As part of a special issue of Cell — containing a collection of reviews and perspectives papers on the human genome and its role in disease research, personalized medicine, and society as a whole — Stanford University's Michael Snyder and colleagues consider the challenges associated with current gene-environment models, while presenting an alternative hierarchical analytical framework for modeling complex interactions between genes and the environment in a personalized medicine or precision health setting. Results from a simulation study using published GWAS data, for example, suggests that "the current practice based on linear models and additive genetics is appropriate for diseases with a linear genotype-phenotype mapping," the authors explain, "but is over-simplified if disease etiologies are complex and non-linear, namely involving extensive interactions among genetic components."
Researchers from the University of Pennsylvania and elsewhere outline an apparent overlap between embryonic stem cells active in mouse development and the progenitor cells that form new neurons in the adult mouse brain. The team relied on a combination of immunostaining, single-cell lineage tracing, RNA sequencing, ATAC-seq, and other approaches to assess samples from developing mouse embryos and from the adult mouse brain, including progenitor cells involved in neurogenesis in part of the hippocampus called the dentate gyrus. Based on the gene expression profiles, chromatin modification patterns, and other molecular features in such samples, the authors suggest neurogenesis in dentate gyrus region of the brain may "represent a lifelong extension of development that maintains heightened plasticity in the mammalian hippocampus," though they note that there appears to be "differential regulation of precursors to adult neural progenitors in different brain regions."
Finally, an international team led by investigators at the Wellcome Sanger Institute look at the dynamics of mutagenic processes in human cancer cell lines and patient-derived xenograft models, uncovering intermittent bursts of mutagenesis involving the cytidine deaminase DNA editing enzyme APOBEC. The researchers initially identified the APOBEC mutational signature — among others — with available exome sequencing data for 1,001 human cancer cell lines and 577 patient-derived xenografts, along with sequences for more than 2,700 cancers profiled for the International Cancer Genome Consortium. They also relied on new genome, exome, or single-cell sequences for serial samples from dozens of human cancer cell line stocks to see new and historical mutations in a handful of solid and blood cancer types. Distinct mutational signatures had specific dynamics and persistence patterns, the authors explain, noting that the APOBEC signature, in particular, "exhibited substantial fluctuations in mutation rate over time with episodic bursts of mutations." GenomeWeb has more on the study, here.