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Search Results: 1 - 10 of 207679 matches for " Andrew G Clark "
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Associations between Variation in X Chromosome Male Reproductive Genes and Sperm Competitive Ability in Drosophila melanogaster
Leah Greenspan,Andrew G. Clark
International Journal of Evolutionary Biology , 2011, DOI: 10.4061/2011/214280
Abstract: Variation in reproductive success has long been thought to be mediated in part by genes encoding seminal proteins. Here we explore the effect on male reproductive phenotypes of X-linked polymorphisms, a chromosome that is depauperate in genes encoding seminal proteins. Using 57 X chromosome substitution lines, sperm competition was tested both when the males from the wild-extracted line were the first to mate (“defense” crosses), followed by a tester male, and when extracted-line males were the second to mate, after a tester male (“offfense” crosses). We scored the proportion of progeny sired by each male, the fecundity, the remating rate and refractoriness to remating, and tested the significance of variation among lines. Eleven candidate genes were chosen based on previous studies, and portions of these genes were sequenced in all 57 lines. A total of 131 polymorphisms were tested for associations with the reproductive phenotypes using linear models. Nine polymorphisms in 4 genes were found to show significant associations (at a 5% FDR). Overall, it appears that the X chromosomes harbor abundant variation in sperm competition, especially considering the paucity of seminal protein genes. This suggests that much of the male reproductive variation lies outside of genes that encode seminal proteins. 1. Introduction In nature, Drosophila melanogaster females often mate with multiple partners [1–3]. Due to the female fly’s ability to store sperm, having multiple partners provides an evolutionary advantage for female flies allowing them to choose the strongest and most fit sperm to fertilize their eggs. Females’ tendency to remate has provided an opportunity for selection to operate on differential sperm success, and this opportunity is thought to have resulted in robust sperm competition among male fruit flies. In order for male flies to sire as many progeny as possible, their ejaculate must either provide a means for their sperm to outcompete other sperm in order to fertilize as many eggs as possible, or it may contain substances that discourage the female fly from remating [4]. Although recent studies have shown that males vary in their ability to gain fertilizations under competitive conditions, the precise mechanism is unknown. Factors that influence the outcome of sperm competition and postcopulatory sexual selection include differences in sperm delivery and storage, seminal fluid composition, female egg laying rate, and female remating latency [4, 5]. Sexual antagonism occurs when there is an evolutionary advantage of a trait in one sex that reduces
Sex-Differential Selection and the Evolution of X Inactivation Strategies
Tim Connallon ,Andrew G. Clark
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003440
Abstract: X inactivation—the transcriptional silencing of one X chromosome copy per female somatic cell—is universal among therian mammals, yet the choice of which X to silence exhibits considerable variation among species. X inactivation strategies can range from strict paternally inherited X inactivation (PXI), which renders females haploid for all maternally inherited alleles, to unbiased random X inactivation (RXI), which equalizes expression of maternally and paternally inherited alleles in each female tissue. However, the underlying evolutionary processes that might account for this observed diversity of X inactivation strategies remain unclear. We present a theoretical population genetic analysis of X inactivation evolution and specifically consider how conditions of dominance, linkage, recombination, and sex-differential selection each influence evolutionary trajectories of X inactivation. The results indicate that a single, critical interaction between allelic dominance and sex-differential selection can select for a broad and continuous range of X inactivation strategies, including unequal rates of inactivation between maternally and paternally inherited X chromosomes. RXI is favored over complete PXI as long as alleles deleterious to female fitness are sufficiently recessive, and the criteria for RXI evolution is considerably more restrictive when fitness variation is sexually antagonistic (i.e., alleles deleterious to females are beneficial to males) relative to variation that is deleterious to both sexes. Evolutionary transitions from PXI to RXI also generally increase mean relative female fitness at the expense of decreased male fitness. These results provide a theoretical framework for predicting and interpreting the evolution of chromosome-wide expression of X-linked genes and lead to several useful predictions that could motivate future studies of allele-specific gene expression variation.
