Genetic variation caused by active retrotransposons in the humangenome 公开

Bennett, E. Andrew (2008)

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Abstract Genetic variation caused by active retrotransposons in the human genome By E. Andrew Bennett Nearly one third of our genome belongs to three families of active retrotransposons: L1, Alu, and SVA, that continue to create genetic variation and cause disease in humans. We developed several novel methods to detect the contribution transposable elements have made to human genetic diversity, and identified 25-35% of transposon insertion polymorphisms commonly found in human populations. Our method improved on previous assays by identifying different families of recently mobile elements equally. Using this same approach, we identified nearly 11,000 species-specific transposon insertions that have mobilized in the past 6 million years in humans and chimps. We found that humans possess a more diverse and active collection of retrotransposon subfamilies, and have sustained almost twice as many new insertion events since our last common ancestor. The majority of recent insertions in both humans and chimps were caused by Alu elements. There are over 1 million Alus in humans and they collectively occupy 10% of our genome. It was unclear however, how many of these remained active, and what constituted an active Alu sequence. In order to define the requirements for Alu activity, we performed a comprehensive analysis using conservation data and retrotransposition assays. We show that active Alu elements display a high degree of sequence variation, but must conserve nucleotides that enable them to bind to SRP9/14 proteins. Furthermore, we show the affinity for SRP9/14 binding has decreased since the earliest Alus evolved from 7SL RNA. We estimate that at least 10,000 of the Alus in our genome are capable of causing new genetic variation through future retrotransposition.

Table of Contents

Table of Contents Chapter 1. Introduction 1 Introduction to retrotransposons 2 Impact of retrotransposons in humans 12 Scope of the dissertation 19 Chapter 2. Single nucleotide polymorphisms (SNPs) that map to gaps in the 22 human SNP map Introduction 23 Materials and methods 26 Results 32 Discussion 35 Chapter 3. Natural genetic variation caused by transposable elements in humans 42 Introduction 43 Materials and methods 48 Results 54 Discussion 80 Chapter 4. Recently mobilized transposons in the human and chimpanzee 89 genomes Introduction 90 Results 92 Materials and methods 109 Chapter 5. Active Alu retrotransposons in the human genome 112 Introduction 113

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