Sandra R. Richardson

@article{ewing_nanopore_2020,

title = {Nanopore Sequencing Enables Comprehensive Transposable Element Epigenomic Profiling},

author = {Adam D Ewing and Nathan Smits and Francisco J Sanchez-Luque and Jamila Faivre and Paul M Brennan and Sandra R Richardson and Seth W Cheetham and Geoffrey J Faulkner},

url = {http://www.sciencedirect.com/science/article/pii/S1097276520307310},

doi = {10.1016/j.molcel.2020.10.024},

issn = {1097-2765},

year  = {2020},

date = {2020-01-01},

urldate = {2020-11-30},

journal = {Molecular Cell},

abstract = {Transposable elements (TEs) drive genome evolution and are a notable source of pathogenesis, including cancer. While CpG methylation regulates TE activity, the locus-specific methylation landscape of mobile human TEs has to date proven largely inaccessible. Here, we apply new computational tools and long-read nanopore sequencing to directly infer CpG methylation of novel and extant TE insertions in hippocampus, heart, and liver, as well as paired tumor and non-tumor liver. As opposed to an indiscriminate stochastic process, we find pronounced demethylation of young long interspersed element 1 (LINE-1) retrotransposons in cancer, often distinct to the adjacent genome and other TEs. SINE-VNTR-Alu (SVA) retrotransposons, including their internal tandem repeat-associated CpG island, are near-universally methylated. We encounter allele-specific TE methylation and demethylation of aberrantly expressed young LINE-1s in normal tissues. Finally, we recover the complete sequences of tumor-specific LINE-1 insertions and their retrotransposition hallmarks, demonstrating how long-read sequencing can simultaneously survey the epigenome and detect somatic TE mobilization.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{salvador-palomeque_dynamic_2019,

title = {Dynamic Methylation of an L1 Transduction Family during Reprogramming and Neurodifferentiation},

author = {Carmen Salvador-Palomeque and Francisco J Sanchez-Luque and Patrick R J Fortuna and Adam D Ewing and Ernst J Wolvetang and Sandra R Richardson and Geoffrey J Faulkner},

url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425141/},

doi = {10.1128/MCB.00499-18},

issn = {0270-7306},

year  = {2019},

date = {2019-01-01},

urldate = {2019-06-07},

journal = {Mol Cell Biol},

volume = {39},

number = {7},

abstract = {The retrotransposon LINE-1 (L1) is a significant source of endogenous mutagenesis in humans. In each individual genome, a few retrotransposition-competent L1s (RC-L1s) can generate new heritable L1 insertions in the early embryo, primordial germ line, and germ cells., The retrotransposon LINE-1 (L1) is a significant source of endogenous mutagenesis in humans. In each individual genome, a few retrotransposition-competent L1s (RC-L1s) can generate new heritable L1 insertions in the early embryo, primordial germ line, and germ cells. L1 retrotransposition can also occur in the neuronal lineage and cause somatic mosaicism. Although DNA methylation mediates L1 promoter repression, the temporal pattern of methylation applied to individual RC-L1s during neurogenesis is unclear. Here, we identified a de novo L1 insertion in a human induced pluripotent stem cell (hiPSC) line via retrotransposon capture sequencing (RC-seq). The L1 insertion was full-length and carried 5ʹ and 3ʹ transductions. The corresponding donor RC-L1 was part of a large and recently active L1 transduction family and was highly mobile in a cultured-cell L1 retrotransposition reporter assay. Notably, we observed distinct and dynamic DNA methylation profiles for the de novo L1 and members of its extended transduction family during neuronal differentiation. These experiments reveal how a de novo L1 insertion in a pluripotent stem cell is rapidly recognized and repressed, albeit incompletely, by the host genome during neurodifferentiation, while retaining potential for further retrotransposition.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{sanchez-luque_line-1_2019,

