Project Grant R35GM154595

MOLECULAR MECHANISMS AND EVOLUTION OF NATURAL TELOMERIC VARIATION - PROJECT SUMMARY THIS PROPOSAL WILL STUDY THE PLANT MONKEYFLOWER (MIMULUS) TO ADDRESS WHY TELOMERE LENGTHS VARY BETWEEN INDIVIDUALS, AND HOW THAT VARIATION AFFECTS AN ORGANISM'S FITNESS AND ULTIMATELY ITS EVOLUTION. TELOMERES ARE DNA-PROTEIN COMPLEXES FOUND AT ENDS OF EUKARYOTIC CHROMOSOMES AND HAVE THE CRUCIAL ROLE OF PROTECTING CHROMOSOME ENDS FROM GENOMIC INSTABILITY. CHANGES IN THE TELOMERE LENGTH CAN HAVE CATASTROPHIC CONSEQUENCES FOR AN ORGANISM, FOR INSTANCE IN HUMANS ABERRANT TELOMERE LENGTHS CAN LEAD TO TUMORIGENESIS AND AGING-RELATED DISEASES. PARADOXICALLY, DESPITE THE POTENTIAL DELETERIOUS CONSEQUENCES, TELOMERE LENGTHS ARE HIGHLY VARIABLE WITHIN NATURAL ORGANISMS INDICATING A POTENTIAL FUNCTIONAL MECHANISM MAINTAINS VARIABLE TELOMERE LENGTHS WITHIN POPULATIONS. UNCOVERING THE MECHANISMS OF TELOMERE LENGTH REGULATION AND UNDERSTANDING THE BIOLOGICAL SIGNIFICANCE OF NATURAL TELOMERIC VARIATION IS CRUCIAL, AS IT PROVIDES THE FRAMEWORK FOR UNDERSTANDING HUMAN TELOMERE VARIATION WITH POTENTIAL RELEVANCE FOR UNDERSTANDING HUMAN PREDISPOSITION TO AGING AND ASSOCIATED DISEASES. HOWEVER, THE CAUSES AND THE BIOLOGICAL CONSEQUENCES OF TELOMERE LENGTH VARIATION ARE POORLY UNDERSTOOD, AND ADDRESSING THIS GAP IN KNOWLEDGE IS THE LONG-TERM GOAL OF MY LAB. AS A FIRST STEP TO ACHIEVE THIS GOAL MY RESEARCH HAS ESTABLISHED PLANTS AS A NOVEL SYSTEM TO STUDY TELOMERE GENETICS AND EVOLUTION. I DISCOVERED PLANT TELOMERE LENGTHS ARE ASSOCIATED WITH VARIATION IN REPRODUCTIVE LIFE-HISTORY TRAITS (I.E. TIME TO FLOWERING) AND ADAPTIVE EVOLUTION HAS SHAPED THE GENETIC VARIANTS CONTROLLING THE TELOMERE LENGTH VARIATION. BASED ON THESE OBSERVATIONS I PROPOSE A HYPOTHESIS THAT TELOMERE LENGTH AFFECTS CELLULAR DEVELOPMENT BY INFLUENCING STEM CELLS IN GROWTH CENTERS, AND THIS ULTIMATELY HAS CONSEQUENCES FOR DEVELOPMENT OF THE WHOLE ORGANISM. THIS HYPOTHESIS FUNDAMENTALLY EXPLAINS WHY TELOMERE LENGTH VARIES WITHIN AND BETWEEN POPULATIONS. THIS PROPOSAL WILL EMPIRICALLY TEST THIS HYPOTHESIS BY USING MIMULUS AS A MODEL AND TAKE A MECHANISTIC APPROACH OF UNDERSTANDING THE FUNCTION AND EVOLUTION OF TELOMERE LENGTH VARIATION AND ITS CAUSAL LINK WITH DEVELOPMENTAL GROWTH. BECAUSE THE MOLECULAR COMPONENTS OF THE TELOMERE ARE LARGELY CONSERVED BETWEEN ANIMALS AND PLANTS, THIS STUDY HAS THE POTENTIAL TO UNCOVER THE MOLECULAR AND EVOLUTIONARY RULES OF TELOMERE FUNCTION THAT ARE SHARED ACROSS EUKARYOTES. THE PROPOSED WORK WILL INVESTIGATE THE MECHANISTIC LINK BETWEEN THE TELOMERE LENGTH AND CELLULAR DEVELOPMENT OF PLURIPOTENT STEM CELLS THAT DIFFERENTIATE INTO WHOLE PLANT. WORK WILL ALSO INVESTIGATE THE EVOLUTIONARY CONSEQUENCES ARISING FROM THE LINK BETWEEN TELOMERE AND DEVELOPMENTAL GROWTH, EXAMINING ITS ROLE IN DRIVING THE ADAPTIVE EVOLUTION OF TELOMERE REGULATING GENES AND ITS ROLE IN SELECTING FOR THE LIFE-HISTORY STRATEGY IN NATURAL POPULATIONS. ULTIMATELY, THIS RESEARCH WILL ESTABLISH THE BASIC FRAMEWORK FOR UNDERSTANDING THE MOLECULAR AND EVOLUTIONARY EFFECTS ARISING FROM THE TELOMERE, WITH RESULTS THAT CAN HAVE BROAD APPLICABILITY FOR OTHER ORGANISMS, INCLUDING HUMANS.