Kaori Iida

A test of translational selection at 'silent' sites in the human genome: base composition comparisons in alternatively spliced genes

Natural selection appears to discriminate among synonymous codons to enhance translational efficiency in a wide range of prokaryotes and eukaryotes. Codon bias is strongly related to gene expression levels in these species. In addition, between-gene variation in silent DNA divergence is inversely correlated with codon bias. However, in mammals, between-gene comparisons are complicated by distinctive nucleotide-content bias (isochores) throughout the genome. In this study, we attempted to identify translational selection by analyzing the DNA sequences of alternatively spliced genes in humans and in Drosophila melanogaster. Among codons in an alternatively spliced gene, those in constitutively expressed exons are translated more often than those in alternatively spliced exons. Thus, translational selection should act more strongly to bias codon usage and reduce silent divergence in constitutive than in alternative exons. By controlling for regional forces affecting base-composition evolution, this within-gene comparison makes it possible to detect codon selection at synonymous sites in mammals. We found that GC-ending codons are more abundant in constitutive than alternatively spliced exons in both Drosophila and humans. Contrary to our expectation, however, silent DNA divergence between mammalian species is higher in constitutive than in alternative exons.

PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice

BackgroundDeficiency of the PERK eIF2α kinase in humans and mice results in postnatal exocrine pancreatic atrophy as well as severe growth and metabolic anomalies in other organs and tissues. To determine if the exocrine pancreatic atrophy is due to a cell-autonomous defect, the Perk gene was specifically ablated in acinar cells of the exocrine pancreas in mice.ResultsWe show that expression of PERK in the acinar cells is required to maintain their viability but is not required for normal protein synthesis and secretion. Exocrine pancreatic atrophy in PERK-deficient mice was previously attributed to uncontrolled ER-stress followed by apoptotic cell death based on studies in cultured fibroblasts. However, we have found no evidence for perturbations in the endoplasmic reticulum or ER-stress and show that acinar cells succumb to a non-apoptotic form of cell death, oncosis, which is associated with a pronounced inflammatory response and induction of the pancreatitis stress response genes. We also show that mice carrying a knockout mutation of PERKs downstream target, ATF4, exhibit pancreatic deficiency caused by developmental defects and that mice ablated for ATF4s transcriptional target CHOP have a normal exocrine pancreas.ConclusionWe conclude that PERK modulates secretory capacity of the exocrine pancreas by regulating cell viability of acinar cells.

Glucose dehydrogenase is required for normal sperm storage and utilization in female Drosophila melanogaster.

SUMMARY Female sperm storage is a key factor for reproductive success in a variety of organisms, including Drosophila melanogaster. The spermathecae, one of the Drosophila sperm storage organs, has been suggested as a long-term storage organ because its secreted substances may enhance the quality of sperm storage. Glucose dehydrogenase (GLD) is widely expressed and secreted in the spermathecal ducts among species of the genus Drosophila. This highly conserved expression pattern suggests that this enzyme might have an important role in female fertility. Here, we examine the function of GLD in sperm storage and utilization using Gld-null mutant females. The absence of GLD reduced the amount of sperm stored in the spermathecae and led to a highly asymmetrical sperm distribution in the two spermathecal capsules of the mutant females. The storage defect was especially severe when the mutant females were crossed to a Gld-mutant male that had previously mated a few hours before the experimental cross. Under this mating condition, the mutant females stored in the spermathecae only one-third of the sperm amount of the wild-type control females. In addition, the mutant females used stored sperm at a slower rate over a longer period compared with wild-type females. Thus, our results indicate that GLD facilitates both sperm uptake and release through the spermathecal ducts.

