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PNAS Papers on Rat Clues to Human Migration, Thyroid Cancer, PolyG-DS

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

A team from the Humboldt University Berlin, the University of Haifa, and elsewhere presents findings from an ancient DNA and fossil morphology analysis focused on an extinct eastern crested rat sub-species, Lophiomys imhausi maremortum sub-species nova — a large, rare rodent with a distribution that offers hints to potential human migration routes across the Levant. Starting with bone samples going back some 42,000 to 103,000 years from at least 16 rat representatives at the Cave of the Skulls near the Dead Sea, the researchers attempted to sequence four Lophiomys individuals, generating one ancient mitochondrial genome sequence that was subsequently compared to sequences from dozens of other rodent species. "The reported paleomitogenome is the oldest so far in the Levant, opening the door for future paleo-DNA analyses in the region," they write, adding that their species distribution models point to habitable corridors that connected eastern parts of Africa with the Levant in the past. "This finding strengthens the hypothesis that early human dispersals were prompted by climactic changes and Late Pleistocene intercontinental connectivity."

Investigators at the Chinese Academy of Medical Sciences, Beijing Hospital, and Mingma Technologies describe inherited WDR77 gene mutations with apparent ties to familial papillary thyroid cancer (PTC) risk in a paper scheduled to appear in PNAS this week. Using exome sequencing, the team searched for suspicious germline mutations in half a dozen PTC cases from two unrelated families affected by non-syndromic forms of familial, non-medullary thyroid cancer (FNMTC), identifying two loss-of-function mutations in WDR77 — part of a transmethylase enzyme complex implicated in histone H3 modifications in other animals. The authors considered the potential consequences of the germline alterations with follow-up experiments on thyroid cancer cells missing the WDR77 gene, along with RNA sequencing analyses on patient-derived thyroid tissues from an individual carrying a WDR77 mutation. "Taken together, our findings reveal a predisposing gene of FNMTC and expand the variant profile predisposing to FNMTC," they report.

A University of Washington-led team outlines a next-generation sequencing strategy aimed at assessing polyguanine tract (PolyG) repeats and related cell lineage types, clonal cell populations, and clonal expansions, including those involving mutated cells that may progress to cancer. "The ability to detect pre-cancerous clones and reconstruct cancer evolution is important for early cancer detection and improving prevention and treatment strategies," the researchers explain, noting that their PolyG-DS sequencing method relies on CRISPR-Cas9-based targeting to enrich for PolyG loci fragments as well as duplex sequencing approaches for error correction. For their proof-of-principle experiments, they applied PolyG-DS method to ulcerative colitis samples, uncovering clonal cell expansions containing precancerous alterations, and to primary, metastatic, and matched normal samples from an individual with high-grade serous carcinoma ovarian cancer. "Because PolyG-DS is driver mutation agnostic," they write, "it provides a universal, cost-effective approach for assessing tumor evolution across cancer types."