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

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

F1000Research ◽

10.12688/f1000research.9495.3 ◽

2017 ◽

Vol 5 ◽

pp. 2520 ◽

Cited By ~ 1

Author(s):

Anchal Sharma ◽

Asgar Hussain Ansari ◽

Renu Kumari ◽

Rajesh Pandey ◽

Rakhshinda Rehman ◽

...

Keyword(s):

Oxidative Stress ◽

Corpus Callosum ◽

Human Brain ◽

Frontal Cortex ◽

Oxidative Stress Marker ◽

Somatic Variation ◽

Single Nucleotide ◽

Normal Human Brain ◽

Normal Human ◽

The Brain

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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Global differential expression of genes located in the Down Syndrome Critical Region in normal human brain

Colombia Medica ◽

10.25100/cm.v45i4.1640 ◽

2014 ◽

pp. 154-161 ◽

Cited By ~ 8

Author(s):

Julio Cesar Montoya ◽

Dianora Fajardo ◽

Ángela Peña ◽

Adalberto Sánchez ◽

Martha C Domínguez ◽

...

Keyword(s):

Gene Expression ◽

Down Syndrome ◽

Human Brain ◽

Critical Region ◽

Expression Profiles ◽

Brain Atlas ◽

Normal Human Brain ◽

Normal Human ◽

The Brain ◽

Brain Homeostasis

Background: The information of gene expression obtained from databases, have made possible the extraction and analysis of data related with several molecular processes involving not only in brain homeostasis but its disruption in some neuropathologies; principally in Down syndrome and the Alzheimer disease. Objective: To correlate the levels of transcription of 19 genes located in the Down Syndrome Critical Region (DSCR) with their expression in several substructures of normal human brain. Methods: There were obtained expression profiles of 19 DSCR genes in 42 brain substructures, from gene expression values available at the database of the human brain of the Brain Atlas of the Allen Institute for Brain Sciences", (http://human.brain-map.org/). The co-expression patterns of DSCR genes in brain were calculated by using multivariate statistical methods. Results: Highest levels of gene expression were registered at caudate nucleus, nucleus accumbens and putamen among central areas of cerebral cortex. Increased expression levels of RCAN1 that encode by a protein involved in signal transduction process of the CNS were recorded for PCP4 that participates in the binding to calmodulin and TTC3; a protein that is associated with differentiation of neurons. That previously idenjpgied brain structures play a crucial role in the learning process, in different class of memory and in motor skills. Conclusion: The precise regulation of DSCR gene expression is crucial to maintain the brain homeostasis, especially in those areas with high levels of gene expression associated with a remarkable process of learning and cognition.

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Hydroxysteroid sulfotransferase 2B1b expression and localization in normal human brain

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci.2011.117 ◽

2011 ◽

Vol 8 (1) ◽

Cited By ~ 4

Author(s):

Emily D. Salman ◽

Ona Faye-Petersen ◽

Charles N. Falany

Keyword(s):

Protein Expression ◽

Human Brain ◽

Fetal Brain ◽

Immunohistochemical Analysis ◽

Adult Brain ◽

Sterol Metabolism ◽

Normal Human Brain ◽

Mrna And Protein Expression ◽

Normal Human ◽

The Brain

AbstractSteroid sulfonation in the human brain has not been well characterized. The major sulfotransferase (SULT) isoforms that conjugate steroids in humans are SULT1E1, SULT2A1, and SULT2B1b. SULT2B1b catalyzes the sulfonation of 3β-hydroxysteroids, including neurosteroids dehydroepiandrosterone and pregnenolone, as well as cholesterol and several hydroxycholesterols. SULT2B1b mRNA and protein expression were detected in adult and fetal human brain sections, whereas neither mRNA, nor protein expression were identified for SULT1E1 or SULT2A1. Using immunohistochemical analysis, SULT2B1b expression was detected in neurons and oligodendrocytes in adult brain and in epithelial tissues in 28-week-old fetal brain. Sulfonation of cholesterol, oxysterols, and neurosteroids in the brain is apparently catalyzed by SULT2B1b since expression of neither SULT2A1 nor SULT1E1 was detected in human brain sections. SULT2B1b mRNA and protein were also detected in human U373-MG glioblastoma cells. Both mRNA and protein expression of liver X receptor (LXR)-β, but not LXR-α, were detected in U373-MG cells, and LXR-β activation resulted in a decrease in SULT2B1b protein expression. Since hydroxycholesterols are important physiological LXR activators, this suggests a role for regulation of sterol metabolism by LXR and SULT2B1b. Therefore, elucidating key enzymes in the metabolism of cholesterol and neurosteroids could help define the properties of steroid conjugation in the human brain.

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