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Somatic retrotransposition alters the genetic landscape of the human brain.
Nature. 2011 Nov 24; 479(7374):534-7
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21 Nov 2011
Confirmation
DOI: 10.3410/f.13368962.14739060
Although there is a growing consensus around retransposition in germ cells, this paper provides one of the more substantive pieces of evidence of somatic retransposition in the brain.
The authors used a genome-wide resequencing method designed to enrich select retrotransposons of the L1, Alu and SVA...Continue reading
The authors used a genome-wide resequencing method designed to enrich select retrotransposons of the L1, Alu and SVA...Continue reading
Although there is a growing consensus around retransposition in germ cells, this paper provides one of the more substantive pieces of evidence of somatic retransposition in the brain.
The authors used a genome-wide resequencing method designed to enrich select retrotransposons of the L1, Alu and SVA families in a small number (three) of brains in three regions. The hippocampus showed the most events and the caudate nucleus the least. Unlike germline events, these retranspositions did not spare gene-rich regions, presumably because they are not under selection pressure because they are not transmitted to further generations. The differential rates of retransposition in different parts of the brain suggest an effect of milieu/microenvironment and hint at ways in which additional phenotypic (including behavioural) complexity might be provided by this non-inherited source of individual variation.
One methodological concern regarding this study was how the authors defined somatic mutations not seen in other databases and in the three donors. This concern is likely to be addressed by the many follow-on studies to which this study will lead.
The authors used a genome-wide resequencing method designed to enrich select retrotransposons of the L1, Alu and SVA families in a small number (three) of brains in three regions. The hippocampus showed the most events and the caudate nucleus the least. Unlike germline events, these retranspositions did not spare gene-rich regions, presumably because they are not under selection pressure because they are not transmitted to further generations. The differential rates of retransposition in different parts of the brain suggest an effect of milieu/microenvironment and hint at ways in which additional phenotypic (including behavioural) complexity might be provided by this non-inherited source of individual variation.
One methodological concern regarding this study was how the authors defined somatic mutations not seen in other databases and in the three donors. This concern is likely to be addressed by the many follow-on studies to which this study will lead.
Disclosures
None declared
Add Comment
Kohane I: F1000Prime Recommendation of [Baillie JK et al., Nature 2011, 479(7374):534-7]. In F1000Prime, 21 Nov 2011; DOI: 10.3410/f.13368962.14739060. F1000Prime.com/13368962#eval14739060
23 Nov 2011
New Finding
DOI: 10.3410/f.13368962.14742089
We found this article interesting because it provides the first detailed account of the mosaicism of the genome of brain cells to provide new perspectives as to the origin of neurological diseases.
Although the human genome is traditionally considered to be identical in all normal somatic cells, with...Continue reading
Although the human genome is traditionally considered to be identical in all normal somatic cells, with...Continue reading
We found this article interesting because it provides the first detailed account of the mosaicism of the genome of brain cells to provide new perspectives as to the origin of neurological diseases.
Although the human genome is traditionally considered to be identical in all normal somatic cells, with the exception of lymphocytes, this perspective has recently become subject to revision. In a recent report in Nature, it is thus shown that the genome in somatic cells of the brain of several individuals has new and numerous insertions of retrotransposons that change the corresponding genetic landscapes. Retrotransposons represent genetic elements that can amplify themselves to integrate into the genome at numerous positions on an evolutionary scale. While more than half of the human genome is derived from transposable elements, only a minority of the three subclasses (L1, Alu and SVA) are functionally active. Although retrotransposed elements are usually silenced epigenetically they can become activated during early development as well as in association with diseases. The recent observation that there exists copy number variation of L1 elements in brain cells {1,2} indicated that the mobilization of L1 elements during neurogenesis could generate heterogenous genotypes that might predispose to various diseases. Using high-throughput sequencing analysis of sequences enriched for retrotransposon sequences, Baillie et al. identified thousands of novel retrotransposed elements in brain cells, i.e. they could not be found in the germline, of several individuals. Most interestingly, retrotransposition targeted primarily transcription units with L1-preferring introns and Alu, and, to a lesser degree, SVA-preferring exons. Such patterns of somatic integration events may not only modulate the expression levels of affected transcriptional units in the case of L1 but also change the coding potential in the instances of Alu and SVA. Beyond robustly establishing that the genotype of brain cells is mosaic, Baillie et al. also report that such genetic heterogeneity might predispose to a variety of neurological diseases. For example, the HDAC1 gene, which is associated with psychiatric diseases and cancer, had an L1 element retrotransposed in one of its introns in one individual. Moreover, Alu was inserted into one of the exons of RAI1, which is linked with schizophrenia and Smith-Magenis syndrome. Although hard evidence is lacking with respect to any cause and consequence, the sheer number of de novo retrotransposition in somatic cells makes it unlikely to not have a functional consequence. Apart from the tantalizing link to human diseases, it will be fascinating to learn to what extent, if at all, de novo retrotransposition occurs in the brain of healthy individuals to modulate behavioural patterns.
