Dr. Richardson has been a Research Officer in the Genome Plasticity and Disease group at Mater Research Institute–University of Queensland in Brisbane, Australia since September 2013, where her primary research focus is the activity of LINE-1 retrotransposons in the mammalian germline and early embryo. She completed her PhD in July 2013 in the laboratory of Professor John V. Moran in the Department of Human Genetics at the University of Michigan in Ann Arbor, USA. She obtained a Bachelor of Science in 2005 from the department of Microbiology and Molecular Genetics at Michigan State University, East Lansing, USA.read more
Dr. Richardson is interested in the dynamic relationship between transposable elements (TEs) and mammalian genomes. TE-mediated mutagenesis is an endogenous source of genetic diversity both within an individual (genetic mosaicism), and between individuals. On an evolutionary time scale, TE activity, along with other endogenous and exogenous mutagenic forces, provides the “raw material” for natural selection and the evoultion of gene function and regulation. However, at the level of the individual organism, TE mutagenesis of critical genes and regulatory regions can cause complete unviability, or result in genetic disease. Thus, mammalian genomes have evolved numerous defense pathways to restrict TE mutagenesis.
Dr. Richardson’s PhD and postdoctoral work has centered on the activity and regulation of the retrotransposon LINE-1, which is the only autonomous TE presently active in human genomes. LINE-1 regulation occurs at many levels, including epigenetic repression and small RNA-based defence pathways. The focus of her PhD thesis was regulation of LINE-1 by the APOBEC3 (A3) family of restriction factors. The human A3 family comprises seven members which have activity against exogenous retroviruses as well as endogenous TEs. APOBEC3A is the strongest inhibitor of LINE-1 activity, and the main finding of Dr. Richardson’s PhD thesis was to uncover the molecular mechanism of this restriction.
Dr. Richardson’s focus on LINE-1 regulation during her PhD led to her current research interest: in the face of numerous restriction mechanisms, at what point during mammalian development, and how frequently, do new heritable LINE-1 insertions occur? Her recent work in the Faulkner laboratory has established that a new endogenous LINE-1 insertion occurs in at least one in 8 mouse genomes, and that these insertions primarily arise in the pluripotent cells of the early embryo, prior to germline specification. However, she also uncovered a signficiant proportion of LINE-1 retrotransposition events occurring in early primordial germ cells, giving rise to germline-restricted genetic mosaicism. Notably, the early primordial germline represents a previously unappreciated developmental stage for the generation of heritable LINE-1 insertions.
Ewing, Adam D; Smits, Nathan; Sanchez-Luque, Francisco J; Faivre, Jamila; Brennan, Paul M; Richardson, Sandra R; Cheetham, Seth W; Faulkner, Geoffrey J
In: Molecular Cell, 2020, ISSN: 1097-2765.
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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.
Salvador-Palomeque, Carmen; Sanchez-Luque, Francisco J; Fortuna, Patrick R J; Ewing, Adam D; Wolvetang, Ernst J; Richardson, Sandra R; Faulkner, Geoffrey J
In: Mol Cell Biol, 39 (7), 2019, ISSN: 0270-7306.
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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.
Sanchez-Luque, Francisco J; Kempen, Marie-Jeanne H C; Gerdes, Patricia; Vargas-Landin, Dulce B; Richardson, Sandra R; Troskie, Robin-Lee; Jesuadian, Samuel J; Cheetham, Seth W; Carreira, Patricia E; Salvador-Palomeque, Carmen; García-Cañadas, Marta; Muñoz-Lopez, Martin; Sanchez, Laura; Lundberg, Mischa; Macia, Angela; Heras, Sara R; Brennan, Paul M; Lister, Ryan; Garcia-Perez, Jose L; Ewing, Adam D; Faulkner, Geoffrey J
LINE-1 Evasion of Epigenetic Repression in Humans (Journal Article)
In: Molecular Cell, 0 (0), 2019, ISSN: 1097-2765.
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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
Richardson, Sandra R; Faulkner, Geoffrey J
In: BioEssays, 40 (6), pp. 1700189, 2018, ISSN: 1521-1878.
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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.
Nguyen, Thu H M; Carreira, Patricia E; Sanchez-Luque, Francisco J; Schauer, Stephanie N; Fagg, Allister C; Richardson, Sandra R; Davies, Claire M; Jesuadian, Samuel J; Kempen, Marie-Jeanne H C; Troskie, Robin-Lee; James, Cini; Beaven, Elizabeth A; Wallis, Tristan P; Coward, Jermaine I G; Chetty, Naven P; Crandon, Alexander J; Venter, Deon J; Armes, Jane E; Perrin, Lewis C; Hooper, John D; Ewing, Adam D; Upton, Kyle R; Faulkner, Geoffrey J
L1 Retrotransposon Heterogeneity in Ovarian Tumor Cell Evolution (Journal Article)
In: Cell Reports, 23 (13), pp. 3730–3740, 2018, ISSN: 2211-1247.
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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.
Schauer, Stephanie N; Carreira, Patricia E; Shukla, Ruchi; Gerhardt, Daniel J; Gerdes, Patricia; Sanchez-Luque, Francisco J; Nicoli, Paola; Kindlova, Michaela; Ghisletti, Serena; Santos, Alexandre Dos; Rapoud, Delphine; Samuel, Didier; Faivre, Jamila; Ewing, Adam D; Richardson, Sandra R; Faulkner, Geoffrey J
In: Genome Research, 2018, ISSN: 1088-9051, 1549-5469.
