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Impact of gene copy number variation on anesthesia in Drosophila melanogaster.

ABSTRACT: BACKGROUND:Chromosomal deletions and duplications, which result in halving or doubling of copy number in a block of genes, are an important source of variation between individuals. Phenotypic effects of copy number variation are commonly observed, but effects on sensitivity to volatile anesthetics have not been assessed in any organism. METHODS:The potency with which halothane depresses the righting reflex of fruit flies was measured in congenic Drosophila strains, each of which was heterozygous for a deletion of average size 400 kb. Over 200 strains were examined, thereby scanning approximately half of the fly genome. RESULTS:Although the vast majority of deletion heterozygotes were indistinguishable from the control, eight had significantly altered sensitivity to halothane. Genetic tests supported the hypothesis that the change in anesthetic sensitivity was the result of reduction in copy number and not adventitious mutations in the strains. Among the eight outliers, the difference in halothane potency ranged from a 25% increase to a 15% decrease. Changes of similar magnitude but distinctive patterns were found when these lines were tested with enflurane, isoflurane, and sevoflurane. CONCLUSIONS:Variation in gene copy number has a significant impact on anesthetic sensitivity in Drosophila melanogaster. The level of transcription of a few genes must thus be limiting for a normal response to volatiles. Coupling between gene copy and gene expression is universal, and the components of the fly's nervous system are highly conserved; therefore, this work provides a rationale for investigating the clinical impact of copy number variation.

SUBMITTER: Alone DP

PROVIDER: S-EPMC2701505 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Impact of gene copy number variation on anesthesia in Drosophila melanogaster.

Alone Debasmita P DP Rodriguez Jason C JC Noland Cameron L CL Nash Howard A HA

Anesthesiology 20090701 1

<h4>Background</h4>Chromosomal deletions and duplications, which result in halving or doubling of copy number in a block of genes, are an important source of variation between individuals. Phenotypic effects of copy number variation are commonly observed, but effects on sensitivity to volatile anesthetics have not been assessed in any organism.<h4>Methods</h4>The potency with which halothane depresses the righting reflex of fruit flies was measured in congenic Drosophila strains, each of which w ...[more]

PMID: 19546691

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Project description:Copy number variants (CNVs) reshape gene structure, modulate gene expression, and contribute to significant phenotypic variation. Previous studies have revealed CNV patterns in natural populations of Drosophila melanogaster and suggested that selection and mutational bias shape genomic patterns of CNV. While previous CNV studies focused on heterogeneous strains, here we established a number of second-chromosome substitution lines to uncover CNV characteristics when homozygous. The percentage of genes harboring CNVs is higher than found in previous studies. More CNVs are detected in homozygous than heterozygous substitution strains, suggesting the comparative genomic hybridization arrays underestimate CNV owing to heterozygous masking. We incorporated previous gene expression data collected from some of the same substitution lines to investigate relationships between CNV gene dosage and expression. Most genes present in CNVs show no evidence of increased or diminished transcription, and the fraction of such dosage-insensitive CNVs is greater in heterozygotes. More than 70% of the dosage-sensitive CNVs are recessive with undetectable effects on transcription in heterozygotes. A deficiency of singletons in recessive dosage-sensitive CNVs supports the hypothesis that most CNVs are subject to negative selection. On the other hand, relaxed purifying selection might account for the higher number of protein-protein interactions in dosage insensitive CNVs than in dosage-sensitive CNVs. Dosage-sensitive CNVs that are up-regulated and down-regulated coincide with copy number increases and decreases. Our results help clarify the relation between CNV dosage and gene expression in the D. melanogaster genome. To determine copy number variation, the genomic DNA from five homozygous and two heterozygous second chromosome substitution lines were extracted and compared to another second chromosome substitution line. Gene expression levels can be referred to at Series GSE12191 (Lemos et al. (2008) PMID:18791071).

Dataset Information

Impact of gene copy number variation on anesthesia in Drosophila melanogaster.

Publications

Impact of gene copy number variation on anesthesia in Drosophila melanogaster.

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