ABSTRACT
Speciation is a fundamental evolutionary process but the genetic changes accompanying speciation are difficult to determine since true species do not produce viable and fertile offspring. Partially reproductively isolated incipient species are useful for assessing genetic changes that occur prior to speciation. Drosophila melanogaster from Zimbabwe, Africa are partially sexually isolated from other D. melanogaster populations whose males have poor mating success with Zimbabwe females. We used the North American D. melanogaster Genetic Reference Panel (DGRP) to show that there is significant genetic variation in mating success of DGRP males with Zimbabwe females, to map genetic variants and genes associated with variation in mating success and to determine whether mating success to Zimbabwe females is associated with other quantitative traits previously measured in the DGRP. Incipient sexual isolation is highly polygenic and associated with the common African inversion In(3R)K and the amount of the sex pheromone 5,9-heptacosadiene in DGRP females. We functionally validated the effect of eight candidate genes using RNA interference to provide testable hypotheses for future studies investigating the molecular genetic basis of incipient sexual isolation in D. melanogaster.
Subject(s)
Drosophila melanogaster , Reproductive Isolation , Animals , Drosophila melanogaster/genetics , Drosophila melanogaster/physiology , Male , Female , Zimbabwe , Genetic Speciation , Genetic Variation , Sexual Behavior, Animal , Sex AttractantsABSTRACT
Aspergillus flavus is an agriculturally important fungus that causes ear rot of maize and produces aflatoxins, of which B1 is the most carcinogenic naturally-produced compound. In the US, the management of aflatoxins includes the deployment of biological control agents that comprise two nonaflatoxigenic A. flavus strains, either Afla-Guard (member of lineage IB) or AF36 (lineage IC). We used genotyping-by-sequencing to examine the influence of both biocontrol agents on native populations of A. flavus in cornfields in Texas, North Carolina, Arkansas, and Indiana. This study examined up to 27,529 single-nucleotide polymorphisms (SNPs) in a total of 815 A. flavus isolates, and 353 genome-wide haplotypes sampled before biocontrol application, three months after biocontrol application, and up to three years after initial application. Here, we report that the two distinct A. flavus evolutionary lineages IB and IC differ significantly in their frequency distributions across states. We provide evidence of increased unidirectional gene flow from lineage IB into IC, inferred to be due to the applied Afla-Guard biocontrol strain. Genetic exchange and recombination of biocontrol strains with native strains was detected in as little as three months after biocontrol application and up to one and three years later. There was limited inter-lineage migration in the untreated fields. These findings suggest that biocontrol products that include strains from lineage IB offer the greatest potential for sustained reductions in aflatoxin levels over several years. This knowledge has important implications for developing new biocontrol strategies.
Subject(s)
Aflatoxins , Aspergillus flavus , Aspergillus flavus/genetics , Aflatoxins/genetics , Biological Control Agents , Zea mays/genetics , Zea mays/microbiology , Recombination, GeneticABSTRACT
We used Drosophila melanogaster to map the genetic basis of naturally occurring variation in voluntary consumption of cocaine and methamphetamine. We derived an outbred advanced intercross population (AIP) from 37 sequenced inbred wild-derived lines of the Drosophila melanogaster Genetic Reference Panel (DGRP), which are maximally genetically divergent, have minimal residual heterozygosity, are not segregating for common inversions, and are not infected with Wolbachia pipientis We assessed consumption of sucrose, methamphetamine-supplemented sucrose, and cocaine-supplemented sucrose and found considerable phenotypic variation for consumption of both drugs, in both sexes. We performed whole-genome sequencing and extreme quantitative trait locus (QTL) mapping on the top 10% of consumers for each replicate, sex, and condition and an equal number of randomly selected flies. We evaluated changes in allele frequencies among high consumers and control flies and identified 3,033 variants significantly (P < 1.9 × 10-8) associated with increased consumption, located in or near 1,962 genes. Many of these genes are associated with nervous system development and function, and 77 belong to a known gene-gene interaction subnetwork. We assessed the effects of RNA interference (RNAi) on drug consumption for 22 candidate genes; 17 had a significant effect in at least one sex. We constructed allele-specific AIPs that were homozygous for alternative candidate alleles for 10 single-nucleotide polymorphisms (SNPs) and measured average consumption for each population; 9 SNPs had significant effects in at least one sex. The genetic basis of voluntary drug consumption in Drosophila is polygenic and implicates genes with human orthologs and associated variants with sex- and drug-specific effects.