title = {LINE-1 Evasion of Epigenetic Repression in Humans},

author = {Francisco J Sanchez-Luque and Marie-Jeanne H C Kempen and Patricia Gerdes and Dulce B Vargas-Landin and Sandra R Richardson and Robin-Lee Troskie and Samuel J Jesuadian and Seth W Cheetham and Patricia E Carreira and Carmen Salvador-Palomeque and Marta Garc\'{i}a-Ca\~{n}adas and Martin Mu\~{n}oz-Lopez and Laura Sanchez and Mischa Lundberg and Angela Macia and Sara R Heras and Paul M Brennan and Ryan Lister and Jose L Garcia-Perez and Adam D Ewing and Geoffrey J Faulkner},

url = {https://www.cell.com/molecular-cell/abstract/S1097-2765(19)30396-X},

doi = {10.1016/j.molcel.2019.05.024},

issn = {1097-2765},

year  = {2019},

date = {2019-01-01},

urldate = {2019-06-24},

journal = {Molecular Cell},

volume = {0},

number = {0},

abstract = {textlessh2textgreaterSummarytextless/h2textgreatertextlessptextgreaterEpigenetic silencing defends against LINE-1 (L1) retrotransposition in mammalian cells. However, the mechanisms that repress young L1 families and how L1 escapes to cause somatic genome mosaicism in the brain remain unclear. Here we report that a conserved Yin Yang 1 (YY1) transcription factor binding site mediates L1 promoter DNA methylation in pluripotent and differentiated cells. By analyzing 24 hippocampal neurons with three distinct single-cell genomic approaches, we characterized and validated a somatic L1 insertion bearing a 3ʹ transduction. The source (donor) L1 for this insertion was slightly 5ʹ truncated, lacked the YY1 binding site, and was highly mobile when tested textitin vitro. Locus-specific bisulfite sequencing revealed that the donor L1 and other young L1s with mutated YY1 binding sites were hypomethylated in embryonic stem cells, during neurodifferentiation, and in liver and brain tissue. These results explain how L1 can evade repression and retrotranspose in the human body.textless/ptextgreater},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{richardson_heritable_2018,

title = {Heritable L1 Retrotransposition Events During Development: Understanding Their Origins},

author = {Sandra R Richardson and Geoffrey J Faulkner},

url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/bies.201700189},

doi = {10.1002/bies.201700189},

issn = {1521-1878},

year  = {2018},

date = {2018-06-01},

urldate = {2018-08-28},

journal = {BioEssays},

volume = {40},

number = {6},

pages = {1700189},

abstract = {The retrotransposon Long Interspersed Element 1 (LINE-1 or L1) has played a major role in shaping the sequence composition of the mammalian genome. In our recent publication, “Heritable L1 retrotransposition in the mouse primordial germline and early embryo,” we systematically assessed the rate and developmental timing of de novo, heritable endogenous L1 insertions in mice. Such heritable retrotransposition events allow L1 to exert an ongoing influence upon genome evolution. Here, we place our findings in the context of earlier studies, and highlight how our results corroborate, and depart from, previous research based on human patient samples and transgenic mouse models harboring engineered L1 reporter genes. In parallel, we outline outstanding questions regarding the stage-specificity, regulation, and functional impact of embryonic and germline L1 retrotransposition, and propose avenues for future research in this field.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nguyen_l1_2018,

title = {L1 Retrotransposon Heterogeneity in Ovarian Tumor Cell Evolution},

author = {Thu H M Nguyen and Patricia E Carreira and Francisco J Sanchez-Luque and Stephanie N Schauer and Allister C Fagg and Sandra R Richardson and Claire M Davies and Samuel J Jesuadian and Marie-Jeanne H C Kempen and Robin-Lee Troskie and Cini James and Elizabeth A Beaven and Tristan P Wallis and Jermaine I G Coward and Naven P Chetty and Alexander J Crandon and Deon J Venter and Jane E Armes and Lewis C Perrin and John D Hooper and Adam D Ewing and Kyle R Upton and Geoffrey J Faulkner},