Expansion and evolution of insect GMC oxidoreductases

BackgroundThe GMC oxidoreductases comprise a large family of diverse FAD enzymes that share a homologous backbone. The relationship and origin of the GMC oxidoreductase genes, however, was unknown. Recent sequencing of entire genomes has allowed for the evolutionary analysis of the GMC oxidoreductase family.ResultsAlthough genes that encode enzyme families are rarely linked in higher eukaryotes, we discovered that the majority of the GMC oxidoreductase genes in the fruit fly (D. melanogaster), mosquito (A. gambiae), honeybee (A. mellifera), and flour beetle (T. castaneum) are located in a highly conserved cluster contained within a large intron of the flotillin-2 (Flo-2) gene. In contrast, the genomes of vertebrates and the nematode C. elegans contain few GMC genes and lack a GMC cluster, suggesting that the GMC cluster and the function of its resident genes are unique to insects or arthropods. We found that the development patterns of expression of the GMC cluster genes are highly complex. Among the GMC oxidoreductases located outside of the GMC gene cluster, the identities of two related enzymes, glucose dehydrogenase (GLD) and glucose oxidase (GOX), are known, and they play major roles in development and immunity. We have discovered that several additional GLD and GOX homologues exist in insects but are remotely similar to fungal GOX.ConclusionWe speculate that the GMC oxidoreductase cluster has been conserved to coordinately regulate these genes for a common developmental or physiological function related to ecdysteroid metabolism. Furthermore, we propose that the GMC gene cluster may be the birthplace of the insect GMC oxidoreductase genes. Through tandem duplication and divergence within the cluster, new GMC genes evolved. Some of the GMC genes have been retained in the cluster for hundreds of millions of years while others might have transposed to other regions of the genome. Consistent with this hypothesis, our analysis indicates that insect GOX and GLD arose from a different ancestral GMC gene than that of fungal GOX.

Learning from Philip Morris: Japan Tobacco's strategies regarding evidence of tobacco health harms as revealed in internal documents from the American tobacco industry

Japan is in the midst of a rapid increase in tobacco-related disease mortality, following the rapid growth of smoking after WWII. Stomach cancer was the countrys leading cause of cancer death for most of the 20th century, until lung cancer took over this position in 1993. Cigarettes are the major cause of lung cancer in Japan, but the countrys leading manufacturer, Japan Tobacco, two thirds of which is owned by the Japanese government, continues to question whether tobacco is a major cause of disease and death. Japanese courts do not have the power to subpoena a companys internal records, which has made it difficult to document Japan Tobaccos strategies concerning tobacco and health. Our interpretation of online archives of internal documents from American tobacco companies, however, is that Japan Tobacco has long known about the potential health risks involved in smoking and has sought to obstruct effective tobacco control. Beginning in the mid-1980s, these efforts were often co-ordinated with American tobacco manufacturers. The documentary evidence shows that cigarette manufacturer Philip Morris in particular assisted with and sometimes also supervised Japan Tobaccos actions and statements on smoking and health. In one instance, data gathered for an article published by the Japan Public Monopoly Corporation (Japan Tobaccos predecessor) were deliberately altered to lower the reported value of a hazard indicator (nicotine concentration in the air). International collaboration has made it easier for companies such as Japan Tobacco to develop effective anti-antismoking strategies. Evidence of such global industry collaborations might grow as lawsuits begin to be filed in other nations.

Practice and Politics in Japanese Science: Hitoshi Kihara and the Formation of a Genetics Discipline

This paper examines the history of Japanese genetics in the 1920s to 1950s as seen through the work of Hitoshi Kihara, a prominent wheat geneticist as well as a leader in the development of the discipline in Japan. As Kihara’s career illustrates, Japanese genetics developed quickly in the early twentieth century through interactions with biologists outside Japan. The interactions, however, ceased due to the war in the late 1930s, and Japanese geneticists were mostly isolated from outside information until the late 1940s. During the isolation in wartime and under the postwar U.S. Occupation, Kihara adapted to political changes. During wartime, he developed a research institute focusing on applied biology of various crops, which conformed to the national need to address food scarcity. After the war, he led the campaign for the establishment of a national institute of genetics and negotiated with American Occupation officers. The Americans viewed this Japanese effort with suspicion because of the rising popularity of the controversial theory of the Russian agronomist, Trofim Lysenko, in Japan. The institute was approved in 1949 partly because Kihara was able to bridge the gap between the American and Japanese sides. With Kihara’s flexible and generous leadership, Japanese genetics steadily developed, survived the wartime, and recovered quickly in the postwar period. The article discusses Kihara’s interest in cytoplasmic inheritance and his synthetic approach to genetics in this political context, and draws attention to the relation between Kihara’s genetics and agricultural practice in Japan.

