Transcriptional upregulation of four genes of the lysine biosynthetic pathway by homocitrate accumulation in Penicillium chrysogenum: homocitrate as a sensor of lysine-pathway distress

The lysine biosynthetic pathway has to supply large amounts of α-aminoadipic acid for penicillin biosynthesis in Penicillium chrysogenum. In this study, we have characterized the P. chrysogenum L2 mutant, a lysine auxotroph that shows highly increased expression of several lysine biosynthesis genes (lys1, lys2, lys3, lys7). The L2 mutant was found to be deficient in homoaconitase activity since it was complemented by the Aspergillus nidulans lysF gene. We have cloned a gene (named lys3) that complements the L2 mutation by transformation with a P. chrysogenum genomic library, constructed in an autonomous replicating plasmid. The lys3-encoded protein showed high identity to homoaconitases. In addition, we cloned the mutant lys3 allele from the L2 strain that showed a G1534 to A1534 point mutation resulting in a Gly495 to Asp495 substitution. This mutation is located in a highly conserved region adjacent to two of the three cysteine residues that act as ligands to bind the iron-sulfur cluster required for homoaconitase activity. The L2 mutant accumulates homocitrate. Deletion of the lys1 gene (homocitrate synthase) in the L2 strain prevented homocitrate accumulation and reverted expression levels of the four lysine biosynthesis genes tested to those of the parental prototrophic strain. Homocitrate accumulation seems to act as a sensor of lysine-pathway distress, triggering overexpression of four of the lysine biosynthesis genes.Fil: Teves, Franco. Universidad de León; EspañaFil: Lamas Maceiras, Mónica. Universidad de León; EspañaFil: García Estrada, Carlos. Instituto de Biotecnología de León; EspañaFil: Casqueiro, Javier. Instituto de Biotecnología de León; España. Universidad de León; EspañaFil: Naranjo, Leopoldo. Universidad de León; EspañaFil: Ullán, Ricardo V.. Instituto de Biotecnología de León; EspañaFil: Scervino, Jose Martin. Instituto de Biotecnología de León; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigaciones en Biodiversidad y Medioambiente. Universidad Nacional del Comahue. Centro Regional Universidad Bariloche. Instituto de Investigaciones en Biodiversidad y Medioambiente; ArgentinaFil: Wu, Xiaobin. Instituto de Biotecnología de León; EspañaFil: Velasco Conde, Tania. Instituto de Biotecnología de León; EspañaFil: Martín, Juan F.. Instituto de Biotecnología de León; España. Universidad de León; Españ

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Inter-clonal variation in functional traits in response to drought for a genetically homogeneous Mediterranean conifer

Mediterranean trees are expected to be exposed to an increased aridity in the near future. The lack of genetic variability of stone pine (Pinus pinea L.) could limit the adaptation potential of the species to more severe droughts. However, information on intra-specific variability in adaptive traits that might confer potential drought tolerance is scant for stone pine. In this study, we explored the adaptation potential of stone pine to water deficit through variability of key functional traits. In particular, inter-clonal variation in whole plant performance in response to water deficit was studied. The role of inter-clonal variation in functional traits and phenotypic plasticity as determinants of whole plant performance under water deficit were also assessed. Relative growth rate (RGR) and key morphological and physiological traits were studied in ramets of 20 different clones of stone pine from a wide range of populations in the Iberian Peninsula. The plants were grown in climatic chamber under controlled environmental conditions and were submitted to an experimental water deficit of 20 days. The results showed significant inter-clonal variation in total dry mass, RGR, biomass partitioning specific leaf area (SLA), leaf area ratio (LAR), net photosynthetic rate (An), stomatal conductance (gs) and intrinsic water use efficiency (WUEi). Significant phenotypic plasticity in response to drought was found for An, gs and WUEi but it did not differ among clones. The clones could be clustered into different groups according to the variability of the studied traits in a principal components analysis. LAR, SLA and net photosynthetic rates explained most of the variation. A combination of traits (high LAR and low WUEi) agreeing with a water spending strategy rather than with a water saving strategy seemed to underlie enhanced RGR under water deficit. Stone pine showed high phenotypic plasticity and significant intra-specific variation in functional traits in response to water deficit. The pattern of variation found in morphological and physiological traits might allow adaptation to short term water deficit in this species

Novel genes and sex differences in COVID-19 severity.

Here we describe the results of a genome-wide study conducted in 11 939 COVID-19 positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (p < 5x10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (p = 1.3x10-22 and p = 8.1x10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (p = 4.4x10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (p = 2.7x10-8) and ARHGAP33 (p = 1.3x10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, p = 4.1x10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥ 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided