The genetic architecture of quantitative traits: lessons from Drosophila
01 Jun 2004-Current Opinion in Genetics & Development (Curr Opin Genet Dev)-Vol. 14, Iss: 3, pp 253-257
TL;DR: Studies in Drosophila have revealed large numbers of pleiotropic genes that interact epistatically to regulate quantitative traits, and large number of QTLs with sex-, environment- and genotype-specific effects, which offer valuable lessons for understanding the genetic basis of variation for complex traits in other organisms, including humans.
About: This article is published in Current Opinion in Genetics & Development.The article was published on 2004-06-01. It has received 213 citations till now. The article focuses on the topics: Genetic architecture & Quantitative trait locus.
Citations
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TL;DR: It is concluded that interactions at thelevel of genes are not likely to generate much interaction at the level of variance, and that additive variance typically accounts for over half, and often close to 100%, of the total genetic variance.
Abstract: The relative proportion of additive and non-additive variation for complex traits is important in evolutionary biology, medicine, and agriculture. We address a long-standing controversy and paradox about the contribution of non-additive genetic variation, namely that knowledge about biological pathways and gene networks imply that epistasis is important. Yet empirical data across a range of traits and species imply that most genetic variance is additive. We evaluate the evidence from empirical studies of genetic variance components and find that additive variance typically accounts for over half, and often close to 100%, of the total genetic variance. We present new theoretical results, based upon the distribution of allele frequencies under neutral and other population genetic models, that show why this is the case even if there are non-additive effects at the level of gene action. We conclude that interactions at the level of genes are not likely to generate much interaction at the level of variance.
985 citations
Cites background from "The genetic architecture of quantit..."
...Complete or partial dominance of genes is common, at least for those of large effect; and epistatic gene action has been reported in some QTL experiments [8,69]....
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TL;DR: In this article, the authors review various strategies for small RNA-based gene silencing, and describe in detail the design and application of amiRNAs in many plant species.
Abstract: Comprehensive analysis of gene function requires the detailed examination of mutant alleles In Arabidopsis thaliana, large collections of sequence-indexed insertion and chemical mutants provide potential loss-of-function alleles for most annotated genes However, limitations for phenotypic analysis include gametophytic or early sporophytic lethality, and the ability to recombine mutant alleles in closely linked genes, especially those present as tandem duplications Transgene-mediated gene silencing can overcome some of these shortcomings through tissue-specific, inducible and partial gene inactivation, or simultaneous targeting of several, sequence-related genes In addition, gene silencing is a convenient approach in species or varieties for which exhaustive mutant collections are not yet available Typically, gene function is reduced post-transcriptionally, effected by small RNAs that act in a sequence-specific manner by base pairing to complementary mRNA molecules A recently introduced approach is the use of artificial microRNAs (amiRNAs) Here, we review various strategies for small RNA-based gene silencing, and describe in detail the design and application of amiRNAs in many plant species
659 citations
TL;DR: The number and effect size of risk loci that underlie complex disease constrained by the disease parameters of prevalence and heritability are investigated and an approach to assess the genetic risk of a disease in healthy individuals is proposed, based on dense genome-wide SNP panels.
Abstract: Empirical studies suggest that the effect sizes of individual causal risk alleles underlying complex genetic diseases are small, with most genotype relative risks in the range of 1.1-2.0. Although the increased risk of disease for a carrier is small for any single locus, knowledge of multiple-risk alleles throughout the genome could allow the identification of individuals that are at high risk. In this study, we investigate the number and effect size of risk loci that underlie complex disease constrained by the disease parameters of prevalence and heritability. Then we quantify the value of prediction of genetic risk to disease using a range of realistic combinations of the number, size, and distribution of risk effects that underlie complex diseases. We propose an approach to assess the genetic risk of a disease in healthy individuals, based on dense genome-wide SNP panels. We test this approach using simulation. When the number of loci contributing to the disease is >50, a large case-control study is needed to identify a set of risk loci for use in predicting the disease risk of healthy people not included in the case-control study. For diseases controlled by 1000 loci of mean relative risk of only 1.04, a case-control study with 10,000 cases and controls can lead to selection of approximately 75 loci that explain >50% of the genetic variance. The 5% of people with the highest predicted risk are three to seven times more likely to suffer the disease than the population average, depending on heritability and disease prevalence. Whether an individual with known genetic risk develops the disease depends on known and unknown environmental factors.
