How do mammalian transposons induce genetic variation? A conceptual framework

In this essay, we discuss new insights into the wide‐ranging impacts of mammalian transposable elements (TE) on gene expression and function. Nearly half of each mammalian genome is comprised of these mobile, repetitive elements. While most TEs are ancient relics, certain classes can move from one chromosomal location to another even now. Indeed, striking recent data show that extensive transposition occurs not only in the germline over evolutionary time, but also in developing somatic tissues and particular human cancers. While occasional germline TE insertions may contribute to genetic variation, many other, similar TEs appear to have little or no impact on neighboring genes. However, the effects of somatic insertions on gene expression and function remain almost completely unknown. We present a conceptual framework to understand how the ages, allele frequencies, molecular structures, and especially the genomic context of mammalian TEs each can influence their various possible functional consequences.

[1]  D. Largaespada,et al.  Extensive somatic L1 retrotransposition in colorectal tumors , 2012, Genome research.

[2]  Jennifer L. Rabe,et al.  hnRNPL and nucleolin bind LINE-1 RNA and function as host factors to modulate retrotransposition , 2012, Nucleic acids research.

[3]  D. Mager,et al.  Transposable elements: an abundant and natural source of regulatory sequences for host genes. , 2012, Annual review of genetics.

[4]  E. Lee,et al.  Single-Neuron Sequencing Analysis of L1 Retrotransposition and Somatic Mutation in the Human Brain , 2012, Cell.

[5]  Nathan C. Sheffield,et al.  The accessible chromatin landscape of the human genome , 2012, Nature.

[6]  Luke Isbel,et al.  Endogenous retroviruses in mammals: An emerging picture of how ERVs modify expression of adjacent genes , 2012, BioEssays : news and reviews in molecular, cellular and developmental biology.

[7]  Nadav S. Bar,et al.  Landscape of transcription in human cells , 2012, Nature.

[8]  D. Haussler,et al.  29 Mammalian Genomes Reveal Novel Exaptations of Mobile Elements for Likely Regulatory Functions in the Human Genome , 2012, PloS one.

[9]  Lovelace J. Luquette,et al.  Landscape of Somatic Retrotransposition in Human Cancers , 2012, Science.

[10]  Magali Jaillard,et al.  Microarray-Based Sketches of the HERV Transcriptome Landscape , 2012, PloS one.

[11]  Thomas M. Keane,et al.  The genomic landscape shaped by selection on transposable elements across 18 mouse strains , 2012, Genome Biology.

[12]  Sergey Koren,et al.  The bonobo genome compared with the chimpanzee and human genomes , 2012, Nature.

[13]  D. C. Hancks,et al.  Active human retrotransposons: variation and disease. , 2012, Current opinion in genetics & development.

[14]  Jesse R. Dixon,et al.  Topological Domains in Mammalian Genomes Identified by Analysis of Chromatin Interactions , 2012, Nature.

[15]  Christine A Iacobuzio-Donahue,et al.  A new branch on the tree: next-generation sequencing in the study of cancer evolution. , 2012, Seminars in cell & developmental biology.

[16]  D. Ray,et al.  Survey Sequencing Reveals Elevated DNA Transposon Activity, Novel Elements, and Variation in Repetitive Landscapes among Vesper Bats , 2012, Genome biology and evolution.

[17]  Hana Kim,et al.  Retrotransposons as a major source of epigenetic variations in the mammalian genome , 2012, Epigenetics.

[18]  A. Munnich,et al.  Mutation in a primate-conserved retrotransposon reveals a noncoding RNA as a mediator of infantile encephalopathy , 2012, Proceedings of the National Academy of Sciences.

[19]  R. Stephens,et al.  Mouse endogenous retroviruses can trigger premature transcriptional termination at a distance , 2012, Genome research.

[20]  E. Whitelaw,et al.  Understanding transgenerational epigenetic inheritance via the gametes in mammals , 2012, Nature Reviews Genetics.

[21]  Michael D. Wilson,et al.  Waves of Retrotransposon Expansion Remodel Genome Organization and CTCF Binding in Multiple Mammalian Lineages , 2012, Cell.

[22]  J. V. Moran,et al.  Ataxia telangiectasia mutated (ATM) modulates long interspersed element-1 (L1) retrotransposition in human neural stem cells , 2011, Proceedings of the National Academy of Sciences.

