Browsing by Subject "Biological Evolution"
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Item A Developmental Algorithm for Synapse-Specific Wiring of the Drosophila Visual Map(2017-08-11) Agi, Egemen; Terman, Jonathan R.; Hiesinger, Peter Robin; Krämer, Helmut; Huber, Kimberly M.During brain development, genetic information and environmental input drive neural circuit assembly that requires matching of correct pre- and post-synaptic partners. In cases when environmental input has no instructive role in synaptic partner selection, genetic information alone must suffice to specify synapses in neural circuits. However, how a limited amount of genetic information is translated into developmental algorithms for synapse specification is unclear. A major thrust of the field has been the quest to identify guidance cues and molecular matchmaking codes underlying brain wiring. In this work, I present a complementary approach, in which the characterization of the developmental algorithm based on simple rules is the primary focus, and the molecules executing these rules secondary. I propose that simple rules underlying developmental algorithms can be sufficient to establish seemingly complex wiring diagrams without an elaborate matchmaking code between synaptic partners. I used Drosophila visual map, which is a genetically encoded neural circuit, as a model system to test my hypothesis. During visual map formation, around 4800 photoreceptors simultaneously project to their correct target layer 'lamina' in the brain to find their correct synaptic partners. I developed a 2-photon microscopy-based, intravital imaging technique with which I could observe the development of individual photoreceptor growth cones at the spatiotemporal resolution of filopodial dynamics over 24 hours during visual map formation. Based on these imaging data, I spearheaded a group effort to formulate and computationally test simple rules that are sufficient for photoreceptors to sort to their correct partners without a requirement for precise matchmaking codes. A key prediction of the model was that the post-synaptic partners may not act as target cues for the pre-synaptic photoreceptors. In the second part of my thesis, I tested this hypothesis by ablating and blocking membrane dynamics of post-synaptic partners. My findings indicate that indeed post-synaptic partners of photoreceptors do not act as target cues for photoreceptors, but are necessary during a preceding step in the developmental algorithm to ensure correct wiring. In brief, results I presented in this work support the idea that correct synaptic partner selection can be achieved through a developmental algorithm based on simple rules that sorts correct cells together prior to synapse formation.Item Doctors need evolution the way engineers need physics, but they don't get it because of politics(2018-09-11) Nesse, Randolph M.[Note: The slides are not available from this event.] The past 25 years have seen many new applications of evolutionary biology in medicine. Some investigate why natural selection has left systems vulnerable, expanding medicine's perspective from that of a mechanic to that of an engineer. Others use phylogenetic methods to trace relationships among organisms, especially pathogens. These advances have inspired a score of books, new journals, a new scientific society, and undergraduate courses in most universities. However, no medical school teaches evolutionary biology the way other basic sciences are taught, so most doctors have misconceptions that are the equivalent of engineers believing in perpetual motion. Historical, practical, political and religious factors conspire to keep evolutionary biology separate from medicine. Clinical mistakes and slowed research progress result. Recognition of the problem and the opportunity are growing but solutions are likely to be piecemeal until a new generation of doctors assumes leadership positions.Item Exploiting Evolutionary Tradeoffs to Fight Evolution of Antibiotic Resistance(2019-08-02) Tamer, Yusuf Talha; Reynolds, Kimberly A.; Rosen, Michael K.; Koh, Andrew Y.; Toprak, ErdalEvolution of antibiotic resistance is a growing public health problem around the world, and the identification of novel antimicrobials is no longer a viable approach to tackling this problem. To design smart technologies that take the evolutionary dimension into account, it is essential to understand the evolutionary process underlying the development of resistance. In nature, a single organism cannot be the most fit under all possible conditions, implying that bacterial populations that evolve resistance to antimicrobials should be less fit under other conditions. In this thesis, we report two examples of two tradeoffs in antibiotic-resistant bacterial populations. First, by studying biophysical and biochemical properties of the dihydrofolate reductase (DHFR) enzyme in Escherichia coli, we found that some mutations that conferred resistance to trimethoprim, a DHFR inhibitor, decreased drug affinity while substantially increasing substrate affinity. In addition, many of the epistatic interactions between such mutations were due to changes in the catalytic activities of DHFR mutants, rather than changes in trimethoprim affinity. We found that the high-order epistasis in catalytic power of DHFR (kcat and Km) created a rugged fitness landscape under trimethoprim selection. Taken together, these data provide a concrete illustration of how epistatic coupling at the level of biochemical parameters can give rise to complex fitness landscapes, suggesting new strategies for developing mutant specific inhibitors. In the second part of the thesis, we report that E. coli cells that evolved resistance against aminoglycosides pleiotropically evolved hypersensitivity against non-aminoglycoside antibiotics. A point mutation in a the potassium channel called TrkH decreases antibiotic efflux by altering the bacterial membrane potential. To mimic this phenotype, we designed and successfully used peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) to silence efflux genes. Specifically, by silencing the acrA gene, we transiently induced antibiotic hypersensitivity in E. coli. This sequence-specific perturbation decreased the minimum lethal dose of several antibiotics. Moreover, this approach enables combination therapies using several pairs of antagonistic drugs with non-overlapping resistance mechanisms.Item Functional Prions in Mammalian Innate Immune Signaling(2014-07-07) Cai, Xin; Zinn, Andrew