646 citations
Cites background from "The genetic architecture of quantit..."
...www.genome.org suggests that gene gene interactions are likely to be important in some complex traits (Mackay 2004)....
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TL;DR: Genetic studies that ignore sex-specific effects in their design and interpretation could fail to identify a significant proportion of the genes that contribute to risk for complex diseases.
Abstract: Sexual dimorphism in anatomical, physiological and behavioural traits are characteristics of many vertebrate species. In humans, sexual dimorphism is also observed in the prevalence, course and severity of many common diseases, including cardiovascular diseases, autoimmune diseases and asthma. Although sex differences in the endocrine and immune systems probably contribute to these observations, recent studies suggest that sex-specific genetic architecture also influences human phenotypes, including reproductive, physiological and disease traits. It is likely that an underlying mechanism is differential gene regulation in males and females, particularly in sex steroid-responsive genes. Genetic studies that ignore sex-specific effects in their design and interpretation could fail to identify a significant proportion of the genes that contribute to risk for complex diseases.
632 citations
TL;DR: It is shown that genome-wide high-resolution mapping of multiple phenotypes can be achieved using a stock of genetically heterogeneous mice, and a conservative and robust bootstrap analysis is developed to map 843 QTLs.
Abstract: Difficulties in fine-mapping quantitative trait loci (QTLs) are a major impediment to progress in the molecular dissection of complex traits in mice. Here we show that genome-wide high-resolution mapping of multiple phenotypes can be achieved using a stock of genetically heterogeneous mice. We developed a conservative and robust bootstrap analysis to map 843 QTLs with an average 95% confidence interval of 2.8 Mb. The QTLs contribute to variation in 97 traits, including models of human disease (asthma, type 2 diabetes mellitus, obesity and anxiety) as well as immunological, biochemical and hematological phenotypes. The genetic architecture of almost all phenotypes was complex, with many loci each contributing a small proportion to the total variance. Our data set, freely available at http://gscan.well.ox.ac.uk, provides an entry point to the functional characterization of genes involved in many complex traits.
572 citations
References
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Book•
01 Jan 1981
TL;DR: The genetic constitution of a population: Hardy-Weinberg equilibrium and changes in gene frequency: migration mutation, changes of variance, and heritability are studied.
Abstract: Part 1 Genetic constitution of a population: Hardy-Weinberg equilibrium. Part 2 Changes in gene frequency: migration mutation. Part 3 Small populations - changes in gene frequency under simplified conditions. Part 4 Small populations - less simplified conditions. Part 5 Small populations - pedigreed populations and close inbreeding. Part 6 Continuous variation. Part 7 Values and means. Part 8 Variance. Part 9 Resemblance between relatives. Part 10 Heritability. Part 11 Selection - the response and its prediction. Part 12 Selection - the results of experiments. Part 13 Selection - information from relatives. Part 14 Inbreeding and crossbreeding - changes of mean value. Part 15 Inbreeding and crossbreeding - changes of variance. Part 16 Inbreeding and crossbreeding - applications. Part 17 Scale. Part 18 Threshold characters. Part 19 Correlated characters. Part 20 Metric characters under natural selection.
20,288 citations
Mark Raymond Adams1, Susan E. Celniker2, Robert A. Holt1, Cheryl A. Evans1 +191 more•Institutions (23)
TL;DR: The nucleotide sequence of nearly all of the approximately 120-megabase euchromatic portion of the Drosophila genome is determined using a whole-genome shotgun sequencing strategy supported by extensive clone-based sequence and a high-quality bacterial artificial chromosome physical map.
Abstract: The fly Drosophila melanogaster is one of the most intensively studied organisms in biology and serves as a model system for the investigation of many developmental and cellular processes common to higher eukaryotes, including humans. We have determined the nucleotide sequence of nearly all of the approximately 120-megabase euchromatic portion of the Drosophila genome using a whole-genome shotgun sequencing strategy supported by extensive clone-based sequence and a high-quality bacterial artificial chromosome physical map. Efforts are under way to close the remaining gaps; however, the sequence is of sufficient accuracy and contiguity to be declared substantially complete and to support an initial analysis of genome structure and preliminary gene annotation and interpretation. The genome encodes approximately 13,600 genes, somewhat fewer than the smaller Caenorhabditis elegans genome, but with comparable functional diversity.
