Postmitotic cell longevity–associated genes: a transcriptional signature of postmitotic maintenance in neural tissues

Different cell types have different post-mitotic maintenance requirements. Nerve cells, however, are unique in this respect as they need to survive and preserve their functional complexity for the entire lifetime of the organism and failure at any level of their supporting mechanisms, leads to a wide range of neurodegenerative conditions. Whether these differences across tissues arise from the activation of distinct cell type-specific maintenance mechanisms or the differential activation of a common molecular repertoire is not known. In order to identify the transcriptional signature of post-mitotic cellular longevity (PMCL), we compared whole genome transcriptome data from human tissues ranging in longevity from 120 days to over 70 years and found a set of 81 genes whose expression levels are closely associated with increased cell longevity. Using expression data from ten independent sources, we found that these genes are more highly co-expressed in longer living tissues and are enriched in specific biological processes and transcription factors targets compared to randomly selected gene samples. Crucially, we found that PMCL-associated genes are down-regulated in the cerebral cortex and substantia nigra of Alzheimer’s and Parkinson’s disease patients as well as Hutchinson-Gilford progeria-derived fibroblasts, and that this down regulation is specifically linked to their underlying association with cellular longevity. Moreover, we found that sexually dimorphic brain expression of PMCL-associated genes reflects sexual differences in lifespan in humans and macaques. Taken together our results suggest that PMCL-associated genes are part of a generalized machinery of post-mitotic maintenance and functional stability in both neural and non-neural cells and support the notion of a common molecular repertoire differentially engaged in different cell types with different survival requirements

Causes and consequences of purifying selection on SARS-CoV-2

Owing to a lag between a deleterious mutation’s appearance and its selective removal, gold-standard methods for mutation rate estimation assume no meaningful loss of mutations between parents and offspring. Indeed, from analysis of closely related lineages, in SARS-CoV-2, the Ka/Ks ratio was previously estimated as 1.008, suggesting no within-host selection. By contrast, we find a higher number of observed SNPs at 4-fold degenerate sites than elsewhere and, allowing for the virus’s complex mutational and compositional biases, estimate that the mutation rate is at least 49–67% higher than would be estimated based on the rate of appearance of variants in sampled genomes. Given the high Ka/Ks one might assume that the majority of such intrahost selection is the purging of nonsense mutations. However, we estimate that selection against nonsense mutations accounts for only ∼10% of all the “missing” mutations. Instead, classical protein-level selective filters (against chemically disparate amino acids and those predicted to disrupt protein functionality) account for many missing mutations. It is less obvious why for an intracellular parasite, amino acid cost parameters, notably amino acid decay rate, is also significant. Perhaps most surprisingly, we also find evidence for real-time selection against synonymous mutations that move codon usage away from that of humans. We conclude that there is common intrahost selection on SARS-CoV-2 that acts on nonsense, missense, and possibly synonymous mutations. This has implications for methods of mutation rate estimation, for determining times to common ancestry and the potential for intrahost evolution including vaccine escape

Transcription, mRNA export, and immune evasion shape the codon usage of viruses

The nucleotide composition, dinucleotide composition, and codon usage of many viruses differ from their hosts. These differences arise because viruses are subject to unique mutation and selection pressures that do not apply to host genomes; however, the molecular mechanisms that underlie these evolutionary forces are unclear. Here, we analyzed the patterns of codon usage in 1,520 vertebrate-infecting viruses, focusing on parameters known to be under selection and associated with gene regulation. We find that GC content, dinucleotide content, and splicing and m(6)A modification-related sequence motifs are associated with the type of genetic material (DNA or RNA), strandedness, and replication compartment of viruses. In an experimental follow-up, we find that the effects of GC content on gene expression depend on whether the genetic material is delivered to the cell as DNA or mRNA, whether it is transcribed by endogenous or exogenous RNA polymerase, and whether transcription takes place in the nucleus or cytoplasm. Our results suggest that viral codon usage cannot be explained by a simple adaptation to the codon usage of the host—instead, it reflects the combination of multiple selective and mutational pressures, including the need for efficient transcription, export, and immune evasion

