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This Week in Nature: Sep 13, 2018

In Nature this week, a University of Washington team reports on the use of saturation genome editing to evaluate the function of nearly 4,000 single-nucleotide variants (SNVs) across 13 exons that are critical to the function of the tumor-suppressor gene BRCA, and measure subsequent cell survival in haploid human cells. They identify more than 400 non-functional missense SNVs, as well as roughly 300 SNVs that disrupt expression. Notably, the functional scores are highly concordant with established assessments of pathogenicity. "We predict that these results will be immediately useful for the clinical interpretation of BRCA1 variants, and that this approach can be extended to overcome the challenge of variants of uncertain significance in additional clinically actionable genes," the authors write. GenomeWeb has more on this, here.

Also in Nature, an international research team describes a new system to identify genome-wide off-target effects of CRISPR-Cas9 genome editing. Called verification ofin vivo off-targets, or VIVO, the approach involves identifying potential off-target sites and then confirming whether any such sites have been altered after genome editing. The investigators demonstrate VIVO in mice, designing both promiscuous and highly specific guide RNAs targeted to the PCSK9 gene and showing that the former induce substantial off-target effects while the latter can direct efficient gene editing with no detectable off-targeting. "VIVO provides a general strategy for defining and quantifying the off-target effects of gene-editing nucleases in whole organisms, thereby providing a blueprint to foster the development of therapeutic strategies that use in vivo gene editing," the researchers say. GenomeWeb also has more on this, here.

And in Nature Communications, a group led by scientists from the Max Planck Institute presents an analysis of ancient DNA that provides insights into the social organization and migration of the Longobards — a 6th-century group that ruled large swaths of Italy for more than 200 years. The researchers sequenced and analyzed the genomic DNA of 63 individuals buried in two cemeteries associated with the Longobards, and found that each of the cemeteries was primarily organized around one large pedigree, "suggesting that biological relationships played an important role in these early medieval societies." The cemeteries were found to also include individuals from at least two two different groups with different ancestry and funeral customs. Evidence of admixture, meanwhile, supports a proposed theory that the Longobards migrated to Italy from what is now western Hungary. And there's more on this here, too.