Although the human genome is traditionally considered to be identical in all normal somatic cells, with the exception of lymphocytes, this perspective has recently become subject to revision. In a recent report in Nature, it is thus shown that the genome in somatic cells of the brain of several individuals has new and numerous insertions of retrotransposons that change the corresponding genetic landscapes. Retrotransposons represent genetic elements that can amplify themselves to integrate into the genome at numerous positions on an evolutionary scale. While more than half of the human genome is derived from transposable elements, only a minority of the three subclasses (L1, Alu and SVA) are functionally active. Although retrotransposed elements are usually silenced epigenetically they can become activated during early development as well as in association with diseases. The recent observation that there exists copy number variation of L1 elements in brain cells {1,2} indicated that the mobilization of L1 elements during neurogenesis could generate heterogenous genotypes that might predispose to various diseases. Using high-throughput sequencing analysis of sequences enriched for retrotransposon sequences, Baillie et al. identified thousands of novel retrotransposed elements in brain cells, i.e. they could not be found in the germline, of several individuals. Most interestingly, retrotransposition targeted primarily transcription units with L1-preferring introns and Alu, and, to a lesser degree, SVA-preferring exons. Such patterns of somatic integration events may not only modulate the expression levels of affected transcriptional units in the case of L1 but also change the coding potential in the instances of Alu and SVA. Beyond robustly establishing that the genotype of brain cells is mosaic, Baillie et al. also report that such genetic heterogeneity might predispose to a variety of neurological diseases. For example, the HDAC1 gene, which is associated with psychiatric diseases and cancer, had an L1 element retrotransposed in one of its introns in one individual. Moreover, Alu was inserted into one of the exons of RAI1, which is linked with schizophrenia and Smith-Magenis syndrome. Although hard evidence is lacking with respect to any cause and consequence, the sheer number of de novo retrotransposition in somatic cells makes it unlikely to not have a functional consequence. Apart from the tantalizing link to human diseases, it will be fascinating to learn to what extent, if at all, de novo retrotransposition occurs in the brain of healthy individuals to modulate behavioural patterns.
References
Disclosures
None declared
Ohlsson R and Gondor A: F1000Prime Recommendation of [Baillie JK et al., Nature 2011, 479(7374):534-7]. In F1000Prime, 23 Nov 2011; DOI: 10.3410/f.13368962.14742089. F1000Prime.com/13368962#eval14742089
13 Mar 2012
New Finding
DOI: 10.3410/f.13368962.15442061
In this excellent study, the authors identify retrotransposons, small mobile elements that replicate throughout eukaryotic genomes, which demonstrate somatic expansion in the human hippocampus and caudate nucleus, particularly in transcriptionally active regions of the genome. Existing genetic association...Continue reading
In this excellent study, the authors identify retrotransposons, small mobile elements that replicate throughout eukaryotic genomes, which demonstrate somatic expansion in the human hippocampus and caudate nucleus, particularly in transcriptionally active regions of the genome. Existing genetic association studies and sequencing studies using peripherally derived DNA would have missed neural-specific retrotransposon expansion, which could potentially have an important impact upon protein expression and thus disease aetiology. The role of somatic retrotransposition in human neurological disease needs to be explored.
Disclosures
None declared
Ramagopalan S and Handel A: F1000Prime Recommendation of [Baillie JK et al., Nature 2011, 479(7374):534-7]. In F1000Prime, 13 Mar 2012; DOI: 10.3410/f.13368962.15442061. F1000Prime.com/13368962#eval15442061
03 Apr 2012
Stephen Robertson
F1000 Genomics & Genetics
Dunedin School of Medicine, University of Otago,
Dunedin, New Zealand.
F1000 Genomics & Genetics
Dunedin School of Medicine, University of Otago,
Dunedin, New Zealand.
