Manuscript title: Novel monoallelically-expressed genes and relaxation of imprinting with advanced age in the dorsolateral prefrontal cortex.
| abbreviation | concept |
|---|---|
| (R)MAE | (random) monoallelic expression |
| SCZ | schizophrenia |
Rationale and expectations
Functional roles
- in immune and olfactory system clear function: RMAE ensures one cell—one receptor
- hypothetical function of RMAE in brain?
- MHC association to SCZ => immunity. Mechanism in SCZ? Autoimmune disease?
- other roles (beyond immunity)?
Andy: generate diversity and/or dosage regulation (Dscam paper by Neves,…, Chess, neuronal identity); mammals neurexin, pcdh protocadherin
- hypothetical function of imprinting?
Andy: being diploid is generally beneficial but: battle between sexes growth control males boost growth promoting genes (e.g. IGF2); females suppress; Heigh’s theory
Onset and extent of RMAE
- X-inactivation expected to be polyclonal in brain sample “the unsurprising notion that most samples are polyclonal with respect to X inactivation” (p.5). Basis of expectation?
- RMAE expected to be monoclonal? Why? Developmental onset of RMAE?
- in limphoblastoid cell lines: RMAE is widespread (occurs in 5-10 % of genes, Gimelbrant et al) consistent with role in immunity
- known extent of RMAE in other cell lines or tissue types? Does extent correlate with functional imporatnce in some tissue?
Andy: 0.7 % indicates that RMAE has less importance in the brain than in the immune systems*
Molecular mechanisms
- expected lenght of epigenetic marks
- imprinting
- RMAE
Andy: local duplication ORs; H region
Methodology
- quantity of interest: allelic imbalance (avoid skewness: confusing terminology)
- should we care for error rates? Currently heuristics: “To be conservative about calling monoallelic expression” (p.4)
- are there gold standard data for MAE?
- invest in statistical modeling of allelic imbalance?
- length of epigenetic marks: correlation between loci (SNPs)
- dissect sources of variability: across subjects, cell clones/tissues, technical noise (read depth, quality,…)
Findings
Extent of MAE
ms p.3: the discordance rate (monoallelic RNA genotype in the context of a heterozygous DNA genotype) was 0.71%”
how about consistency with 5-10 % (Gimelbrant et al)?
Andy: two papers by Gregg,…, Dulac, which was followed up by DeVeale et al