Presence-absence variation in <em>A.</em> <em>thaliana</em> is primarily associated with genomic signatures consistent with relaxed selective constraints

The sequencing of multiple genomes of the same plant species has revealed polymorphic gene and exon loss. Genes associated with disease resistance are overrepresented among those showing structural variations, suggesting an adaptive role for gene and exon presence–absence variation (PAV). To shed light on the possible functional relevance of polymorphic coding region loss and the mechanisms driving this process, we characterized genes that have lost entire exons or their whole coding regions in 17 fully sequenced Arabidopsis thaliana accessions. We found that although a significant enrichment in genes associated with certain functional categories is observed, PAV events are largely restricted to genes with signatures of reduced essentiality: PAV genes tend to be newer additions to the genome, tissue specific, and lowly expressed. In addition, PAV genes are located in regions of lower gene density and higher transposable element density. Partial coding region PAV events were associated with only a marginal reduction in gene expression level in the affected accession and occurred in genes with higher levels of alternative splicing in the Col-0 accession. Together, these results suggest that although adaptive scenarios cannot be ruled out, PAV events can be explained without invoking them

Modular and coordinated expression of immune system regulatory and signaling components in the developing and adult nervous system

During development, the nervous system (NS) is assembled and sculpted through a concerted series of neurodevelopmental events orchestrated by a complex genetic programme. While neural-specific gene expression plays a critical part in this process, in recent years, a number of immune-related signaling and regulatory components have also been shown to play key physiological roles in the developing and adult NS. While the involvement of individual immune-related signaling components in neural functions may reflect their ubiquitous character, it may also reflect a much wider, as yet undescribed, genetic network of immune–related molecules acting as an intrinsic component of the neural-specific regulatory machinery that ultimately shapes the NS. In order to gain insights into the scale and wider functional organization of immune-related genetic networks in the NS, we examined the large scale pattern of expression of these genes in the brain. Our results show a highly significant correlated expression and transcriptional clustering among immune-related genes in the developing and adult brain, and this correlation was the highest in the brain when compared to muscle, liver, kidney and endothelial cells. We experimentally tested the regulatory clustering of immune system (IS) genes by using microarray expression profiling in cultures of dissociated neurons stimulated with the pro-inflammatory cytokine TNF-alpha, and found a highly significant enrichment of immune system-related genes among the resulting differentially expressed genes. Our findings strongly suggest a coherent recruitment of entire immune-related genetic regulatory modules by the neural-specific genetic programme that shapes the NS

Modular reorganization of the global network of gene regulatory interactions during perinatal human brain development.

BACKGROUND During early development of the nervous system, gene expression patterns are known to vary widely depending on the specific developmental trajectories of different structures. Observable changes in gene expression profiles throughout development are determined by an underlying network of precise regulatory interactions between individual genes. Elucidating the organizing principles that shape this gene regulatory network is one of the central goals of developmental biology. Whether the developmental programme is the result of a dynamic driven by a fixed architecture of regulatory interactions, or alternatively, the result of waves of regulatory reorganization is not known. RESULTS Here we contrast these two alternative models by examining existing expression data derived from the developing human brain in prenatal and postnatal stages. We reveal a sharp change in gene expression profiles at birth across brain areas. This sharp division between foetal and postnatal profiles is not the result of pronounced changes in level of expression of existing gene networks. Instead we demonstrate that the perinatal transition is marked by the widespread regulatory rearrangement within and across existing gene clusters, leading to the emergence of new functional groups. This rearrangement is itself organized into discrete blocks of genes, each targeted by a distinct set of transcriptional regulators and associated to specific biological functions. CONCLUSIONS Our results provide evidence of an acute modular reorganization of the regulatory architecture of the brain transcriptome occurring at birth, reflecting the reassembly of new functional associations required for the normal transition from prenatal to postnatal brain development

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues