PubMed Health⌕ Search

Biomedical subjects

Ian Dworkin

Publications and source records attributed to Ian Dworkin.

10 recordsLinked to original sources
PubMed2006

Epidermal growth factor receptor and transforming growth factor-beta signaling contributes to variation for wing shape in Drosophila melanogaster.

Wing development in Drosophila is a common model system for the dissection of genetic networks and their roles during development. In particular, the RTK and TGF-beta regulatory networks appear to be involved with numerous aspects of wing development, including patterning, cell determination, growth, proliferation, and survival in the developing imaginal wing disc. However, little is known as to how subtle changes in the function of these genes may contribute to quantitative variation for wing shape, per se. In this study 50 insertional mutations, representing 43 loci in the RTK, Hedgehog, TGF-beta pathways, and their genetically interacting factors were used to study the role of these networks on wing shape. To concurrently examine how genetic background modulates the effects of the mutation, each insertion was introgressed into two wild-type genetic backgrounds. Using geometric morphometric methods, it is shown that the majority of these mutations have profound effects on shape but not size of the wing when measured as heterozygotes. To examine the relationships between how each mutation affects wing shape hierarchical clustering was used. Unlike previous observations of environmental canalization, these mutations did not generally increase within-line variation relative to their wild-type counterparts. These results provide an entry point into the genetics of wing shape and are discussed within the framework of the dissection of complex phenotypes.

Animals↗
PubMed2005

Tests for the replication of an association between Egfr and natural variation in Drosophila melanogaster wing morphology.

BACKGROUND: Quantitative differences between individuals stem from a combination of genetic and environmental factors, with the heritable variation being shaped by evolutionary forces. Drosophila wing shape has emerged as an attractive system for genetic dissection of multi-dimensional traits. We utilize several experimental genetic methods to validation of the contribution of several polymorphisms in the Epidermal growth factor receptor (Egfr) gene to wing shape and size, that were previously mapped in populations of Drosophila melanogaster from North Carolina (NC) and California (CA). This re-evaluation utilized different genetic testcrosses to generate heterozygous individuals with a variety of genetic backgrounds as well as sampling of new alleles from Kenyan stocks. RESULTS: Only one variant, in the Egfr promoter, had replicable effects in all new experiments. However, expanded genotyping of the initial sample of inbred lines rendered the association non-significant in the CA population, while it persisted in the NC sample, suggesting population specific modification of the quantitative trait nucleotide QTN effect. CONCLUSION: Dissection of quantitative trait variation to the nucleotide level can identify sites with replicable effects as small as one percent of the segregating genetic variation. However, the testcross approach to validate QTNs is both labor intensive and time-consuming, and is probably less useful than resampling of large independent sets of outbred individuals.

Animals↗
PubMed2005

Replication of an Egfr-wing shape association in a wild-caught cohort of Drosophila melanogaster.

Linkage disequilibrium mapping has been used extensively in medical and evolutionary genetics to map causal polymorphisms within genes associated with disease status or phenotypic variation for a trait. However, the initial findings of most nonhuman studies have not been replicated in subsequent studies, due in part to false positives, as well as additional factors that can render true positives unreplicable. These factors may be more severe when the initial study is performed using an experimental population of organisms reared under controlled lab conditions. We demonstrate that despite considerable phenotypic differences for wing shape between a lab-reared experimental population and a wild-caught cohort of Drosophila melanogaster, an association between a putative regulatory polymorphism in Egfr and wing shape can be replicated. These results are discussed both within the framework of future association-mapping studies and within the context of the evolutionary dynamics of alleles in populations.

Alleles↗
PubMed2005

A study of canalization and developmental stability in the sternopleural bristle system of Drosophila melanogaster.

Among the explanations for minimizing the effects of extraneous variation has been canalization and developmental stability. However, there is little agreement as to whether these two processes reflect a common set of mechanisms. This confusion is inflated due to the lack of consensus as to a precise definition of canalization. In this study, canalization in the sternopleural bristle system is used to investigate the relationships between measures of canalization and developmental stability by comparing how a panel of naturally derived lines responds to both genetic and environmental perturbations. No evidence for a common mechanism between the different measures of canalization was observed. Furthermore, a hypothesis regarding a common mechanism for environmental and genetic canalization was tested, and no evidence was found to support it. However, there is evidence for a relationship between at least one form of canalization and developmental stability.

Analysis of Variance↗
PubMed2004

Uncovering cryptic genetic variation.

Cryptic genetic variation is the dark matter of biology: it is variation that is not normally seen, but that might be an essential source of physiological and evolutionary potential. It is uncovered by environmental or genetic perturbations, and is thought to modify the penetrance of common diseases, the response of livestock and crops to artificial selection and the capacity of populations to respond to the emergence of a potentially advantageous macro-mutation. We argue in this review that cryptic genetic variation is pervasive but under-appreciated, we highlight recent progress in determining the nature and identity of genes that underlie cryptic genetic effects and we outline future research directions.