url = {http://www.sciencedirect.com/science/article/pii/S2211124718308714},

doi = {10.1016/j.celrep.2018.05.090},

issn = {2211-1247},

year  = {2018},

date = {2018-06-01},

urldate = {2018-08-28},

journal = {Cell Reports},

volume = {23},

number = {13},

pages = {3730--3740},

abstract = {Summary 

LINE-1 (L1) retrotransposons are a source of insertional mutagenesis in tumor cells. However, the clinical significance of L1 mobilization during tumorigenesis remains unclear. Here, we applied retrotransposon capture sequencing (RC-seq) to multiple single-cell clones isolated from five ovarian cancer cell lines and HeLa cells and detected endogenous L1 retrotransposition in vitro. We then applied RC-seq to ovarian tumor and matched blood samples from 19 patients and identified 88 tumor-specific L1 insertions. In one tumor, an intronic de novo L1 insertion supplied a novel cis-enhancer to the putative chemoresistance gene STC1. Notably, the tumor subclone carrying the STC1 L1 mutation increased in prevalence after chemotherapy, further increasing STC1 expression. We also identified hypomethylated donor L1s responsible for new L1 insertions in tumors and cultivated cancer cells. These congruent in vitro and in vivo results highlight L1 insertional mutagenesis as a common component of ovarian tumorigenesis and cancer genome heterogeneity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{schauer_l1_2018,

title = {L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis},

author = {Stephanie N Schauer and Patricia E Carreira and Ruchi Shukla and Daniel J Gerhardt and Patricia Gerdes and Francisco J Sanchez-Luque and Paola Nicoli and Michaela Kindlova and Serena Ghisletti and Alexandre Dos Santos and Delphine Rapoud and Didier Samuel and Jamila Faivre and Adam D Ewing and Sandra R Richardson and Geoffrey J Faulkner},

url = {http://genome.cshlp.org/content/early/2018/04/11/gr.226993.117},

doi = {10.1101/gr.226993.117},

issn = {1088-9051, 1549-5469},

year  = {2018},

date = {2018-01-01},

urldate = {2018-08-28},

journal = {Genome Research},

abstract = {The retrotransposon Long Interspersed Element 1 (LINE-1 or L1) is a continuing source of germline and somatic mutagenesis in mammals. Deregulated L1 activity is a hallmark of cancer, and L1 mutagenesis has been described in numerous human malignancies. We previously employed retrotransposon capture sequencing (RC-seq) to analyze hepatocellular carcinoma (HCC) samples from patients infected with hepatitis B or hepatitis C virus and identified L1 variants responsible for activating oncogenic pathways. Here, we have applied RC-seq and whole-genome sequencing (WGS) to an Abcb4 (Mdr2)−/− mouse model of hepatic carcinogenesis and demonstrated for the first time that L1 mobilization occurs in murine tumors. In 12 HCC nodules obtained from 10 animals, we validated four somatic L1 insertions by PCR and capillary sequencing, including TF subfamily elements, and one GF subfamily example. One of the TF insertions carried a 3′ transduction, allowing us to identify its donor L1 and to demonstrate that this full-length TF element retained retrotransposition capacity in cultured cancer cells. Using RC-seq, we also identified eight tumor-specific L1 insertions from 25 HCC patients with a history of alcohol abuse. Finally, we used RC-seq and WGS to identify three tumor-specific L1 insertions among 10 intra-hepatic cholangiocarcinoma (ICC) patients, including one insertion traced to a donor L1 on Chromosome 22 known to be highly active in other cancers. This study reveals L1 mobilization as a common feature of hepatocarcinogenesis in mammals, demonstrating that the phenomenon is not restricted to human viral HCC etiologies and is encountered in murine liver tumors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Richardson2017-hr,

title = {Heritable L1 retrotransposition in the mouse primordial  germline and early embryo},

