Resumen de A Comparative Genomics Study of Human and Chimpanzee Evolution Natural Selection, Function, and Disease

Leonardo Arbiza Brustin

• I Introduction 17 1 Understanding Ourselves From a Comparative Standpoint 19 1.1 An Age Old Pursuit . . . . . . . . . . . . . . . . . . . . . . . . . 19 1.2 A Review of Some of the Most Relevant Studies . . . . . . . . . . 21 2 Natural Selection and the Neutral Theory of Molecular Evolu- tion 25 2.1 A Brief History of Molecular Evolution . . . . . . . . . . . . . . . 25 2.2 Testing for Deviations from Neutrality . . . . . . . . . . . . . . . 27 3 ML Codon Based Methods 31 3.1 A Probabilistic Maximum Likelihood Framework . . . . . . . . . 31 3.2 Different ML Models: branch, site, and branch-site methods . . . 33 3.3 Testing Evolutionary Hypotheses Using ML Models . . . . . . . . 35 II Objectives 37 III Materials and Methods 41 3.4 Test Based Inferences of Natural Selection at a Genomic Scale . 43 3.4.1 Data Obtention and Preparation for Analyses . . . . . . . 43 3.4.2 Relative Rate Estimation and Quality Filters . . . . . . . 43 3.4.3 Branch-site Tests of Positive Selection and Relaxation of Selective Constraints . . . . . . . . . . . . . . . . . . . . . 44 3.5 Natural Selection and Biological Function . . . . . . . . . . . . . 45 3.6 Natural Selection at the Organ System Level . . . . . . . . . . . 45 3.6.1 Data Obtention and Preparation for Analyses . . . . . . . 45 3.6.1.1 Expression Databases and Definition of Tissue Specificity . . . . . . . . . . . . . . . . . . . . . 45 3.6.1.2 DNA sequences and Orthology Relations . . . . 46 3.6.2 Testing for Positive Selection and Branch Model Based Estimates of Evolutionary Rates . . . . . . . . . . . . . . 47 iv CONTENTS 3.7 Natural Selection and Disease . . . . . . . . . . . . . . . . . . . . 48 3.7.1 Data Obtention and Preparation for Analyses . . . . . . . 48 3.7.1.1 Mutational Frequency Databases . . . . . . . . . 48 3.7.1.2 Structural Information . . . . . . . . . . . . . . 48 3.7.1.3 DNA Sequences and Orthology Relations . . . . 49 3.7.2 Site Based Tests of Positive Selection and Estimates of Selective Pressures at the Codon Level . . . . . . . . . . . 49 3.7.3 Statistical Analysis . . . . . . . . . . . . . . . . . . . . . . 51 IV Results 53 4 Test Based Inferences of Natural Selection at a genomic Scale 55 4.1 Testing the Molecular Clock Hypothesis . . . . . . . . . . . . . . 55 4.2 Testing for Positive Selection and Relaxation of Selective Constraints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 4.3 PS and Nonsynonymous Rate Acceleration . . . . . . . . . . . . 58 5 Natural Selection and Biological Function 61 5.1 Functional Analysis of Accelerated Genes in Human and Chimp 61 5.2 Functional Analysis of Positively Selected Genes . . . . . . . . . 63 5.3 Ancestral and Derived Trends of Relaxation and Positive Selection 65 5.4 Functional Roles of PSG in Human and in Chimp . . . . . . . . 68 5.5 Distribution of Functional Classes by Evidence of PS . . . . . . . 73 6 Natural Selection at the Organ System Level 79 6.1 Determination of Tissue Specific Genes . . . . . . . . . . . . . . . 79 6.2 Differences Among Primates and Murids . . . . . . . . . . . . . . 80 6.3 Differences Among Humans and Chimpanzees . . . . . . . . . . . 83 6.4 Differences Among Tissue Specific Gene Categories . . . . . . . . 83 6.5 Comparison Between Statistical Methods . . . . . . . . . . . . . 87 6.6 PS Tests on Tissue Specific Genes . . . . . . . . . . . . . . . . . 87 7 Natural Selection and Disease 91 7.1 Distribution of Disease-Associated Mutations in p53 . . . . . . . 91 7.2 Characterization of Selective Constraints on p53 Codon Sites . . 92 7.3 Mapping Selective Pressures in the Structure of p53 . . . . . . . 95 7.4 Selective Pressures and Mutations Associated with Cancer in p53 101 7.5 Testing Associations Between ¿ and Disease in Human Genes . . 104 8 Contributed Resources 109 8.1 Predicting Deleterious Mutations within the Pupas Suite Server . 109 8.2 Testing for Molecular Adaptation and Rate Estimation within the Phylemon Server . . . . . . . . . . . . . . . . . . . . . . . . . 113 CONTENTS v V Discussion 119 9 Summarizing Discussion 121 9.1 Test Based Inferences of Natural Selection . . . . . . . . . . . . . 121 9.2 Natural Selection and Biological Function . . . . . . . . . . . . . 123 9.3 Natural Selection at the Organ System Level . . . . . . . . . . . 126 9.4 Natural Selection and Disease . . . . . . . . . . . . . . . . . . . . 128 9.5 Contributed Resources . . . . . . . . . . . . . . . . . . . . . . . . 130 9.6 Further Considerations . . . . . . . . . . . . . . . . . . . . . . . . 131