6,180 citations
"The genetic architecture of quantit..." refers methods in this paper
...Finally, the genome sequence [6] and multiple platforms for whole genome transcriptional profiling facilitate genomic approaches for identifying genes affecting quantitative traits, and variation in quantitative traits....
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TL;DR: A new method of QTL mapping is proposed and analyzed in this paper by combining interval mapping with multiple regression, an interval test in which the test statistic on a marker interval is made to be unaffected by QTLs located outside a defined interval.
Abstract: Adequate separation of effects of possible multiple linked quantitative trait loci (QTLs) on mapping QTLs is the key to increasing the precision of QTL mapping. A new method of QTL mapping is proposed and analyzed in this paper by combining interval mapping with multiple regression. The basis of the proposed method is an interval test in which the test statistic on a marker interval is made to be unaffected by QTLs located outside a defined interval. This is achieved by fitting other genetic markers in the statistical model as a control when performing interval mapping. Compared with the current QTL mapping method (i.e., the interval mapping method which uses a pair or two pairs of markers for mapping QTLs), this method has several advantages. (1) By confining the test to one region at a time, it reduces a multiple dimensional search problem (for multiple QTLs) to a one dimensional search problem. (2) By conditioning linked markers in the test, the sensitivity of the test statistic to the position of individual QTLs is increased, and the precision of QTL mapping can be improved. (3) By selectively and simultaneously using other markers in the analysis, the efficiency of QTL mapping can be also improved. The behavior of the test statistic under the null hypothesis and appropriate critical value of the test statistic for an overall test in a genome are discussed and analyzed. A simulation study of QTL mapping is also presented which illustrates the utility, properties, advantages and disadvantages of the method.
3,131 citations
"The genetic architecture of quantit..." refers methods in this paper
...QTLs are mapped in the usual manner by linkage to polymorphic molecular markers, utilizing statistical methods designed to account for multiple QTLs [19] and appropriate control for the experiment-wise falsepositive error rate [20]....
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Book•
01 Dec 1989
TL;DR: This manual covers three approaches to the field: analysis of neural development, recording and imaging activities in the nervous system, and analysis of behavior.
Abstract: Drosophila Neurobiology-Bing Zhang 2010 Based on Cold Spring Harbor Laboratory's long-running course, Drosophila Neurobiology: A Laboratory Manual offers detailed protocols and background material for researchers interested in using Drosophila as an experimental model for investigating the nervous system. This manual covers three approaches to the field: analysis of neural development, recording and imaging activities in the nervous system, and analysis of behavior. Techniques described include molecular, genetic, electrophysiological, imaging, behavioral and developmental methods.
2,026 citations
"The genetic architecture of quantit..." refers methods in this paper
...This includes mutagenesis using P transposable elements [2] and RNA interference [3 ] to identify genes regulating quantitative traits....
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...Drosophila collected from nature can be screened for genotypes with extreme trait phenotypes, either by inbreeding whole genomes to homozygosity or cloning single chromosomes using balancer stocks [2]....
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TL;DR: Two extensions of the permutation-based method for estimating empirical threshold values are presented, which yield critical values that can be used to construct tests for the presence of minor QTL effects while accounting for effects of known major QTL.
Abstract: The problem of detecting minor quantitative trait loci (QTL) responsible for genetic variation not explained by major QTL is of importance in the complete dissection of quantitative characters. Two extensions of the permutation-based method for estimating empirical threshold values are presented. These methods, the conditional empirical threshold (CET) and the residual empirical threshold (RET), yield critical values that can be used to construct tests for the presence of minor QTL effects while accounting for effects of known major QTL. The CET provides a completely nonparametric test through conditioning on markers linked to major QTL. It allows for general nonadditive interactions among QTL, but its practical application is restricted to regions of the genome that are unlinked to the major QTL. The RET assumes a structural model for the effect of major QTL, and a threshold is constructed using residuals from this structural model. The search space for minor QTL is unrestricted, and RET-based tests may be more powerful than the CET-based test when the structural model is approximately true.
1,153 citations
"The genetic architecture of quantit..." refers methods in this paper
...QTLs are mapped in the usual manner by linkage to polymorphic molecular markers, utilizing statistical methods designed to account for multiple QTLs [19] and appropriate control for the experiment-wise falsepositive error rate [20]....
[...]