author = {Sandra R Richardson and Patricia Gerdes and Daniel J Gerhardt and Francisco J Sanchez-Luque and Gabriela-Oana Bodea and Martin Mu{~n}oz-Lopez and Samuel J Jesuadian and Marie-Jeanne H C Kempen and Patricia E Carreira and Jeffrey A Jeddeloh and Jose L Garcia-Perez and Haig H Kazazian Jr and Adam D Ewing and Geoffrey J Faulkner},

url = {http://dx.doi.org/10.1101/gr.219022.116},

year  = {2017},

date = {2017-08-01},

journal = {Genome Res.},

volume = {27},

number = {8},

pages = {1395--1405},

abstract = {LINE-1 (L1) retrotransposons are a noted source of genetic 

 diversity and disease in mammals. To expand its genomic 

 footprint, L1 must mobilize in cells that will contribute 

 their genetic material to subsequent generations. Heritable L1 

 insertions may therefore arise in germ cells and in 

 pluripotent embryonic cells, prior to germline specification, 

 yet the frequency and predominant developmental timing of such 

 events remain unclear. Here, we applied mouse retrotransposon 

 capture sequencing (mRC-seq) and whole-genome sequencing (WGS) 

 to pedigrees of C57BL/6J animals, and uncovered an L1 

 insertion rate of $geq$1 event per eight births. We traced 

 heritable L1 insertions to pluripotent embryonic cells and, 

 strikingly, to early primordial germ cells (PGCs). New L1 

 insertions bore structural hallmarks of target-site primed 

 reverse transcription (TPRT) and mobilized efficiently in a 

 cultured cell retrotransposition assay. Together, our results 

 highlight the rate and evolutionary impact of heritable L1 

 retrotransposition and reveal retrotransposition-mediated 

 genomic diversification as a fundamental property of 

 pluripotent embryonic cells in vivo.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Gerdes2016-yk,

title = {Transposable elements in the mammalian embryo: pioneers 

 surviving through stealth and service},

author = {Patricia Gerdes and Sandra R Richardson and Dixie L Mager and Geoffrey J Faulkner},

url = {http://dx.doi.org/10.1186/s13059-016-0965-5},

year  = {2016},

date = {2016-05-01},

journal = {Genome Biol.},

volume = {17},

pages = {100},

abstract = {Transposable elements (TEs) are notable drivers of genetic 

 innovation. Over evolutionary time, TE insertions can supply 

 new promoter, enhancer, and insulator elements to 

 protein-coding genes and establish novel, species-specific 

 gene regulatory networks. Conversely, ongoing TE-driven 

 insertional mutagenesis, nonhomologous recombination, and 

 other potentially deleterious processes can cause sporadic 

 disease by disrupting genome integrity or inducing abrupt gene 

 expression changes. Here, we discuss recent evidence 

 suggesting that TEs may contribute regulatory innovation to 

 mammalian embryonic and pluripotent states as a means to ward 

 off complete repression by their host genome.},

keywords = {},

pubstate = {},

tppubtype = {article}

}

@article{Gerdes2016-ga,

title = {TET enzymes: double agents in the transposable element-host 

 genome conflict},

author = {Patricia Gerdes and Sandra R Richardson and Geoffrey J Faulkner},

url = {http://dx.doi.org/10.1186/s13059-016-1124-8},

year  = {2016},

date = {2016-01-01},

journal = {Genome Biol.},

volume = {17},

number = {1},

pages = {259},

abstract = {The mouse genome is replete with retrotransposon sequences, 

 from evolutionarily young elements with mutagenic potential 

 that must be controlled, to inactive molecular fossils whose 

 sequences can be domesticated over evolutionary time to 

 benefit the host genome. In an exciting new study, de la Rica 

 and colleagues have uncovered a complex relationship between 

 ten-eleven translocation (TET) proteins and retrotransposons 

 in mouse embryonic stem cells (ESCs), implicating TETs as 

 enhancers in the exaptation and function of retroelement 

 sequences. Furthermore, they have demonstrated that active 

 demethylation of retrotransposons does not correlate with 

 their increased expression in ESCs, calling into question 

 long-held assumptions regarding the importance of DNA 

 demethylation for retrotransposon expression, and revealing 

 novel epigenetic players in retrotransposon control.Please see 

 related Research article: 

