How deep evolutionary history can affect human health

Transcription

1 How deep evolutionary history can affect human health Ahmed Ihab MD, PhD Associate Prof. of Molecular Medicine Date : 13 / 10 / 2016

2 Objectives By the end of this session you should be able to: 1. Distinguish between competing theories to explain the singular origin of the eukaryotic cell 2. Understand how the evolutionary interactions between host cell and endosymbiont can drive the evolution of deep functional traits of all eukaryotes, such as sexes and senescence, and underpin the broad structure and physiology of modern mammalian cells 3. Appreciate that selection forces acting to maintain or improve fitness over generations can actually lower fitness within generations, especially after reproductive maturity 4. Understand how different systems, such as fertility, aerobic capacity and environmental adaptability can impact on the diseases of old age.

3 The three domains of life

4 An evolutionary scandal All complex life is eukaryotic. The eukaryotic cell only arose once in 4 billion years. Eukaryotes share universal traits like the nucleus, mitosis, sex, phagocytosis, organelles, etc. Prokaryotes show virtually no tendency to evolve morphological complexity, or any these eukaryotic traits. BUT if each these traits evolved step by step, and each step has a selective advantage, why did none evolve in prokaryotes?

5 Eyes evolved independently scores times why not sex or the nucleus?

6

7 A black hole at the heart of biology All eukaryotes share traits essentially absent from prokaryotes: Nucleus, nuclear membrane, nuclear pore complexes, nucleolus, straight chromosomes, telomeres, introns and exons, spliceosomes Separation of transcription (nucleus) and translation (cytosolic ribosomes) Reciprocal sex (two-step meiosis and syngamy), mitosis, tubulin spindle Dynamic cytoskeleton, motor proteins, eukaryotic cilia and flagella Phagocytosis Endomembrane systems, (ER, golgibody, lysosomes, mitochondria) Generally much larger genomes and cell volumes Below LECA there is a phylogenomic event horizon As soon as all these traits were established in LECA, there was a big-bang radiation of the eukaryotic supergroups why?

8 All eukaryotes have or had mitochondria Giardia lamblia (mitosomes) Entamoeba (mitosomes) Trichomonas (hydrogenosomes) Microsporidia (derived fungi) These cells were all thought to be true evolutionary intermediates but turn out not to be: they are all ecological intermediates that became simpler. All of them once had mitochondria and lost them by reductive evolution. The Last Eukaryotic Common Ancestortherefore had mitochondria

9 Some genomic evidence suggests that the eukaryotic cell arose via a stochastic (and very rare) endosymbiosis between two prokaryotes The search engine of natural selection, acting on vast populations of cells over billions of years, does not intrinsically give rise to complexity

10 Host cell: an Archaeon a) Based on 29 concatenated sequences of highly conserved informational proteins; b) based on 63 concatenated protein sequences. RNA trees with wider sampling give same result.

11 Two, not three, primary domains of life Phylogenetic studies show that eukaryotes branch within archaea, hence only two primary domains The host cell for the eukaryotes was an archaeon Williams TA et al. An archaeal origin of eukaryotes supports only two primary domains of life. Nature 504: ; 2013.

12 A cell within a cell What good is that?

13 What did mitochondria do for us? 1.Compartmentalisation? No, many prokaryotes compartmentalise themselves 2.Aerobic respiration? No, many prokaryotes respire oxygen and many mitochondria don t 3.Protection against oxygen toxicity? No, mitochondria are the main source of ROS leak 4.Speed of respiration? No, gram per gram many prokaryotes respire faster

14 Eukaryotes versus prokaryotes

15 ATP expenditure in microbes

16 Energy per gene

17 Prokaryotes respire over their cell membrane

18 Cells need genes to control respiration Mitochondrial genes enabled eukaryotes to expand in size over 4-5 orders of magnitude Paramecium

19 Test case giant bacteria

20 Extreme polyploidy in giant bacteria Epulopiscium nucleoids Thiomargarita nucleoids

21 The problem with full genomes

22 What happens in eukaryotes? A cell within a cell has it s own cell division machinery enabling it to divide independently within the host cell

23

24

25 Reductive evolution of endosymbiont genomes Rickettsia Carsonella Buchnera Wolbachia Unlike extreme polyploidy, individual cells can compete with each other, and the fastest replicators (with the smallest genomes) WIN. Consequence: genome size gets smaller