Subject(s)
Cocaine/pharmacology , Drosophila Proteins/genetics , Epistasis, Genetic , Methamphetamine/pharmacology , Polymorphism, Single Nucleotide , Quantitative Trait Loci , Sex Characteristics , Animals , Drosophila Proteins/metabolism , Drosophila melanogaster , Female , Genome-Wide Association Study , Humans , MaleABSTRACT
The genetics of phenotypic responses to changing environments remains elusive. Using whole-genome quantitative gene expression as a model, here we study how the genetic architecture of regulatory variation in gene expression changed in a population of fully sequenced inbred Drosophila melanogaster strains when flies developed in different environments (25 °C and 18 °C). We find a substantial fraction of the transcriptome exhibited genotype by environment interaction, implicating environmentally plastic genetic architecture of gene expression. Genetic variance in expression increases at 18 °C relative to 25 °C for most genes that have a change in genetic variance. Although the majority of expression quantitative trait loci (eQTLs) for the gene expression traits in the two environments are shared and have similar effects, analysis of the environment-specific eQTLs reveals enrichment of binding sites for two transcription factors. Finally, although genotype by environment interaction in gene expression could potentially disrupt genetic networks, the co-expression networks are highly conserved across environments. Genes with higher network connectivity are under stronger stabilizing selection, suggesting that stabilizing selection on expression plays an important role in promoting network robustness.
Subject(s)
Drosophila melanogaster/genetics , Gene-Environment Interaction , Animals , Female , Gene Expression , Gene Expression Regulation , Gene Regulatory Networks , Genes, Insect , Genetic Variation , Genotype , Male , Quantitative Trait Loci , RNA-Seq , Temperature , TranscriptomeABSTRACT
A major challenge in modern biology is to understand how naturally occurring variation in DNA sequences affects complex organismal traits through networks of intermediate molecular phenotypes. This question is best addressed in a genetic mapping population in which all molecular polymorphisms are known and for which molecular endophenotypes and complex traits are assessed on the same genotypes. Here, we performed deep RNA sequencing of 200 Drosophila Genetic Reference Panel inbred lines with complete genome sequences and for which phenotypes of many quantitative traits have been evaluated. We mapped expression quantitative trait loci for annotated genes, novel transcribed regions, transposable elements, and microbial species. We identified host variants that affect expression of transposable elements, independent of their copy number, as well as microbiome composition. We constructed sex-specific expression quantitative trait locus regulatory networks. These networks are enriched for novel transcribed regions and target genes in heterochromatin and euchromatic regions of reduced recombination, as well as genes regulating transposable element expression. This study provides new insights regarding the role of natural genetic variation in regulating gene expression and generates testable hypotheses for future functional analyses.
Subject(s)
Drosophila melanogaster/genetics , Gene Expression Regulation , Gene Regulatory Networks , Animals , DNA Transposable Elements , Drosophila melanogaster/metabolism , Drosophila melanogaster/microbiology , Female , Genetic Variation , High-Throughput Nucleotide Sequencing , Male , Microbiota/genetics , Quantitative Trait Loci , Sequence Analysis, RNAABSTRACT
Understanding the genetic basis of variation in life span is a major challenge that is difficult to address in human populations. Evolutionary theory predicts that alleles affecting natural variation in life span will have properties that enable them to persist in populations at intermediate frequencies, such as late-life-specific deleterious effects, antagonistic pleiotropic effects on early and late-age fitness components, and/or sex- and environment-specific or antagonistic effects. Here, we quantified variation in life span in males and females reared in 3 thermal environments for the sequenced, inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP) and an advanced intercross outbred population derived from a subset of DGRP lines. Quantitative genetic analyses of life span and the micro-environmental variance of life span in the DGRP revealed significant genetic variance for both traits within each sex and environment, as well as significant genotype-by-sex interaction (GSI) and genotype-by-environment interaction (GEI). Genome-wide association (GWA) mapping in both populations implicates over 2,000 candidate genes with sex- and environment-specific or antagonistic pleiotropic allelic effects. Over 1,000 of these genes are associated with variation in life span in other D. melanogaster populations. We functionally assessed the effects of 15 candidate genes using RNA interference (RNAi): all affected life span and/or micro-environmental variance of life span in at least one sex and environment and exhibited sex-and environment-specific effects. Our results implicate novel candidate genes affecting life span and suggest that variation for life span may be maintained by variable allelic effects in heterogeneous environments.
