
Genomic Analysis of Human Population Structure by David Andrew Eccles A thesis submitted to the Victoria University of Wellington in fulfilment of the requirements for the degree of Doctor of Philosophy in Biomedical Science. Victoria University of Wellington 2011 Abstract Recent developments in technology and computation have encouraged a shift towards a whole-genome approach to genetic analysis. Two key contributors to this shift, the Human Genome Project and the HapMap project, sparked an interest in studying the genetic patterns found in par- ticular groups of individuals. The Maori population of New Zealand is an ideal, yet untapped, model for such studies due to recent partial mixture of two distinct population groups, and a culture of good documentation of genealogical information. A previous study carried out by the author found observable genetic differences between Maori and European populations in markers of forensic significance, yet no particular genetic patterns were found that were uniquely Maori. This study extends the previous work by developing methods to determine to what scale these differences exist, as well as demonstrating that a knowledge of these differences and methods could be used to improve current practices for clinical diagnosis. The current project began by taking a ‘candidate gene’ approach, study- ing two regions where there were known large genetic differences between Maori and European individuals: the region of Alcohol Dehydrogenase genes on Chromosome 4 (Chapter2), and the Monoamine Oxidase A gene region on Chromosome X (Chapter3). In both of these regions, large frequency differences were observed between Maori and non-Maori popu- lations at both a single mutation level, and at a haplotype level. Despite the differences that were observed, no particular combinations of mutations could be considered uniquely Maori or uniquely non-Maori, so studies were expanded to the entire genome. This epansion was made possible due to the recent and continuing developments in genome-wide technology and advancements in computational speed and efficiency. Once it was possible to carry out a genome-wide study of genetic differences, the goal of research changed from determining whether or not Maori and Euro- pean individuals were uniquely different at a genotype level, to how small a marker set could be produced while maintaining population-uniqueness at a genotype level. A method that uses bootstrap sub-sampling and other internal valida- tion techniques has been developed for the generation of such a signature set for a Maori tribe (Ngati Rakaipaaka), and the generated set has been validated in other similar populations (Chapter4). As a consequence of producing this set, the degree of European admixture was estimated in the tribe (28.7%), with over 15% of individuals within Rakaipaaka found to have no discernible European genomic ancestry. In a validation of the signature set generation method itself, the marker selection procedure was repeated for Type 1 Diabetes, a disease with high heritability. An analysis of case and control individuals using this sig- nature set found that the generated set is able to perform better than a genome-wide reference set of mutations known to be associated with Type 1 Diabetes. This validation study, other potential uses, and a more de- tailed discussion of the signature set generation method are presented in Chapter5. Acknowledgements Friends and Family My PhD study began in 2005, and I was tasked with finding suitable dis- tractions and motivations to help me get through to the end. My parents and friends have been supportive of my research right through, even in the tricky (and very long) “still writing” stage of my project. I was introduced to Jessica Campbell at the Interface computer club sometime near the beginning of my research, and found in her an energetic nature that would keep me going through the tough times. I proposed to her about three years after the start of this PhD project (not entirely coincidental), having decided that my research was essentially complete and finishing off the remainder of the writing wouldn’t take all that long. We were married at the end of January 2009 under the name Eccles (a name from both our families back 5 generations), and now have a son, Peter Peregrin Matthew Eccles. Family life has been a welcome distraction, and has probably allowed me to retain much of the sanity I had before PhD study began. iii iv Work Colleagues I would like to specially thank Collette Bromhead from the Medical Lab- oratory (now Aotea Pathology), for sending me down the track of PhD study in the first place – a chat with Collette convinced me that research at a PhD level would be essential for my future work and research prospects. Through working as her molecular biology laboratory cleaner during the fi- nal stages of her PhD research, I gained some understanding of the suffering and rewards associated with doctoral study. Thanks also go out to staff at ESR, especially members of the Population and Environmental Health group, who have kept me grounded in reality with respect to the financial and