 http://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-1096-8.},

keywords = {},

pubstate = {},

tppubtype = {article}

}

@article{Sanchez-Luque2016-vi,

title = {Retrotransposon Capture Sequencing (RC-Seq): A Targeted, 

 High-Throughput Approach to Resolve Somatic L1 

 Retrotransposition in Humans},

author = {Francisco J Sanchez-Luque and Sandra R Richardson and Geoffrey J Faulkner},

url = {http://dx.doi.org/10.1007/978-1-4939-3372-3_4},

year  = {2016},

date = {2016-01-01},

journal = {Methods Mol. Biol.},

volume = {1400},

pages = {47--77},

abstract = {Mobile genetic elements (MGEs) are of critical importance in 

 genomics and developmental biology. Polymorphic and somatic 

 MGE insertions have the potential to impact the phenotype of 

 an individual, depending on their genomic locations and 

 functional consequences. However, the identification of 

 polymorphic and somatic insertions among the plethora of 

 copies residing in the genome presents a formidable technical 

 challenge. Whole genome sequencing has the potential to 

 address this problem; however, its efficacy depends on the 

 abundance of cells carrying the new insertion. Robust 

 detection of somatic insertions present in only a subset of 

 cells within a given sample can also be prohibitively 

 expensive due to a requirement for high sequencing depth. 

 Here, we describe retrotransposon capture sequencing (RC-seq), 

 a sequence capture approach in which Illumina libraries are 

 enriched for fragments containing the 5' and 3' termini of 

 specific MGEs. RC-seq allows the detection of known 

 polymorphic insertions present in an individual, as well as 

 the identification of rare or private germline insertions not 

 previously described. Furthermore, RC-seq can be used to 

 detect and characterize somatic insertions, providing a 

 valuable tool to elucidate the extent and characteristics of 

 MGE activity in healthy tissues and in various disease states.},

keywords = {},

pubstate = {},

tppubtype = {article}

}

@article{kopera_line-1_2016,

title = {LINE-1 Cultured Cell Retrotransposition Assay},

author = {Huira C Kopera and Peter A Larson and John B Moldovan and Sandra R Richardson and Ying Liu and John V Moran},

doi = {10.1007/978-1-4939-3372-3_10},

issn = {1940-6029},

year  = {2016},

date = {2016-01-01},

journal = {Methods in Molecular Biology (Clifton, N.J.)},

volume = {1400},

pages = {139--156},

abstract = {The Long INterspersed Element-1 (LINE-1 or L1) retrotransposition assay has facilitated the discovery and characterization of active (i.e., retrotransposition-competent) LINE-1 sequences from mammalian genomes. In this assay, an engineered LINE-1 containing a retrotransposition reporter cassette is transiently transfected into a cultured cell line. Expression of the reporter cassette, which occurs only after a successful round of retrotransposition, allows the detection and quantification of the LINE-1 retrotransposition efficiency. This assay has yielded insight into the mechanism of LINE-1 retrotransposition. It also has provided a greater understanding of how the cell regulates LINE-1 retrotransposition and how LINE-1 retrotransposition impacts the structure of mammalian genomes. Below, we provide a brief introduction to LINE-1 biology and then detail how the LINE-1 retrotransposition assay is performed in cultured mammalian cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{sanchez-luque_retrotransposon_2016,

title = {Retrotransposon Capture Sequencing (RC-Seq): A Targeted, High-Throughput Approach to Resolve Somatic L1 Retrotransposition in Humans},

author = {Francisco J Sanchez-Luque and Sandra R Richardson and Geoffrey J Faulkner},

