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Genome Biology Papers on Neurodegenerative Disorder Methylation, Somatic Brain Changes, More

A University of Queensland-led team describes a dozen shared DNA methylation features in blood samples from individuals with neurodegenerative disorders like Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Parkinson's disease. Starting with array-based blood DNA methylation profiles for nearly 5,600 individuals with ALS, Parkinson's Alzheimer's, schizophrenia, or rheumatoid arthritis, along with methylation profiles for more than 4,300 unaffected controls, the researchers focused in on 12 differentially methylated sites and immune cell type features that were shared across neurodegenerative conditions. "[W]e identified shared [differentially methylated positions] in whole blood, and similar [cell type proportion] distribution patterns between neurodegenerative disorders that point to shared pathogenic mechanisms, which are likely a reflection of neuroinflammatory dysregulation" they report.

Members of the Brain Somatic Mosaicism Network present findings from a somatic variant analysis of post-mortem brain samples. After evaluating several variant calling approaches with simulated DNA mixing analyses, the team searched for somatic SNPs in post-mortem samples from the dorsolateral prefrontal cortex brain region and from dural fibroblast samples from the same neurotypical individual using parallel whole-genome sequencing, single-cell sequencing, or exome sequencing analyses at more than a dozen study sites. Together, the authors uncovered 43 validated somatic SNPs, while coming up with best practices for mosaic variant calling in this context. "This study provides a unified set of best practices to detect somatic [single-nucleotide variants (SNVs)] in non-cancerous tissues," they write, adding that the work "should serve as a guide to assess the contributions of somatic SNVs to neuropsychiatric diseases."

Australian researchers explore expression quantitative trait loci (eQTL) across several cell types in donated fibroblast cultures and induced pluripotent stem cells (iPSC) generated from them. Using single-cell RNA sequencing, the team characterized more than 64,000 cultured dermal fibroblast cells from 79 skin biopsy donor individuals, along with almost 20,000 iPSCs originating from 31 fibroblast lines — data that made it possible to pick out genetic variants linked to expression profiles in half a dozen fibroblast cell types and four cell types found in the iPSC set. "[T]he results we present here strongly support the hypothesis of true cell type-specific eQTLs," the authors note, adding that the study "identified novel cis-eQTLs for genes that characterize cell types during iPSC reprogramming, located in functional genomic regions that reflect reprogramming efficiency based on epigenetic profiles."