clinical side of genomic research. Supervisors My supervisors, Geoff Chambers and Rod Lea, provided me with the opportunity to attend the 11thInternational Congress of Human Genetics towards the end of the first year of my PhD project. As a fresh, starry-eyed graduate researcher, I took in as much as possible, and was rewarded with an excellent grounding in current genetic research. The opportunity to present posters at the conference also made me aware of how other fellow researchers might perceive my work. Rod Lea’s frequent requests for me to carry out more bioinformatics work allowed me to try out my research in the “real world”, and enabled me to debug and test my theories – an opportunity that seems to be fairly rare in PhD research. Geoff Chambers’ help with academic style and grace has improved my presentation skills considerably. I’ve progressed from a student who got tongue-tied and frozen half-way through a talk on ADH genetics, to a researcher who has managed to self-publish his first book. v The Grapevine Shortly before I began my PhD project, I asked a few people if they would be interested to receive updates on my progress. While I’ve only sent off a few emails to these people (via a mailing list that I named “The PhD Grapevine”), it’s been wonderful to have these people around to listen to my tangential thoughts: Collette Bromhead, Te Runanga A Rangitane O Wairau, Gael Price, Graham and Elaine Langton, Daniel Briggs, Donald Gordon, Melanie Gibson, Liz Richardson, Adele Whyte, Laura Feasey, Helena Woods, Michelle Hunt, Claire Swain, John Beal, Jessica Eccles, Kirsten McEwen, my parents Noel and Faye Hall, and my nana Joan Hall. Te Iwi o Rakaipaaka A significant component of my research has involved the analysis of genetic and ancestry data from Te Iwi o Rakaipaaka. I am very grateful that they have entrusted their data to me, and hope that the results and insights from my research can give them a bit more understanding of what this genetic stuff all means. Free and Open Source Software Free and Open Source Software (FOSS) has been used extensively in this project, both in creating this thesis, and in carrying out analysis of genetic data. A number of FOSS programs in particular have been the mainstay of my research tools: Emacs Editing of text documents, program code LATEX Thesis, Presentations, Publications vi Scribus Posters Inkscape Illustrations GIMP Picture/Photo editing Perl Data conversion / aggregation R Graphing, statistical analysis Openoffice.org Writing 6-month reports, spreadsheet summaries of data Plink Genome-wide data analysis Haploview Haplotype block diagrams Proofreading I also thank my wonderful proofreaders, who have commented on my thesis during its creation, provided constructive criticism, and lent me an extra set of eyes: Geoff Chambers, Rod Lea, Jessica Eccles, Murray Darroch, and Faye Hall. Funding Finally, as always, I thank the financial contributors to my study. I hope that I have been able to give back a little to the community in exchange for the financial support of my study, and look forward to future community presentations of my research: Environmental Science and Research Ltd. (ESR) Population and Environ- mental Health Scholarship, travel and conference costs vii Victoria University of Wellington (VUW) Computer equipment, labora- tory reagents, travel and conference costs Studylink Student allowance Wellington Medical Research Foundation (WMRF) Travel and conference costs viii Contents Abstracti Acknowledgements iii Contents ix List of Tables xvii List of Figures xix Terminology and Abbreviations xxiii 1 Introduction1 1.1 An Introduction to Bioinformatics...............3 1.2 Genetic Concepts.........................4 1.2.1 DNA............................4 1.2.2 Mutation..........................6 1.2.3 Chromosomes and Inheritance.............9 1.2.4 Recombination...................... 11 1.3 Population Genetics Concepts.................. 14 ix x 1.3.1 Linkage Disequilibrium................. 14 1.3.2 The Haplotype Block Theory.............. 16 1.3.3 Admixture......................... 17 1.4 Genomic and Bioinformatic Concepts............. 18 1.4.1 Human Genome Project................. 18 1.4.2 HapMap.......................... 19 1.4.3 Genome-Wide Association Studies........... 21 1.4.4 Common AssociationStatistics............. 24 1.4.5 Contingency Table Analysis............... 26 1.4.6 Population Sampling and Statistical Uncertainty... 29 1.4.7 Computer Programs used in This Thesis....... 32 1.5 The Maori Population...................... 37 1.5.1 Polynesian Origins.................... 37 1.5.2 Settlement of New Zealand............... 40 1.5.3 European Colonisation.................. 41 1.5.4 Population Genetic Insights............... 41 1.5.5 Maori Health....................... 43 1.6 Hypothesis and Key Questions................. 44 2 The ADH Gene Region 47 2.1 Overview.............................. 47 2.2 Background............................ 48 2.2.1 Historical Maori Drinking Patterns..........
Details
-
File Typepdf
-
Upload Time-
-
Content LanguagesEnglish
-
Upload UserAnonymous/Not logged-in
-
File Pages264 Page
-
File Size-