26 Genome size shrinks in symbiotic bacteria

27 The energy savings of gene loss - Energy savings from 5% gene loss from 100 endosymbionts equates to 4 microns of de novo synthesis and assembly of actin filament every second - Mitochondria lost 99% of their genes, and there can be 300,000 mitochondria in amoebae

28 Energy per genome

29 The defining signature of eukaryotes: genomic asymmetry

30 Why endosymbiosis is necessary?

31 It follows that Complex life requires genomic asymmetry giant nuclear genomes supported by tiny mitochondrial genomes Mitochondrial and nuclear genes MUST work together (co-adapt) for respiration to work BUT the two genomes differ in tempo and mode of evolution there must be selection for function

32 Selection for co-adaptation High proportion of neutral mutations in both mitochondrial and nuclear genes encoding mitochondrial proteins Evolutionary concordance in amino-acid substitution rates in subunits encoded by mitochondrial and nuclear genomes Lower respiratory rates in various mtdna cybrids(but transcription and translation less sensitive) Introgression of mitochondria against alien nuclear background undermines fitness, survival, exercise capacity, growth and development

33 How does selection for mitonuclear function work? - Selection for optimal mitonuclear function is achieved by mtdna homoplasmy - Same principles apply to all forms of mitochondrial mutation - Heteroplasmy must undermine mitonuclear function unless defective mitochondria can be selectively eliminated

34

35

36 Sexes increase mitochondrial variance between cells UPI + bottleneck generates clonal populations of mitochondria, both good and bad BPI generates heteroplasmic mitochondria, hard for selection to distinguish between Sex increases variance in nuclear genes between individuals Two sexes increases variance in mitochondrial genes between individuals Recombination between mitochondrial genes is BAD because it decreases variance

37 How does selection work at molecular level?

38 What if the genomes don t match? APOPTOSIS High ROS leak, low ATP, loss of cytochrome c = apoptosis ROS = reactive oxygen species, e.g. superoxide, hydrogen peroxide Explains the double role of cytochrome c in respiration and apoptosis a discovery first greeted with general stupefaction (Hengartner, Nature 1998)

39 Why does apoptosis involve mitochondria and the respiratory protein cytochrome c? This arrangement makes perfect sense if mitonuclear coadpatation is central to cell physiology If the two genomes do not function well together, the biophysical outcome is high ROS leak, oxidation of membrane lipids, release of cytochrome c, and apoptosis Apoptosis can then be seen as a type of functional selection for mismatched mitochondrial and nuclear genomes The end of a cell by Odra Noel

40 The price of selection for mitonuclearmatch: INFERTILITY Oocyte maturation and atresia But can t select for intergenomic coadaptation during Dictyate as nuclear background is not yet determined Embryonic development 40% of pregnancies end in early occult miscarriage (Zinaman et al, 1996). Childhood/adult life mitochondrial diseases lower fecundity and survival

41 Origin of species? Marine copepod Tigriopus californicus Santa Cruz Island California Hybrids between isolated populations lead to mitonuclear incompatibilities and loss of fitness A step en route to speciation?

42 How good does mitonuclear match need to be?

43 How good does mitonuclear match need to be?

44 Apoptotic threshold is variable

45 Trade-off between aerobic fitness, fertility, adaptability and ageing High threshold, high ROS leak Low aerobic capacity High tolerance of heteroplasmy High incidence of mitochondrial diseases Good adaptability to environmental change High fertility High incidence of chronic inflammatory diseases Fast ageing Low threshold, low ROS leak High aerobic capacity Low tolerance of heteroplasmy Low incidence of mitochondrial diseases Poor adaptability to environmental change Low fertility Low incidence of chronic inflammatory diseases Slow ageing

46 Conclusions The eukaryotic cell arose ONCE in 4 billion years of evolution, possibly as a stochastic consequence of an endosymbiosis between two prokaryotes The distinction between eukaryotes and prokaryotes is not the nucleus alone but the extreme genomic asymmetry in which tiny mitochondrial genomes support a massive nuclear genome A mosaic respiratory chain is necessary for the existence of complex life ROS leak enables selection for mitonuclear coadaptation via apoptosis Species with high aerobic demands should have a low apoptotic threshold Low threshold = long lifespan, low fertility, low adaptability, and vice versa