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Genome-Wide Identification of Mammalian GENOME -WIDE IDENTIFICATION OF MAMMALIAN DEFENSINS AND FUNCTIONAL ANALYSIS OF A NOVEL DEFENSIN -RELATED PEPTIDE By AMAR AJIT PATIL Bachelor of Veterinary Science & Animal Husbandry Dr. P.D.K.V. Agricultural University Akola , Maharashtra, Ind ia 2000 Master of Veterinary Science in Animal Biotechnology Indian Veterinary Research Institute Izatnagar , Uttar Pradesh, India 2002 Submitted to the Faculty of the Graduate College of the Oklahoma State University in part ial fulfillment of the requirements for the Degree of DOCTOR OF PHILOSOPHY December , 2006 GENOME -WIDE IDENTIFICATION OF MAMMALIAN DEFENSINS AND FUNCTIONAL ANALYSIS OF A NOVEL DEFENSIN -RELATED PEPTIDE Dissertation Approved: Guolo ng Zhang Dissertation Adviser Clinton Krehbiel Chair Haobo Jiang Lin Liu A. Gordon Emslie Dean of the Graduate College ii ACKNOWLEDGEMENT I would like to take this opportunity to thank everybody who helped me to obtain my doctoral degr ee. I will always cherish my memory of all those who helped to enrich experiences of my life. I express profound gratitude towards my advisor, Dr. Guolong Zhang , for his consistent support, constructive counsel, painstaking efforts and inspiring guidance. His role throughout my graduate studies has been much more than formal obligation as an advisor. I shall always appreciate his faith in my capabilities. I would like to thank my supervisory committee members, Drs. Clinton Krehbiel, Rodn ey Geisert, Haobo Ji ang and Lin Liu for taking time to serve on committee and their help and support. I would also like to thank my lab members, Jessie Xiao, Yibin Cai, Yugendar Bomminenni, Anthony Luyai , and Willie Li for their pleasant company, help and advice. Words are n ot enough to describe my parent’s sacrifices and patience for my education. Their love, affection and prayer always inspire me during ups and downs of my life. I would like to thank the most beautiful and wonderful thing that has ever happened to me, my wi fe Yogita. She has been very supportive of my research endeavor and has sacrificed a lot of weekend time so that I can finish my Ph.D. I would also like to thank my in -laws for their encouragement and patience as they are waiting for both of us to visit In dia. Lastly, I would like to thank my brother Atul, brother in -law Yogesh and the rest of my family and friends for their support. iii TABLE OF CONTENTS Chapter Page I. INTRODUCTION ................................ ................................ ................................ .... 1 II. REVIEW OF LITERATURE……………………………………………………… 3 Clas sification of host defense peptides ................................ ................................ .... 4 Pleotropic effects of host defense peptides ................................ .............................. 7 Structure -activity relationship ................................ ................................ ................ 14 Strategies for peptide design and synthesis ................................ ........................... 18 Current therapeutic development and clinical application ................................ ..... 22 Conclusion and future prospect ................................ ................................ ............. 24 References ................................ ................................ ................................ .............. 25 III. RAPID EVOLUTION AND DIVERSIFICATION OF M AMMALIAN -DEFENSINS AS REVEALE D BY COMPARATIVE ANA LYSIS OF RODENT AND PRIMATE GENES …………………………………………….. 53 Abstract ................................ ................................ ................................ .................. 54 Introduction ................................ ................................ ................................ ............ 55 Materials and methods ................................ ................................ ........................... 58 Results ................................ ................................ ................................ .................... 62 Discussion ................................ ................................ ................................ .............. 74 Acknowledgments ................................ ................................ ................................ .. 79 References ................................ ................................ ................................ .............. 80 Figure legends ................................ ................................ ................................ ........ 86 Supplementary material ................................ ................................ ......................... 96 IV. CROSS -SPECIES ANALYSIS OF MAMMALIAN -DEFENSIN GENE FAMILY: PRESENCE OF SYNTENIC GENE CLUSTERS AND PREFERENTIAL EXPRESS ION IN THE MALE REPR ODUCTIVE TRACT……………… …………………………………………………… ….. .. ..9 9 iv Abstract ................................ ................................ ................................ ................ 100 Introduction ................................ ................................ ................................ .......... 101 Materials and methods ................................ ................................ ......................... 103 Results ................................ ................................ ................................ .................. 106 Discussion ................................ ................................ ................................ ............ 120 Acknowledgments ................................ ................................ ................................ 126 References ................................ ................................ ................................ ............ 126 Figure legends ................................ ................................ ................................ ...... 135 Supplementary Material ................................ ................................ ....................... 146 V. RATTUSIN, A NOVEL -DEFENSIN -RELATED PEPTIDE WITH SALT INSENSITIVE A NTIBACTERIAL PROPERT IES …………………………… 160 Abstract ................................ ................................ ................................ ................ 161 Introduction ................................ ................................ ................................ .......... 162 Materials and methods ................................ ................................ ......................... 164 Results ................................ ................................ ................................ .................. 170 Discussion ................................ ................................ ................................ ............ 17 3 Acknowledgments ................................ ................................ ................................ 17 6 References ................................ ................................ ................................ ............ 17 7 Figure legends ................................ ................................ ................................ ...... 18 3 VI. SUMMARY AND FUTURE PROSPECT………………………………… ….. 19 7 v LIST OF TABLES Table Page CHAPTER III 1. Sequences of primers used for RT -PCR analysis of rat -defensins ……….. .. .89 2. Demonstration of positive selection in 11 phylogenetically i ndependent pairs of mammalian -defensin genes ……………………… ......9 0 CHAPTER IV Supplementary table 1. GenBank acce ssion numbers of mammalian -defensin cDNA sequences ………………………………………………… 15 2 Supplementary table 2. Sequences of p rimer used for RT -PCR analysis of rat -defensins ………………………………………………………………..1 56 CHAPTER V 1. Antibacterial spectrum of rattusin ………………………………….………... 18 6 2. Antibacterial activity of pro -rattusin ................................ ............................... .18 7 vi LIST OF FIGURES Figu re Page CHAPTER III 1. Amino acid sequence alignment of novel -defensins and -defensin - related sequences in the primates , rat and mouse……………………………... 91 2. Tissue expression patterns of novel rat -defensins ….……….. .…………… ..9 2 3. Phylogenetic tree of mammalian -defensins ………………………………... .9 3 4. Alignment of the second exon sequences of rodent -defensin -related s equences with three rat enteric -defensins ………………………………… ..94 5. Genomic organizations of -defensin clusters in the primates, rat, and mouse ……………………………… ……………………………………...9 5 Supplementary Fig ure 1. Sequence alignment of the exon encoding the signal peptide and prosegments of three orthologous genes in the human (DEFA7P ), chimpanzee ( PTAD7 ), and olive baboon ( PAAD3 )……………….9 7 Supplementary Fig ure 2. Amino acid sequence alignment of a total of 82 known and newly identified -defensins and -defensin -related sequences in the primates and glires ……………………………………………………... .9 8 CHAPTER IV 1. Amino acid sequence alignment of rat -defensins …………………………..1 39 2. Identification of novel -defensins in human and m ous e……… ………… ….1 40 3. Genomic organization of syntenic mammalian -defensin gene s……………1 41 4. Structural organizations of mammalian -defensin genes ………………..…..1 42 5. Phylogenetic tree of mammalian -defensins ………………………………...14 3 6. Tissu e expression patterns of rat -defensins ….……………….. …………...14 4 7. Developmental regulation pattern of rat -defensins in epididymis and testis ……………… ………………………………………………………….14 5 Supplementary Fig ure 1. Amino acid sequence alignment of t he canine -defensin gene family ……………………………………………………….14 8 Supplementary Fig ure 2. Amino acid sequence alignment of the human -defensin gene family ………………………………….……………………14 9 Supplementary Fig ure 3.
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