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The Influence of Genetic Variation in Gene Expression

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The Influence of Genetic Variation in Gene Expression The Influence of Genetic Variation in Gene Expression Eva King-Fan Chan A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy 2007 School of Biotechnology and Biomolecular Sciences University of New South Wales Certificate of originality I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged. ______________________ Eva Chan 18th July 2007 i Abstract Abstract Variations in gene expression have long been hypothesised to be the major cause of individual differences. An initial focus of this research thesis is to elucidate the genetic regulatory architecture of gene expression. Expression quantitative trait locus (eQTL) mapping analyses have been performed on expression levels of over 22,000 mRNAs from three tissues of a panel of recombinant inbred mice. These analyses are “single-locus” where “linkage” (i.e. significant correlation) between an expression trait and a putative eQTL is considered independently of other loci. Major conclusions from these analyses are: 1. Gene expression is mainly influenced by genetic (sequence) variations that act in trans rather than in cis; 2. Subsets of genes are controlled by master regulators that influence multiple genes; 3. Gene expression is a polygenic trait with multiple regulators. Single-locus mapping analyses are not designed for detecting multiple regulators of gene expression, and so observation of multiple-linkages (i.e. one expression trait mapped to multiple eQTLs) formed the basis of the second objective of this research project: to investigate the relationship between multiple-linkages and genotype pattern-association. A locus-pair is said to have associated genotype patterns if they have similar inheritance pattern across a panel of individuals, and these are attributed to one of fours sources: 1. linkage disequilibrium between loci located on the same chromosome; 2. non-syntenic association; 3. random association; 4. un-associated. ii Abstract To understand the validity of multiple-linkages observed in single-locus mapping studies, a newly developed method, bqtl.twolocus, is applied to confirm two-locus effects for a total of 898 out of 1,233 multiple-linkages identified from the three studies mentioned above as well as from seven publicly available eQTL-mapping studies. Combining these results with information of genotype pattern-association, a subset of 478 multiple- linkages has been deduced for which there is high confidence to be real. iii Acknowledgements Acknowledgements Three-and-a-half years and it is now over. It had been intellectually challenging, stressful at times (most of the time), frustrating (still can’t believe I have not yet thrown anything at the computer despite my many threats to do so), but all-in-all it had been a thoroughly enjoyable experience. Needless to say, the person I would like to thank most is my supervisor, Peter Little, from whom I learnt the true meaning of “research”. Peter is an exceptional mentor and I am truly grateful for his guidance and the privilege to share in his passion. Three very special people I would very much like to acknowledge are Rohan Williams, Mark Cowley, and Chris Cotsapas, with whom I have shared the lab over the pass several years. It is near impossible to count all that I have learnt from Rohan and I’d like to thank him for his advices, encouragements, and friendship. Many thanks to Mark for being my IT guru and for showing me scientists need not be overly eccentric (and that it is okay to listen to pop). Thanks also to Chris for his endless efforts to stimulate the unwary mind with everything and anything. Much appreciation to David Nott, our resident Statistician, who has on so many occasions helped simplify a complicated problem to an elegant Bayesian model. Acknowledgements also to many students that have contributed directly or indirectly to my work: Jeremy Pulvers, Michael Liu, Oscar Luo, and Andrew Liu. Thanks to my internal reviewers Ian Dawes and Andrew Brown. iv Publications Publications Published papers Rohan B H Williams, Chris J Cotsapas, Mark J Cowley, Eva Chan, David J Nott, Peter F R Little. 2006 Normalization procedures and detection of linkage signal in genetical-genomics experiments. Nature Genetics 38: 855- 856. Chris J. Cotsapas, Rohan B.H. Williams, Jeremy N. Pulvers, David J. Nott, Eva K.F. Chan, Mark J. 2006 Genetic dissection of gene regulation in multiple mouse tissues. Mammalian Genome 17 (6): 490-495. David J. Nott, Zeming Yua, Eva Chan, Chris Cotsapas, Mark Cowley, Jeremy Pulvers, Rohan Williams and Peter Little. Hierarchical Bayes variable selection and microarray experiments. Journal of Multivariate Analysis (accepted) Papers in preparation Eva KF Chan, Mark J Cowley, Rohan BH Williams, Chris J Cotsapas, David J Nott, Peter FR Little. 2006 Multiple linkages in eQTL studies of mice, rats, and yeast. (in preparation) Rohan BH Williams, Eva KF Chan, Mark J Cowley, Peter FR Little. The influence of genetic variation on gene expression. Genome Research (invited review). Mark J Cowley, Chris J Cotsapas, Rohan BH Williams, Eva KF Chan, Jeremy N Pulvers, Michael Y Liu, David J Nott, Peter FR Little. The effects of genetic variation on gene expression in multiple tissues. (submitted) Refereed Published Conference Proceedings Cotsapas C, Chan E, Kirk M, Tanaka M, Little P. 2003 Genetic variation and the control of transcription IN Cold Spring Harbour Symposia on Quantitative Biology, Symposium 68, pp. 109-114. v Table of Contents Table of Contents Certificate of originality ........................................................................................................ i Abstract ................................................................................................................................ ii Acknowledgements ............................................................................................................. iv Publications .......................................................................................................................... v Published papers .............................................................................................................. v Papers in preparation ....................................................................................................... v Refereed Published Conference Proceedings .................................................................. v Table of Contents ................................................................................................................ vi Table of Figures................................................................................................................... ix Table of Tables.................................................................................................................. xiii 1. Introduction.................................................................................................................1 1.1. Natural variation................................................................................................ 1 1.2. Gene expression regulatory variation ................................................................ 3 1.2.1. Cis-acting regulatory elements................................................................. 4 1.2.2. Trans-acting regulatory factors................................................................ 5 1.3. Mapping expression quantitative trait loci ........................................................ 8 1.3.1. eQTL mapping approaches ...................................................................... 8 1.3.2. Segregating populations......................................................................... 10 1.4. Microarrays and expression traits.................................................................... 13 1.4.1. Normalisation of expression data........................................................... 16 1.5. Marker genotype patterns................................................................................ 18 1.6. Single-locus mapping ...................................................................................... 21 1.6.1. Significance test and multiple testing .................................................... 23 1.7. Multi-locus mapping ....................................................................................... 27 1.8. Aim and hypotheses ........................................................................................ 34 1.8.1. Influence of genetic variation on mRNA levels (Chapter 3).................. 34 1.8.2. Multi-locus influence of gene expression variation (Chapter 4)............ 34 1.8.3. Influence of genotype pattern association in multiple linkage (Chapter 5) ............................................................................................. 35 2. Materials and Methods.............................................................................................
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