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Evolution of U12-Type Intron and Its Role in Gene Expression Regulation

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Evolution of U12-Type Intron and Its Role in Gene Expression Regulation Jessin Janice James Peter Evolution of U12-type intron and its role in gene expression regulation 2012 Biology Evolution of U12-type intron and its role in gene expression regulation Inaugural-Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften im Fachbereich Biologie der Mathematisch-Naturwissenschaftlichen Fakultät der Westfälischen Wilhelms-Universität Münster vorgelegt von Jessin Janice James Peter aus Uvari, Tirunelveli, India im February 2012 Dekan: Prof. Dr. Dirk Prüfer Erster Gutachter: Prof. Dr. Wojciech Makałowski Zweiter Gutachter: Prof. Dr. Joachim Kurtz Tag der mündlichen Prüfung: ............................................................................................ Tag der Promotion: ............................................................................................ Preface…………………………………………………………………… 1 Acknowledgements……………………………………………………… 2 Summary………………………………………………………………… 3 I. Introduction…………………………………………………………… 5 1. Introns………………………………………………………………. 6 1.1. Discovery of introns……………………………………….. 7 1.2. Classification of introns……………………………………. 8 1.3. Introns origin………………………………………………. 8 1.3.1. Intron early hypothesis…………………………... 9 1.3.2. Intron late hypothesis……………………………. 9 1.4. Distribution of introns……………………………………... 10 2. Splicing……………………………………………………………... 11 2.1. Mechanism………………………………………………… 12 2.2. Spliceosome………………………………………………... 13 2.3. Spliceosomal pathway……………………………………... 14 3. U12-type introns……………………………………………………. 15 3.1. Discovery of U12-type introns…………………………….. 16 3.2. Structure of U12-type introns……………………………… 17 4. Minor spliceosome………………………………………………….. 17 4.1. Discovery of minor spliceosome…………………………... 18 4.2. Structure and assembly…………………………………….. 18 5. Origin of minor introns……………………………………………... 20 5.1. Burge‟s hypotheses………………………………………… 20 5.1.1. The fission-fusion hypothesis…………………… 20 5.1.2. Parasitic invasion………………………………... 22 5.1.3. Codivergence……………………………………. 22 5.2. Lynch‟s hypothesis………………………………………… 23 5.3. Koonin‟s hypothesis……………………………………….. 23 6. Distribution of minor introns and spliceosomal components………. 24 7. Evolution of minor introns………………………………………….. 25 8. Aim of PhD studies…………………………………………………. 26 8.1. U12-type spliceosomal introns in Insecta……………………. 26 8.2. Role of U12-type introns in gene expression……………… 27 8.3. Surprising high numbers of twintrons in vertebrata………... 29 II. Publications………………………………………………………….. 30 1. U12-type spliceosomal introns in Insecta…………………………….. 31 Introduction…………………………………………………….. 33 Materials and methods…………………………………………. 36 Results and discussion…………………………………………. 40 Supplementary materials………………………………………. 58 2. Role of U12-type introns in gene expression regulation…………... 67 Introduction…………………………………………………….. 69 Materials and methods…………………………………………. 73 Results and discussion…………………………………………. 77 Supplementary materials……………………………………….. 100 3. Surprising high number of twintrons in Vertebrata…………………... 159 Introduction……………………………………………………. 161 Materials and methods…………………………………………. 165 Results and Discussion…………………………………………. 168 Supplementary materials……………………………………….. 181 III. Conclusion…………………………………………………………... 186 IV. Appendix…………………………………………………………….. 191 Curriculum-vitae……………………………………………….. 192 Publications…………………………………………………….. 193 Conferences attended…………………………………………... 195 Preface This thesis contains three studies that explore the evolution of U12-type introns, their role in the gene expression and twintrons in vertebrates. Among the three studies, Chapter 1 is accepted for publication in the International Journal of Biological Sciences. Chapter 2 is currently under the preparation of manuscript and will be communicated soon to BMC Genomics. The final chapter will be communicated to Molecular Biology and Evolution. U12-type Spliceosomal Introns of Insecta Authors: Jessin Janice1, Amit Pande1, January Weiner1, 2, Chiao-Feng Lin1, 3, and Wojciech Makałowski1# My contribution: I carried out most of the comparative genome analysis, functional annotation of U12-type introns, interpretation of data, and drafted the manuscript. Role of U12-type introns in gene expression regulation Authors: Jessin Janice1, Kathrin Poos1 and Wojciech Makałowski1# My contribution: I carried out the comparative genome analysis, interpretation of data, and drafted the manuscript. Surprising high numbers of twintrons in Vertebrata Authors: Jessin Janice1, and Wojciech Makałowski1# My contribution: I carried out all the analyses, interpretation of data, and drafted the manuscript. 