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Two mechanisms underlying biological robustness
https://ir.soken.ac.jp/records/2703
https://ir.soken.ac.jp/records/2703ad928a92-9b0d-417f-b1d2-0ad24a0bddd0
| 名前 / ファイル | ライセンス | アクション |
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要旨・審査要旨 (355.5 kB)
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| Item type | 学位論文 / Thesis or Dissertation(1) | |||||||
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| 公開日 | 2012-04-03 | |||||||
| タイトル | ||||||||
| タイトル | Two mechanisms underlying biological robustness | |||||||
| タイトル | ||||||||
| タイトル | Two mechanisms underlying biological robustness | |||||||
| 言語 | en | |||||||
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| 言語 | eng | |||||||
| 資源タイプ | ||||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_46ec | |||||||
| 資源タイプ | thesis | |||||||
| 著者名 |
田中, 健太郎
× 田中, 健太郎
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| フリガナ |
タナカ, ケンタロウ
× タナカ, ケンタロウ
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| 著者 |
TANAKA, Kentaro
× TANAKA, Kentaro
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| 学位授与機関 | ||||||||
| 学位授与機関名 | 総合研究大学院大学 | |||||||
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| 学位名 | 博士（理学） | |||||||
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| 内容記述タイプ | Other | |||||||
| 内容記述 | 総研大甲第1457号 | |||||||
| 研究科 | ||||||||
| 値 | 生命科学研究科 | |||||||
| 専攻 | ||||||||
| 値 | 18 遺伝学専攻 | |||||||
| 学位授与年月日 | ||||||||
| 学位授与年月日 | 2011-09-30 | |||||||
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| 値 | 2011 | |||||||
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| 内容記述タイプ | Other | |||||||
| 内容記述 | Biological robustness refers to the invariance of phenotypes in the face of perturbations including environmental fluctuations, mutations and stochastic noises in molecular interactions. There are different mechanisms underlying biological robustness. For instance, heat shock proteins, as molecular chaperone, prevent protein miss-folding at stress temperature; certain network architectures reduce the level of expression noise; and multiple signaling pathways often act in parallel and ensure normal development. However, we still know little about the full spectrum of mechanisms for biological robustness and how living systems have acquired them. To address these issues, here I focused on two mechanisms that confer robustness against perturbations: gene duplication and a repair mechanism for fate-map shift caused by extra copies of bicoid (bcd) gene in Drosophila melanogaster. Gene duplication contributes to biological robustness by masking the effect of deleterious loss-of-function mutations. While previous theoretical studies of gene duplication have mainly focused on the gene silencing process after fixation, the process leading to fixation is more important for a newly arisen duplicated gene, because the majority of duplications would be lost before reaching a significant frequency in a population. In addition, it is generally accepted that non-heritable perturbations such as environmental fluctuations and stochastic noises are more important driving forces for evolution of robustness than heritable ones. In CHAPTER 2, I addressed whether a newly arisen single gene duplication can fix and be functionally preserved in a population under mutation pressure alone. From an analytical study and series of simulations, it was shown that the fixation probability with preservation of functional copies becomes twice the loss-of-function mutation rate (uc) when the population size (N), the degree of dominance of mutations (h) and the recombination rate between the duplicate genes (c) are all sufficiently large (Nuc > 1, h > 0.1, and c > uc). This preservation of functional copies at both duplicated loci was observed for a long time. By contrast, when the gene is haplo-sufficient, one copy of the duplicates would lose its function soon after its origination. These results suggest that a large population tends to lose haplo-insufficient genes from the genome in the course of evolution. Acquisition of gene duplications throughout a genome will increase the chance for evolutional novelty. While functional redundancy by gene duplication contributes to biological robustness, organisms have also acquired the ability to actively respond to heritable and non-heritable perturbations. Such an example can be seen in the repair of fate-map shift caused by extra copies of bcd genes in Drosophila melanogaster (CHAPTER 3). The maternal effect gene bcd serves as a morphogen and establishes the body pattern along the anterior-posterior axis in early embryo. Embryos from females carrying six copies of bcd genes (6xbcd condition) show the fate-map shift and expansion of prospective head domain. Nevertheless, they still develop into almost normal adults, suggesting a repair mechanism for this fate-map shift. A previous study reported that cell death plays an important role in the repair of the expanded head region. However, there are many questions left unanswered. In this thesis, I addressed the following three issues. (i) Is there genetic variation in sensitivity to the 6xbcd condition among individuals? If so, then (ii) how much genetic variation exists? (iii) What is the genetic basis of excessive cell death occurring in this repair process? In part 1 of CHAPTER 3, to address the first and the second issues, I established 40 second-chromosome strains derived from a natural population. The average relative viability of homozygous flies was 1.05 in the control condition of 2xbcd and 0.82 in the 6xbcd condition; the variance was 0.05 in 2xbcd and 0.10 6xbcd. Although both the average and variance showed significant differences between the two conditions, the wild-derived strains were generally resistant to the 6xbcd condition, indicating the importance of the repair mechanism in natural condition. In this variation survey, I obtained one strain that is highly resistant to the 6xbcd condition (r#109) and three strains that are sensitive to the fate-map shift (s#114, s#154 and s#254). These exceptional strains suggest that there is repair gene(s) that is required for normal development especially in the 6xbcd condition. In part 2 of CHAPTER 3, I addressed the last question: the genetic basis of cell death in this repair process. To identify genes required in the fate-map shift repair, I firstly conducted two screenings: genetic screening by a series of deletion strains and microarray expression analysis. From the screening of 151 deficiency strains, I obtained two candidate genomic regions showing halo-insufficiency in the 6xbcd condition. From the microarray expression analysis, I found 83 genes up-regulated in the 6xbcd condition compared with the 2xbcd condition. Among these 83 up-regulated genes, 11 genes were up-regulated more than 2-fold and, indeed, one of them (cg15479) is located in one of the candidate genomic regions identified from deletion screening. Next, I tested the necessity of cg15479 gene in the repair. This gene was expressed in the prospective head region in embryo and enhanced expression of cg15479 was required for normal egg hatchability in the 6xbcd condition. I also conducted transgenic approach via GAL4-UAS system to reveal the function of cg15479. Ectopic expression of cg15479 in imaginal discs reduced the size of wing and eye in a cell-autonomous manner and this size reduction was caused by Caspase-independent cell death. Interestingly, while ectopic expression of p53 can lead to death of any types of cell, induction of cell death by cg15479 seems to depend on whether the cell fate is determined or not; cell death effectively occurred in proliferating or less differentiated tissues but not after the fate determination. Lastly, I found that the number of substitutions per site is lower for non-synonymous than for synonymous substitutions, indicating functional constraint on this gene. Taken together, the present results suggest that cg15479 plays a crucial role in active elimination of undesirable cells in this repair system. For robustness, different mechanisms act at different levels; functional redundancy by duplicated genes acts at transcriptional level, while the repair mechanism for the fate-map shift acts at tissue or organ level. Multiple mechanisms act together to confer robustness and allow the accumulation of hidden genetic variation with a wide spectrum of mutations in natural populations. Exploring the hierarchical structure of biological robustness will be an important task for future research. |
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| 値 | 有 | |||||||
