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The Genetic Architecture of Variation in Humans and Dogs

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The Genetic Architecture of Variation in Humans and Dogs THE GENETIC ARCHITECTURE OF VARIATION IN HUMANS AND DOGS by ELDON GOODWIN PRINCE Presented to the Faculty of the Graduate School of The University of Texas at Arlington in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY THE UNIVERSITY OF TEXAS AT ARLINGTON May 2014 Copyright © by Eldon Goodwin Prince 2014 All Rights Reserved ii Acknowledgements I am grateful for the guidance of my two advisors at UT Arlington, Trey Fondon and Jeff Demuth. I appreciate Jeff's mentoring and patience during the first two years of my degree. Trey created an intellectually demanding environment that has helped me to grow personally and professionally; I am grateful for his insights that heavily influence this work, and hope to have assimilated some of his patterns of critical thinking during the past few years. I thank my I-Engage students Emil Burdeos, Courtney Elledge, and Bethany Minter for their hard work and participating in many enlightening and fun conversations. Kristen Correll and Michael Chau contributed substantially to this work by helping to measure and genotype mixed-breed dogs. Shreyas Krishnan and many other graduate students and lab members have been genuine friends to me and my family; your kindness will not soon be forgotten. In addition, I thank Esther Betrán, André Pires da Silva, Todd Castoe, and Cédric Feschotte for valuable instruction and feedback. I also appreciate the Biology Department office staff for their assistance. Throughout this process I have received constant inspiration from my supremely patient and dedicated wife, Stephanie Prince. I could not have completed this work without her listening ear, lucid questions, and detailed proofreading. I thank my children Sophie, Elinor, and Goodwin for their inspiration and being willing to live so long without a backyard. I am grateful for the continuous support I have received from my siblings Edd, Patti, Sarabeth, John, Daniel, Joseph, Dallan, and Pauline. I am indebted to David and Pam Richards for their love and for letting me take their daughter to Texas. My parents Leon and Leah Prince have been pillars of strength and I thank them for their encouragement. Finally, I recognize the omnipresent role my grandparents Douglas and Beth Prince and Edd and Pauline Goodwin have played in shaping who I am. April 18, 2014 iii Abstract THE GENETIC ARCHITECTURE OF VARIATION IN HUMANS AND DOGS Eldon Goodwin Prince, Ph.D. The University of Texas at Arlington, 2014 Supervising Professor: John W. Fondon III, Ph.D. Genetic architecture is broadly defined as the structure of how genes come together to produce phenotypes. Primary aspects of genetic architecture include how many and which genes contribute to phenotypic variation. The genetic architecture of human height has been studied for over a century; indeed it is the classic quantitative trait with hundreds of contributing variants. As genome-wide studies of genetic architecture are extended beyond just humans, the genetic basis of polygenic traits like height can be compared between species. Such interspecies comparisons reveal how many of the same loci contribute to variation within each species. The extent to which the same loci contribute to intraspecific variation depends on species relatedness and reflects underlying constraints on genetic variability and variation. In this study genome-wide associations are compared between humans and dogs to estimate how many of the same loci contribute to intraspecific height variation. Due to the highly polygenic nature of height variation, one might predict that relatively few loci will be shared between species as distantly related as the human and dog. Contrary to this prediction, I find that at least 25 orthologous regions contribute to intraspecific height variation in humans and dogs, indicating perhaps less obvious constraints on genetic variability and variation. iv Height is decomposed in dogs using genome-wide associations to identify loci that are associated with limb, torso, and neck variation. To extend this approach, several height QTLs are correlated with bone measurements in an independent panel of mixed- breed dogs. The prevailing interpretation that morphological traits are genetically simple in dogs relative to humans is then tested. Central to the interpretation of genetic simplicity in dogs is the story of IGF1, a gene thought to explain the majority of size variation. The QTL effect size of IGF1 is tested in the aforementioned panel of mixed-breed dogs and I find that it explains much less variation than previously reported. This experiment and others call into question the Mendelian effect size previously attributed to IGF1 and the associated interpretation of genetic simplicity for dog morphology. One of the evolutionary forces that can impact the genetic architecture of traits is meiotic recombination. Preceding the exchange of genetic material between homologous chromosome pairs, double-strand breaks occur via proteins like Spo11 in yeast. Since all crossovers are the result of double-strand breaks, and these breaks are non-randomly distributed throughout the genome, many researchers have sought to understand the process that regulates where double-strand breaks occur. In addition, although not all double-strand breaks result in genetic crossover, the DNA repair process to rejoin them can be both biased and mutagenic. The protein PRDM9 is associated with almost all meiotic double-strand breaks in mice and is thought to play a similarly central role in humans, although the protein is absent in canids. Curiously, the loss of PRDM9 in the canid lineage also coincides with a genome-wide destabilization of repetitive GC content. I conclude this work with a study of the consequences of losing the meiotic recombination-associated protein PRDM9 and the mutagenic role this loss has likely had in shaping the canid lineage. v Table of Contents Acknowledgements .............................................................................................................iii Abstract .............................................................................................................................. iv List of Illustrations .............................................................................................................. ix List of Tables ......................................................................................................................xii Chapter 1 The Extent of Height QTL Sharing in Humans and Dogs .................................. 1 Introduction ..................................................................................................................... 1 Components of Genetic Architecture .............................................................................. 3 The Number of Loci That Contribute to Variation ....................................................... 3 When the Same Loci Contribute to Variation ............................................................. 4 Underlying Causative Mutations ................................................................................. 6 Setting Up the Comparison Between Humans and Dogs .............................................. 8 Human Height Variation ............................................................................................. 8 Dog Height Variation ................................................................................................ 15 History of Height in Humans ..................................................................................... 17 History of Height in Dogs .......................................................................................... 23 Genetic Architecture of Human Height ..................................................................... 26 Genetic Architecture of Dog Height .......................................................................... 28 Comparison of the Genetic Basis of Human and Dog Height Variation ....................... 29 Human Height QTLs ................................................................................................. 30 Dog Height QTLs ...................................................................................................... 30 Decomposition of Height .......................................................................................... 34 Functional Analysis of Dog Height QTLs.................................................................. 37 Selective Sweep Analysis of Dog Height QTLs ....................................................... 38 Identification of Shared Height QTLs ....................................................................... 40 vi Assessment of the Extent of QTL Sharing ............................................................... 43 Notable QTLs ........................................................................................................... 46 Why Some QTLs Are Missing .................................................................................. 48 Conclusion .................................................................................................................... 49 Chapter 2 Effect Size Distributions for Height in Humans and Dogs ................................ 51 Introduction ................................................................................................................... 51 The Effect Size Distribution of Human Height .............................................................. 52 The Problem of Missing Heritability .........................................................................
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