Open Access Highly Accessed Research article

A gain-of-function screen to identify genes that reduce lifespan in the adult of Drosophila melanogaster

Minoru Nakayama15, Tomoki Ishibashi2, Hiroyuki O Ishikawa16, Hiroyasu Sato3, Takao Usui3, Takayuki Okuda3, Hiroyuki Yashiro3, Hironori Ishikawa3, Yoshie Taikou3, Asako Minami3, Kengo Kato3, Masataka Taki3, Toshiro Aigaki4, Wataru Gunji3, Masaya Ohtsu3, Yasufumi Murakami13, Sei-ichi Tanuma1, Alice Tsuboi2, Mai Adachi2, Junpei Kuroda2, Takeshi Sasamura2, Tomoko Yamakawa2 and Kenji Matsuno2*

Author Affiliations

1 Genome and Drug Research Center, Tokyo University of Science, Noda, Chiba 278-8510, Japan

2 Department of Biological Sciences, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan

3 Department of Biological Science and Technology, Tokyo University of Science, Noda, Chiba 278-8510, Japan

4 Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan

5 Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Kita-ku, Kyoto 603-8555, Japan

6 Graduate School of Science, Chiba University, Chiba, Chiba 263-8522, Japan

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BMC Genetics 2014, 15:46  doi:10.1186/1471-2156-15-46

Published: 16 April 2014

Abstract

Background

Several lines of evidence associate misregulated genetic expression with risk factors for diabetes, Alzheimer’s, and other diseases that sporadically develop in healthy adults with no background of hereditary disorders. Thus, we are interested in genes that may be expressed normally through parts of an individual’s life, but can cause physiological defects and disease when misexpressed in adulthood.

Results

We attempted to identify these genes in a model organism by arbitrarily misexpressing specific genes in adult Drosophila melanogaster, using 14,133 Gene Search lines. We identified 39 “reduced-lifespan genes” that, when misexpressed in adulthood, shortened the flies’ lifespan to less than 30% of that of control flies. About half of these genes have human orthologs that are known to be involved in human diseases. For about one-fourth of the reduced-lifespan genes, suppressing apoptosis restored the lifespan shortened by their misexpression. We determined the organs responsible for reduced lifespan when these genes were misexpressed specifically in adulthood, and found that while some genes induced reduced lifespan only when misexpressed in specific adult organs, others could induce reduced lifespan when misexpressed in various organs. This finding suggests that tissue-specific dysfunction may be involved in reduced lifespan related to gene misexpression. Gene ontology analysis showed that reduced-lifespan genes are biased toward genes related to development.

Conclusions

We identified 39 genes that, when misexpressed in adulthood, shortened the lifespan of adult flies. Suppressing apoptosis rescued this shortened lifespan for only a subset of the reduced-lifespan genes. The adult tissues in which gene misexpression caused early death differed among the reduced-lifespan genes. These results suggest that the cause of reduced lifespan upon misexpression differed among the genes.

Keywords:
Genetic screen; Drosophila; Apoptosis; Reduced lifespan; Gene misexpression