The Complete Genome Sequences, Unique Mutational Spectra, and Developmental Potency of Adult Neurons Revealed by Cloning

Hazen, Jennifer L.; Faust, Gregory G.; Rodríguez, Alberto Rodríguez; Ferguson, William C.; Shumilina, Svetlana; Clark, Royden A.; Boland, Michael J.; Martin, Greg S.; Chubukov, Pavel; Tsunemoto, Rachel; Torkamani, Ali; Kupriyanov, Sergey; Hall, Ira M.; Baldwin, Kristin K.

doi:10.1016/j.neuron.2016.02.004

Cited by 85 publications

(83 citation statements)

References 95 publications

(138 reference statements)

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“…Within the healthy human brain, a single neuron is estimated to contain on average ~800–2000 SNVs, with 80% of the SNVs being C>T transitions enriched in actively transcribed genes when analyzed by whole genome sequencing of single cells amplification in vitro [11]. A study of single mouse neurons using nuclear transfer for whole genome amplification estimates ~100 SNVs per mouse neuron with ~40% of the SNVs being C>T transitions [8]. …”

Section: Variant Types and Mechanisms Generating Mosaicismmentioning

confidence: 99%

Insights into the role of somatic mosaicism in the brain

Paquola

Erwin

Gage

2017

Current Opinion in Systems Biology

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Somatic mosaicism refers to the fact that cells within an organism have different genomes. It is now clear that somatic mosaicism occurs in all brains and that somatic mutations in a subset of cells can cause various rare neurodevelopmental disorders. However, for most individuals, the extent and consequences of somatic mosaicism are largely unknown. The complexity and unique features of the brain suggest that somatic mosaicism can play an important role in behavior and cognition. Here we review recent manuscripts showing instances of somatic mosaicism in the brain and estimating its extent and possible biological consequences. The consequences of somatic mosaicism span vast dimensions -from a single-locus variant, to genes and gene networks, to cells, to the interactions of the mosaic cells via neural networks affecting behavior and cognition. We highlight how systems biology approaches are particularly well suited for the complex emerging field of brain somatic mosaicism.

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Section: Variant Types and Mechanisms Generating Mosaicismmentioning

confidence: 99%

Insights into the role of somatic mosaicism in the brain

Paquola

Erwin

Gage

2017

Current Opinion in Systems Biology

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“…In the mammalian germline and early embryo, L1 escapes repression to mobilize and create heritable insertions to ensure its evolutionary success (Kano et al 2009;Faulkner and Garcia-Perez 2017;Richardson et al 2017). More recently, somatic L1 mobilization has been revealed as a characteristic of normal neuronal cells in rodents and humans, and L1 dysregulation has been associated with neurological diseases (Muotri et al 2005(Muotri et al , 2010Baillie et al 2011;Coufal et al 2011;Evrony et al 2012;Upton et al 2015;Erwin et al 2016;Hazen et al 2016).…”

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confidence: 99%

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

et al. 2018

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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 T F subfamily elements, and one G F subfamily example. One of the T F insertions carried a 3 ′ transduction, allowing us to identify its donor L1 and to demonstrate that this full-length T F 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.

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“…Moreover, more than 70% of these transversion events were found in the frontal cortex while DNA from the corpus callosum harbored the homozygotes for the reference alleles ( Figure 4). Recently, two studies 18, 19 have looked into somatic SNVs at the single neuron level. Although, neither of these studies report enrichment of G:C>T:A transversions, but these transversions are the second most abundant class of somatic variations as reported by Hazen et al 19 (16% of total somatic variations) in their dataset.…”

Section: Discussionmentioning

confidence: 99%

“…Recent reports have also started revealing the importance of such variations in neurological disorders 10 . But there have been very few systematic studies so far exploring the nature, extent and impact of somatic variations at the single nucleotide resolution in neuron-rich parts of the healthy human brain 18, 19 .…”

Section: Introductionmentioning

confidence: 99%

Human brain harbors single nucleotide somatic variations in functionally relevant genes possibly mediated by oxidative stress

et al. 2017

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Somatic variation in DNA can cause cells to deviate from the preordained genomic path in both disease and healthy conditions. Here, using exome sequencing of paired tissue samples, we show that the normal human brain harbors somatic single base variations measuring up to 0.48% of the total variations. Interestingly, about 64% of these somatic variations in the brain are expected to lead to non-synonymous changes, and as much as 87% of these represent G:C>T:A transversion events. Further, the transversion events in the brain were mostly found in the frontal cortex, whereas the corpus callosum from the same individuals harbors the reference genotype. We found a significantly higher amount of 8-OHdG (oxidative stress marker) in the frontal cortex compared to the corpus callosum of the same subjects (p<0.01), correlating with the higher G:C>T:A transversions in the cortex. We found significant enrichment for axon guidance and related pathways for genes harbouring somatic variations. This could represent either a directed selection of genetic variations in these pathways or increased susceptibility of some loci towards oxidative stress. This study highlights that oxidative stress possibly influence single nucleotide somatic variations in normal human brain.

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The Complete Genome Sequences, Unique Mutational Spectra, and Developmental Potency of Adult Neurons Revealed by Cloning

Cited by 85 publications

References 95 publications

Insights into the role of somatic mosaicism in the brain

Insights into the role of somatic mosaicism in the brain

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

Human brain harbors single nucleotide somatic variations in functionally relevant genes possibly mediated by oxidative stress

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