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.
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.
Authors: R A Hoskins; C R Nelson; B P Berman; T R Laverty; R A George; L Ciesiolka; M Naeemuddin; A D Arenson; J Durbin; R G David; P E Tabor; M R Bailey; D R DeShazo; J Catanese; A Mammoser; K Osoegawa; P J de Jong; S E Celniker; R A Gibbs; G M Rubin; S E Scherer Journal: Science Date: 2000-03-24 Impact factor: 47.728
Authors: George H Perry; Amir Ben-Dor; Anya Tsalenko; Nick Sampas; Laia Rodriguez-Revenga; Charles W Tran; Alicia Scheffer; Israel Steinfeld; Peter Tsang; N Alice Yamada; Han Soo Park; Jong-Il Kim; Jeong-Sun Seo; Zohar Yakhini; Stephen Laderman; Laurakay Bruhn; Charles Lee Journal: Am J Hum Genet Date: 2008-01-24 Impact factor: 11.025
Authors: José A Matta; Paul M Cornett; Rosa L Miyares; Ken Abe; Niaz Sahibzada; Gerard P Ahern Journal: Proc Natl Acad Sci U S A Date: 2008-06-23 Impact factor: 11.205
Authors: David A Wheeler; Maithreyan Srinivasan; Michael Egholm; Yufeng Shen; Lei Chen; Amy McGuire; Wen He; Yi-Ju Chen; Vinod Makhijani; G Thomas Roth; Xavier Gomes; Karrie Tartaro; Faheem Niazi; Cynthia L Turcotte; Gerard P Irzyk; James R Lupski; Craig Chinault; Xing-zhi Song; Yue Liu; Ye Yuan; Lynne Nazareth; Xiang Qin; Donna M Muzny; Marcel Margulies; George M Weinstock; Richard A Gibbs; Jonathan M Rothberg Journal: Nature Date: 2008-04-17 Impact factor: 49.962
Authors: Shuying Gao; David J Sandstrom; Harold E Smith; Brigit High; Jon W Marsh; Howard A Nash Journal: Anesthesiology Date: 2013-03 Impact factor: 7.892