The Irish potato famine pathogen Phytophthora infestans originated in central Mexico rather than the Andes

Phytophthora infestans is a destructive plant pathogen best known for causing the disease that triggered the Irish potato famine and remains the most costly potato pathogen to manage worldwide. Identification of P. infestan’s elusive center of origin is critical to understanding the mechanisms of repeated global emergence of this pathogen. There are two competing theories, placing the origin in either South America or in central Mexico, both of which are centers of diversity of Solanum host plants. To test these competing hypotheses, we conducted detailed phylogeographic and approximate Bayesian computation analyses, which are suitable approaches to unraveling complex demographic histories. Our analyses used microsatellite markers and sequences of four nuclear genes sampled from populations in the Andes, Mexico, and elsewhere. To infer the ancestral state, we included the closest known relatives Phytophthora phaseoli, Phytophthora mirabilis, and Phytophthora ipomoeae, as well as the interspecific hybrid Phytophthora andina. We did not find support for an Andean origin of P. infestans; rather, the sequence data suggest a Mexican origin. Our findings support the hypothesis that populations found in the Andes are descendants of the Mexican populations and reconcile previous findings of ancestral variation in the Andes. Although centers of origin are well documented as centers of evolution and diversity for numerous crop plants, the number of plant pathogens with a known geographic origin are limited. This work has important implications for our understanding of the coevolution of hosts and pathogens, as well as the harnessing of plant disease resistance to manage late blight.The potato pathogen Phytophthora infestans, the causal agent of potato late blight, is the plant pathogen that has most greatly impacted humanity to date. This pathogen is best known for its causal involvement in the Irish potato famine after introduction of the HERB-1 strain to Ireland from the Americas in the 19th century (1). To this day, potato late blight remains a major threat to food security and carries a global cost conservatively estimated at more than $6 billion per year (2). In the 1980s, a single asexual lineage named US-1, possibly derived from the same metapopulation as HERB-1 (1), dominated global populations, whereas a genetically diverse and sexual population of P. infestans in central Mexico led to formulation of the hypothesis identifying Mexico as this pathogen’s center of origin (3, 4). A competing hypothesis argues that the center of origin of the potato, the South American Andes, is the center of origin of P. infestans (5). This hypothesis recently gained prominence after an analysis demonstrated ancestral variation in Andean lineages of P. infestans (5). Other evidence supporting this hypothesis includes infection of native Solanum hosts and an Andean distribution for Phytophthora andina, a phylogenetic relative of P. infestans (6).Evidence supporting a Mexican center of origin is substantial, but inconclusive (4). Two close relatives of P. infestans, Phytophthora ipomoeae and Phytophthora mirabilis, are endemic to central Mexico (7, 8). P. ipomoeae and P. mirabilis cause disease on two endemic plant host groups, Ipomoea spp. and Mirabilis jalapa, respectively. Populations of P. infestans in the Toluca Valley, southwest of Mexico City, are genetically diverse, are in Hardy–Weinberg equilibrium, and contain mating types A1 and A2 in the expected 1:1 ratio for sexual populations (9, 10). Before a migration event from Mexico to Europe in the 1970s (11, 12), only A1 mating types of P. infestans were found worldwide outside of central Mexico, limiting other populations to asexual reproduction (13). Tuber-bearing native Solanum species occur throughout the Toluca Valley (14). Of the R genes that have been used to confer resistance to strains of P. infestans in potato, the majority described to date originated from Solanum demissum or Solanum edinense in the Toluca Valley, with some discovered in South America (15).Support for the alternate hypothesis that P. infestans originated in the Andes is based on a coalescent analysis conducted by Gómez-Alpizar et al. (5). This analysis used the nuclear RAS locus and the mitochondrial P3 and P4 regions to infer rooted gene genealogies that showed ancestral lineages rooted in the Andes. Furthermore, the Mexico sample harbored less nucleotide diversity than the Andean population. P. andina was identified as the ancestral lineage for the mitochondrial genealogy; however, P. mirabilis and P. ipomoeae were not included in that study. P. andina has since been shown to be a hybrid species derived from P. infestans and a Phytophthora sp. unknown to science (16). Surprisingly, populations of P. infestans and P. andina are clonal in South America and are not in Hardy–Weinberg equilibrium (6, 17–19). Thus, the question of whether P. infestans originated in the Andes or central Mexico remained unresolved.Powerful approaches for determining the demographic and evolutionary history of organisms are now available (20). Many of these approaches rely on the power of coalescent theory for inferring the genealogical history of a species based on a representative population sample (21–23). Bayesian phylogeography uses geographic information in light of phylogenetic uncertainty to provide model-based inference of geographic locations of ancestral strains (24). The isolation with migration (IM) model and associated software uses likelihood-based inference to infer divergence time between evolutionary lineages (25). Approximate Bayesian computation (ABC) makes use of coalescent simulations and likelihood-free inference to contrast complex demographic scenarios. Each of these methods has proven useful in reconstructing the demography of pests and pathogens (24, 26–29).The objective of the present study was to reconcile the two competing hypotheses on the origin of P. infestans using Bayesian phylogenetics and ABC. We sampled key populations of P. infestans from central Mexico and the Andes and expanded on the analysis of Gómez-Alpizar et al. (5) by sequencing additional nuclear loci to assess support for the center of origin across multiple loci. To determine ancestral state, we added sequences from the sister taxa P. andina, P. mirabilis, P. ipomoeae, and Phytophthora phaseoli, all of which belong to Phytophthora clade 1c (30, 31). Finally, we aimed to reconcile the biology of P. infestans in Mexico with the findings of Gómez-Alpizar et al. (5) of ancestral variation in the Andes.     

Effects of canagliflozin on initiation of insulin and other antihyperglycaemic agents in the CANVAS Program

This study compared initiation of insulin and other antihyperglycaemic agents (AHAs) with canagliflozin versus placebo for participants with type 2 diabetes and a history/high risk of cardiovascular disease in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. After 1 year, fewer participants treated with canagliflozin versus placebo initiated any AHA (7% vs. 16%), insulin (3% vs. 9%) or any non-insulin AHA (5% vs. 12%) (P < .001 for all); overall AHA initiation rates increased over time but were consistently lower with canagliflozin compared with placebo. During the study, the likelihood of initiating insulin was 2.7 times lower for participants treated with canagliflozin compared with placebo (hazard ratio, 0.37; 95% CI: 0.31, 0.43; P < .001). The time difference between 10% of patients in the canagliflozin and placebo groups being initiated on insulin from the beginning of the trial was about 2 years. Time to initiation of other AHAs, including metformin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sulphonylureas, was also delayed for canagliflozin versus placebo (P < .001 for each). Compared with placebo, canagliflozin delayed the need for initiation of other AHAs and delayed time to insulin therapy, an outcome that is important to many people with diabetes.