Genetics and “Breeding as a Science” : Kihara Hitoshi and the Development of Genetics in Japan in the First Half of the Twentieth Century

Through the career of Kihara Hitoshi, a prominent plant geneticist in Japan, I show that genetics in Japan developed by maintaining a close connection with agriculture throughout the first half of the twentieth century. To exploit the socioeconomic context that valued applied science, Kihara gradually made the practical aspect of his projects more explicit and consequently created projects that were both basic and applied science. These projects not only allowed his group to expand successfully during wartime but also influenced the group’s scientific approach. To gain full understanding of an organism, investigators took a multidisciplinary approach beyond genetics, an approach similar to what the Russian geneticist Nikolai Vavilov described in advocating “breeding as a science.” Genetics, being placed within “breeding as a science,” was also affected, and Kihara began advocating physiological genetics, along the lines advanced by German geneticist Richard Goldschmidt. The story of Kihara’s career reveals how the national emphasis on agriculture had a significant impact on the disciplinary growth of genetics in Japan as well as on Japanese biologists’ approach to organisms and genes.

‘The industry must be inconspicuous’: Japan Tobacco’s corruption of science and health policy via the Smoking Research Foundation

Objective To investigate how and why Japan Tobacco, Inc. (JT) in 1986 established the Smoking Research Foundation (SRF), a research-funding institution, and to explore the extent to which SRF has influenced science and health policy in Japan. Methods We analysed documents in the Truth Tobacco Industry Documents archive, along with recent Japanese litigation documents and published documents. Results JT’s effort to combat effective tobacco control was strengthened in the mid-1980s, following privatisation of the company. While remaining under the protection of Japan’s Ministry of Finance, the semiprivatised company lost its ‘access to politicos’, opening up a perceived need for collaboration with global cigarette makers. One solution, arrived at through clandestine planning with American companies, was to establish a third-party organisation, SRF, with the hope of capturing scientific and medical authority for the industry. Guarded by powerful people in government and academia, SRF was launched with the covert goal of influencing tobacco policy both inside and outside Japan. Scholars funded by SRF have participated in international conferences, national advisory committees and tobacco litigation, in most instances helping the industry to maintain a favourable climate for the continued sale of cigarettes. Conclusions Contrary to industry claims, SRF was never meant to be independent or neutral. With active support from foreign cigarette manufacturers, SRF represents the expansion into Asia of the denialist campaign that began in the USA in 1953.

A controversial idea as a cultural resource: The Lysenko controversy and discussions of genetics as a ‘democratic’ science in postwar Japan

The Japanese discussion of the theory of Soviet agronomist Trofim D. Lysenko began in the postwar years under the American occupation. Leftists introduced Lysenko’s theory immediately after the war as part of a postwar scientists’ movement. Unlike many American geneticists, who sharply criticized the theory, Japanese geneticists initially participated in the discussion in an even-handed way; their scientific interests in the roles of cytoplasm and the environment in heredity shaped their initial sympathetic reaction. As the Cold War divide deepened, however, Japanese scientists began expressing sharp anti-Lysenko criticisms that resembled the American criticisms. Interestingly, throughout the period, Japanese geneticists’ overall aim in the discussion remained largely unchanged: to effectively reconstruct their discipline and maintain its proper image and authority. However, the shift in their reaction occurred due to an evolving sociopolitical context, especially the shift in the meaning of ‘democratic’ science from a science that employed democratic processes to a science of a liberal-democratic state. Regarding Lysenko’s idea as a cultural resource could help to explain how and why it was treated differently in different places, and why a controversy emerged in certain contexts but not in others.