doi = {10.1007/978-1-4939-3372-3_4},

issn = {1940-6029},

year  = {2016},

date = {2016-01-01},

journal = {Methods in Molecular Biology (Clifton, N.J.)},

volume = {1400},

pages = {47--77},

abstract = {Mobile genetic elements (MGEs) are of critical importance in genomics and developmental biology. Polymorphic and somatic MGE insertions have the potential to impact the phenotype of an individual, depending on their genomic locations and functional consequences. However, the identification of polymorphic and somatic insertions among the plethora of copies residing in the genome presents a formidable technical challenge. Whole genome sequencing has the potential to address this problem; however, its efficacy depends on the abundance of cells carrying the new insertion. Robust detection of somatic insertions present in only a subset of cells within a given sample can also be prohibitively expensive due to a requirement for high sequencing depth. Here, we describe retrotransposon capture sequencing (RC-seq), a sequence capture approach in which Illumina libraries are enriched for fragments containing the 5' and 3' termini of specific MGEs. RC-seq allows the detection of known polymorphic insertions present in an individual, as well as the identification of rare or private germline insertions not previously described. Furthermore, RC-seq can be used to detect and characterize somatic insertions, providing a valuable tool to elucidate the extent and characteristics of MGE activity in healthy tissues and in various disease states.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Carreira2016-vr,

title = {Evidence for L1-associated DNA rearrangements and negligible  L1 retrotransposition in glioblastoma multiforme},

author = {Patricia E Carreira and Adam D Ewing and Guibo Li and Stephanie N Schauer and Kyle R Upton and Allister C Fagg and Santiago Morell and Michaela Kindlova and Patricia Gerdes and Sandra R Richardson and Bo Li and Daniel J Gerhardt and Jun Wang and Paul M Brennan and Geoffrey J Faulkner},

url = {http://dx.doi.org/10.1186/s13100-016-0076-6},

year  = {2016},

date = {2016-01-01},

journal = {Mob. DNA},

volume = {7},

number = {1},

pages = {21},

abstract = {LINE-1 (L1) retrotransposons are a notable endogenous source of 

 mutagenesis in mammals. Notably, cancer cells can support unusual 

 L1 retrotransposition and L1-associated sequence rearrangement 

 mechanisms following DNA damage. Recent reports suggest that L1 

 is mobile in epithelial tumours and neural cells but, 

 paradoxically, not in brain cancers.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Upton2015-qu,

title = {Ubiquitous L1 mosaicism in hippocampal neurons},

author = {Kyle R Upton and Daniel J Gerhardt and Samuel J Jesuadian and Sandra R Richardson and Francisco J S\'{a}nchez-Luque and Gabriela O Bodea and Adam D Ewing and Carmen Salvador-Palomeque and Marjo S van der Knaap and Paul M Brennan and Adeline Vanderver and Geoffrey J Faulkner},

url = {http://dx.doi.org/10.1016/j.cell.2015.03.026},

year  = {2015},

date = {2015-04-01},

journal = {Cell},

volume = {161},

number = {2},

pages = {228--239},

abstract = {Somatic LINE-1 (L1) retrotransposition during neurogenesis is 

 a potential source of genotypic variation among neurons. As a 

 neurogenic niche, the hippocampus supports pronounced L1 

 activity. However, the basal parameters and biological impact 

 of L1-driven mosaicism remain unclear. Here, we performed 

 single-cell retrotransposon capture sequencing (RC-seq) on 

 individual human hippocampal neurons and glia, as well as 

 cortical neurons. An estimated 13.7 somatic L1 insertions 

 occurred per hippocampal neuron and carried the sequence 

 hallmarks of target-primed reverse transcription. Notably, 

 hippocampal neuron L1 insertions were specifically enriched in 

 transcribed neuronal stem cell enhancers and hippocampus 

 genes, increasing their probability of functional relevance. 