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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.
Richardson, Sandra R; Gerdes, Patricia; Gerhardt, Daniel J; Sanchez-Luque, Francisco J; Bodea, Gabriela-Oana; noz-Lopez, Martin Mu; Jesuadian, Samuel J; Kempen, Marie-Jeanne H C; Carreira, Patricia E; Jeddeloh, Jeffrey A; Garcia-Perez, Jose L; Jr, Haig H Kazazian; Ewing, Adam D; Faulkner, Geoffrey J
In: Genome Res., 27 (8), pp. 1395–1405, 2017.
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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.
Sanchez-Luque, Francisco J; Richardson, Sandra R; Faulkner, Geoffrey J
Analysis of Somatic LINE-1 Insertions in Neurons (Incollection)
In: Genomic Mosaicism in Neurons and Other Cell Types, pp. 219–251, Humana Press, New York, NY, 2017, ISBN: 978-1-4939-7279-1 978-1-4939-7280-7, (DOI: 10.1007/978-1-4939-7280-7_12).
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The method described here is designed to detect and localize somatic genome variation caused by the human retrotransposon LINE-1 (L1) in the genome of neuronal cells. This method combines single-cell manipulation and whole genome amplification technology with a hybridization-based, high-throughput sequencing method called Retrotransposon Capture sequencing (RC-seq) for the precise analysis of the L1 insertion content of single cell genomes. The method is divided into four major sections: extraction of neuronal nuclei and single nuclei isolation; whole genome amplification; RC-seq; and experimental validation of putative insertions.
Gerdes, Patricia; Richardson, Sandra R; Mager, Dixie L; Faulkner, Geoffrey J
In: Genome Biol., 17 , pp. 100, 2016.
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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.
Gerdes, Patricia; Richardson, Sandra R; Faulkner, Geoffrey J
In: Genome Biol., 17 (1), pp. 259, 2016.
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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:
Sanchez-Luque, Francisco J; Richardson, Sandra R; Faulkner, Geoffrey J
In: Methods Mol. Biol., 1400 , pp. 47–77, 2016.
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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.
Kopera, Huira C; Larson, Peter A; Moldovan, John B; Richardson, Sandra R; Liu, Ying; Moran, John V
LINE-1 Cultured Cell Retrotransposition Assay (Journal Article)
In: Methods in Molecular Biology (Clifton, N.J.), 1400 , pp. 139–156, 2016, ISSN: 1940-6029.
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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.
Sanchez-Luque, Francisco J; Richardson, Sandra R; Faulkner, Geoffrey J
In: Methods in Molecular Biology (Clifton, N.J.), 1400 , pp. 47–77, 2016, ISSN: 1940-6029.
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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.
Carreira, Patricia E; Ewing, Adam D; Li, Guibo; Schauer, Stephanie N; Upton, Kyle R; Fagg, Allister C; Morell, Santiago; Kindlova, Michaela; Gerdes, Patricia; Richardson, Sandra R; Li, Bo; Gerhardt, Daniel J; Wang, Jun; Brennan, Paul M; Faulkner, Geoffrey J
In: Mob. DNA, 7 (1), pp. 21, 2016.
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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.
Upton, Kyle R; Gerhardt, Daniel J; Jesuadian, Samuel J; Richardson, Sandra R; Sánchez-Luque, Francisco J; Bodea, Gabriela O; Ewing, Adam D; Salvador-Palomeque, Carmen; van der Knaap, Marjo S; Brennan, Paul M; Vanderver, Adeline; Faulkner, Geoffrey J
Ubiquitous L1 mosaicism in hippocampal neurons (Journal Article)
In: Cell, 161 (2), pp. 228–239, 2015.
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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.
Richardson, Sandra R; Doucet, Aurélien J; Kopera, Huira C; Moldovan, John B; Garcia-Perez, José Luis; Moran, John V
The Influence of LINE-1 and SINE Retrotransposons on Mammalian Genomes (Journal Article)
In: Microbiology Spectrum, 3 (2), pp. MDNA3–0061–2014, 2015, ISSN: 2165-0497.
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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.
Richardson, Sandra R; Salvador-Palomeque, Carmen; Faulkner, Geoffrey J
In: Bioessays, 36 (5), pp. 475–481, 2014.
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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.
Richardson, Sandra R; Narvaiza, Iñigo; Planegger, Randy A; Weitzman, Matthew D; Moran, John V
APOBEC3A deaminates transiently exposed single-strand DNA during LINE-1 retrotransposition (Journal Article)
In: eLife, 3 , pp. e02008, 2014, ISSN: 2050-084X.
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.
Richardson, Sandra R; Morell, Santiago; Faulkner, Geoffrey J
L1 retrotransposons and somatic mosaicism in the brain (Journal Article)
In: Annu. Rev. Genet., 48 , pp. 1–27, 2014.
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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
Carreira, Patricia E; Richardson, Sandra R; Faulkner, Geoffrey J
L1 retrotransposons, cancer stem cells and oncogenesis (Journal Article)
In: FEBS J., 281 (1), pp. 63–73, 2014.
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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.
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