Animals↗
PubMed2004

Nucleotide variation in the Egfr locus of Drosophila melanogaster.

The Epidermal growth factor receptor is an essential gene with diverse pleiotropic roles in development throughout the animal kingdom. Analysis of sequence diversity in 10.9 kb covering the complete coding region and 6.4 kb of potential regulatory regions in a sample of 250 alleles from three populations of Drosophila melanogaster suggests that the intensity of different population genetic forces varies along the locus. A total of 238 independent common SNPs and 20 indel polymorphisms were detected, with just six common replacements affecting >1475 amino acids, four of which are in the short alternate first exon. Sequence diversity is lowest in a 2-kb portion of intron 2, which is also highly conserved in comparison with D. simulans and D. pseudoobscura. Linkage disequilibrium decays to background levels within 500 bp of most sites, so haplotypes are generally restricted to up to 5 polymorphisms. The two North American samples from North Carolina and California have diverged in allele frequency at a handful of individual SNPs, but a Kenyan sample is both more divergent and more polymorphic. The effect of sample size on inference of the roles of population structure, uneven recombination, and weak selection in patterning nucleotide variation in the locus is discussed.

Analysis of Variance↗
PubMed2003

Evidence that Egfr contributes to cryptic genetic variation for photoreceptor determination in natural populations of Drosophila melanogaster.

One objective of quantitative genetics is to identify the nucleotide variants within genes that contribute to phenotypic variation and susceptibility [1]. In an evolutionary context, this means characterizing the molecular polymorphisms that modify the penetrance and expressivity of perturbed traits. A survey of association between 267 SNPs in almost 11 kb of the D. melanogaster Egfr and the degree of eye roughening due to a gain-of-function Egfr(E1) allele crossed into 210 isogenic wild-type lines provides evidence that a handful of synonymous substitutions supply cryptic variation for photoreceptor determination. Ten sites exceed Bonferroni threshold for association in two sets of crosses to different Egfr(E1) backgrounds including a particularly significant cluster of sites in tight linkage disequilibrium toward the 3' end of the coding region. Epistatic interaction of this cluster with one other site enhances the expressivity of this haplotype. Replication of the strongest associations with an independent sample of 302 phenotypically extreme individuals derived from 1000 crosses of Egfr(E1) to freshly trapped males was achieved using modified case-control and transmission-disequilibrium tests. A tendency for the rarer alleles to have more disrupted eye development suggests that mutation-selection balance is a possible mechanism contributing to maintaining cryptic variation for Egfr.

Alleles↗
PubMedDate not supplied

The environmental and genetic regulation of obake expressivity: morphogenetic fields as evolvable systems.

The morphogenetic field, a fundamental concept of classical embryology, is once again being invoked to describe developmental processes. Because the evolution of adult structures requires the modification of development, the ways in which morphogenetic fields can change over time may yield insights into evolutionary possibilities. We considered how the duplication/multiplication of a morphogenetic field in fruit flies, caused by the previously described obake (obk) mutation, is regulated by genetic and environmental factors. Mutations of genes in the canonical antenna-producing imaginal disc pathway suppressed duplication as expected, although the results suggested that other pathways might also be involved. Overgrowth mutations, expected to increase duplication, actually suppressed it. Mutations in the heat-shock protein gene Hsp83 did not uniformly enhance obk expressivity as hypothesized. Using third chromosomes extracted from wild-derived lines, natural genetic variation for modifiers of obk function was found to be extensive. Larval crowding suppressed the obk phenotype, but there was no evidence of trade-offs between body or head size and arista number. Our results suggest that a complex interplay of genetic and environmental factors in the regulation of fields may be responsible for ample natural variation in the expressivity of adult phenotypes, affording multiple opportunities for selection and evolutionary modification.

Alleles↗
PubMedDate not supplied

Evidence for canalization of Distal-less function in the leg of Drosophila melanogaster.

A considerable body of theory pertaining to the evolution of canalization has emerged recently, yet there have been few empirical investigations of their predictions. To address this, patterns of canalization and trait correlation were investigated under the individual and joint effects of the introgression of a loss-of-function allele of the Distal-less gene and high-temperature stress on a panel of iso-female lines. Variation was examined for number of sex comb teeth and the length of the basi-tarsus on the pro-thoracic leg of male Drosophila melanogaster. I demonstrate that whereas there is evidence for trait canalization, there is no evidence to support the hypothesis of the evolution of genetic canalization as a response to microenvironmental canalization. Furthermore, I demonstrate that although there are genetic correlations between these traits, there is no association between their measures of canalization. I discuss the prospects of the evolutionary lability of the Distal-less gene within the context of changes in genetic variation and covariation.

Animals↗