[23]  M. Batzer,et al.  Repetitive Elements May Comprise Over Two-Thirds of the Human Genome , 2011, PLoS genetics.

[24]  G. Faulkner,et al.  Is somatic retrotransposition a parasitic or symbiotic phenomenon? , 2011, Mobile genetic elements.

[25]  S. Bergmann,et al.  The evolution of gene expression levels in mammalian organs , 2011, Nature.

[26]  Ira M. Hall,et al.  Genome sequencing of mouse induced pluripotent stem cells reveals retroelement stability and infrequent DNA rearrangement during reprogramming. , 2011, Cell stem cell.

[27]  Thomas M. Keane,et al.  Mouse genomic variation and its effect on phenotypes and gene regulation , 2011, Nature.

[28]  J. Mattick,et al.  Somatic retrotransposition alters the genetic landscape of the human brain , 2011, Nature.

[29]  Steven J. M. Jones,et al.  Retrotransposon-Induced Heterochromatin Spreading in the Mouse Revealed by Insertional Polymorphisms , 2011, PLoS genetics.

[30]  H. Kazazian,et al.  Retrotransposition of marked SVA elements by human L1s in cultured cells. , 2011, Human molecular genetics.

[31]  J. V. Moran,et al.  Dynamic interactions between transposable elements and their hosts , 2011, Nature Reviews Genetics.

[32]  Adrian M. Stütz,et al.  A Comprehensive Map of Mobile Element Insertion Polymorphisms in Humans , 2011, PLoS genetics.

[33]  H. Firpi,et al.  Enhancers in embryonic stem cells are enriched for transposable elements and genetic variations associated with cancers , 2011, Nucleic acids research.

[34]  H. Kazazian,et al.  Whole-genome resequencing allows detection of many rare LINE-1 insertion alleles in humans. , 2011, Genome research.

[35]  Feng Cui,et al.  Impact of Alu repeats on the evolution of human p53 binding sites , 2011, Biology Direct.

[36]  L. Maquat,et al.  lncRNAs transactivate Staufen1-mediated mRNA decay by duplexing with 3'UTRs via Alu elements , 2010, Nature.

[37]  Eric C. Rouchka,et al.  Assessment of genetic variation for the LINE-1 retrotransposon from next generation sequence data , 2010, BMC Bioinformatics.

[38]  F. Lyko,et al.  Demethylation of a LINE-1 antisense promoter in the cMet locus impairs Met signalling through induction of illegitimate transcription , 2010, Oncogene.

[39]  Fred H. Gage,et al.  L1 retrotransposition in neurons is modulated by MeCP2 , 2010, Nature.

[40]  B. Czerniak,et al.  Genome architecture marked by retrotransposons modulates predisposition to DNA methylation in cancer. , 2010, Genome research.

[41]  Robert W. Williams,et al.  A Transposon in Comt Generates mRNA Variants and Causes Widespread Expression and Behavioral Differences among Mice , 2010, PloS one.

[42]  J. V. Moran,et al.  Epigenetic silencing of engineered L1 retrotransposition events in human embryonic carcinoma cells , 2010, Nature.

[43]  F. Gage,et al.  LINE-1 retrotransposons: mediators of somatic variation in neuronal genomes? , 2010, Trends in Neurosciences.

[44]  G. Bourque,et al.  Transposable elements have rewired the core regulatory network of human embryonic stem cells , 2010, Nature Genetics.

[45]  Dong Seon Kim,et al.  Human-specific antisense transcripts induced by the insertion of transposable element. , 2010, International journal of molecular medicine.

[46]  Ryan E. Mills,et al.  Natural Mutagenesis of Human Genomes by Endogenous Retrotransposons , 2010, Cell.

[47]  Agnes Hotz-Wagenblatt,et al.  Characteristics of Transposable Element Exonization within Human and Mouse , 2010, PloS one.

[48]  Ralph Stadhouders,et al.  Derepression of an endogenous long terminal repeat activates the CSF1R proto-oncogene in human lymphoma , 2010, Nature Medicine.

[49]  Ira M. Hall,et al.  Genome-wide mapping and assembly of structural variant breakpoints in the mouse genome. , 2010, Genome research.

[50]  H. Kimura,et al.  Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET , 2010, Nature.

