2. Robustness mechanisms in biology Rüdiger W. Brause

3. sheet 2 NiSIS Workshop, Mallorca 2006 R.Brause: Nature-inspired Robustness Introduction Robustness, NOT evolvability or stability for  disturbances in ecosystems  cell response to environmental or genetic change  computer performance at input errors, disk failures, network overload  resilience of a political institution during societal flux  viability of a technological product in wildly changing markets Robustness = aspect of structural network stability

4. sheet 3 NiSIS Workshop, Mallorca 2006 R.Brause: Nature-inspired Robustness What is biological robustness ? DEF small variances of a state Hermisson, Wagner 2005 health, fitness, phenotype against changes in underlying working conditions toxic conditions, mutations, environment changes,… compared to variance of other states to the same changes. Different from pure Adaptivityturning to a desired state Structural stabilityparam. changes lead to another structure with same behavior

5. sheet 4 NiSIS Workshop, Mallorca 2006 R.Brause: Nature-inspired Robustness Phenotypic robustness Principles Canalization Phenotype development in multi-hill fitness landscape: Only path (channel) with best fitness is taken. Here, phenotypic change by landscape change stays small. (Precondition: genetic variance). Evolutionary neutrality Huge phenotype differences, but small fitness differences: no evolutionary selection. (e.g. electrophoretic data variance of species)

6. sheet 5 NiSIS Workshop, Mallorca 2006 R.Brause: Nature-inspired Robustness Molecular mechanisms Redundancy Paralogues copies of molecules: function promote doubling does not double effect concentrations, e.g.  transcription factors  signal transduction proteins,  metabolic pathway genes  genes encoding antibody peptides

7. sheet 6 NiSIS Workshop, Mallorca 2006 R.Brause: Nature-inspired Robustness Molecular mechanisms Counter-effect of multiple copies : molecular costs are too high for fast replication & translation, e.g. viruses, bacteria. Anti-Redundancy suppression of deleterious variance high redundancy  accumulation of deleterious mutations(Muller‘s ratchet) ! AR- mechanisms needed for robustness !

8. sheet 7 NiSIS Workshop, Mallorca 2006 R.Brause: Nature-inspired Robustness Suppression of bad mutations Mutation repair and buffering Repair mechanism types for unreliable DNA copy  Excision repair: removing damaged regions  Mismatch repair: replacing non-complementary bases on double helix strands  Direct repair:reversal of nucleotide damage  Codon repair:code units of messenger mRNA sequence on transfer tRNA recognized. In case of nonsense codons, tRNA suppressed.  Nonsense-mediated mRNA decay: mRNA is supervised in cell by NMD.

9. sheet 8 NiSIS Workshop, Mallorca 2006 R.Brause: Nature-inspired Robustness Suppression of bad mutations Mutation repair and buffering (cont.) Checkpoint genes in eukaryotes (kernel based cells) e.g. p53  Stop cell development until all damage is repaired: concentration of p53 high in cells with high err. product concentration. Trigger DNA repair on threshold overshooting.  Damage too high: p53, TNF triggers cell death (apoptosis) Imprinting  masking of gene mutations (buffering) by comparing DNA strings  methylation of differences (MIP)

10. sheet 9 NiSIS Workshop, Mallorca 2006 R.Brause: Nature-inspired Robustness Suppression of bad mutations Mutation result repair and buffering Protein quality control by chaperons Checking of passing proteins, endoplasmic reticulum-induced protein degradation: no accumulation of unfolded proteins. Autophagy breaking and recycling of translated protein products of oncogenes by overexpression of the beclin gene Dominance modifiers dominant genes correct influence of defective genes on enzymatic pathways. Main reason for alleles of diploid organisms to cause no phenotypic effects.

11. sheet 10 NiSIS Workshop, Mallorca 2006 R.Brause: Nature-inspired Robustness Suppression of bad mutations Mutation result enhancement Enhancement of damages  phenotypic differences  natural selection by Accumulation of errors in long living cells: programmed cell death for long living individuals by telomere chromosome caps loss of key error repair genes (mitochondria)

12. sheet 11 NiSIS Workshop, Mallorca 2006 R.Brause: Nature-inspired Robustness Robustness by statistics codon bias codon = (c 1,c 2,c 3 ) with c i  {A,G,C,T}, 4 3 = 64 codons possible. Only 20 amino acids  ex. redundancy with pdf of nucleotides. But: pdf typical for species,  uniform pdf of mutations can be eliminated. genetic bottleneck generation transformation diploid  haploid  diploid enables strip off of deleterious mutations.  Good for small populations (small offspring, small selection).  Large populations: no bottleneck needed (bacteria, viruses).

13. sheet 12 NiSIS Workshop, Mallorca 2006 R.Brause: Nature-inspired Robustness Conclusion Robustness in biology is achieved by different mechanisms. Redundancy is used, like in technical systems. But Anti-redundancy is also necessary, to get rid of hidden (buffered) bad mutations Different organisms have different molecular mechanisms, dependent on their complexity and offspring mechanisms.