S-2), respectively, suggesting that this is a polygenic trait in rainbow trout. These markers have great potential for use in marker-assisted selection (MAS) for IPN resistance and provide the basis for cloning of IPN resistance genes. Clarification of the genetic bases of complex traits has broad implications for fundamental research, but will also be of practical benefit to fish breeding.

Animals↗
PubMed2005

Association Cluster Detector: a tool for heuristic detection of significance clusters in whole-genome scans.

UNLABELLED: Whole genome scans analyze large sets of genetic markers, mainly single nucleotide polymorphisms, over the entire genome in order to find variants and regions associated with complex traits so these can be further investigated. Analyzing the results of such scans becomes difficult due to multiple testing problems and to the genomic distributions of recombination, linkage disequilibrium and true associations, which generate an extremely complex network of dependences between markers. Here we present Association Cluster Detector (ACD), a simple tool aiming to ease the analysis of the results of whole genome scans. ACD facilitates correction for multiple tests using several standard procedures and implements a sliding-window heuristic method that helps in detecting potentially interesting candidate regions by exploiting the property of non-random distribution of significantly associated markers. AVAILABILITY: The tool can be downloaded from http://www.upf.es/cexs/recerca/bioevo/softanddata.htm

Algorithms↗
PubMed2004

Evaluating associations of haplotypes with traits.

Haplotypes have played a major role in the study of highly-penetrant single-gene disorders, and recent evidence that the human genome has hot-spots and cold-spots for recombination have suggested that haplotype-based methods may play a key role in the study of common complex traits. This report reviews the motivation of using haplotypes for the study of the genetic basis of human traits, ranging from biologic function, to statistical power advantages of haplotypes, to linkage disequilibrium fine-mapping. Recent developments of regression models for haplotype analyses are reviewed, offering a synthesis of current methods, as well as their limitations and areas that require further research. Regression models provide significant advantages, such as the ability to control for non-genetic covariates, the effects of the haplotypes can be modeled, step-wise selection can be used to screen for a subset of markers that explain most of the association, haplotype x environment interactions can be evaluated, and regression diagnostics are well developed. Despite these strengths, the current regression methods tend to lack the sophisticated population genetic perspectives offered by coalescent and other similar approaches. Future work that links regression methods with population genetic models may prove beneficial.

Chromosome Mapping↗
PubMed2004

Isolates and their potential use in complex gene mapping efforts.

Linkage disequilibrium (LD), detectable with microsatellites in disease alleles over wide genetic intervals in population isolates, has facilitated mapping and positional cloning of numerous disease genes. We, among others, have shown that the LD intervals reach up to 1 Mb in general alleles of young subisolates, and that this feature most probably offers an avenue for the initial locus positioning for complex traits. Development of efficient SNP genotyping and characterization of haploblock structure of the human genome have introduced new prospects to LD-based fine mapping and haplotype-association studies. Encouraging associations have been reported for several complex diseases. Final breakthroughs in mapping of complex disease loci have emerged on large pedigrees in population isolates. Conversely, ignoring genealogical makeup of the study population seems to disclose false negative and false positive associations, directing resources down the drain.

Chromosome Mapping↗
PubMed1993

Plant genetics: out with the old, in with the new?

Plant breeding represents an evolving technology based largely on genetic principles. Approximately one-half of the increased yields of major crop plants can be attributed to the genetic improvement of the crop. Although the breeding technology and undergirding science are sound, additional information on the biochemical pathways underlying agronomic and quality traits and their genetic control would allow new genetic technologies to be used more fully. Current developments in molecular biology, plant cell and tissue culture, genetic engineering, and use of molecular genetics will facilitate the selection of complex traits. Genetic improvement of plants in the future will be based on an integration of modern plant-breeding methods and the new genetic technologies. Thus, the new genetic approaches do not represent a replacement technology but will add to the arsenal of tools available for improving crops.

Agriculture↗
PubMed2026

Determinants of functional burden pleiotropy and gene dosage responses across human traits.