New Finding
DOI: 10.3410/f.13368962.15768160
This landmark study documents widespread and extensive somatic retrotransposition in the human brain using massively parallel sequencing and a retrotransposon capture technique. The massively parallel sequencing data indicate that there are many novel events that occur at a somatic level that are not...Continue reading
This landmark study documents widespread and extensive somatic retrotransposition in the human brain using massively parallel sequencing and a retrotransposon capture technique. The massively parallel sequencing data indicate that there are many novel events that occur at a somatic level that are not represented in either in the blood cells of the same individuals or in the reference sequence of the human genome. A more modest number of germline events were detected, indicating that the germline is more ironclad in its 'defense' of these events whilst the brain clearly has a great deal more permissivity.
Over 24,000 separate events were detected by the RC-seq capture technique, many of these only represented by a single read. While one interpretation of this finding is that these events are rare and therefore hard to detect in number, another is that some could be due to technical artefacts. It will be of much interest to learn more in the future of how extensively these novel events can be validated (29 were attempted, with most successfully validated in this study) to see how widespread this phenomenon is. Similarly interesting will be some data on a range of tissues from various ages to see if retrotransposition occurs lifelong or is temporarily restricted to certain developmental time points. Whether a significant amount of neurological pathology might have its source from the somatic mechanism is a question of much interest as well.
Over 24,000 separate events were detected by the RC-seq capture technique, many of these only represented by a single read. While one interpretation of this finding is that these events are rare and therefore hard to detect in number, another is that some could be due to technical artefacts. It will be of much interest to learn more in the future of how extensively these novel events can be validated (29 were attempted, with most successfully validated in this study) to see how widespread this phenomenon is. Similarly interesting will be some data on a range of tissues from various ages to see if retrotransposition occurs lifelong or is temporarily restricted to certain developmental time points. Whether a significant amount of neurological pathology might have its source from the somatic mechanism is a question of much interest as well.
Disclosures
None declared
Robertson S: F1000Prime Recommendation of [Baillie JK et al., Nature 2011, 479(7374):534-7]. In F1000Prime, 03 Apr 2012; DOI: 10.3410/f.13368962.15768160. F1000Prime.com/13368962#eval15768160
15 Sep 2012
Good for Teaching, New Finding
DOI: 10.3410/f.13368962.793460463
These findings are a great reminder that the DNA sequence we inherit at the time of conception is less important than many would have us believe. The authors searched for insertion sites for retrotransposons in different regions of the brains of three humans. What jumped out most for me was: a) there...Continue reading
These findings are a great reminder that the DNA sequence we inherit at the time of conception is less important than many would have us believe. The authors searched for insertion sites for retrotransposons in different regions of the brains of three humans. What jumped out most for me was: a) there were HUGE numbers of insertion sites (up to tens of thousands); b) there were varying profiles of insertions in different brain regions (the hippocampus was a particular hot spot) and different individuals; and c) insertion sites were preferentially in coding regions. In other words, there is massive and region-specific 'somatic genome mosaicism' in the human brain.
Disclosures
None declared
Sapolsky R: F1000Prime Recommendation of [Baillie JK et al., Nature 2011, 479(7374):534-7]. In F1000Prime, 15 Sep 2012; DOI: 10.3410/f.13368962.793460463. F1000Prime.com/13368962#eval793460463
F1000Prime Recommendations, Dissents and Comments for [Baillie JK et al., Nature 2011, 479(7374):534-7]. In F1000Prime, 22 May 2013; F1000Prime.com/13368962
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Retrotransposons are mobile genetic elements that use a germline 'copy-and-paste' mechanism to spread throughout metazoan genomes. At least 50 per cent of the human genome is derived from retrotransposons, with three active families (L1, Alu and SVA) associated with insertional mutagenesis and disease. Epigenetic and post-transcriptional suppression block retrotransposition in somatic cells, excluding early embryo development and some malignancies. Recent reports of L1 expression and copy number variation in the human brain suggest that L1 mobilization may also occur during later development. However, the corresponding integration sites have not been mapped. Here we apply a high-throughput method to identify numerous L1, Alu and SVA germline mutations, as well as 7,743 putative somatic L1 insertions, in the hippocampus and caudate nucleus of three individuals. Surprisingly, we also found 13,692 somatic Alu insertions and 1,350 SVA insertions. Our results demonstrate that retrotransposons mobilize to protein-coding genes differentially expressed and active in the brain. Thus, somatic genome mosaicism driven by retrotransposition may reshape the genetic circuitry that underpins normal and abnormal neurobiological processes.
©2011 Macmillan Publishers Limited. All rights reserved
DOI: 10.1038/nature10531
PMID: 22037309
