Recent advances in Drosophila genomics.
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Animals↗
Biomedical subjects
Kevin P White
Publications and source records attributed to Kevin P White.
Duplicate genes increase gene expression diversity within and between species.
Using microarray gene expression data from several Drosophila species and strains, we show that duplicated genes, compared with single-copy genes, significantly increase gene expression diversity during development. We show further that duplicate genes tend to cause expression divergences between Drosophila species (or strains) to evolve faster than do single-copy genes. This conclusion is also supported by data from different yeast strains.
Animals↗
Probabilistic inference of molecular networks from noisy data sources.
Information on molecular networks, such as networks of interacting proteins, comes from diverse sources that contain remarkable differences in distribution and quantity of errors. Here, we introduce a probabilistic model useful for predicting protein interactions from heterogeneous data sources. The model describes stochastic generation of protein-protein interaction networks with real-world properties, as well as generation of two heterogeneous sources of protein-interaction information: research results automatically extracted from the literature and yeast two-hybrid experiments. Based on the domain composition of proteins, we use the model to predict protein interactions for pairs of proteins for which no experimental data are available. We further explore the prediction limits, given experimental data that cover only part of the underlying protein networks. This approach can be extended naturally to include other types of biological data sources.
Algorithms↗
Fibromyalgia: the answer is blowin' in the wind.
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Clinical Competence↗
Developments in developmental genomics.
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Animals↗
Protein-DNA interaction mapping using genomic tiling path microarrays in Drosophila.
We demonstrate the use of a chromosomal walk (or "tiling path") printed as DNA microarrays for mapping protein-DNA interactions across large regions of contiguous genomic DNA in Drosophila melanogaster. Microarrays were constructed with genomic DNA fragments 430-920 bp in length, covering 2.9 million base pairs of the Adh-cactus region of chromosome 2 and 85,000 base pairs of the 82F region of chromosome 3. We performed DNA localization mapping for the heterochromatin protein HP1 and for the sequence-specific GAGA transcription factor, producing a comprehensive, high-resolution map of in vivo protein-DNA interactions throughout these regions of the Drosophila genome.
Amino Acid Motifs↗
Analysis of the eye developmental pathway in Drosophila using DNA microarrays.
Pax-6 genes encode evolutionarily conserved transcription factors capable of activating the gene-expression program required to build an eye. When ectopically expressed in Drosophila imaginal discs, Pax-6 genes induce the eye formation on the corresponding appendages of the adult fly. We used two different Drosophila full-genome DNA microarrays to compare gene expression in wild-type leg discs versus leg discs where eyeless, one of the two Drosophila Pax-6 genes, was ectopically expressed. We validated these data by analyzing the endogenous expression of selected genes in eye discs and identified 371 genes that are expressed in the eye imaginal discs and up-regulated when an eye morphogenetic field is ectopically induced in the leg discs. These genes mainly encode transcription factors involved in photoreceptor specification, signal transducers, cell adhesion molecules, and proteins involved in cell division. As expected, genes already known to act downstream of eyeless during eye development were identified, together with a group of genes that were not yet associated with eye formation.
Animals↗
Evolution of gene expression in the Drosophila melanogaster subgroup.
Little is known about broad patterns of variation and evolution of gene expression during any developmental process. Here we investigate variation in genome-wide gene expression among Drosophila simulans, Drosophila yakuba and four strains of Drosophila melanogaster during a major developmental transition--the start of metamorphosis. Differences in gene activity between these lineages follow a phylogenetic pattern, and 27% of all of the genes in these genomes differ in their developmental gene expression between at least two strains or species. We identify, on a gene-by-gene basis, the evolutionary forces that shape this variation and show that, both within the transcriptional network that controls metamorphosis and across the whole genome, the expression changes of transcription factor genes are relatively stable, whereas those of their downstream targets are more likely to have evolved. Our results demonstrate extensive evolution of developmental gene expression among closely related species.