Pleiotropic and monotonic effects of gene dosage are central to understanding comorbidities in developmental pediatric and psychiatric disorders, yet the underlying biological processes are not well characterized. Here we develop a functional burden analysis to investigate the association of all protein-coding copy-number variants, genome-wide, with 43 complex traits in approximately 500,000 UK Biobank participants. We test variant associations disrupting 172 tissue or cell-type gene sets, finding associations for all traits, which we replicate in the All of Us cohort. Functional burden pleiotropy, defined as the number of traits significantly associated with a gene set, correlates with genetic constraint and is higher for brain than non-brain functions, even after normalizing for genetic constraint. Levels of pleiotropy, measured by burden correlation, are similar in deletions and loss-of-function single-nucleotide variants, and higher than in common variants and duplications. Most gene dosage responses are non-monotonic, with deletions and duplications showing same-direction effects, and monotonic responses decrease with genetic constraint. We observe associations between functional gene sets and traits for either deletions or duplications, but rarely both, with negatively correlated effect sizes. Together, these results link genetic constraint and brain-specific mechanisms to the whole-body multimorbidity of neurodevelopmental and psychiatric conditions.

Humans↗
PubMed2005

Gene expression microarray studies in polygenic psychiatric disorders: applications and data analysis.

Gene expression microarrays have become a mainstream technology that can provide valuable insight into psychiatric disorders. Gene expression studies in post mortem brain samples of schizophrenia and bipolar disorder have the potential to yield novel clues about the pathophysiology of these complex trait disorders. In the present review, a short introduction of the genetic and molecular background of schizophrenia and bipolar disorder is followed by a discussion of the basic concept and limits of gene expression microarray technology, and the complexities surrounding the analysis of thousands of gene transcripts. Although this review is intended for use in most platforms, it has a particular focus on the commercially available Affymetrix system. Various computer programs and their principal features are discussed, and it is shown how these programs can be applied to reveal a biological context of microarray findings. I will demonstrate how the programs can help to judge the results rather than focus on their statistical principles. The strength of gene array experiments is their emphasis on broad, biological themes, rather than on specific genes, and proper biostatistical approaches are important to ensure reproducibility of the findings. All results should be verified by independent means. This review is intended to help brain researchers who want to apply gene expression microarray technology to conceptualize research strategies and sample analysis.

Biomedical Research↗
PubMed1994

RFLP mapping of genes conferring complete and partial resistance to blast in a durably resistant rice cultivar.

Moroberekan, a japonica rice cultivar with durable resistance to blast disease in Asia, was crossed to the highly susceptible indica cultivar, CO39, and 281 F7 recombinant inbred (RI) lines were produced by single seed descent. The population was evaluated for blast resistance in the greenhouse and the field, and was analyzed with 127 restriction fragment length polymorphism (RFLP) markers. Two dominant loci associated with qualitative resistance to five isolates of the fungus were tentatively named Pi-5(t) and Pi-7(t). They were mapped on chromosomes 4 and 11, respectively. To identify quantitative trait loci (QTLs) affecting partial resistance, RI lines were inoculated with isolate PO6-6 of Pyricularia oryzae in polycyclic tests. Ten chromosomal segments were found to be associated with effects on lesion number (P < 0.0001 and LOD > 6.0). Three of the markers associated with QTLs for partial resistance had been reported to be linked to complete blast resistance in previous studies. QTLs identified in greenhouse tests were good predictors of blast resistance at two field sites. This study illustrates the usefulness of RI lines for mapping a complex trait such as blast resistance and suggests that durable resistance in the traditional variety, Moroberekan, involves a complex of genes associated with both partial and complete resistance.

Chromosome Mapping↗
PubMed2002

Molecular basis of the Cd36 chromosomal deletion underlying SHR defects in insulin action and fatty acid metabolism.

The human insulin resistance syndromes---type 2 diabetes, obesity, combined hyperlipidemia, and essential hypertension---are genetically complex disorders whose molecular basis is largely unknown. The spontaneously hypertensive rate (SHR) is a model of these human syndromes. In the SHR/NCrlBR strain, a chromosomal deletion event that occurred at the Cd36 locus during the evolution of this SHR strain has been proposed as a cause of defective insulin action and fatty acid metabolism. In this study, three copies of the Cd36 gene, one transcribed copy and two pseudogenes, were identified in normal rat strains, but only a single gene in SHR/NCrlBR. Analysis of SHR genomic sequence localized the chromosomal deletion event between intron 4 of the normally transcribed copy of the gene and intron 4 of the second pseudogene. The deletion led to the creation of a single chimeric Cd36 gene in SHR/NCrlBR. The boundaries of the recombination/deletion junction identified within intron 4 were surrounded by long interspersed nuclear elements (LINEs) and DNA topoisomerase I recognition sequences. An 8-bp deletion at the intron 14/exon 15 boundary of the second pseudogene abolishes the putative splice acceptor site and is the cause of an aberrant 3' UTR previously observed in SHR/NCrlBR. We conclude that in SHR/NCrlBR, the complex trait of insulin resistance and defective fatty acid metabolism is caused by Cd36 deficiency, resulting from a chromosomal deletion caused by unequal recombination. This demonstrates that chromosomal deletions caused by unequal recombination can be a cause of quantitative or complex mammalian phenotypes.