Subject(s)
Drosophila Proteins/genetics , Drosophila melanogaster/physiology , Longevity/genetics , Animals , Drosophila melanogaster/genetics , Female , Gene-Environment Interaction , Genetic Variation , Genome-Wide Association Study , Male , RNA Interference , TemperatureABSTRACT
Physical resiliency declines with age and comorbid conditions. In humans, angiotensin-converting enzyme (ACE) has been associated with attenuation of the decline in physical performance with age. ACE-inhibitor compounds, commonly prescribed for hypertension, often have beneficial effects on physical performance however the generality of these effects are unclear. Here, we tested the effects of the ACE-inhibitor Lisinopril on life span, and age-specific speed, endurance, and strength using three genotypes of the Drosophila melanogaster Genetic Reference Panel. We show that age-related decline in physical performance and survivorship varies with genetic background. Lisinopril treatment increased mean life span in all Drosophila Genetic Reference Panel lines, but its effects on life span, speed, endurance, and strength depended on genotype. We show that genotypes with increased physical performance on Lisinopril treatment experienced reduced age-related protein aggregation in muscle. Knockdown of skeletal muscle-specific Ance, the Drosophila ortholog of ACE, abolished the effects of Lisinopril on life span, implying a role for skeletal muscle Ance in survivorship. Using transcriptome profiling, we identified genes involved in stress response that showed expression changes associated with genotype and age-dependent responsiveness to Lisinopril. Our results demonstrate that Ance is involved in physical decline and demonstrate genetic variation in phenotypic responses to an ACE inhibitor.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Drosophila Proteins/metabolism , Drosophila melanogaster/drug effects , Lisinopril/pharmacology , Longevity/drug effects , Peptidyl-Dipeptidase A/metabolism , Animals , Drosophila melanogaster/genetics , Genotype , Male , Phenotype , TranscriptomeABSTRACT
Longevity varies among individuals, but how natural genetic variation contributes to variation in lifespan is poorly understood. Drosophila melanogaster presents an advantageous model system to explore the genetic underpinnings of longevity, since its generation time is brief and both the genetic background and rearing environment can be precisely controlled. The bellwether (blw) gene encodes the α subunit of mitochondrial ATP synthase. Since metabolic rate may influence lifespan, we investigated whether alternative haplotypes in the blw promoter affect lifespan when expressed in a co-isogenic background. We amplified 521 bp upstream promoter sequences containing alternative haplotypes and assessed promoter activity both in vitro and in vivo using a luciferase reporter system. The AG haplotype showed significantly greater expression of luciferase than the GT haplotype. We then overexpressed a blw cDNA construct driven by either the AG or GT haplotype promoter in transgenic flies and showed that the AG haplotype also results in greater blw cDNA expression and a significant decrease in lifespan relative to the GT promoter haplotype, in male flies only. Thus, our results show that naturally occurring regulatory variants of blw affect lifespan in a sex-specific manner.
Subject(s)
Alleles , Drosophila/physiology , Longevity/genetics , Mitochondrial Proton-Translocating ATPases/genetics , Promoter Regions, Genetic , Protein Subunits/genetics , Animals , Female , Gene Expression Regulation , Gene Knockdown Techniques , Male , Mitochondrial Proton-Translocating ATPases/chemistry , Polymorphism, Single Nucleotide , RNA InterferenceABSTRACT
Senescence, i.e., functional decline with age, is a major determinant of health span in a rapidly aging population, but the genetic basis of interindividual variation in senescence remains largely unknown. Visual decline and age-related eye disorders are common manifestations of senescence, but disentangling age-dependent visual decline in human populations is challenging due to inability to control genetic background and variation in histories of environmental exposures. We assessed the genetic basis of natural variation in visual senescence by measuring age-dependent decline in phototaxis using Drosophila melanogaster as a genetic model system. We quantified phototaxis at 1, 2, and 4 wk of age in the sequenced, inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP) and found an average decline in phototaxis with age. We observed significant genetic variation for phototaxis at each age and significant genetic variation in senescence of phototaxis that is only partly correlated with phototaxis. Genome-wide association analyses in the DGRP and a DGRP-derived outbred, advanced intercross population identified candidate genes and genetic networks associated with eye and nervous system development and function, including seven genes with human orthologs previously associated with eye diseases. Ninety percent of candidate genes were functionally validated with targeted RNAi-mediated suppression of gene expression. Absence of candidate genes previously implicated with longevity indicates physiological systems may undergo senescence independent of organismal life span. Furthermore, we show that genes that shape early developmental processes also contribute to senescence, demonstrating that senescence is part of a genetic continuum that acts throughout the life span.
Subject(s)
Aging/genetics , Biological Variation, Individual , Drosophila Proteins/genetics , Drosophila melanogaster/genetics , Eye Proteins/genetics , Gene Regulatory Networks , Genome , Animals , Drosophila Proteins/metabolism , Drosophila melanogaster/growth & development , Drosophila melanogaster/metabolism , Eye Proteins/metabolism , Gene Expression Regulation, Developmental , Genetic Variation , Genome-Wide Association Study , Humans , Phototaxis , Quantitative Trait Loci , Vision, Ocular/geneticsABSTRACT
Mutation and natural selection shape the genetic variation in natural populations. Here, we directly estimated the spontaneous mutation rate by sequencing new Drosophila mutation accumulation lines maintained with minimal natural selection. We inferred strong stabilizing natural selection on quantitative traits because genetic variation among wild-derived inbred lines was much lower than predicted from a neutral model and the mutational effects were much larger than allelic effects of standing polymorphisms. Stabilizing selection could act directly on the traits, or indirectly from pleiotropic effects on fitness. However, our data are not consistent with simple models of mutation-stabilizing selection balance; therefore, further empirical work is needed to assess the balance of evolutionary forces responsible for quantitative genetic variation.
Subject(s)
Drosophila/genetics , Genetic Variation , Mutation Rate , Animals , Mutation Accumulation , Quantitative Trait Loci , Selection, GeneticABSTRACT
Body pigmentation in insects and other organisms is typically variable within and between species and is often associated with fitness. Regulatory variants with large effects at bab1, t and e affect variation in abdominal pigmentation in several populations of Drosophila melanogaster. Recently, we performed a genome wide association (GWA) analysis of variation in abdominal pigmentation using the inbred, sequenced lines of the Drosophila Genetic Reference Panel (DGRP). We confirmed the large effects of regulatory variants in bab1, t and e; identified 81 additional candidate genes; and validated 17 candidate genes (out of 28 tested) using RNAi knockdown of gene expression and mutant alleles. However, these analyses are imperfect proxies for the effects of segregating variants. Here, we describe the results of an extreme quantitative trait locus (xQTL) GWA analysis of female body pigmentation in an outbred population derived from light and dark DGRP lines. We replicated the effects on pigmentation of 28 genes implicated by the DGRP GWA study, including bab1, t and e and 7 genes previously validated by RNAi and/or mutant analyses. We also identified many additional loci. The genetic architecture of Drosophila pigmentation is complex, with a few major genes and many other loci with smaller effects.