1 Acknowledgements Foremost, I would like to express my sincere gratitude to my supervisor Prof. Dr. Wojciech Makałowski for his support, encouragement, enthusiasm and great patience. His contribution to this thesis has been substantial through numerous discussions and (although sometimes illegible!) manuscript feedback. I could not have imagined having a better advisor and a mentor for my PhD study. I would like to thank my co-supervisors Prof. Dr. Joachim Kurtz, Prof. Dr. Jürgen Brosius, for their kind support, advice and help. I sincerely acknowledge Dr. Eberhard Korsching for showing concern in all aspects of my PhD studies. I am deeply indebted to my colleagues Amit Pande, Kathrin Poos, Dr. January Weiner, and Dr. Chiao-Feng Lin, who worked with me and provided the environment for sharing their experiences, as well as participated in exciting team works. I am indebted to my colleagues for providing a stimulating and fun environment to learn and work. I am especially grateful to Jasmin Dröge, whom I would first approach, almost for every little thing, Dorota Buczek, with whom I had the best moments at Poznan and Portugal and often in the bus (!), Marcin Jakalski who has helped me with lots of technical stuffs, Norbert Grundman for helping with programs and technical stuffs and Dr. Gyorgy Abrusan. I would like to thank Wolfgang Garbers for making the official things simple. It my pleasure to thank all my beloved friends especially, Smrutisanjita Behera and Mrinal Pande for their love, advice, care, and also for the healthy food, they fed me. I would also like to thank Robiya Joseph for her love and spiritual support. I would also thank two little ones, Siddharth Pande and Shashwat Pande for their warm love and additional energy. They brought smile on my face in the time of stress and loneliness. I would also like to thank my mom, dad, and sister. I am forever thankful them for all the freedom and love. I am grateful to Sudhagar for his immense patience (!), care, and much more. Fianlly, I would like to thank God, for his blessings. 2 Summary U12-type introns are a smaller class of spliceosomal introns, which are found in lesser than 0.5% of the total intronic population in eukaryotes. These are spliced by a distinct class of spliceosome called the minor spliceosome, whereas rest of the introns called U2-type introns are spliced by major spliceosome. These introns are identified through their highly conserved 5‟ splice site motif A/GTATCCTT and a less conserved branch point site motif CCTTAAC. Though these U12-type introns are very few in population, they are conserved across the plant and animal kingdom. These introns have a relatively recent history. Hence, their origin, evolutionary pattern and functions are yet obscure. At the same time, U12-type introns are seen in widely divergent eukaryotes, substantiating an essential functional basis. U12-type introns widely inhabit the information processing genes such as transcription regulation, regulation of cell division and a wide range of ion channel genes. Hence, it is interesting to understand the significance of the U12-type introns and the associated splicing system. In this thesis, evolution, organization and the role of U12-type introns in gene expression regulation are studied and discussed in three different chapters. The first study illustrates the study of U12-type introns in twenty different insect genomes that have been recently sequenced, covering 350 million years of metazoan evolution. It is found that U12- type introns are getting deleted from the dipteran genomes as compared to other insects and particularly, subtype switching within U12-type introns are not as frequent as thought before. U12-type intron deletion is more likely to occur than conversion to U2-type intron. Only two genes have U12-type intron that is conserved throughout the insect phylogeny and one amongst them is a twintron having signals for both the spliceosomes, suggesting the significance of twintrons in gene expression regulation. 3 The second study comprises the expression profiling of U12-type intron containing genes and their paralogs, in humans and mice to understand the role of U12-type introns in gene expression regulation. It is reported earlier that the presence of U12-type introns downregulate the expression of the host gene. The results here show that U12-type intron containing genes have shown dissimilar expression patterns, contradicting the earlier works. Results from global level gene expression analyses suggest that U12-type introns are not a rate limiting factors in gene expression. Rather other local factors such as cis-elements, transcription factors, function of the gene in the pathway, tissue specific etc have importance in regulation. On the whole, the expression of the host genes containing U12-type introns does not change considerably. The third study consists of studies on twintronic arrangements. The first study on insects‟ genomes reveals that insect genomes harbor two twintrons and may act
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