DNA methylation is required to maintain both DNA replication timing precision and 3D genome organization integrity

DNA replication timing and three-dimensional (3D) genome organization are associated with distinct epigenome patterns across large domains. However, whether alterations in the epigenome, in particular cancer-related DNA hypomethylation, affects higher-order levels of genome architecture is still unclear. Here, using Repli-Seq, single-cell Repli-Seq, and Hi-C, we show that genome-wide methylation loss is associated with both concordant loss of replication timing precision and deregulation of 3D genome organization. Notably, we find distinct disruption in 3D genome compartmentalization, striking gains in cell-to-cell replication timing heterogeneity and loss of allelic replication timing in cancer hypomethylation models, potentially through the gene deregulation of DNA replication and genome organization pathways. Finally, we identify ectopic H3K4me3-H3K9me3 domains from across large hypomethylated domains, where late replication is maintained, which we purport serves to protect against catastrophic genome reorganization and aberrant gene transcription. Our results highlight a potential role for the methylome in the maintenance of 3D genome regulation

A 1000-year-old case of Klinefelter's syndrome diagnosed by integrating morphology, osteology, and genetics.

Xavier Roca-Rada, Sofia Tereso, Adam B Rohrlach, André Brito, Matthew P Williams, Cláudia Umbelino, Francisco Curate, Ira W Deveson, Yassine Souilmi, António Amorim, Pedro C Carvalho, Bastien Llamas, João C Teixeir

Assessment of Inter-Laboratory Differences in SARS-CoV-2 Consensus Genome Assemblies between Public Health Laboratories in Australia

Whole-genome sequencing of viral isolates is critical for informing transmission patterns and for the ongoing evolution of pathogens, especially during a pandemic. However, when genomes have low variability in the early stages of a pandemic, the impact of technical and/or sequencing errors increases. We quantitatively assessed inter-laboratory differences in consensus genome assemblies of 72 matched SARS-CoV-2-positive specimens sequenced at different laboratories in Sydney, Australia. Raw sequence data were assembled using two different bioinformatics pipelines in parallel, and resulting consensus genomes were compared to detect laboratory-specific differences. Matched genome sequences were predominantly concordant, with a median pairwise identity of 99.997%. Identified differences were predominantly driven by ambiguous site content. Ignoring these produced differences in only 2.3% (5/216) of pairwise comparisons, each differing by a single nucleotide. Matched samples were assigned the same Pango lineage in 98.2% (212/216) of pairwise comparisons, and were mostly assigned to the same phylogenetic clade. However, epidemiological inference based only on single nucleotide variant distances may lead to significant differences in the number of defined clusters if variant allele frequency thresholds for consensus genome generation differ between laboratories. These results underscore the need for a unified, best-practices approach to bioinformatics between laboratories working on a common outbreak problem

The retroelement Lx9 puts a brake on the immune response to virus infection

The notion that mobile units of nucleic acid known as transposable elements can operate as genomic controlling elements was put forward over six decades ago. However, it was not until the advancement of genomic sequencing technologies that the abundance and repertoire of transposable elements were revealed, and they are now known to constitute up to two-thirds of mammalian genomes3,4 . The presence of DNA regulatory regions including promoters, enhancers and transcription-factor-binding sites within transposable elements5–8 has led to the hypothesis that transposable elements have been co-opted to regulate mammalian gene expression and cell phenotype8–14. Mammalian transposable elements include recent acquisitions and ancient transposable elements that have been maintained in the genome over evolutionary time. The presence of ancient conserved transposable elements correlates positively with the likelihood of a regulatory function, but functional validation remains an essential step to identify transposable element insertions that have a positive effect on fitness. Here we show that CRISPR–Cas9- mediated deletion of a transposable element—namely the LINE-1 retrotransposon Lx9c11—in mice results in an exaggerated and lethal immune response to virus infection. Lx9c11 is critical for the neogenesis of a non-coding RNA (Lx9c11-RegoS) that regulates genes of the Schlafen family, reduces the hyperinflammatory phenotype and rescues lethality in virus-infected Lx9c11−/− mice. These findings provide evidence that a transposable element can control the immune system to favour host survival during virus infection.Nenad Bartonicek, Romain Rouet, Joanna Warren, Claudia Loetsch, Gabriela Santos Rodriguez, Stacey Walters, Francis Lin, David Zahra, James Blackburn, Jillian M. Hammond, Andre L. M. Reis, Ira W. Deveson, Nathan Zammit, Mahdi Zeraati, Shane Grey, Daniel Christ, John S. Mattick, Tatyana Chtanova, Robert Brink, Marcel E. Dinger, Robert J. Weatheritt, Jonathan Sprent, Cecile Kin