Animals↗
PubMed1998

Genetic epidemiology of binging and vomiting.

BACKGROUND: Bulimia nervosa is typically defined as the combination of the behaviours of binging and vomiting. We sought to clarify the relationship of these behaviours from a genetic epidemiological perspective. METHOD: Using data on the lifetime history of binging and vomiting from a personally interviewed population-based sample of female twins (n = 1897), we applied bivariate twin modelling to estimate the sources of variation for these traits. RESULTS: The association between having ever binged (23.6%) and having ever induced vomiting (4.8%) was very strong (odds ratio = 8.78, P << 0.0001). The best-fitting model indicated that lifetime binging and vomiting were both heritable (46% and 72%) and influenced by individual-specific environmental factors (54% and 28%). The overlap between the genetic (ra = 0.74) and individual-specific environmental factors (re = 0.48) for the two traits was substantial. No violations of the equal environmental assumption were evident. CONCLUSIONS: Including binging and vomiting under the rubric of bulimia nervosa appears to be appropriate. Our data are consistent with the identification of binging and vomiting as complex traits resulting from the interplay of multiple genes and individual-specific environmental influences. In contrast to 'environmentalist' theories, our results suggest that genetic influences may be of particular relevance to the aetiology of binging and vomiting.

Adult↗
PubMed2005

Is there a "migratory syndrome" common to all migrant birds?

Bird migration has been assumed, mostly implicitly, to represent a distinct class of animal behavior, with deep and strong homologies in the various phenotypic expressions of migratory behavior between different taxa. Here the evidence for the existence of what could be called a "migratory syndrome," a tightly integrated, old group of adaptive traits that enables birds to commit themselves to highly organized seasonal migrations, is assessed. A list of problems faced by migratory birds is listed first and the traits that migratory birds have evolved to deal with these problems are discussed. The usefulness of comparative approaches to investigate which traits are unique to migrants is then discussed. A provisional conclusion that, perhaps apart from a capacity for night-time compass orientation, there is little evidence for deeply rooted coadapted trait complexes that could make up such a migratory syndrome, is suggested. Detailed analyses of the genetic and physiological architecture of potential adaptations to migration, combined with a comparative approach to further identify the phylogenetic levels at which different adaptive traits for migration have evolved, are recommended.

Adaptation, Physiological↗
PubMed1999

The cytotoxic T lymphocyte antigen-4 is a major Graves' disease locus.

Graves' disease (GD) is an autoimmune thyroid disorder that is inherited as a complex trait. We have genotyped 77 affected sib-pairs with autoimmune thyroid disease for eight polymorphic markers spanning the cytotoxic T lymphocyte antigen-4 ( CTLA-4 ) region of chromosome 2q31-q33, and for five markers spanning the major histocompatibility complex ( MHC ) region of chromosome 6p21. Non-parametric analysis showed linkage of GD to the CTLA-4 region with a peak non-parametric linkage (NPL) score of 3.43 ( P = 0.0004) at the marker D2S117. The proportion of affected full-sibs sharing zero alleles (z0) reached a minimum of 0.113 close to D2S117, giving a locus-specific lambdas for this region of 2.2. Families with brother-sister sib-pairs showed a peak NPL of 3.46 ( P = 0.0003, lambdas > 10) at D2S117, compared with 2.00 ( P = 0.02, lambdas = 1.9) in the families with only affected females, suggesting a stronger influence in families with affected males. Association between GD and the G allele of the Thr17Ala polymorphism within the CTLA-4 gene ( CTLA4A/G ) was observed using unaffected sib controls ( P = 0.005). Lesser evidence for linkage was found at the MHC locus, with a peak NPL score of 1.95 ( P = 0.026), between the markers D6S273 and TNFalpha. We demonstrate that the CTLA-4 locus (lambdas = 2.2) and the MHC locus (lambdas = 1.6) together confer approximately 50% of the inherited susceptibility to GD disease in our population.

Abatacept↗