Thirty years ago we knew that retrotransposons made up at least half of our genomes, but little about their role in biology. The human genome has since been sequenced and the position of all retrotransposons in the reference sequence has been determined. However, as of today, the function of retrotransposons still remains elusive. We know much more about the diseases associated with their movement and the host defenses we all have against them. This volume explores an array of diseases in humans associated with L1 retrotransposon movement within the human genome, including some cancers such as colon cancer and neuropsychiatric disorders such as schizophrenia. The chapters explore the diversity of retrotransposons, their different biological mechanisms, the role of L1 in their movement, and their contribution to human diseases. This book posits that somatic events caused by retrotransposons have implications for mosaicism and are often associated with cancers. Germline events are common, occur quite early in development, and are a cause of single gene diseases. All in all, the authors implicate L1 retrotransposons as major sources of human diversity and advocate for their continued study.
Author(s): Abram Gabriel
Publisher: World Scientific Publishing
Year: 2022
Language: English
Pages: 260
City: Singapore
Contents
Preface
Chapter 1 The Diversity of Reverse Transcriptases
1. Introduction
2. Retroelements in Bacteria, Archaea, and their Viruses
2.1. Group II introns
2.2. Retrons
2.3. Diversity-generating retroelements
2.4. Abortive infection systems: AbiA, AbiK, and Abi-P2
2.5. Other uncharacterized retroelements
3. Eukaryotic Reverse Transcriptases
3.1. Domesticated RTs: Telomerase, Prp8, and RVT genes
3.2. Classification of eukaryotic retrotransposons
3.3. RT types and mechanisms of retrotransposon proliferation
3.4. RTs of non-LTR retrotransposons
3.5. RTs of Penelope-like elements
4. Concluding Remarks
Acknowledgments
References
Chapter 2 Ty3 and Related LTR-Retrotransposon Reverse Transcriptases
1. Introduction
2. Background/Historical Perspective
3. tRNA-primed Initiation of (−) Strand DNA Synthesis
4. RNase H-mediated (−) Strand DNA Transfer
5. Polypurine Tract (PPT)-primed (+) Strand DNA Synthesis
6. Role of the Ty3 RT Thumb Subdomain in Substrate Recognition
7. DNA Polymerase and RNase H Active Sites
7.1 DNA polymerase
7.2 RNase H
8. Bringing Things Together: Crystal Structure of a Ty3 RT-RNA/DNA Hybrid
9. Topological Similarities between Ty3 and HIV-1 RT
10. A Final Word: Roles for Integrase in Ty3 Reverse Transcription?
Acknowledgments
References
Chapter 3 Experimental Systems for the Study of Non-LTR (LINE) Retrotransposons
1. Overview
2. Target-primed Reverse Transcription (R2 from Bombyx mori as a Model)
3. Infertility and Germ Cell Phenotypes (I Factor from Drosophila Melanogaster as a Model)
4. Host Factor Identification (In Vitro Proteomics)
5. Host Factor Identification (Genetics in Cell Culture and Yeast)
6. Moving Forward — The Role for Model Organisms
References
Chapter 4 Alu Elements and Human Disease
1. Transposable Elements
2. “Aluology”
2.1 Alu evolution
2.2 Alu retrotransposition
2.3 Alu expression
3. Alu Elements and Human Disease
3.1 Alu insertional mutagenesis
3.2 Post-insertional impact of Alu insertion
3.2.1 Alu expression and disease
3.2.2 Post-insertional impact (non-allelic homologous recombination)
3.2.3 Post-insertional impact (epigenetics, transcription regulation)
3.2.4 Post-insertional impact (RNA processing, exonization, and polyadenylation)
3.2.5 Post-insertional impact (RNA editing)
4. Summary
References
Chapter 5 Retrotransposition as a Cause of Human Disease: An Update
1. Retrotransposition Events in Large Clinical Studies
2. Retrotransposition in Small Studies and Case Reports
3. Conclusion
References
Chapter 6 LINE-1 Retrotransposons, Stem Cells, and Human Neurodevelopmental Disorders
1. L1 Retrotransposition can Occur in the Early Stages of Human Embryonic Development
2. Controlling L1 Activity in Stem Cells: Epigenetic Mechanisms Repress L1 Expression During Early Embryogenesis
3. The Role of L1 Retrotransposons During Embryonic Development
4. L1 Retrotransposon Activity in Adult Stem Cells
5. L1 and Neurodevelopmental Disorders
References
Chapter 7 Retrotransposition Mechanisms and Host Factors
1. Background
2. Retrotransposon Types and Classification
2.1 LTR retrotransposons
2.2 Non-LTR retrotransposons
3. Retrotransposition Mechanisms
3.1 LTR retrotransposons and their similarities to retroviruses
3.2 Non-LTR retrotransposons
4. Host Factors
4.1 Background
4.2 Assays for retrotransposition
5. Ty1 Host Factors
5.1 Priming factors
5.2 Integration specificity
5.3 Other host factor interactions
6. LINE-1 Host Factors
6.1 L1 Background
6.2 Transcriptional regulation and mRNA processing
6.3 L1 ORF2 expression
6.4 DNA replication and DNA repair
6.5 L1 TPRT and integration
7. Conclusions
Acknowledgments
Chapter 8 Retrotransposons in the Mammalian Brain
1. Introduction
2. Exaptation of Retrotransposons for Functional Roles in the Brain
2.1 ERVs and LTR-containing retrotransposons
2.2 SINEs
2.3 LINEs
3. Somatic Retrotransposition
3.1 Development
3.2 Adult neurogenesis
3.3 Mature neurons
4. Retrotransposition and Human Disease
4.1 Schizophrenia
4.2 Autism and Rett syndrome
4.3 Alzheimer’s disease
5. Alternative Mechanisms of Retrotransposon Toxicity
5.1 Autoimmunity
5.2 DNA damage
6. Moving Forward
References
Chapter 9 LINE-1 Mobilization in Cancers: More the Rule than the Exception
1. Introduction
2. L1 Cancer Genetics
3. Reactivation of L1 in Cancer
3.1 Transcription regulation
3.2 mRNA processing and editing
3.3 Translation
3.4 RNP formation and post-translational modifications
3.5 DNA repair of an insertion
3.6 Immune activation within a tissue
4. Conclusion: Assessing for Translational Impact of L1 Activity in Cancer
Acknowledgments
References
Index