[51]  David I. K. Martin,et al.  CpG Methylation of a Silent Controlling Element in the Murine Avy Allele Is Incomplete and Unresponsive to Methyl Donor Supplementation , 2010, PloS one.

[52]  Natalia Volfovsky,et al.  MouseIndelDB: a database integrating genomic indel polymorphisms that distinguish mouse strains , 2009, Nucleic Acids Res..

[53]  A. Levine,et al.  p53 responsive elements in human retrotransposons , 2009, Oncogene.

[54]  M. Batzer,et al.  The impact of retrotransposons on human genome evolution , 2009, Nature Reviews Genetics.

[55]  H. Kazazian,et al.  Many LINE1 elements contribute to the transcriptome of human somatic cells , 2009, Genome Biology.

[56]  E. Kirkness,et al.  Mobile elements create structural variation: analysis of a complete human genome. , 2009, Genome research.

[57]  Gene W. Yeo,et al.  L1 retrotransposition in human neural progenitor cells , 2009, Nature.

[58]  E. Ostertag,et al.  L1 retrotransposition occurs mainly in embryogenesis and creates somatic mosaicism. , 2009, Genes & development.

[59]  J. Kawai,et al.  The regulated retrotransposon transcriptome of mammalian cells , 2009, Nature Genetics.

[60]  J. Coffin,et al.  Effects of retroviruses on host genome function. , 2008, Annual review of genetics.

[61]  M. Belfort,et al.  The take and give between retrotransposable elements and their hosts. , 2008, Annual review of genetics.

[62]  E. Liu,et al.  Evolution of the mammalian transcription factor binding repertoire via transposable elements. , 2008, Genome research.

[63]  G. Ast,et al.  Intronic Alus Influence Alternative Splicing , 2008, PLoS genetics.

[64]  C. Feschotte Transposable elements and the evolution of regulatory networks , 2008, Nature Reviews Genetics.

[65]  D. Ray,et al.  Multiple waves of recent DNA transposon activity in the bat, Myotis lucifugus. , 2008, Genome research.

[66]  P. Deininger,et al.  The impact of multiple splice sites in human L1 elements. , 2008, Gene.

[67]  P. Deininger,et al.  Mammalian non-LTR retrotransposons: for better or worse, in sickness and in health. , 2008, Genome research.

[68]  Ying Zhang,et al.  Genome-Wide Assessments Reveal Extremely High Levels of Polymorphism of Two Active Families of Mouse Endogenous Retroviral Elements , 2008, PLoS genetics.

[69]  R. Jaenisch,et al.  Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice , 2008, Oncogene.

[70]  C. Feschotte,et al.  DNA transposons and the evolution of eukaryotic genomes. , 2007, Annual review of genetics.

[71]  D. Haussler,et al.  Species-specific endogenous retroviruses shape the transcriptional network of the human tumor suppressor protein p53 , 2007, Proceedings of the National Academy of Sciences.

[72]  G. Hannon,et al.  The Piwi-piRNA Pathway Provides an Adaptive Defense in the Transposon Arms Race , 2007, Science.

[73]  F. Gage,et al.  The necessary junk: new functions for transposable elements. , 2007, Human molecular genetics.

[74]  A. Gentles,et al.  Evolutionary dynamics of transposable elements in the short-tailed opossum Monodelphis domestica. , 2007, Genome research.

[75]  P. D. de Jong,et al.  L1 retrotransposition can occur early in human embryonic development. , 2007, Human molecular genetics.

[76]  J. Takeda,et al.  Retrotransposons Influence the Mouse Transcriptome: Implication for the Divergence of Genetic Traits , 2007, Genetics.

[77]  Bronwen L. Aken,et al.  Genome of the marsupial Monodelphis domestica reveals innovation in non-coding sequences , 2007, Nature.

[78]  David Haussler,et al.  Thousands of human mobile element fragments undergo strong purifying selection near developmental genes , 2007, Proceedings of the National Academy of Sciences.

[79]  B. Davidson,et al.  RNA polymerase III transcribes human microRNAs , 2006, Nature Structural &Molecular Biology.

[80]  Vetle I. Torvik,et al.  Alu elements within human mRNAs are probable microRNA targets. , 2006, Trends in genetics : TIG.