Algorithms↗
Genotyping African haplotypes in ATM using a co-spotted single-base extension assay.
Human genetic analysis, including population genetic studies, increasingly calls for cost-effective, high-throughput methods for the rapid screening of single nucleotide polymorphisms (SNPs) across many individuals. The modified single-base extension assay described here (arrayed SBE) is a highly accurate and robust method for SNP genotyping that can deliver genotypes at 3.5 cents each, following PCR. Specifically, amino-modified probe/target pairs were prehybridized, then co-spotted in a microarray format prior to enzymatic addition of allele-specific nucleotides. Probe/target identity was determined solely by its physical location on the array rather than by hybridization to a complementary target, resulting in a call rate of 99-100%. These innovations result in an inexpensive, accurate assay with exceptional signal-to-noise ratios, depending on the glass surface employed. Comparison of glass slides from three different manufacturers indicated that aldehyde-based Zyomyx slides provided superior performance for this assay. Arrayed SBE was applied to study the geographic distribution of three African-specific haplotypes in the human ATM gene. Four selectively neutral markers, which define the haplotypes H5, H6, and H7, were screened in a total of 415 individuals. Region-specific haplotype frequencies were consistent with patterns of human migration across and outside of Africa, suggesting a possible haplotype origin in East Africa. Arrayed SBE was a robust tool for this analysis that could be applied to any situation requiring the genotyping of a few SNPs in many individuals.
Africa, Eastern↗
The relationship between cognitive appraisal, affect, and catastrophizing in patients with chronic pain.
A study was conducted to clarify the nature of catastrophizing, a construct that is frequently referred to in the chronic pain literature. Information regarding 3 affective experience and 3 affect regulation dimensions was gathered from a heterogeneous sample of 104 chronic pain patients by using a semistructured clinical interview and the Affect Regulation and Experience Q-Sort (AREQ). Self-report questionnaires included visual analog pain scales, the Coping Strategies Questionnaire (CSQ), Multidimensional Pain Inventory (MPI), McGill Pain Questionnaire (MPQ), and Center for Epidemiological Studies Depression scale (CES-D). Hierarchical multiple regression was used to demonstrate the relative contributions of affective and cognitive appraisal components of catastrophizing. Thirty-one percent of the variance in CSQ-Catastrophizing scores was explained by a combination of cognitive appraisal variables (perceived ability to control pain; MPI Life Control) and AREQ scores, even after adjusting for pain severity and chronicity, age, and sex of participants. Results of the study strongly suggest that, rather than thinking of catastrophizing primarily as a cognitive coping construct, it should be described as an elaborate construct made up of both cognitive appraisal and affective components. Implications for tailoring interventions to match individual styles of affect regulation are discussed.
Adaptation, Psychological↗
Tissue-specific gene expression and ecdysone-regulated genomic networks in Drosophila.
During insect metamorphosis, each tissue displays a unique physiological and morphological response to the steroid hormone 20-hydroxyecdysone (ecdysone). We assayed gene expression in five tissues during metamorphosis onset. Larval-specific tissues display major changes in genome-wide expression profiles, whereas tissues that survive into adulthood display few changes. In one larval tissue, the salivary gland, we used a computational approach to identify a regulatory motif and a cognate transcription factor involved in regulating a set of coexpressed genes. During the metamorphosis of another tissue, the midgut, genes encoding factors from the hedgehog, Notch, EGF, dpp, and wingless pathways are activated by the ecdysone regulatory network. Mutation of the ecdysone receptor abolishes their induction. Cell cycle genes are also activated during the initiation of midgut metamorphosis, and they are also dependent on ecdysone signaling. These results establish multiple new connections between the ecdysone regulatory network and other well-studied regulatory networks.
Amino Acid Sequence↗
Fibromyalgia syndrome in an Amish community: a controlled study to determine disease and symptom prevalence.
