Tandem Duplications in the Human Genome

Profound knowledge about the nature of mutational processes is essential for a comprehensive understanding of the evolutionary mechanisms that change genomes over time. The aim of the thesis is to elucidate the role of DNA insertions and deletions in this context. Compared with nucleotide substitutions, these types of mutations are far less understood. We perform a detailed genome-wide analysis of short DNA insertions and deletions that recently occurred in the human lineage. Our main finding is that insertions are predominately tandem duplications of adjacent sequence segments. We investigate the implications of this observation on possible molecular mechanisms of indel generation, large-scale statistical features of genomic base composition, and significance estimation of sequence alignment similarity scores.Preface i 1 Introduction 1 1.1 Molecular biology and evolution . . . . . . . . . . . . . . . . . . . . . 1 1.2 Mutational processes . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 1.3 Inferring mutation characteristics . . . . . . . . . . . . . . . . . . . . 10 1.4 Background models of DNA sequences . . . . . . . . . . . . . . . . . 18 1.5 Thesis organization . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 2 DNA insertions and deletions in the human lineage 21 2.1 Identification of indels in the human lineage . . . . . . . . . . . . . . 21 2.2 Tandem duplications and molecular mechanisms . . . . . . . . . . . . 25 2.3 Indels in protein-coding regions . . . . . . . . . . . . . . . . . . . . . 35 3 Tandem duplications and genomic correlations 43 3.1 Dynamical model of sequence evolution . . . . . . . . . . . . . . . . . 44 3.2 Sequence growth and average composition . . . . . . . . . . . . . . . 46 3.3 Stationary two-point correlations . . . . . . . . . . . . . . . . . . . . 49 3.4 Finite-size distribution of the composition bias . . . . . . . . . . . . . 55 3.5 Symmetry breaking and universality . . . . . . . . . . . . . . . . . . 58 3.6 Dynamical correlations . . . . . . . . . . . . . . . . . . . . . . . . . . 62 3.7 General four-letter model and web service CorGen . . . . . . . . . . . 66 3.8 Origin of genomic correlations . . . . . . . . . . . . . . . . . . . . . . 71 4 Genomic correlations and sequence alignment statistics 75 4.1 Sequence alignment and significance assessment . . . . . . . . . . . . 75 4.2 The Gaussian approximation . . . . . . . . . . . . . . . . . . . . . . . 77 4.3 Numerical results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 4.4 Consequences for genomic alignments . . . . . . . . . . . . . . . . . . 84 5 Summary 87 Bibliography 89 Notation and abbreviations 103 Zusammenfassung 10