Biology subjects

Chess, A.

Publications and source records attributed to Chess, A..

6 recordsLinked to original sources

bioRxiv2022

Enrichment of somatic mutations in schizophrenia brain targets prenatally active transcription factor bindings sites

Schizophrenia (SCZ) is a complex neuropsychiatric disorder in which both germline genetic mutations and maternal factors, such as infection and immune activation, have been implicated, but how these two strikingly different mechanisms might converge on the same phenotype is unknown. During development, cells accumulate somatic, mosaic mutations in ways that can be shaped by the cellular environment or endogenous processes, but these early developmental mutational patterns have not been studied in SCZ. Here we analyzed deep (267x) whole-genome sequencing (WGS) of DNA from cerebral cortical neurons isolated from 61 SCZ and 25 control postmortem brains to capture mutations occurring before or during fetal neurogenesis. SCZ cases showed a >15% increase in genome-wide sSNV compared to controls (p < 2e-10). Remarkably, mosaic T>G mutations and CpG transversions (CpG>GpG or CpG>ApG) were 79- and 62-fold enriched, respectively, at transcription factor binding sites (TFBS) in SCZ, but not in controls. The pattern of T>G mutations resembles mutational processes in cancer attributed to oxidative damage that is sterically blocked from DNA repair by transcription factors (TFs) bound to damaged DNA. The CpG transversions similarly suggest unfinished DNA demethylation resulting in abasic sites that can also be blocked from repair by bound TFs. Allele frequency analysis suggests that both localized mutational spikes occur in the first trimester. We call this prenatal mutational process "skiagenesis" (from the Greek skia, meaning shadow), as these mutations occur in the shadow of bound TFs. Skiagenesis reflects as-yet unidentified prenatal factors and is associated with SCZ risk in a subset ([~]13%) of cases. In turn, mutational disruption of key TFBS active in fetal brain is well positioned to create SCZ-specific gene dysregulation in concert with germline risk genes. Skiagenesis provides a fingerprint for exploring how epigenomic regulation and prenatal factors such as maternal infection or immune activation may shape the developmental mutational landscape of human brain.

genomics↗

bioRxiv2020

EKLF/KLF1 expression defines a unique macrophage subset during mouse erythropoiesis

Erythroblastic islands are a specialized niche that contain a central macrophage surrounded by erythroid cells at various stages of maturation. However, identifying the precise genetic and transcriptional control mechanisms in the island macrophage remains difficult due to macrophage heterogeneity. Using unbiased global sequencing and directed genetic approaches focused on early mammalian development, we find that fetal liver macrophage exhibit a unique expression signature that differentiates them from erythroid and adult macrophage cells. The importance of EKLF/KLF1 in this identity is shown by expression analyses in EKLF-/- and in EKLF-marked macrophage cells. Single cell sequence analysis simplifies heterogeneity and identifies clusters of genes important for EKLF-dependent macrophage function and novel cell surface biomarkers. Remarkably, this singular set of macrophage island cells appears transiently during embryogenesis. Together these studies provide a detailed perspective on the importance of EKLF in establishment of the dynamic gene expression network within erythroblastic islands in the developing embryo and provide the means for their efficient isolation.

developmental biology↗

bioRxiv2020

Comprehensive identification of somatic nucleotide variants in human brain tissue

Post-zygotic mutations incurred during DNA replication, DNA repair, and other cellular processes lead to somatic mosaicism. Somatic mosaicism is an established cause of various diseases, including cancers. However, detecting mosaic variants in DNA from non-cancerous somatic tissues poses significant challenges, particularly if the variants only are present in a small fraction of cells. Here, the Brain Somatic Mosaicism Network conducted a coordinated, multi-institutional study to: (i) examine the ability of existing methods to detect simulated somatic single nucleotide variants (SNVs) in DNA mixing experiments; (ii) generate multiple replicates of whole genome sequencing data from the dorsolateral prefrontal cortex, other brain regions, dura mater, and dural fibroblasts of a single neurotypical individual; (iii) devise strategies to discover somatic SNVs; and (iv) apply various approaches to validate somatic SNVs. These efforts led to the identification of 43 bona fide somatic SNVs that ranged in variant allele fractions from ~0.005 to ~0.28. Guided by these results, we devised best practices for calling mosaic SNVs from 250X whole genome sequencing data in the accessible portion of the human genome that achieve 90% specificity and sensitivity. Finally, we demonstrated that analysis of multiple bulk DNA samples from a single individual allows the reconstruction of early developmental cell lineage trees. Thus, this study provides a unified set of best practices to detect somatic SNVs in non-cancerous tissues. The data and methods are freely available to the scientific community and should serve as a guide to assess the contributions of somatic SNVs to neuropsychiatric diseases.