OBJECTIVES: To estimate the point prevalence of fibromyalgia syndrome (FM) in Amish adults and to compare the prevalence of chronic pain, chronic widespread pain, FM, chronic fatigue, and debilitating fatigue in the Amish versus non-Amish rural and urban controls. The a priori assumption was that, if litigation and/or compensation availability have major effects on FM prevalence, then FM prevalence in the Amish should approach zero. METHODS: We surveyed 242 Amish adults in a small rural community southeast of London, Ontario, Canada. Individuals were screened using a validated screening instrument. Those reporting chronic, widespread pain were examined for FM using published classification criteria. Amish results were compared to results collected in a random telephone survey of 492 non-Amish adults living in rural Southwestern Ontario and 3395 non-Amish adults previously surveyed in London. RESULTS: Pain lasting at least one week in the preceding 3 months was reported by 34.3% of the Amish; pain in the upper extremities by 25.4%, in the lower extremities by 22.5%, and in the trunk by 28.1%. Twenty-six (15 women, 11 men) reported chronic, widespread pain. Eleven FM cases were confirmed among women (age adjusted point prevalence, p = 10.4%) and 2 among men (p = 3.7%) for an overall age and sex adjusted prevalence of 7.3% (95% CI 5.3, 9.7); this was both statistically greater than zero (p < 0.0001) and greater than in either control population (both p < 0.05). CONCLUSION: FM is relatively common among the Amish.
Adolescent↗
Gene expression during the life cycle of Drosophila melanogaster.
Molecular genetic studies of Drosophila melanogaster have led to profound advances in understanding the regulation of development. Here we report gene expression patterns for nearly one-third of all Drosophila genes during a complete time course of development. Mutations that eliminate eye or germline tissue were used to further analyze tissue-specific gene expression programs. These studies define major characteristics of the transcriptional programs that underlie the life cycle, compare development in males and females, and show that large-scale gene expression data collected from whole animals can be used to identify genes expressed in particular tissues and organs or genes involved in specific biological and biochemical processes.
Algorithms↗
Genome expression analysis of Anopheles gambiae: responses to injury, bacterial challenge, and malaria infection.
The complex gene expression responses of Anopheles gambiae to microbial and malaria challenges, injury, and oxidative stress (in the mosquito and/or a cultured cell line) were surveyed by using cDNA microarrays constructed from an EST-clone collection. The expression profiles were broadly subdivided into induced and down-regulated gene clusters. Gram+ and Gram- bacteria and microbial elicitors up-regulated a diverse set of genes, many belonging to the immunity class, and the response to malaria partially overlapped with this response. Oxidative stress activated a distinctive set of genes, mainly implicated in oxidoreductive processes. Injury up- and down-regulated gene clusters also were distinctive, prominently implicating glycolysis-related genes and citric acid cycle/oxidative phosphorylation/redox-mitochondrial functions, respectively. Cross-comparison of in vivo and in vitro responses indicated the existence of tightly coregulated gene groups that may correspond to gene pathways.
Animals↗
Does the label "fibromyalgia" alter health status, function, and health service utilization? A prospective, within-group comparison in a community cohort of adults with chronic widespread pain.
OBJECTIVE: To determine if assigning the label of fibromyalgia (FM) to individuals with chronic widespread pain has a significant effect on long-term health status, function, and health service utilization. METHODS: In the London Fibromyalgia Epidemiology Study, 100 individuals with FM were identified by screening 3,395 non-institutionalized adults. Only 28 of the 100 had been previously diagnosed with FM; for 72, the diagnostic label was new. All 28 with prediagnosed FM were female compared with 58 of the 72 newly diagnosed cases. In a prospective, within-group comparison, we compared previously non-labeled FM cases at study entry (prelabeling) and at 18 and 36 months followup (postlabeling) with respect to general health status, fibromyalgia-related symptoms, and all items from the Fibromyalgia Impact Questionnaire (FIQ) (including total FIQ score, and several measures of health service utilization) to see if health status, function, and health services utilization had changed, using paired t-tests. We also compared percentage reporting work disability at baseline and 18 months using Pearson's chi(2). RESULTS: Fifty-six (78%) of the original 72 newly diagnosed FM cases were available for reassessment at 18 months, and 43 (60%) at 36 months. Although physical functioning decreased slightly over time, there also was a statistically significant improvement in satisfaction with health, and newly diagnosed FM cases reported fewer symptoms and major symptoms over the long term. No other differences in clinical status or health service use occurred over time. CONCLUSION: The FM label does not have a meaningful adverse affect on clinical outcome over the long term. Further research is necessary to document the short- and long-term effect of labeling in the chronic pain patient.
