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PNAS Papers on Ancient Orkney, Cancer Immune Evasion, Functional Analysis of Psychiatric Risk Gene

Editor's Note: Some of the articles described below are not yet available at the PNAS site but are scheduled to be posted this week.

A team from the UK, Germany, Ireland, and Portugal presents findings from an ancient DNA analysis of Bronze Age individuals in Orkney — a noted Neolithic cultural hub where there has been scant evidence of a subsequent Beaker culture that was present in mainland Britain. With sequence data for 22 Bronze Age and three Iron Age representatives from northwest Orkney, the researchers saw signs of migration into Orkney. Although some Mesolithic mitochondrial lineages and local Neolithic ancestry persisted in male lineages well into the Iron Age, Pontic-Caspian Steppe ancestry and incoming mitochondrial DNA lineages also turned up. "We find clear evidence for Early Bronze Age immigration into Orkney," the authors report, "but with an extraordinary pattern: continuity from the Neolithic on the male line of descent but immigration from continental Europe on the female side, echoed in the genome-wide picture."

Investigators at Harvard, Brigham and Women's Hospital, the Dana-Farber Cancer Institute, and the Broad Institute search for cancer immune evasion contributors with a CRISPR-Cas9-based gene-editing screen. By systematically targeting some 500 tumor suppressor genes, the team saw signs that chromatin and transcriptional regulators — particularly CTCF and cohesin ring components such as STAG2 or RAD21 — can dial down PD-L1 immune checkpoint activity in human cells. Likewise, the authors note, levels of PD-L2 and major histocompatibility complex (MHC) class I on the cell surface rose in the absence of RAD21, prompting follow-up analyses on the transcriptional consequences of lower-than-usual STAG2 levels. "Our findings … elucidate transcriptional changes of immune-related pathways as well as up-regulation of key immune regulatory molecules including PD-L1, PD-L2, and MHC in cohesin-deficient cells," they note, "which could have significant implications on [the] cancer microenvironment of cohesin-deficient tumors."

A Swedish-led team explores previously described ties between psychiatric conditions and the voltage-gated calcium channel-coding gene CACNA1C. With mouse knockout model and cell line experiments, including imaging, electrophysiological assays, and RT-qPCR-based screens for CACNA1C-related neuronal ion channel gene expression during neural differentiation, the investigators found brain development and behavioral differences in mice missing the calcium channel gene. From such findings, they call the CACNA1C gene product a "molecular switch" that may contribute to psychiatric disease susceptibility via calcium channel activity in neural progenitor cells. "Our findings reveal that disruption of Cacna1c perturbs spontaneous [calcium ion] activity in neural progenitors," the authors say, "affecting cerebral cortical development and causing anxiety in adulthood."

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