Comparative profiling of the transcriptional response to infection in two species of Drosophila by short-read cDNA sequencing
Timothy B Sackton, Andrew G Clark
BMC Genomics , 2009, DOI: 10.1186/1471-2164-10-259
Abstract: We use short read sequencing technology (Illumina/Solexa) to compare the transcriptional response to infection between the well studied model system Drosophila melanogaster and the distantly related drosophilid D. virilis. We first demonstrate that Illumina/Solexa sequencing of cDNA from infected and uninfected D. melanogaster recapitulates previously published microarray studies of the transcriptional response to infection in this species, validating our approach. We then show that patterns of transcription of homologous genes differ considerably between D. melanogaster and D. virilis, and identify potential candidates for novel components of the D. virilis immune system based on transcriptional data. Finally, we use a proteomic approach to characterize the protein constituents of the D. virilis hemolymph and validate our transcriptional data.These results suggest that the acquisition of novel components of the immune system, and particularly novel effector proteins, may be a common evolutionary phenomenon.Host-pathogen interactions are ubiquitous in nature, leading to coevolutionary dynamics that are predicted to drive rapid evolution of the immune system. It is now increasingly clear that this coevolutionary "arms race" leads to increased rates of protein evolution in genes encoding components of the immune system across a large number of taxa [1-7]. Recent work in mosquitoes [8,9] and fruit flies [5] has suggested that the immune system may also be unusual in the rate at which new genes are recruited into the system, and existing components of the system turn over by gene duplication or loss. Genes encoding effector proteins (proteins involved in bacterial killing and clearance), and particularly antimicrobial peptides (AMPs), often have lineage-restricted patterns of homology and show very rapid rates of gene turnover within gene families [5]. Most strikingly, two multigene families – the Drosomycin antimicrobial peptide family [10] and the Turandot family [11,
Gene-Based Testing of Interactions in Association Studies of Quantitative Traits
Li Ma ,Andrew G. Clark,Alon Keinan
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003321
Abstract: Various methods have been developed for identifying gene–gene interactions in genome-wide association studies (GWAS). However, most methods focus on individual markers as the testing unit, and the large number of such tests drastically erodes statistical power. In this study, we propose novel interaction tests of quantitative traits that are gene-based and that confer advantage in both statistical power and biological interpretation. The framework of gene-based gene–gene interaction (GGG) tests combine marker-based interaction tests between all pairs of markers in two genes to produce a gene-level test for interaction between the two. The tests are based on an analytical formula we derive for the correlation between marker-based interaction tests due to linkage disequilibrium. We propose four GGG tests that extend the following P value combining methods: minimum P value, extended Simes procedure, truncated tail strength, and truncated P value product. Extensive simulations point to correct type I error rates of all tests and show that the two truncated tests are more powerful than the other tests in cases of markers involved in the underlying interaction not being directly genotyped and in cases of multiple underlying interactions. We applied our tests to pairs of genes that exhibit a protein–protein interaction to test for gene-level interactions underlying lipid levels using genotype data from the Atherosclerosis Risk in Communities study. We identified five novel interactions that are not evident from marker-based interaction testing and successfully replicated one of these interactions, between SMAD3 and NEDD9, in an independent sample from the Multi-Ethnic Study of Atherosclerosis. We conclude that our GGG tests show improved power to identify gene-level interactions in existing, as well as emerging, association studies.
Faster-X Evolution of Gene Expression in Drosophila
Richard P. Meisel ,John H. Malone,Andrew G. Clark
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1003013
Abstract: DNA sequences on X chromosomes often have a faster rate of evolution when compared to similar loci on the autosomes, and well articulated models provide reasons why the X-linked mode of inheritance may be responsible for the faster evolution of X-linked genes. We analyzed microarray and RNA–seq data collected from females and males of six Drosophila species and found that the expression levels of X-linked genes also diverge faster than autosomal gene expression, similar to the “faster-X” effect often observed in DNA sequence evolution. Faster-X evolution of gene expression was recently described in mammals, but it was limited to the evolutionary lineages shortly following the creation of the therian X chromosome. In contrast, we detect a faster-X effect along both deep lineages and those on the tips of the Drosophila phylogeny. In Drosophila males, the dosage compensation complex (DCC) binds the X chromosome, creating a unique chromatin environment that promotes the hyper-expression of X-linked genes. We find that DCC binding, chromatin environment, and breadth of expression are all predictive of the rate of gene expression evolution. In addition, estimates of the intraspecific genetic polymorphism underlying gene expression variation suggest that X-linked expression levels are not under relaxed selective constraints. We therefore hypothesize that the faster-X evolution of gene expression is the result of the adaptive fixation of beneficial mutations at X-linked loci that change expression level in cis. This adaptive faster-X evolution of gene expression is limited to genes that are narrowly expressed in a single tissue, suggesting that relaxed pleiotropic constraints permit a faster response to selection. Finally, we present a conceptional framework to explain faster-X expression evolution, and we use this framework to examine differences in the faster-X effect between Drosophila and mammals.
