Bovine tuberculosis (bTB) poses serious risks to animal welfare and economy, as well as to public health as a zoonosis. Its etiological agent, Mycobacterium bovis, belongs to the Mycobacterium tuberculosis complex (MTBC), a group of genetically monomorphic organisms featured by a remarkably high overall nucleotide identity (99.9%). Indeed, this characteristic is of major concern for correct typing and determination of strain-specific traits based on sequence diversity. Due to its historical economic dependence on cattle production, Uruguay is deeply affected by the prevailing incidence of Mycobacterium bovis. With the world’s highest number of cattle per human, and its intensive cattle production, Uruguay represents a particularly suited setting to evaluate genomic variability among isolates, and the diversity traits associated to this pathogen. We compared 186 genomes from MTBC strains isolated worldwide, and found a highly structured population in M. bovis. The analysis of 23 new M. bovis genomes, belonging to strains isolated in Uruguay evidenced three groups present in the country. Despite presenting an expected highly conserved genomic structure and sequence, these strains segregate into a clustered manner within the worldwide phylogeny. Analysis of the non-pe/ppe differential areas against a reference genome defined four main sources of variability, namely: regions of difference (RD), variable genes, duplications and novel genes. RDs and variant analysis segregated the strains into clusters that are concordant with their spoligotype identities. Due to its high homoplasy rate, spoligotyping failed to reflect the true genomic diversity among worldwide representative strains, however, it remains a good indicator for closely related populations. This study introduces a comprehensive population structure analysis of worldwide M. bovis isolates. The incorporation and analysis of 23 novel Uruguayan M. bovis genomes, sheds light onto the genomic diversity of this pathogen, evidencing the existence of greater genetic variability among strains than previously contemplated.

The phylogeographical history of the pest fly screwworm, Cochliomyia hominivorax (Coquerel), was studied using partial mitochondrial DNA sequences of the control region, Cytochrome c oxidase (CO) subunit I and CO subunit II from 361 individuals collected across its current geographic range. Analyses showed marked genetic differentiation on a macrogeographic scale. The genetic diversity in the species is structured into four main “regional groups,” corresponding to Cuba, the Dominican Republic, and the North and South Amazon region. Results indicated that the distribution of screwworm genetic diversity was mainly shaped by historical events, i.e., colonization of Caribbean islands, vicariance in the Amazon region and population expansion. Demographic history analyses revealed that the population expansion started ≈20–25,000 yr ago and recently increased exponentially. We hypothesized that the initial period of expansion was probably associated with environmental amelioration in the late Pleistocene and the exponential increase with resource availability in recent times. The population expansion is probably responsible for the low divergence and the lack of genetic and geographic correlation in the South Amazon region but did not erase the genetic structure pattern on a continental scale. The screwworm is one of the most damaging livestock pests in South and Central America, and the pattern of genetic variability distribution reported here suggests that the Caribbean area and the North and South Amazon regions could be considered as independent units for future pest control programs.

Activation-induced cytidine deaminase (AID) initiates somatic hypermutation and class switch recombination of the immunoglobulin genes. As a trade-off for its physiological function, AID also contributes to tumor development through its mutagenic activity. In chronic lymphocytic leukemia (CLL), AID is overexpressed in the proliferative fractions (PFs) of the malignant B lymphocytes, and its anomalous expression has been associated with a clinical poor outcome. Recent preclinical data suggested that ibrutinib and idelalisib, 2 clinically approved kinase inhibitors, increase AID expression and genomic instability in normal and neoplastic B cells. These results raise concerns about a potential mutagenic risk in patients receiving long-term therapy. To corroborate these findings in the clinical setting, we analyzed AID expression and PFs in a CLL cohort before and during ibrutinib treatment. We found that ibrutinib decreases the CLL PFs and, interestingly, also reduces AID expression, which correlates with dampened AKT and Janus Kinase 1 signaling. Moreover, although ibrutinib increases AID expression in a CLL cell line, it is unable to do so in primary CLL samples. Our results uncover a differential response to ibrutinib between cell lines and the CLL clone and imply that ibrutinib could differ from idelalisib in their potential to induce AID in treated patients. Possible reasons for the discrepancy between preclinical and clinical findings, and their effect on treatment safety, are discussed.

Extreme drought events have increased in frequency during the 20th century triggered by global change. Thus, understanding tree-growth resilience across different terrestrial biomes has become a key goal in forest ecology. Here, we evaluate the tree-growth resilience to severe drought in the only Mediterranean-type Ecosystems of South America, using five isolated populations ofNothofagus macrocarpa. For each tree, in each sampling site, we obtained wood cores and fresh leaves for dendrochronological and population genetic analysis, respectively. An evaluation was conducted on growth resilience components in response to the most extreme drought of the 20th century in central Chile (i.e., 1968, with ∼80% of rainfall deficit), and the influence of genetic variability, biogeography, and tree size. We hypothesize that even though current remnant populations ofN. macrocarpaare small and isolated, they have locally withstood changes in climate, and that they will be genetically diverse and have a high resilience to extreme droughts. We used nuclear microsatellite markers to estimate tree genetic variability inN. macrocarpaand investigate its correlation with phenotypic traits. We found a higher resistance in the two southernmost populations (mesic sites) than in the three northern populations (xeric sites), however those three xeric populations showed a higher recovery. In addition, a significant clear positive linear correlation between precipitation and resistance, and a negative recovery and relative resilience of tree growth to the extreme drought event of 1968 can be seen. High diversity for simple sequence repeats (SSR) markers was observed, although no population structure was inferred. Southern populations had a higher number of private alleles, which may be an indication of their long-lasting persistence under mesic conditions. Therefore, differences in resilience components are mainly explained by tree size and sites influences, but not genetic diversity. We concluded that observed differences in tree-growth resilience among sites can be explained by a great deal of phenotypic plasticity, fostered by genetically diverse gene pools. We advocate for a genome-wide analysis (i.e., SNP) so as to identify genomic regions correlated with phenotypic traits in order to improve the understanding of the evolutionary processes that shaped this forest resilience over time.