Novel Germline and Somatic Retrotransposon Insertions in Humans Open Access

Iskow, Rebecca Cheryl (2009)

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Novel Germline and Somatic Retrotransposon Insertions in Humans
By Rebecca C. Iskow

Human genetic variation can cause phenotypic differences as well as provide the
substrate for evolutionary forces. Single nucleotide polymorphisms (SNPs) are the most
studied form of genetic variation-however, insertions/deletions, copy number variants,
and transposable elements are under increasing scrutiny. Retrotransposons (a class of
transposable elements) act as endogenous mutagens, and dozens of insertions are
responsible for genetic disorders. The majority of human retrotransposons are
evolutionary relics, however, a subset of retrotransposons remain active. New
retrotransposon insertions are numerous in human populations. We sought to understand
the role that young retrotransposons have played in altering human genomes since the
divergence from chimpanzee, within human populations, and during an individual's
lifetime. First, we developed a computational pipeline to identify lineage-specific
insertions in humans and chimpanzees. We identified 11,000 transposable elements that
were differentially present between these two species. We also selectively sequenced L1
insertion junctions in diverse humans. We found nearly 1,000 previously unknown
retrotransposon polymorphisms. We also found evidence of ongoing and frequent L1
mutagenesis in the germline. We showed that retrotransposition occurs in human lung
tumors. L1 mutagenesis is a mechanism of mutation in human tumors and likely
contributes to genomic instability. We also identified a potential methylation signature
that distinguishes lung tumors that support retrotransposition from those that do not.
Altogether, our data show that L1 has been jumping frequently since the divergence of
human and chimp and continues to jump in the human germline and soma. Our studies
examine human genetic variation through the lens of L1 mutagenesis.

Table of Contents

Table of Contents

Chapter 1. Introduction 1
Transposons in the human genome 2
Retrotransposition and human disease 7
Mechanisms to maintain transposons in populations 9
Retrotransposition may occur in cancer 11
Estimates of retrotransposition rate 14
Efforts to find polymorphic retrotransposons 16
Scope of the dissertation 23

Chapter 2. Recently mobilized transposons in the human and chimpanzee genomes 25
Introduction 26
Methods/Results 26
Discussion 42

Chapter 3. L1 retrotransposition occurs frequently in the human germline 44
Introduction 45
Results 48
Discussion 59
Materials and methods 61

Chapter 4. Frequent mutagenesis of lung tumors by the human L1 retrotransposon 72
Introduction 73

Results 75

Discussion 83

Materials and methods 87

Chapter 5. Discussion 89
Discussion 90
Active L1s contribute to species divergence 92
L1 retrotransposition is a major source of genetic variation in human populations 96

L1 elements are active in tumors 99
Future directions in the hunt for retrotransposons 103

References 106
Appendix 138

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