Genotype and Gene Expression Associations with Immune Function in Drosophila
Timothy B. Sackton ,Brian P. Lazzaro,Andrew G. Clark
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1000797
Abstract: It is now well established that natural populations of Drosophila melanogaster harbor substantial genetic variation associated with physiological measures of immune function. In no case, however, have intermediate measures of immune function, such as transcriptional activity of immune-related genes, been tested as mediators of phenotypic variation in immunity. In this study, we measured bacterial load sustained after infection of D. melanogaster with Serratia marcescens, Providencia rettgeri, Enterococcus faecalis, and Lactococcus lactis in a panel of 94 third-chromosome substitution lines. We also measured transcriptional levels of 329 immune-related genes eight hours after infection with E. faecalis and S. marcescens in lines from the phenotypic tails of the test panel. We genotyped the substitution lines at 137 polymorphic markers distributed across 25 genes in order to test for statistical associations among genotype, bacterial load, and transcriptional dynamics. We find that genetic polymorphisms in the pathogen recognition genes (and particularly in PGRP-LC, GNBP1, and GNBP2) are most significantly associated with variation in bacterial load. We also find that overall transcriptional induction of effector proteins is a significant predictor of bacterial load after infection with E. faecalis, and that a marker upstream of the recognition gene PGRP-SD is statistically associated with variation in both bacterial load and transcriptional induction of effector proteins. These results show that polymorphism in genes near the top of the immune system signaling cascade can have a disproportionate effect on organismal phenotype due to the amplification of minor effects through the cascade.
Contrasting Infection Strategies in Generalist and Specialist Wasp Parasitoids of Drosophila melanogaster
Todd A Schlenke ,Jorge Morales,Shubha Govind,Andrew G Clark
PLOS Pathogens , 2007, DOI: 10.1371/journal.ppat.0030158
Abstract: Although host–parasitoid interactions are becoming well characterized at the organismal and cellular levels, much remains to be understood of the molecular bases for the host immune response and the parasitoids' ability to defeat this immune response. Leptopilina boulardi and L. heterotoma, two closely related, highly infectious natural parasitoids of Drosophila melanogaster, appear to use very different infection strategies at the cellular level. Here, we further characterize cellular level differences in the infection characteristics of these two wasp species using newly derived, virulent inbred strains, and then use whole genome microarrays to compare the transcriptional response of Drosophila to each. While flies attacked by the melanogaster group specialist L. boulardi (strain Lb17) up-regulate numerous genes encoding proteolytic enzymes, components of the Toll and JAK/STAT pathways, and the melanization cascade as part of a combined cellular and humoral innate immune response, flies attacked by the generalist L. heterotoma (strain Lh14) do not appear to initiate an immune transcriptional response at the time points post-infection we assayed, perhaps due to the rapid venom-mediated lysis of host hemocytes (blood cells). Thus, the specialist parasitoid appears to invoke a full-blown immune response in the host, but suppresses and/or evades downstream components of this response. Given that activation of the host immune response likely depletes the energetic resources of the host, the specialist's infection strategy seems relatively disadvantageous. However, we uncover the mechanism for one potentially important fitness tradeoff of the generalist's highly immune suppressive infection strategy.