Subject(s)
Drosophila Proteins/metabolism , Drosophila melanogaster/metabolism , Gene Expression Regulation/physiology , Pigmentation/physiology , Abdomen , Animals , Drosophila Proteins/genetics , Drosophila melanogaster/genetics , Female , Genome-Wide Association Study , Pigmentation/genetics , Polymorphism, Single Nucleotide , Quantitative Trait LociABSTRACT
Understanding how DNA sequence variation is translated into variation for complex phenotypes has remained elusive but is essential for predicting adaptive evolution, for selecting agriculturally important animals and crops, and for personalized medicine. Gene expression may provide a link between variation in DNA sequence and organismal phenotypes, and its abundance can be measured efficiently and accurately. Here we quantified genome-wide variation in gene expression in the sequenced inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP), increasing the annotated Drosophila transcriptome by 11%, including thousands of novel transcribed regions (NTRs). We found that 42% of the Drosophila transcriptome is genetically variable in males and females, including the NTRs, and is organized into modules of genetically correlated transcripts. We found that NTRs often were negatively correlated with the expression of protein-coding genes, which we exploited to annotate NTRs functionally. We identified regulatory variants for the mean and variance of gene expression, which have largely independent genetic control. Expression quantitative trait loci (eQTLs) for the mean, but not for the variance, of gene expression were concentrated near genes. Notably, the variance eQTLs often interacted epistatically with local variants in these genes to regulate gene expression. This comprehensive characterization of population-scale diversity of transcriptomes and its genetic basis in the DGRP is critically important for a systems understanding of quantitative trait variation.
Subject(s)
Drosophila melanogaster/genetics , Transcriptome , Animals , Epistasis, Genetic , Quantitative Trait LociABSTRACT
Natural populations harbor considerable genetic variation for lifespan. While evolutionary theory provides general explanations for the existence of this variation, our knowledge of the genes harboring naturally occurring polymorphisms affecting lifespan is limited. Here, we assessed the genetic divergence between five Drosophila melanogaster lines selected for postponed senescence for over 170 generations (O lines) and five lines from the same base population maintained at a two week generation interval for over 850 generations (B lines). On average, O lines live 70% longer than B lines, are more productive at all ages, and have delayed senescence for other traits than reproduction. We performed population sequencing of pools of individuals from all B and O lines and identified 6,394 genetically divergent variants in or near 1,928 genes at a false discovery rate of 0.068. A 2.6 Mb region at the tip of the X chromosome contained many variants fixed for alternative alleles in the two populations, suggestive of a hard selective sweep. We also assessed genome wide gene expression of O and B lines at one and five weeks of age using RNA sequencing and identified genes with significant (false discovery rate < 0.05) effects on gene expression with age, population and the age by population interaction, separately for each sex. We identified transcripts that exhibited the transcriptional signature of postponed senescence and integrated the gene expression and genetic divergence data to identify 98 (175) top candidate genes in females (males) affecting postponed senescence and increased lifespan. While several of these genes have been previously associated with Drosophila lifespan, most are novel and constitute a rich resource for future functional validation.
Subject(s)
Aging/genetics , Drosophila melanogaster/genetics , Alleles , Animals , Female , Gene Expression/genetics , Genes, Insect/genetics , Genetic Variation/genetics , Genomics/methods , Longevity/genetics , MaleABSTRACT
Royal Jelly (RJ) is a product made by honey bee workers and is required for queen differentiation and accompanying changes in queen body size, development time, lifespan and reproductive output relative to workers. Previous studies have reported similar changes in Drosophila melanogaster in response to RJ. Here, we quantified viability, development time, body size, productivity, lifespan and genome wide transcript abundance of D. melanogaster reared on standard culture medium supplemented with increasing concentrations of RJ. We found that lower concentrations of RJ do induce significant differences in body size in both sexes; higher concentrations reduce size, increase mortality, shorten lifespan and reduce productivity. Increased concentrations of RJ also consistently lengthened development time in both sexes. RJ is associated with changes in expression of 1,581 probe sets assessed using Affymetrix Drosophila 2.0 microarrays, which were enriched for genes associated with metabolism and amino acid degradation. The transcriptional changes are consistent with alterations in cellular processes to cope with excess nutrients provided by RJ, including biosynthesis and detoxification, which might contribute to accelerated senescence and reduced lifespan.