 In addition, bias against intronic L1 insertions sense 

 oriented relative to their host gene was observed, perhaps 

 indicating moderate selection against this configuration in 

 vivo. These experiments demonstrate pervasive L1 mosaicism at 

 genomic loci expressed in hippocampal neurons.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{richardson_influence_2015,

title = {The Influence of LINE-1 and SINE Retrotransposons on Mammalian Genomes},

author = {Sandra R Richardson and Aur\'{e}lien J Doucet and Huira C Kopera and John B Moldovan and Jos\'{e} Luis Garcia-Perez and John V Moran},

doi = {10.1128/microbiolspec.MDNA3-0061-2014},

issn = {2165-0497},

year  = {2015},

date = {2015-01-01},

journal = {Microbiology Spectrum},

volume = {3},

number = {2},

pages = {MDNA3--0061--2014},

abstract = {Transposable elements have had a profound impact on the structure and function of mammalian genomes. The retrotransposon Long INterspersed Element-1 (LINE-1 or L1), by virtue of its replicative mobilization mechanism, comprises ∼17% of the human genome. Although the vast majority of human LINE-1 sequences are inactive molecular fossils, an estimated 80-100 copies per individual retain the ability to mobilize by a process termed retrotransposition. Indeed, LINE-1 is the only active, autonomous retrotransposon in humans and its retrotransposition continues to generate both intra-individual and inter-individual genetic diversity. Here, we briefly review the types of transposable elements that reside in mammalian genomes. We will focus our discussion on LINE-1 retrotransposons and the non-autonomous Short INterspersed Elements (SINEs) that rely on the proteins encoded by LINE-1 for their mobilization. We review cases where LINE-1-mediated retrotransposition events have resulted in genetic disease and discuss how the characterization of these mutagenic insertions led to the identification of retrotransposition-competent LINE-1s in the human and mouse genomes. We then discuss how the integration of molecular genetic, biochemical, and modern genomic technologies have yielded insight into the mechanism of LINE-1 retrotransposition, the impact of LINE-1-mediated retrotransposition events on mammalian genomes, and the host cellular mechanisms that protect the genome from unabated LINE-1-mediated retrotransposition events. Throughout this review, we highlight unanswered questions in LINE-1 biology that provide exciting opportunities for future research. Clearly, much has been learned about LINE-1 and SINE biology since the publication of Mobile DNA II thirteen years ago. Future studies should continue to yield exciting discoveries about how these retrotransposons contribute to genetic diversity in mammalian genomes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Richardson2014-yj,

title = {Diversity through duplication: whole-genome sequencing reveals 

 novel gene retrocopies in the human population},

author = {Sandra R Richardson and Carmen Salvador-Palomeque and Geoffrey J Faulkner},

url = {http://dx.doi.org/10.1002/bies.201300181},

year  = {2014},

date = {2014-05-01},

journal = {Bioessays},

volume = {36},

number = {5},

pages = {475--481},

abstract = {Gene retrocopies are generated by reverse transcription and 

 genomic integration of mRNA. As such, retrocopies present an 

 important exception to the central dogma of molecular biology, 

 and have substantially impacted the functional landscape of 

 the metazoan genome. While an estimated 8,000-17,000 

 retrocopies exist in the human genome reference sequence, the 

 extent of variation between individuals in terms of retrocopy 

 content has remained largely unexplored. Three recent studies 

 by Abyzov et al., Ewing et al. and Schrider et al. have 

 exploited 1,000 Genomes Project Consortium data, as well as 

 other sources of whole-genome sequencing data, to uncover 

 novel gene retrocopies. Here, we compare the methods and 

 results of these three studies, highlight the impact of 

 retrocopies in human diversity and genome evolution, and 

 speculate on the potential for somatic gene retrocopies to 

 impact cancer etiology and genetic diversity among individual 

 neurons in the mammalian brain.},

keywords = {},

pubstate = {},

tppubtype = {article}

}

@article{richardson_apobec3a_2014,

title = {APOBEC3A deaminates transiently exposed single-strand DNA during LINE-1 retrotransposition},

