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Organization of the Class I Region of the Bovine Major ORGANIZATION OF THE CLASS I REGION OF THE BOVINE MAJOR HISTOCOMPATIBILITY COMPLEX (BOLA) AND THE CHARACTERIZATION OF A CLASS I FRAMESHIFT DELETION (BOLA-Adel) PREVALENT IN FERAL BOVIDS A Dissertation by NICOLE RAMLACHAN Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY December 2004 Major Subject: Genetics ORGANIZATION OF THE CLASS I REGION OF THE BOVINE MAJOR HISTOCOMPATIBILITY COMPLEX (BOLA) AND THE CHARACTERIZATION OF A CLASS I FRAMESHIFT DELETION (BOLA-Adel) PREVALENT IN FERAL BOVIDS A Dissertation by NICOLE RAMLACHAN Submitted to Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Approved as to style and content by: _________________________ _________________________ Loren C. Skow Bhanu P. Chowdhary (Chair of Committee) (Member) _________________________ _________________________ James E. Womack Rajesh C. Miranda (Member) (Member) _________________________ _________________________ Geoffrey M. Kapler Evelyn Tiffany-Castiglioni (Chair of Genetics Faculty) (Head of Department) December 2004 Major Subject: Genetics iii ABSTRACT Organization of the Class I Region of the Bovine Major Histocompatibility Complex (BoLA) and the Characterization of a Class I Frameshift Deletion (BoLA-Adel) Prevalent in Feral Bovids. (December 2004) Nicole Ramlachan, B.Sc., University of Guelph, Ontario, Canada; M.Sc., University of Guelph, Ontario, Canada Chair of Advisory Committee: Dr. Loren Skow The major histocompatibility complex (MHC) is a genomic region containing genes of immunomodulatory importance. MHC class I genes encode cell-surface glycoproteins that present peptides to circulating T cells, playing a key role in recognition of self and non-self. Studies of MHC loci in vertebrates have examined levels of polymorphism and molecular evolutionary processes generating diversity. The bovine MHC (BoLA) has been associated with disease susceptibility, resistance and progression. To delineate mechanisms by which MHC class I genes evolved to function optimally in a species like cattle, it is necessary to study genomic organization of BoLA to define gene content, and investigate characteristics of expressed class I molecules. This study describes development of a physical map of BoLA class I region derived from screening two BAC libraries, isolating positive clones and confirming gene content, order and chromosomal location through PCR, novel BAC end sequencing techniques, and selected BAC shotgun cloning and/or sequencing and FISH analysis. To date, this is the most complete ordered BAC array encompassing the BoLA class I region from the class III boundary to the extended class I region. Characterization of a frameshift allele exhibiting trans-species polymorphism in Bos and Bison by flow cytometry, real-time RT-PCR, 1D and 2D gel analysis is also described. This frameshift allele encodes an early termination signal within the antigen recognition site (ARS) of exon 3 of the BoLA BSA-Adel class I gene predicting a truncated class I protein that is iv soluble. An ability to assess MHC diversity in populations and provision of animals with defined MHC haplotypes and genetic content for experimental research is necessary in developing a basis upon which to build functional studies to elucidate associations between haplotype and disease in bovids. The BoLA class I region is immunologically important for disease association studies in an economically important species. This study provides knowledge of gene content and organization within the class I MHC region in cattle, providing a template for more detailed analysis and elucidation of complex disease associations through functional genomics and comparative analysis, as well as evolution of the MHC in bovids to optimize a population’s immune response. v To my parents, brother, sister and nephew, extended family and friends worldwide who share my life’s journey both in body and spirit; for always being there to fuel my passion to cast off my bowlines and explore the unknown, yet always providing a strong anchor and safe harbour for me to dock my heart and soul. “Twenty years from now you will be more disappointed by the things that you didn’t do than by the ones you did do. So throw off the bowlines. Sail away from the safe harbour. Catch the trade winds in your sails. Explore. Dream. Discover.” - Mark Twain vi ACKNOWLEDGEMENTS The motto of my high school alma mater is “per ardua ad astra”, little did I realize then that these words would be representative of my pursuit of a PhD! In my long and sometimes arduous journey to completion of my doctoral program, I have had the privilege to encounter many individuals who have impacted my life and shaped my views of the academic and