Subject(s)
Drosophila melanogaster/drug effects , Fatty Acids/pharmacology , Gene Expression/drug effects , Insect Hormones/pharmacology , Animals , Body Size/drug effects , Dose-Response Relationship, Drug , Drosophila melanogaster/genetics , Drosophila melanogaster/growth & development , Drosophila melanogaster/physiology , Longevity/drug effectsABSTRACT
Aggression is an evolutionarily conserved complex behavior essential for survival and the organization of social hierarchies. With the exception of genetic variants associated with bioamine signaling, which have been implicated in aggression in many species, the genetic basis of natural variation in aggression is largely unknown. Drosophila melanogaster is a favorable model system for exploring the genetic basis of natural variation in aggression. Here, we performed genome-wide association analyses using the inbred, sequenced lines of the Drosophila melanogaster Genetic Reference Panel (DGRP) and replicate advanced intercross populations derived from the most and least aggressive DGRP lines. We identified genes that have been previously implicated in aggressive behavior as well as many novel loci, including gustatory receptor 63a (Gr63a), which encodes a subunit of the receptor for CO2, and genes associated with development and function of the nervous system. Although genes from the two association analyses were largely nonoverlapping, they mapped onto a genetic interaction network inferred from an analysis of pairwise epistasis in the DGRP. We used mutations and RNAi knock-down alleles to functionally validate 79% of the candidate genes and 75% of the candidate epistatic interactions tested. Epistasis for aggressive behavior causes cryptic genetic variation in the DGRP that is revealed by changing allele frequencies in the outbred populations derived from extreme DGRP lines. This phenomenon may pertain to other fitness traits and species, with implications for evolution, applied breeding, and human genetics.
Subject(s)
Aggression , Drosophila Proteins/genetics , Drosophila melanogaster/genetics , Genes, Insect/genetics , Genetic Variation , Animals , Crosses, Genetic , Drosophila Proteins/physiology , Drosophila melanogaster/classification , Drosophila melanogaster/physiology , Epistasis, Genetic , Evolution, Molecular , Genes, Insect/physiology , Genome, Insect/genetics , Humans , Inbreeding , Mutation , RNA Interference , Species SpecificityABSTRACT
The Drosophila melanogaster Genetic Reference Panel (DGRP) is a community resource of 205 sequenced inbred lines, derived to improve our understanding of the effects of naturally occurring genetic variation on molecular and organismal phenotypes. We used an integrated genotyping strategy to identify 4,853,802 single nucleotide polymorphisms (SNPs) and 1,296,080 non-SNP variants. Our molecular population genomic analyses show higher deletion than insertion mutation rates and stronger purifying selection on deletions. Weaker selection on insertions than deletions is consistent with our observed distribution of genome size determined by flow cytometry, which is skewed toward larger genomes. Insertion/deletion and single nucleotide polymorphisms are positively correlated with each other and with local recombination, suggesting that their nonrandom distributions are due to hitchhiking and background selection. Our cytogenetic analysis identified 16 polymorphic inversions in the DGRP. Common inverted and standard karyotypes are genetically divergent and account for most of the variation in relatedness among the DGRP lines. Intriguingly, variation in genome size and many quantitative traits are significantly associated with inversions. Approximately 50% of the DGRP lines are infected with Wolbachia, and four lines have germline insertions of Wolbachia sequences, but effects of Wolbachia infection on quantitative traits are rarely significant. The DGRP complements ongoing efforts to functionally annotate the Drosophila genome. Indeed, 15% of all D. melanogaster genes segregate for potentially damaged proteins in the DGRP, and genome-wide analyses of quantitative traits identify novel candidate genes. The DGRP lines, sequence data, genotypes, quality scores, phenotypes, and analysis and visualization tools are publicly available.