[81]  N. Yang,et al.  L1 retrotransposition is suppressed by endogenously encoded small interfering RNAs in human cultured cells , 2006, Nature Structural &Molecular Biology.

[82]  J. Nathans,et al.  Effects of L1 retrotransposon insertion on transcript processing, localization and accumulation: lessons from the retinal degeneration 7 mouse and implications for the genomic ecology of L1 elements. , 2006, Human molecular genetics.

[83]  M. Speek,et al.  L1 Antisense Promoter Drives Tissue-Specific Transcription of Human Genes , 2006, Journal of biomedicine & biotechnology.

[84]  P. Deininger,et al.  LINE-1 RNA splicing and influences on mammalian gene expression , 2006, Nucleic acids research.

[85]  D. Cooper,et al.  LINE-1 Endonuclease-Dependent Retrotranspositional Events Causing Human Genetic Disease: Mutation Detection Bias and Multiple Mechanisms of Target Gene Disruption , 2006, Journal of biomedicine & biotechnology.

[86]  P. Deininger,et al.  Human retroelements may introduce intragenic polyadenylation signals , 2005, Cytogenetic and Genome Research.

[87]  Fred H. Gage,et al.  Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition , 2005, Nature.

[88]  J. Luban,et al.  Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1 , 2004, Nature.

[89]  Jef D. Boeke,et al.  Transcriptional disruption by the L1 retrotransposon and implications for mammalian transcriptomes , 2004, Nature.

[90]  V. Rakyan,et al.  Transgenerational inheritance of epigenetic states at the murine AxinFu allele occurs after maternal and paternal transmission , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[91]  H. Kazazian,et al.  Tracking an embryonic L1 retrotransposition event , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[92]  Giovanni Parmigiani,et al.  Human L1 Retrotransposition Is Associated with Genetic Instability In Vivo , 2002, Cell.

[93]  N. Zingler,et al.  Methyl-CpG-binding protein 2 represses LINE-1 expression and retrotransposition but not Alu transcription. , 2001, Nucleic acids research.

[94]  J. Mccoy,et al.  Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis , 2000, Nature.

[95]  J. Jurka,et al.  The Long Terminal Repeat of an Endogenous Retrovirus Induces Alternative Splicing and Encodes an Additional Carboxy-Terminal Sequence in the Human Leptin Receptor , 1999, Journal of Molecular Evolution.

[96]  H. Kazazian,et al.  Mobile elements and disease. , 1998, Current opinion in genetics & development.

[97]  C. Walsh,et al.  Cytosine methylation and the ecology of intragenomic parasites. , 1997, Trends in genetics : TIG.

[98]  G. Barsh,et al.  Neomorphic agouti mutations in obese yellow mice , 1994, Nature Genetics.

[99]  K. Kinzler,et al.  Disruption of the APC gene by a retrotransposal insertion of L1 sequence in a colon cancer. , 1992, Cancer research.

[100]  S. Antonarakis,et al.  Haemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man , 1988, Nature.

[101]  Andrew B. Conley,et al.  2012 Landes Bioscience. Do not distribute. Do human transposable element small RNAs serve primarily as genome defenders or genome regulators , 2012 .

[102]  J. V. Moran,et al.  Reprogramming somatic cells into iPS cells activates LINE-1 retroelement mobility. , 2012, Human molecular genetics.

[103]  Z. Izsvák,et al.  A novel active endogenous retrovirus family contributes to genome variability in rat inbred strains. , 2010, Genome research.

[104]  L. Maquat,et al.  SMD and NMD are competitive pathways that contribute to myogenesis: effects on PAX3 and myogenin mRNAs. , 2009, Genes & development.

[105]  Natalia Volfovsky,et al.  Extensive variation between inbred mouse strains due to endogenous L1 retrotransposition. , 2008, Genome research.

[106]  T. Bruxner,et al.  Complex patterns of transcription at the insertion site of a retrotransposon in the mouse. , 2004, Nucleic acids research.

[107]  Mouse Genome Sequencing Consortium Initial sequencing and comparative analysis of the mouse genome , 2002, Nature.

[108]  H. Kazazian Retrotransposon insertions in germ cells and somatic cells. , 2001, Developments in biologicals.

[109]  International Human Genome Sequencing Consortium Initial sequencing and analysis of the human genome , 2001, Nature.