Contract Story

ASST_NON_R21AI201898_075|

INVESTIGATING THE EVOLUTIONARY ORIGINS AND CONSEQUENCES OF STARSHIP-MEDIATED VARIATION IN FUNGI - PROJECT SUMMARY/ABSTRACT OUR OVERARCHING GOAL IS TO UNDERSTAND THE PHENOTYPIC CONSEQUENCES OF UNCONVENTIONAL EVOLUTIONARY PROCESSES. IN PARTICULAR, WE SEEK TO TEST THE HYPOTHESIS THAT A NEWLY IDENTIFIED GROUP OF GIANT TRANSPOSONS CALLED STARSHIPS RE-SHAPE THE EVOLUTION AND BIOLOGICAL PROPERTIES OF FUNGI BY GENERATING NOVEL PHENOTYPIC VARIATION AND HORIZONTALLY TRANSFERRING ADAPTIVE TRAITS UNDER STRESS. A MAJOR CHALLENGE FOR TREATING LIFE-THREATENING FUNGAL INFECTIONS IS THAT STRAINS WITHIN THE SAME SPECIES EXHIBIT SUBSTANTIAL PHENOTYPIC VARIATION THAT COMPLICATES ONE-SIZE-FITS-ALL TREATMENTS. IN THIS EXPLORATORY WORK, WE PROPOSE THAT STARSHIPS ENCODE MOLECULAR FUNCTIONS RESPONSIBLE FOR GENERATING NATURAL PATTERNS OF PHENOTYPIC VARIATION IN PATHOGEN POPULATIONS. OUR PRELIMINARY DATA SUGGEST THAT (1) STARSHIPS CARRY GENETIC CARGO THAT DIVERGENTLY REGULATE TRANSCRIPTIONAL, DEVELOPMENTAL AND METABOLIC FUNGAL PHENOTYPES AND THAT (2) STARSHIPS MEDIATE THE HORIZONTAL TRANSFER OF BIOFILM TRAITS AMONG FUNGAL STRAINS. YET THE UNDERLYING MOLECULAR MECHANISMS DRIVING STARSHIP-MEDIATED VARIATION IN FUNGAL POPULATIONS AND THEIR EVOLUTIONARY CONSEQUENCES REMAIN UNKNOWN. HERE, WE WILL DETERMINE THE EVOLUTIONARY MODES AND TRANSMISSION ROUTES OF STARSHIPS USING THE MODEL ORGANISM AND OPPORTUNISTIC FUNGAL PATHOGEN ASPERGILLUS FUMIGATUS. IN AIM 1, WE WILL DETERMINE IF STARSHIP-ASSOCIATED PARALOGS GENERATE MORE DIVERGENT PHENOTYPIC VARIATION COMPARED WITH THEIR GENOMIC PARALOGS. WE WILL TEST OUR PREDICTION BY COMPARING MULTIVARIATE TRANSCRIPTOMIC, METABOLOMIC AND MORPHOLOGICAL PHENOTYPES OF GENOMIC AND STARSHIP-ASSOCIATED MEMBERS OF THE LAEA-LIKE METHYLTRANSFERASE FAMILY, WHICH INCLUDES THE MASTER REGULATOR OF SECONDARY METABOLISM AND DEVELOPMENT LAEA. OUR FINDINGS WILL PROVIDE NECESSARY DATA TO CRITICALLY ASSESS THE ROLES OF STARSHIPS IN GENERATING EVOLUTIONARY NOVELTY. IN AIM 2, WE WILL CHARACTERIZE THE TRANSMISSION ROUTE AND ENVIRONMENTAL DRIVERS OF STARSHIP-MEDIATED HORIZONTAL GENE TRANSFER. USING A NEWLY DEVELOPED PROTOCOL FOR INDUCING HORIZONTAL STARSHIP TRANSFER IN THE LAB, WE WILL TEST OUR PREDICTION THAT STARSHIP TRANSFER OCCURS INTRACELLULARLY AS OPPOSED TO EXTRACELLULARLY AND THAT TRANSFER RATES ARE GREATEST WHEN FUNGI ARE EXPOSED TO STRESS RELATED TO CARGO GENE FUNCTION. WE WILL USE A GROUP OF STARSHIPS THAT CARRY BIOFILM ARCHITECTURE FACTOR GENES AS A MODEL TO INVESTIGATE HOW STARSHIP TRANSFER MEDIATES THE EVOLUTION OF BIOFILM FORMATION AND HYPOXIC GROWTH AT A POPULATION LEVEL. FINDINGS FROM AIM 2 WILL ADVANCE OUR UNDERSTANDING OF HOW AND WHEN GENETIC INFORMATION IS HORIZONTALLY EXCHANGED AMONG STRAINS OF THE SAME PATHOGEN SPECIES. OUR MULTIDISCIPLINARY TEAM WILL DEPLOY A CONCEPTUALLY INNOVATIVE APPROACH TO INVESTIGATE A RARELY EXAMINED SOURCE OF GENETIC VARIATION AND PHENOTYPIC HETEROGENEITY IN FUNGAL PATHOGENS. IF SUCCESSFUL, WE WILL EXPAND FUTURE WORK TO OTHER HUMAN-ASSOCIATED FUNGI BOTH WITHIN AND BEYOND ASPERGILLUS TO IMPROVE PREDICTIVE MODELS OF PATHOGEN EMERGENCE AND TO IDENTIFY STARSHIP-ASSOCIATED GENES AS THERAPEUTIC TARGETS FOR COMBATING FUNGAL INFECTIONS.