Subject(s)
Drosophila melanogaster/genetics , Genetic Variation , Genome, Insect , Phenotype , Animals , Chromatin/genetics , Chromatin/metabolism , Drosophila melanogaster/microbiology , Female , Genetic Linkage , Genome Size , Genome-Wide Association Study , Genotype , Genotyping Techniques , High-Throughput Nucleotide Sequencing , INDEL Mutation , Linkage Disequilibrium , Male , Molecular Sequence Annotation , Polymorphism, Single Nucleotide , Quantitative Trait, Heritable , Reproducibility of ResultsABSTRACT
Primary open angle glaucoma (POAG) is a common late-onset neurodegenerative disease. Ocular hypertension represents a major risk factor, but POAG etiology remains poorly understood. Some cases of early-onset congenital glaucoma and adult POAG are linked to mutations in myocilin, a secreted protein of poorly defined function. Transgenic overexpression of myocilin in Drosophila and experiments in mice and human populations implicate the unfolded protein response (UPR) in the pathogenesis of glaucoma. We postulate that compromised ability of the UPR to eliminate misfolded mutant or damaged proteins, including myocilin, causes endoplasmic reticulum stress, resulting in functional impairment of trabecular meshwork cells that regulate intraocular pressure. This mechanism of POAG is reminiscent of other age-dependent neurodegenerative diseases that involve accumulation of protein aggregates.
Subject(s)
Endoplasmic Reticulum Stress , Glaucoma/pathology , Unfolded Protein Response , Animals , Cytoskeletal Proteins/metabolism , Eye Proteins/metabolism , Glycoproteins/metabolism , Humans , Neurodegenerative Diseases/pathology , Translational Research, BiomedicalABSTRACT
Epistasis-nonlinear genetic interactions between polymorphic loci-is the genetic basis of canalization and speciation, and epistatic interactions can be used to infer genetic networks affecting quantitative traits. However, the role that epistasis plays in the genetic architecture of quantitative traits is controversial. Here, we compared the genetic architecture of three Drosophila life history traits in the sequenced inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP) and a large outbred, advanced intercross population derived from 40 DGRP lines (Flyland). We assessed allele frequency changes between pools of individuals at the extremes of the distribution for each trait in the Flyland population by deep DNA sequencing. The genetic architecture of all traits was highly polygenic in both analyses. Surprisingly, none of the SNPs associated with the traits in Flyland replicated in the DGRP and vice versa. However, the majority of these SNPs participated in at least one epistatic interaction in the DGRP. Despite apparent additive effects at largely distinct loci in the two populations, the epistatic interactions perturbed common, biologically plausible, and highly connected genetic networks. Our analysis underscores the importance of epistasis as a principal factor that determines variation for quantitative traits and provides a means to uncover genetic networks affecting these traits. Knowledge of epistatic networks will contribute to our understanding of the genetic basis of evolutionarily and clinically important traits and enhance predictive ability at an individualized level in medicine and agriculture.
Subject(s)
Epistasis, Genetic/physiology , Genes, Insect/physiology , Quantitative Trait, Heritable , Animals , Drosophila melanogaster , Polymorphism, Single NucleotideABSTRACT
A major challenge of biology is understanding the relationship between molecular genetic variation and variation in quantitative traits, including fitness. This relationship determines our ability to predict phenotypes from genotypes and to understand how evolutionary forces shape variation within and between species. Previous efforts to dissect the genotype-phenotype map were based on incomplete genotypic information. Here, we describe the Drosophila melanogaster Genetic Reference Panel (DGRP), a community resource for analysis of population genomics and quantitative traits. The DGRP consists of fully sequenced inbred lines derived from a natural population. Population genomic analyses reveal reduced polymorphism in centromeric autosomal regions and the X chromosome, evidence for positive and negative selection, and rapid evolution of the X chromosome. Many variants in novel genes, most at low frequency, are associated with quantitative traits and explain a large fraction of the phenotypic variance. The DGRP facilitates genotype-phenotype mapping using the power of Drosophila genetics.