Evolutionary medicine Petr Müller Molecular and Cellular Pathophysiology • Timeline of evolutionary events that determine human diseases • Evolution and non-genetic adaptation to enviromental changes - lifestyle changes and the effect of cultural evolution • Evolutionary pressure and adaptation in other animal species • Evolutionary trade-offs and and civilization diseases Evolutionary medicine is the study of how evolutionary processes have produced human traits/disease and how evolutionary principles can be applied in medicine. A timeline of evolutionary events → A timeline patterns of human disease risk → Evolutionary medicine and genetic diseases How evolutionary medicine explains complex genetic diseases 1. natural selection does not result in perfect bodies but operates on relative reproductive fitness 2. mismatch between our biological legacy and our modern environments 3. trade-offs, the idea that there are combinations of traits that cannot be simultaneously optimized by natural selection 4. evolutionary conflicts. Traits expressed by complex metazoans are a balanced compromise between different genetic elements and bodily systems Viewing disease through the lens of evolution provides a flexible and powerful framework for defining and classifying disease. genotypes lead to disease in all environments specific pairing of environment and genotype Most diseases fall between these extremes (lines B and C) Reaction norms Representations of how the expressed phenotype for a genotype varies in response to a range of environments. The evolutionary necessity of disease / the impact of environment "Selfish gene theory" Gene-centered view of evolution natural selection does not result in perfect bodies but operates on relative reproductive fitness • Altruism, cooperation, suicide • Transposons, genetic waste information • Sexual selection vs. Natural selection A model of the phylogeny of H. sapiens over the last 600,000 years (vertical axis). Interbreeding between archaic and modern humans HLA-B*73 introgressed from Denisovans into modern humans in western Asia Tibetan people EGLN1 and EPAS1 gene variant, associated with hemoglobin concentration Higher genetic diversity cohabitation of non-relatives cooperation Slaves to wheat: How a grain domesticated us Unlike animals, the survival of humans is currently much less determined by their genetic information. Much more important to human evolutionary fitness has become information obtained non-genetically Neolithic revolution, cooperation and cultural evolution Cultural evolution is the idea that human cultural change––that is, changes in socially transmitted beliefs, knowledge, customs, skills, attitudes, languages, and so on––can be described as a Darwinian evolutionary process Mechanisms of evolutionary adaptations in different animal species The traits related to common human diseases • Cancer • Ageing • Pathogen/infection resistance Cancer and Peto's paradox • the incidence of cancer does not appear to correlate with the number of cells in an organism • In order to build larger and longer-lived bodies, organisms required greater cancer suppression. Evolutionary „trade off“: Body size vs. risk of cancer Mice altered to express "always-on" active TP53 exhibited increased tumor suppression ability, but also showed signs of premature aging. (TP53 cannot be the only explanation) Make more protein Protein synthesis inhibition Adaptive immunity Regeneration and healingCancer Protein aggregation Fitness Energy savings Longevity Weakling Immunocom promised Starvation Autophagy Glucocorticoid signallingmTOR signalling Growth factor AMPK activation Balance of protein production and its regulation Interspecies and intraspecies competition AMPK signalling Autophagy https://www.cellsignal.com/pat hways/ampk-signaling-pathway mTOR and growth factor signalling https://www.cellsignal.com/path ways/mtor-signaling-pathway Autophagy https://www.cellsignal.com/pathwa ys/autophagy-signaling-pathway How can we affect protein homeostasis ? https://www.bio-rad-antibodies.com/blog/history-of-rapamycin.html • Georges Nógrády was trying to understand why the inhabitants of Easter Island, despite walking around barefoot • The Ayerst Pharmaceuticals team was able to identify a new antifungal compound in the soil samples that was produced by the bacterium Streptomyces hygroscopicus • Identification of the mTOR Signaling Network • Rapamycin’s eventual development into a clinical compound (Rapamune), used to prevent organ transplant rejection and treatment for some cancers Prolonged lifespan Treat cancer Impaired healing Immunosuppression Gompertz–Makeham law of mortality The Gompertz–Makeham law states that the human death rate is the sum of an agedependent component (the Gompertz function, named after Benjamin Gompertz), which increases exponentially with age and an age-independent component (the Makeham term, named after William Makeham). Estimated probability of a person dying at each age, for the U.S. in 2003. Mortality rates increase exponentially with age after age 30. Probability of death age- independent component Naked mole rats defy the biological law of aging (Heterocephalus glaber) • rarely get cancer • resistant to some types of pain • survive up to 18 minutes without oxygen. In contrast to the mortality hazards of other mammals, which increased with chronological age, the mortality hazard of naked mole-rats remained constant. The evolution of prolonged life after reproduction primitive indigenous people orcas prolonged post-reproductive lifespans (PRLSs) Mechanisms of innate immunity (fast but non-specific response) Detection of pathogenic microorganisms • Membrane receptors • Intracellular receptors of foreign nucleic acids • Cytokine signalling Intracellular signalling pathways Activation of transcription / gene expression • Expression of cytokines • Activation of specific immune response • Elimination of microorganisms • Use of gene Mechanisms of innate immunity Toll-like receptors (TLRs) TLR TLR NF-κB Activated by extracellular signals from pathogens: Polysacharides, RNA, DNA, proteins, lipopeptides, endotoxins,.. IRFs IFN IFNAR gamma-activated sequences, IFN-stimulated response elements GAS ISRE STAT Cyclic GMP-AMP synthase Cytoplasmic sensor of DNA Cyclic guanosine monophosphate– adenosine monophosphate cGAS ATP+GTPER Stimulator of interferon genes STIN G cGAMP Interferone receptors IRGs – interferone regulated genes Cytokines Host-directed editing enzymes: APOBEC, ADAR, AID.. APOBEC family members APOBEC1 APOBEC2 APOBEC3A APOBEC3B APOBEC3C APOBEC3D APOBEC3F APOBEC3G APOBEC3H APOBEC4 AID (activation induced deaminase) • APOBEC ("apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like") is a family of evolutionarily conserved cytidine deaminases. • Discovered due to their ability to eliminate HIV infection • When misregulated, are a major source of mutation in numerous cancer types. • AID is a part of adaptive immunity; it is responsible for hypermutation of variable immunoglobulin regions in lymphocytes The results suggest that the heterogeneous mutation patterns are mainly reflections of host (i) antiviral mechanisms that are achieved through APOBEC, ADAR, and ZAP proteins, and (ii) probable adaptation against reactive oxygen species. Signatures of Mutational Processes in Human CancerSignature 2 has been attributed to activity of the AID/APOBEC family of cytidine deaminases. Loss of genes in NF-κB signalling pathway Expansion of the APOBEC3 gene locus https://twitter.com/bat1kgenomes?s=20