R.; Beutler, Bruce; Chen, Zhijian J.; Goldstein, Joseph L.Pathogens and cellular danger signals activate mammalian cytosolic sensors such as RIG-I and NLRP3 which signal through respective adaptor proteins MAVS and ASC to produce robust innate immune and inflammatory responses. MAVS and ASC harbor N-terminal CARD and PYRIN domains, respectively, essential for their signaling ability. Using the Sup35 based yeast prion assay, we show that CARD and PYRIN function as bona fide prions in yeast when fused to Sup35C. In response to respective upstream sensors RIG-I and NLRP3, both CARD and PYRIN form self-perpetuating, SDS-resistant polymers that are inherited cytoplasmically through multiple cell divisions. Similar to other cases of prion switch, CARD exhibits nucleation- and polymerization-dependent prion conversion in yeast. Likewise, a yeast prion domain (NM) can functionally replace CARD and PYRIN in mammalian innate immune and inflammasome signaling. Mutations in MAVS and ASC that disrupt their prion activities in yeast also abrogate their ability to signal in mammalian cells. Furthermore, fibers of recombinant PYRIN can convert ASC into functional polymers capable of activating caspase-1. Remarkably, homologous domains from a conserved NOD- like receptor (NWD2) and classic prion (HET-s) in fungi can functionally reconstitute signaling of NLRP3 and ASC PYRINs in mammalian cells. These results indicate that prion- like polymerization is a conserved signal transduction mechanism in innate immunity and inflammation.Item Hypertension and nephrolithiasis: conflicts between evolution and lifestyle(1999-08-05) Moe, Orson W.Item Identification of Receptor Transporting Proteins As Conserved Antiviral Effectors in Vertebrates(2021-05-27) Boys, Ian Nicholas; Shiloh, Michael; Alto, Neal; Yan, Nan; Hancks, Dustin C.; Schoggins, John W.Viruses and their hosts are engaged in "genetic arms races" in which each side attempts to gain the advantage over evolutionary time. Results of these conflicts are wide-ranging: viruses diversify, hosts establish species-specific barriers to some viruses while remaining susceptible to others, and the lines for future genetic conflicts are drawn. In mammals, many antiviral effectors -- proteins that directly inhibit viral infection -- show species- or lineage-specific properties which are believed to be the result of past or ongoing conflicts. Bats harbor a greater diversity of viruses than any other mammalian order, and a growing body of research has described unique adaptations in bats that are in part responsible for, and perhaps a response to, this unique status. We hypothesized that the frequent encounters between bats and viruses would drive unique adaptations in the antiviral effectors that serve on the front lines of virus-host genetic conflicts. We identified RTP4 from the bat Pteropus alecto as a potent inhibitor of flavivirus infection. Mechanistic studies determined that RTP4 is an RNA-binding protein that associates with flavivirus replication machinery, binds replicating viral RNA, and suppresses viral genome amplification. Phylogenomic analysis revealed that RTP4 has evolved under positive selection in several mammalian lineages, consistent with a model in which host-virus conflicts have shaped its evolution as a restriction factor not only in bats but across mammals. We assessed the antiviral efficacy of diverse mammalian RTP4 orthologs and found that orthologs exhibit striking patterns of antiviral specificity. Further highlighting the specificity of the host-virus arms race, experimental evolution demonstrated that a flavivirus can mutate to escape RTP4-imposed restriction in a species-specific manner. In follow-up work, we identified signatures of positive selection in several non-mammalian RTP homologs, indicative of a putative role in innate immunity. We screened a collection of vertebrate RTPs against a panel of viruses and identified antiviral RTPs in the African clawed frog, Xenopus laevis. These antiviral Xenopus RTPs exhibit mosaic phenotypes that resemble those of mammalian RTP4 orthologs. Within the context of our findings with mammalian RTP4, these data suggest that Receptor Transporter Proteins are involved in host-virus genetic conflicts outside of Mammalia.Item Nephrolithiasis: journey through animal evolution and human history(2003-12-11) Moe, Orson W.Item [News](1981-10-07) Rutherford, SusanItem The STARS Evolution Suitcase(2010-11-02) Beach, Corbyn; Calver, Lewis E.To supplement the education and enthusiasm for the subject of evolution in high school, I developed a portable “science suitcase,” containing an animation, a game and a lab, for use in the classroom. The Howard Hughes Medical Institute funded this project through a grant written by Joel Goodman, Ph.D., for the STARS Science Triathlon. I surveyed teachers from the surrounding school districts, researched evolution and existing materials, and built lesson plans for the suitcase components. Teachers in the surrounding community evaluated these components, and I made revisions based on those evaluations. Once the STARS Evolution Suitcase assimilates into the high school curriculum, the teachers and students will demonstrate and evaluate its effectiveness.Item The Tradeoffs for a Viral Mutant with Enhanced Replication Speed(2021-07-26) Lanahan, Matthew Robert; Gammon, Don B.; Orchard, Robert C.; Winter, Sebastian E.RNA viruses exist as genetically heterogeneous populations due to high mutation rates and many of these mutations reduce fitness and/or replication speed. However, it is unknown whether mutations can increase replication speed of a virus already well adapted to replication in cultured cells. By sequentially passaging coxsackievirus B3 in cultured cells and collecting the very earliest progeny, we selected for increased replication speed. We found that a single mutation in a viral capsid protein, VP1-F106L, was sufficient for the fast-replication phenotype. Characterization of this mutant revealed quicker genome release during entry compared to wild-type virus, highlighting a previously unappreciated infection barrier. However, this mutation also reduced capsid stability in vitro and reduced replication and pathogenesis in mice. These results reveal a tradeoff between overall replication speed and fitness. Importantly, this approach -- selecting for the earliest viral progeny -- could be applied to a variety of viral systems and has the potential to reveal unanticipated inefficiencies in viral replication cycles.