Paternally biased X inactivation in mouse neonatal brain
Xu Wang, Paul D Soloway, Andrew G Clark
Genome Biology , 2010, DOI: 10.1186/gb-2010-11-7-r79
Abstract: After RNA-seq data revealed what appeared to be a chromosome-wide bias toward under-expression of paternal alleles in mouse tissue, we applied pyrosequencing to mouse brain cDNA samples from reciprocal cross F1 progeny of divergent strains and found a small but consistent and highly statistically significant excess tendency to under-express the paternal X chromosome.The bias toward paternal X inactivation is reminiscent of marsupials (and extraembryonic tissues in eutherians), suggesting that there may be retained an evolutionarily conserved epigenetic mark driving the bias. Allelic bias in expression is also influenced by the sampling effect of X inactivation and by cis-acting regulatory variation (eQTL), and for each gene we quantify the contributions of these effects in two different mouse strain combinations while controlling for variability in Xce alleles. In addition, we propose an efficient method to identify and confirm genes that escape X inactivation in normal mice by directly comparing the allele-specific expression ratio profile of multiple X-linked genes in multiple individuals.In placental mammals, dosage compensation is achieved during embryonic development by random inactivation of one of the two female X chromosomes [1,2]. In male germline tissue, both sex chromosomes are inactivated through meiotic sex chromosome inactivation. In the mouse placenta, the paternal X chromosome (Xp) is inactivated in extraembryonic tissues. In female zygotes, at the two-cell stage, Xp is activated and X-linked genes are transcribed from both parental X chromosomes. In the mouse, starting from the eight-cell stage, the Xp is inactivated through a process known as imprinted X inactivation [3-5]. Subsequently, the Xp is reactivated and, in the mouse, random X inactivation occurs around the implantation stage (about day 6.5) in the embryonic tissue, with only one of the two X chromosomes remaining activated [6], while the extraembryonic tissues retain imprinted X inactiva
Mutation spectrum of Drosophila CNVs revealed by breakpoint sequencing
Margarida Cardoso-Moreira, J Roman Arguello, Andrew G Clark
Genome Biology , 2012, DOI: 10.1186/gb-2012-13-12-r119
Abstract: By applying split-read methods to a total of 10x coverage of 454 shotgun sequence across 9 lines of D. melanogaster and by re-examining a previously published dataset of CNVs detected using tiling arrays, we identified the precise breakpoints of more than 600 insertions, deletions and duplications. Contrasting these CNVs with those found in humans showed that in both taxa CNV breakpoints fall into three classes: blunt breakpoints; simple breakpoints associated with microhomology; and breakpoints with additional nucleotides inserted/deleted and no microhomology. In both taxa CNV breakpoints are enriched with non-B DNA sequence structures, which may impair DNA replication and/or repair. However, in contrast to human genomes, Non-Allelic Homologous-Recombination (NAHR) plays a negligible role in CNV formation in Drosophila. In flies, non-homologous repair mechanisms are responsible for simple, recurrent and complex CNVs, including insertions of de novo sequence as large as 60 bp.Humans and Drosophila differ considerably in the importance of homology-based mechanisms for the formation of CNVs, likely as a consequence of the differences in the abundance and distribution of both segmental duplications and transposable elements between the two genomes.
Simple models of genomic variation in human SNP density
Raazesh Sainudiin, Andrew G Clark, Richard T Durrett
BMC Genomics , 2007, DOI: 10.1186/1471-2164-8-146
Abstract: Using empirical estimates of recombination rate across the human genome and the observed SNP density distribution, we produce a maximum likelihood estimate of the genomic heterogeneity in the scaled mutation rate θ. Such models produce significantly better fits to the observed SNP density distribution than those that ignore the empirically observed recombinational heterogeneities.Accounting for mutational and recombinational heterogeneities can allow for empirically sound null distributions in genome scans for "outliers", when the alternative hypotheses include fundamentally historical and unobserved phenomena.Understanding the population-genetic forces behind the observed variation among human genome sequences is vital to deciphering the genetic causes of phenotypic variation among humans. The phenomena that influence the density of human SNPs include (1) variation-introducing events that are empirically observable, such as, point-mutations, recombinations, and activities of various transposable elements that may result from the counteraction of various DNA damage and repair pathways [[1], for e.g.], as well as (2) genealogy-affecting events that are historical and generally unobserved, such as population dynamics, population structure, and natural selection. A biological understanding of the observed genomic variation in SNP density, by means of explicit population-genetic models of coalescence in the presence of recombination and mutation, must incorporate any interplay among the heterogeneities in the above phenomena. Here we strive for an empirically sound understanding of the observed human SNP density, as determined by a genome-wide alignment of two different consensus sequences, by accounting for the empirically observable mutational and recombinational heterogeneities under the simplest model of population history (selectively-neutral, constant-sized, random-mating). The two sequences are the NCBI human genome sequence and the sequence produced by Celera Ge
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