genomics↗

bioRxiv2020

Sex differences in the human brain transcriptome of cases with schizophrenia

While schizophrenia differs between males and females in age of onset, symptomatology and the course of the disease, the molecular mechanisms underlying these differences remain uncharacterized. In order to address questions about the sex-specific effects of schizophrenia, we performed a large-scale transcriptome analysis of RNA-seq data from 437 controls and 341 cases from two distinct cohorts from the CommonMind Consortium. Analysis across the cohorts identifies a reproducible gene expression signature of schizophrenia that is highly concordant with previous work. Differential expression across sex is reproducible across cohorts and identifies X- and Y-linked genes, as well as those involved in dosage compensation. Intriguingly, the sex expression signature is also enriched for genes involved in neurexin family protein binding and synaptic organization. Differential expression analysis testing a sex-by-diagnosis interaction effect did not identify any genome-wide signature after multiple testing corrections. Gene coexpression network analysis was performed to reduce dimensionality and elucidate interactions among genes. We found enrichment of co-expression modules for sex-by-diagnosis differential expression signatures, which were highly reproducible across the two cohorts and involve a number of diverse pathways, including neural nucleus development, neuron projection morphogenesis, and regulation of neural precursor cell proliferation. Overall, our results indicate that the effect size of sex differences in schizophrenia gene expression signatures is small and underscore the challenge of identifying robust sex-by-diagnosis signatures, which will require future analyses in larger cohorts.

genomics↗

bioRxiv2018

Dynamic landscape and genetic regulation of RNA editing in schizophrenia

RNA editing is vital for neurodevelopment and the maintenance of normal neuronal function. We surveyed the global landscape and genetic regulation of RNA editing across several hundred schizophrenia and control postmortem brain samples from the CommonMind Consortium covering two regions, the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex. In schizophrenia, RNA editing sites encoding AMPA glutamate receptors and post-synaptic density genes were less edited, while more editing was detected in sites implicated in translational initiation. These sites replicate between brain regions, map to 3UTRs, enrich for common sequence motifs and coincide for RNA binding proteins crucial for neurodevelopment. Importantly, these findings cross-validate in hundreds of non-overlapping DLPFC samples. Furthermore, ~30% of RNA editing sites associate with cis-regulatory variants (edQTLs). Fine-mapping edQTLs with schizophrenia GWAS loci revealed colocalization of 11 edQTLs with 6 GWAS loci. This supports a causal role of RNA editing in risk for schizophrenia. Our findings illustrate widespread altered RNA editing in schizophrenia and its genetic regulation, and shed light onto RNA editing-mediated mechanisms in schizophrenia neuropathology.

neuroscience↗

bioRxiv2018

Unperturbed Expression Bias of Imprinted Genes in Schizophrenia

How gene expression correlates with schizophrenia across individuals is beginning to be examined through analyses of RNA-seq from post-mortem brains of individuals with disease and control brains. Here we focus on variation in allele-specific expression, following up on the Common Mind Consortium (CMC) RNA-seq experiments of nearly 600 human dorsolateral prefrontal cortex (DLPFC) samples. Analyzing the extent of allelic expression bias--a hallmark of imprinting--we find that the number of imprinted human genes is consistent with lower estimates ({approx}0.5% of all genes) and thus contradicts much higher estimates. Moreover, the handful of putatively imprinted genes are all in close genomic proximity to known imprinted genes. Joint analysis of the imprinted genes across hundreds of individuals allowed us to establish how allelic bias depends on various factors. We find that age and genetic ancestry have gene-specific, differential effect on allelic bias. In contrast, allelic bias appears to be independent of schizophrenia.

genomics↗