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PNAS Papers on Danish Genealogy, Bloom Syndrome Complex Assembly, Tumor-Associated Macrophages

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.

Investigators in Denmark, Spain, and the US use Danish genealogy to dig into diagnostic heritability for a paper scheduled to appear in PNAS this week. After bringing together national registry data for more than 9.8 million individuals living in Denmark from the late 1960s to early 2017, the team teased out genealogical patterns going back as far as six generations with data on some 6.8 individuals with one or more relatives in the registry. With this resource, the authors went on to estimate heritability and genetic correlations across 10 diagnostic categories ranging from mental or neurological to gastrointestinal conditions. "The presented resource and analytical framework will contribute to the advancement of precision medicine," they write, "allowing the systematic mapping of heritabilities and genetic correlations of comorbidity patterns and sub-diagnostic traits such as age of onset and treatment response and to inform on clinically relevant phenomena such as assortative mating, non-additive genetics, and shared environment."

A team from Australia and the UK focuses in on the assembly of a Bloom syndrome complex comprised of four proteins — including topoisomerase and helicase enzymes as well as RMI1 and RMI2 replication proteins — known for contributing to genome stability. "Mutations in any component of the Bloom syndrome complex can cause genome instability and a highly cancer-prone disorder called Bloom syndrome," the researchers write, explaining that they used cross-link mass spectrometry, biochemical assays, and other approaches to follow assembly of these complexes. Together, they say, the results "provide structural information about overall [Bloom syndrome] complex assembly and dimerization."

Researchers at the Chinese Academy of Sciences, Beijing Tongren Hospital, and Capital Medical University present mouse model findings pointing to a role for the miR-182 microRNA in tumor-associated macrophage innate immune cell reprogramming — a process that can pave the way for breast cancer progression. Using available transcriptome sequence data, fluorescence in situ hybridization, immunofluorescence, mouse gene knockouts, and other experiments, the team found that dialing down levels of miR-182 or alternatively activated tumor-associated macrophages could dampen tumor progression, while alternative macrophage activation and tumor growth were bumped up by miR-182. "Macrophages … can be educated by tumors to an alternatively activated phenotype that is known to promote tumor progression," they note. "Understanding the mechanism of macrophage education by tumor cells will help the design of new therapeutic approaches."

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