Activities of Daily Living↗
Identification of genes involved in Drosophila melanogaster geotaxis, a complex behavioral trait.
Identifying the genes involved in polygenic traits has been difficult. In the 1950s and 1960s, laboratory selection experiments for extreme geotaxic behavior in fruit flies established for the first time that a complex behavioral trait has a genetic basis. But the specific genes responsible for the behavior have never been identified using this classical model. To identify the individual genes involved in geotaxic response, we used cDNA microarrays to identify candidate genes and assessed fly lines mutant in these genes for behavioral confirmation. We have thus determined the identities of several genes that contribute to the complex, polygenic behavior of geotaxis.
Animals↗
Developmental genomic approaches in model organisms.
Functional genomics technologies can help decipher how information encoded in the genome is translated into morphology, physiology, and behavior during the development of complex organisms. A number of researchers have begun to apply DNA microarrays and other functional genomics approaches to study development. Here we review recent studies that take the first steps toward relating genome-wide information to developmental events, we discuss recent genomics approaches taken in animal model systems used to study human disease, and we outline methods that may be useful for constructing genome-wide maps of developmental processes.
Animals↗
Person-centered approach to care, teaching, and research in fibromyalgia syndrome: justification from biopsychosocial perspectives in populations.
OBJECTIVES: To describe complex interactions of multiple factors believed to contribute to fibromyalgia syndrome (FMS) at a person-centered level to enhance approaches to care, teaching, and research. The main factors addressed were central nervous system sensory sensitization, autonomic nervous system (ANS) activation, neurohumoral perturbations, and psychosocial and environmental stressors. A person-centered approach is defined as attention to major biopsychosocial issues of affected individuals. METHODS: Literature on classification, mechanistic pathways, course and outcomes, and management of FMS was reviewed to assess applications of person-centered approaches to care, teaching, and research. Various biopsychosocial influences were considered in relation to the heterogeneous subjective manifestations of this illness, including central hyperalgesia, ANS and other neurohumoral perturbations, functional hyperexcitability, nonrestorative sleep, and psychologic distress. RESULTS: A person-centered approach to FMS can expand on and strengthen traditional biomedical concepts. Adding such a focus can help to untangle current controversies in the course, outcomes, and treatment of FMS. A person-centered approach can also help in the subgrouping of affected patients for greater specificity in care programs and in improved clinical investigations. In the biomedical model, diverse symptoms of FMS are often addressed separately and apart from their interconnectedness and linkages to the patient's individualized biopsychosocial factors. However, the causes of FMS symptomatology are not likely to be caused by uniform biologic abnormalities across populations. Rather, the syndrome likely results from personal reactivities to varied multifactorial biopsychosocial influences. Common denominators among individuals may include varying degrees of ANS activation (or personal susceptibility to ANS activation), nonrestorative sleep, negative affectivity, and other central pain sensitization mechanisms, among the pathways reviewed. CONCLUSIONS: Innovative analytical methodologies will need to be developed to more effectively investigate complex interacting biopsychosocial dynamics at a person-centered level, including qualitative research, and multifactorial and multilevel techniques. Adding person-centered approaches to biopsychosocial concepts of FMS promises to show new physiopathogenetic insights and more effective treatment than current biomedical models alone. Person-centered approaches enhance patient-physician relationships and help prioritize patients' goals in mutually derived treatment plans.
Adolescent↗