professional world. I would like to thank Dr. Loren C. Skow, whom in his multi-tasking role as advisor, P.I., committee chair, referee, sounding board, hunting/farming/fishing connoisseur, meteorological weather consultant, debater, political advisor and mentor extraordinaire; has been a key component to my success. I have enjoyed tracking worldwide weather patterns and investigating the moderating effects of the Brazos Valley on College Station weather, not to mention discussions on why one should not plant potatoes in July in Texas! Thank you for your persistence, unwavering support, funding (!) and overall respect of my crazy ideas, most of which have come to fruition. You’ve instilled in me belief that I could reach my goals, giving me confidence to do it. I am also very grateful to my committee members: Dr. James E. Womack, Dr. Bhanu Chowdhary and Dr. Rajesh C. Miranda, for their open door policy and invaluable advice, time and overall commitment to supporting me through my graduate program. Thanks for teaching by example and demonstrating that real mentorship exists in the truest sense. I may have faith in academia after all!! I would also like to thank Dr. Terje Radusepp for her invaluable cytogenetic expertise, for providing her skills at the great expense of her personal time and giving me irrefutable physical evidence without which my data would be less likely to stand alone. I would also like to thank her for invaluable discussions and advice for maintaining mental health during my graduate program! In addition, I would like to thank the members of the Skow lab, past and present, for technical assistance and moral support during my project: Dee Honeycutt, Daniel McGilvray, Emily Zayac, Nicole Thornton, Christopher Childers and last but not least, Princess Ashley Gustafson Seabury. Princess Ashley has had to contend with my mood vii swings and rantings as we share an office and a large part of our lives! I promise to cook Pelau for you daily until I graduate as penance. A special thanks to the Seaburys (Chris and Ashley) for going beyond normal confines of friendship and acting as ranch hands during my Oklahoma sample collections! Maybe I’ll make it as a true cowgirl yet y’all! I would also like to thank my extended support group in the TAMU family, including the Collisson lab (Ellen, Anagha, Soon Jeon, Jyothi, and Ryan) for providing cell culture facilities, advice, wisdom and support; the Derr lab (Jim, Natalie and Chris) for samples, analysis and healthy debate; the Womack lab (Jan and Elaine) for fibroblast cell culture; Dr. William Russell in Chemistry for mass spectrometry analysis, Dr. German Rosas-Acosta for assistance in protein purification and Daniel Santillano for support, coffee/margarita breaks and an effective reagent trade! On a personal level I would like to acknowledge my “extended family” here in C.S. who have provided me with a “home away from home” in the truest sense: the Rosas-Mantilla family; Michael, Rocky and Vito Bonafede; Lisa Harrison; Troy Skwor; Melissa Cox and Michael Golding (Local Canucks); MC Ramel, Dave Louis (the only other member of the local chapter of the Trinidad and Tobago club!) and the Pachucos. Thank you for your moral support, advice (albeit at most times unsolicited!) and superferlous good times. You’ve all made my PhD experience unforgettably enjoyable, and yes Dave, I will miss College Station! Finally to my extended family worldwide, thanks for everything, especially to Mummy, Daddy, Neil, Ria and Liam, for believing in me. To everyone who has longed to see the day that their favourite career student finish this last step, after 4 years, 3 labs, 2 countries… Ah done! Je suis fini! Ya termine! So stop asking! Now, if only I could get that MBA I’ve always wanted……just kidding. viii TABLE OF CONTENTS Page ABSTRACT………………………………………………………………………… iii DEDICATION…………………………………………………………………….... v ACKNOWLEDGEMENTS………………………………………………………… vi TABLE OF CONTENTS…………………………………………………………… viii LIST OF FIGURES……………………………………………………………….... x LIST OF TABLES………………………………………………………………….. xiii CHAPTER I INTRODUCTION………………………………………………………….. 1 The major histocompatibility complex (MHC).……………………. 1 General organization and genetic content of the mammalian MHC………………………………………………………………… 3 Comparative analysis of the organization of the MHC across species……………………………..………………………… 6 The role of the major histocompatibility complex in immunity……………………………………………………………. 21 Structure of the class I MHC molecules……………………………. 24 Evolution of the MHC……………………………………………… 35 Expression and phylogenetic analysis of BoLA class I loci………... 49 Hypothesis………………………………………………………….. 51 Specific aims and objectives……………………………………….. 53 II GENOMIC ORGANIZATION OF THE BOVINE
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