Monday, September 27, 2010

Dynamic instability of genomic methylation patterns in pluripotent stem cells #epigenetics #stemcells

Ooi and colleagues conclude:

"Error-prone maintenance methylation will introduce unpredictable phenotypic variation into clonal populations of pluripotent stem cells, and this variation is likely to be much more pronounced in cultured female cells. This epigenetic variability has obvious negative implications for the clinical applications of stem cells."

 Implications for complex phenotypes?

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Wednesday, September 22, 2010

Tuesday, September 21, 2010

Liked: @AMIAInformatix EMR-enabled GWAS on peripheral arterial disease. Kullo et al.

JAMIA recently published a study which shows that EMR can be utilized to characterize phenocopies, phenotypic heterogeneity, and important related variables to support GWAS.  Their evidence supports the use of EMR-linked biorepositories for GWAS. 

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In which S. Mani discusses Kasparov's experiment after losing to Deep Blue... #AI @AMIAInformatix

. . . and the relevance of Kasparov's experiment to medical informatics.

Note on Friedman's ‘fundamental theorem of biomedical informatics’

‘Their skill at manipulating and “coaching” their computers to look very deeply into positions effectively counteracted the superior chess understanding of their grandmaster opponents and the greater computational power of other participants. Weak human + machine + better process was superior to a strong computer alone and, more remarkably, superior to a strong human + machine + inferior process.’ - Kasparov

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Monday, September 20, 2010

Heritability of childhood/adolescent depression. Cross-fostering experiment, IVF.

Genetics of childhood and adolescent depression: insights into etiological heterogeneity and challenges for future genomic research

Rice and colleagues have used a "prenatal cross-fostering' design where pregnant mothers are related or unrelated to their child as a result of in vitro fertilization (IVF) was used to disentangle maternally inherited and environmental influences."
They have noted "Associations between prenatal stress and offspring birth weight, gestational age and antisocial behaviour were seen in both related and unrelated mother-offspring pairs, consistent with there being environmental links. The association between prenatal stress and offspring anxiety in related and unrelated groups appeared to be due to current maternal anxiety/depression rather than prenatal stress. In contrast, the link between prenatal stress and offspring attention deficit hyperactivity disorder was only present in related mother-offspring pairs and therefore was attributable to inherited factors."

Wednesday, September 15, 2010

Personalized Epigenomic Signatures That Are Stable Over Time and Covary with Body Mass Index #epigenetics

Feinberg et al from Sci Transl Med --

"an unbiased genome-scale analysis of ~4 million CpG sites in 74 individuals with comprehensive array-based relative methylation (CHARM) analysis. We found 227 regions that showed extreme interindividual variability [variably methylated regions (VMRs)] across the genome, which are enriched for developmental genes based on Gene Ontology analysis. Furthermore, half of these VMRs were stable within individuals over an average of 11 years, and these VMRs defined a personalized epigenomic signature. Four of these VMRs showed covariation with body mass index consistently at two study visits and were located in or near genes previously implicated in regulating body weight or diabetes."

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Network analysis of differential expression using machine learning approaches

Candidate gene prioritization by network analysis of differential expression using machine learning approaches

Using three of their own strategies to analyze gene expression scores versus Simple Expression Ranking, the 
authors found:

Our results showed that our four strategies could outperform this standard procedure and that the best results were obtained using the Heat Kernel Diffusion Ranking leading to an average ranking position of 8 out of 100 genes, an AUC value of 92.3% and an error reduction of 52.8% relative to the standard procedure approach which ranked the knockout gene in average at position 17 with an AUC value of 83.7%.

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Saturday, September 4, 2010

Valproate induces DNA demethylation in nuclear extracts from adult mouse brain. #epigenetics

"We observed the presence of DNA demethylation activity, which was increased in FC nuclear extracts from mice treated with valproate (VPA, 2.2 mmol/kg, twice a day for 3 days). VPA not only reduces anxiety and cognitive deficits and other symptoms in bipolar disorder (BP) disorder and schizophrenia (SZ) patients but also upregulates Reln and glutamic acid decarboxylase 67 (Gad67) mRNA/protein expression by reducing the methylation of their promoters. We believe that the identification of an enzyme in brain that facilitates DNA-demethylation and an understanding of how drugs induce DNA demethylation are crucial to progress in a new line of pharmacological interventions to treat neurodevelopment, neuropsychiatric and neurodegenerative diseases."

Dong et al. Epigenetics. 2010 Nov 16;5(8). [Epub ahead of print]

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Thursday, September 2, 2010

Epigenetic Transmission of the Impact of Early Stress Across Generations [via @thinkgenome]

After stressing postnatal mice for days 1-14 --

"chronic and unpredictable maternal separation induces depressive-like behaviors and alters the behavioral response to aversive environments in the separated animals when adult. Most of the behavioral alterations are further expressed by the offspring of males subjected to maternal separation, despite the fact that these males are reared normally. Chronic and unpredictable maternal separation also alters the profile of DNA methylation in the promoter of several candidate genes in the germline of the separated males. Comparable changes in DNA methylation are also present in the brain of the offspring and are associated with altered gene expression."

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