author = {Sandra R Richardson and I\~{n}igo Narvaiza and Randy A Planegger and Matthew D Weitzman and John V Moran},

issn = {2050-084X},

year  = {2014},

date = {2014-04-01},

journal = {eLife},

volume = {3},

pages = {e02008},

abstract = {Long INterspersed Element-1 (LINE-1 or L1) retrotransposition poses a mutagenic threat to human genomes. Human cells have therefore evolved strategies to regulate L1 retrotransposition. The APOBEC3 (A3) gene family consists of seven enzymes that catalyze deamination of cytidine nucleotides to uridine nucleotides (C-to-U) in single-strand DNA substrates. Among these enzymes, APOBEC3A (A3A) is the most potent inhibitor of L1 retrotransposition in cultured cell assays. However, previous characterization of L1 retrotransposition events generated in the presence of A3A did not yield evidence of deamination. Thus, the molecular mechanism by which A3A inhibits L1 retrotransposition has remained enigmatic. Here, we have used in vitro and in vivo assays to demonstrate that A3A can inhibit L1 retrotransposition by deaminating transiently exposed single-strand DNA that arises during the process of L1 integration. These data provide a mechanistic explanation of how the A3A cytidine deaminase protein can inhibit L1 retrotransposition.DOI: http://dx.doi.org/10.7554/eLife.02008.001.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Richardson2014-nf,

title = {L1 retrotransposons and somatic mosaicism in the brain},

author = {Sandra R Richardson and Santiago Morell and Geoffrey J Faulkner},

url = {http://dx.doi.org/10.1146/annurev-genet-120213-092412},

year  = {2014},

date = {2014-01-01},

journal = {Annu. Rev. Genet.},

volume = {48},

pages = {1--27},

abstract = {Long interspersed element 1 (LINE-1 or L1) retrotransposons 

 have generated one-third of the human genome, and their 

 ongoing mobility is a source of inter- and intraindividual 

 genetic diversity. Although retrotransposition in metazoans 

 has long been considered a germline phenomenon, recent 

 experiments using cultured cells, animal models, and human 

 tissues have revealed extensive L1 mobilization in rodent and 

 human neurons, as well as mobile element activity in the 

 Drosophila brain. In this review, we evaluate the available 

 evidence for L1 retrotransposition in the brain and discuss 

 mechanisms that may regulate neuronal retrotransposition in 

 vivo. We compare experimental strategies used to map de novo 

 somatic retrotransposition events and present the optimal 

 criteria to identify a somatic L1 insertion. Finally, we 

 discuss the unresolved impact of L1-mediated somatic mosaicism 

 upon normal neurobiology, as well as its potential to drive 

 neurological disease.},

keywords = {},

pubstate = {},

tppubtype = {article}

}

@article{Carreira2014-oa,

title = {L1 retrotransposons, cancer stem cells and oncogenesis},

author = {Patricia E Carreira and Sandra R Richardson and Geoffrey J Faulkner},

url = {http://dx.doi.org/10.1111/febs.12601},

year  = {2014},

date = {2014-01-01},

journal = {FEBS J.},

volume = {281},

number = {1},

pages = {63--73},

abstract = {Retrotransposons have played a central role in human genome 

 evolution. The accumulation of heritable L1, Alu and SVA 

 retrotransposon insertions continues to generate structural 

 variation within and between populations, and can result in 

 spontaneous genetic disease. Recent works have reported 

 somatic L1 retrotransposition in tumours, which in some cases 

 may contribute to oncogenesis. Intriguingly, L1 mobilization 

 appears to occur almost exclusively in cancers of epithelial 

 cell origin. In this review, we discuss how L1 

 retrotransposition could potentially trigger neoplastic 

 transformation, based on the established correlation between 

 L1 activity and cellular plasticity, and the proven capacity 

 of L1-mediated insertional mutagenesis to decisively alter 

 gene expression and functional output.},

keywords = {},

pubstate = {},

tppubtype = {article}

}