Natural products from reconstructed bacterial genomes of the Middle and Upper Paleolithic

Major advances over the past decade in the field of ancient DNA are providing access to past paleogenomic diversity, but the diverse functions and biosynthetic capabilities of this growing paleome remain largely elusive. We investigated the dental calculus of 12 Neanderthals and 52 anatomically modern humans ranging from 100,000 years ago to the present and reconstructed 459 bacterial metagenome-assembled genomes. We identified a biosynthetic gene cluster shared by seven Middle and Upper Paleolithic individuals that allows for the heterologous production of a class of previously unknown metabolites that we name “paleofurans.” This paleobiotechnological approach demonstrates that viable biosynthetic machinery can be produced from the preserved genetic material of ancient organisms, allowing access to natural products from the Pleistocene and providing a promising area for natural product exploration. Description Editor’s summary With advances in the technologies used to extract and analyze ancient DNA, we are learning more about the microorganisms that lived around and within our distant human ancestors and hominin cousins. However, little is yet known about the kinds of molecules these organisms might produce or their roles in health and disease. Klapper et al. extracted metagenome-assembled genomes of bacteria in dental calculus from ancient human and Neandertal remains. Natural product biosynthetic gene clusters in these samples were distinctive, and heterologous expression of these clusters yielded 5-alkylfuran-3-carboxylic acid products that the authors refer to as paleofurans. Such methods for resurrecting ancient microbial natural products may provide insight into the nutrition and health of early hominins—and potentially bioactive compounds lost to time. —Michael A. Funk Ancient metagenomes allow for resurrection of Pleistocene bacterial metabolites.