Colistin represents one of the few available drugs for treating infections caused by carbapenem-resistant Enterobacteriaceae. As such, the recent plasmid-mediated spread of the colistin resistance gene mcr-1 poses a significant public health threat, requiring global monitoring and surveillance. Here, we characterize the global distribution of mcr-1 using a data set of 457 mcr-1-positive sequenced isolates. We find mcr-1 in various plasmid types but identify an immediate background common to all mcr-1 sequences. Our analyses establish that all mcr-1 elements in circulation descend from the same initial mobilization of mcr-1 by an ISApl1 transposon in the mid 2000s (2002–2008; 95% highest posterior density), followed by a marked demographic expansion, which led to its current global distribution. Our results provide the first systematic phylogenetic analysis of the origin and spread of mcr-1, and emphasize the importance of understanding the movement of antibiotic resistance genes across multiple levels of genomic organization.

Genetic clustering algorithms, implemented in programs such as STRUCTURE and ADMIXTURE, have been used extensively in the characterisation of individuals and populations based on genetic data. A successful example is the reconstruction of the genetic history of African Americans as a product of recent admixture between highly differentiated populations. Histories can also be reconstructed using the same procedure for groups that do not have admixture in their recent history, where recent genetic drift is strong or that deviate in other ways from the underlying inference model. Unfortunately, such histories can be misleading. We have implemented an approach, badMIXTURE, to assess the goodness of fit of the model using the ancestry “palettes” estimated by CHROMOPAINTER and apply it to both simulated data and real case studies. Combining these complementary analyses with additional methods that are designed to test specific hypotheses allows a richer and more robust analysis of recent demographic history.

Significance: One of the most enduring and widely debated questions in prehistoric archaeology concerns the origins of Europe’s earliest farmers: Were they the descendants of local hunter-gatherers, or did they migrate from southwestern Asia, where farming began? We recover genome-wide DNA sequences from early farmers on both the European and Asian sides of the Aegean to reveal an unbroken chain of ancestry leading from central and southwestern Europe back to Greece and northwestern Anatolia. Our study provides the coup de grâce to the notion that farming spread into and across Europe via the dissemination of ideas but without, or with only a limited, migration of people.

Individuals with potential exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) do not necessarily develop PCR or antibody positivity, suggesting that some individuals may clear subclinical infection before seroconversion. T cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections^1–3. Here we hypothesize that pre-existing memory T cell responses, with cross-protective potential against SARS-CoV-2 (refs. ^4–11), would expand in vivo to support rapid viral control, aborting infection. We measured SARS-CoV-2-reactive T cells, including those against the early transcribed replication–transcription complex (RTC)^12,13, in intensively monitored healthcare workers (HCWs) who tested repeatedly negative according to PCR, antibody binding and neutralization assays (seronegative HCWs (SN-HCWs)). SN-HCWs had stronger, more multispecific memory T cells compared with a cohort of unexposed individuals from before the pandemic (prepandemic cohort), and these cells were more frequently directed against the RTC than the structural-protein-dominated responses observed after detectable infection (matched concurrent cohort). SN-HCWs with the strongest RTC-specific T cells had an increase in IFI27, a robust early innate signature of SARS-CoV-2 (ref. ¹⁴), suggesting abortive infection. RNA polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and SARS-CoV-2 clades. RNA polymerase was preferentially targeted (among the regions tested) by T cells from prepandemic cohorts and SN-HCWs. RTC-epitope-specific T cells that cross-recognized HCoV variants were identified in SN-HCWs. Enriched pre-existing RNA-polymerase-specific T cells expanded in vivo to preferentially accumulate in the memory response after putative abortive compared to overt SARS-CoV-2 infection. Our data highlight RTC-specific T cells as targets for vaccines against endemic and emerging Coronaviridae.

The mobile resistance gene bla_NDM encodes the NDM enzyme which hydrolyses carbapenems, a class of antibiotics used to treat some of the most severe bacterial infections. The bla_NDM gene is globally distributed across a variety of Gram-negative bacteria on multiple plasmids, typically located within highly recombining and transposon-rich genomic regions, which leads to the dynamics underlying the global dissemination of bla_NDM to remain poorly resolved. Here, we compile a dataset of over 6000 bacterial genomes harbouring the bla_NDM gene, including 104 newly generated PacBio hybrid assemblies from clinical and livestock-associated isolates across China. We develop a computational approach to track structural variants surrounding bla_NDM, which allows us to identify prevalent genomic contexts, mobile genetic elements, and likely events in the gene’s global spread. We estimate that bla_NDM emerged on a Tn125 transposon before 1985, but only reached global prevalence around a decade after its first recorded observation in 2005. The Tn125 transposon seems to have played an important role in early plasmid-mediated jumps of bla_NDM, but was overtaken in recent years by other elements including IS26-flanked pseudo-composite transposons and Tn3000. We found a strong association between bla_NDM-carrying plasmid backbones and the sampling location of isolates. This observation suggests that the global dissemination of the bla_NDM gene was primarily driven by successive between-plasmid transposon jumps, with far more restricted subsequent plasmid exchange, possibly due to adaptation of plasmids to their specific bacterial hosts.