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Genomes and Disease

Genomes and Disease. Genomic data can be used for good or bad. India: 933 girls/ 1000 boys Haryana: 834 girls/ 1000 boys China: 837 girls / 1000 boys. www.womanstats.org. Exclusion from insurance coverage for “pre-existing” genotypes Genetic discrimination Eugenics. Genomes and Disease.

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Genomes and Disease

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  1. Genomes and Disease

  2. Genomic data can be used for good or bad India: 933 girls/ 1000 boys Haryana: 834 girls/ 1000 boys China: 837 girls / 1000 boys www.womanstats.org Exclusion from insurance coverage for “pre-existing” genotypes Genetic discrimination Eugenics

  3. Genomes and Disease How do we translate genome sequence into disease prediction? What is a genetic “disease” as opposed to an acceptable trait? Is it a disease to be short statured? Below average intelligence? Is it a disease to be gay? Do we know enough about genomes and evolution to make germline changes? e.g. Certain alleles of hemoglobin cause Sickle Cell Anemia when homozygous, but protection from Malaria when heterozygous

  4. Development and Disease: Disorders of Human Development

  5. eyeless/Pax6 is necessary and sufficient for eye formation Wild type antennae wing eyeless antennae leg Ectopic expression of eyeless/Pax6 Walter Gehring and colleagues

  6. The eye specification regulatory network

  7. Deep conservation of Pax 6 and eye development

  8. Pax 6 is also required for eye specification in mouse small eye phenotype is caused by being heterozygous for mutations in Pax 6 Homozygotes are lethal with no eyes +/+ Pax 6 -/+ Pax 6 -/- Expression of mouse Pax 6 makes eyes in Drosophila

  9. Pax 6 mutants lead to congenital eye defects in humans Pax6 +/- mutant leads to loss of iris (aniridia) along with other eye defects

  10. Development and Disease: Disorders of Human Development

  11. tinman (nkx2.5) mutants lack a heart

  12. Mutations in Nkx2.5 cause congenital heart defects Patients heterozygous for mutations exhibit a range of defects

  13. A conserved heart specification network

  14. Leading Causes of Death, United States 2007 National Vital Statistics Report May 2010 on data for 2007

  15. The genes that control organ development can also control adult function and homeostasis Nkx2.5 is expressed in the adult mouse heart

  16. Nkx2.5 function is still required post-natally CRE-ER to delete Nkx2.5 at birth Heart contraction defects Reduced ion channel expression 50% mortality after 3 weeks PMID:18689573 Also showed direct Nkx2.5 regulation of ion channel genes

  17. Tinman also regulates heart differentiation/function genes in Drosophila dSUR is a component of an ATP-sensitive K+ channel that regulates heart physiology/stress response dSUR is directly regulated by tinman and pannier (GATA) Reductionof dSUR increases heart failure under stress

  18. The Fly as a surprising model for adult heart physiology, disease and aging aging Disrupted lipid metabolism ion channel disruption

  19. Leading Causes of Death, United States 2007 National Vital Statistics Report May 2010 on data for 2007

  20. What has/can Development teach us about Cancer? -Cell-cell signaling -Cell fate specification and tumor cell origin -Differentiation/cell cycle arrest vs. dedifferentiation/proliferation -Growth control/tissue size restraint vs. independence -Apoptosis -Cell adhesion -Cell migration/metastasis -Vasculature development

  21. Aging: The Inevitable? Disease Walter Breuning, 114 years old (1896-2001) Record: Jeanne Calment, 122 yrs, 164 days

  22. The Oxygen Paradox: Oxygen is essential for aerobic respiration yet oxidative damage is toxic and a likely cause of senescence Reactive oxygen species (ROS) cause: -Membrane fatty acid peroxidation -Protein modification/destruction -DNA damage

  23. Lifespan Protein oxidation control Extra SOD and catalase

  24. The Oxygen Paradox: Oxygen is essential for aerobic respiration yet oxidative damage is toxic and a likely cause of senescence Reactive oxygen species (ROS) cause: -Membrane fatty acid peroxidation -Protein modification/destruction -DNA damage Metabolic Potential: There is an inherent limit to total amount of O2 consumed in a lifetime -Decreased temperature extends lifespan in cold-blooded animals -Flies that can’t fly live 2.5 times longer -Inverse correlation b/w lifespan and reproduction

  25. Caloric Restriction Increases Lifespan Also true for Flies, Worms and Yeast! Mice During times of limited nutrients, it may be advantageious to switch metabolic resources from reproduction to somatic maintenance

  26. BUT, Metabolic Potential Can’t be the Whole Story Cellular senescence is not inevitable: The Germline is immortal Lifespans don’t always fit metabolic potential model: e.g. Mice live 2-3 yrs Rats live 3 yrs Squirrels live 25 yrs Bats live 30-50 yrs e.g. Honey Bees -Queen and worker have same genotype -Worker lives few months -Queen lives up to 5 years -Queen eats copiously and constantly reproduces -It’s Good to be the Queen! Reproduction can be uncoupled from lifespan Can select for long-lived stocks in flies and lifespan mutants in different systems Therefore, lifespan can be genetically programmed

  27. Single Gene Mutations Can Dramatically Affect Lifespan in C. elegans daf-2 age-1 2-3 fold increase in lifespan (=150-200 yrs old for human) daf-2, clk-1 double mutant: 5-7 fold increase in lifespan = 500 years for human!! daf-16 daf-18 Decrease lifespan

  28. Mutants in Dauer Formation Also Show Effects on Lifespan daf = dauer formation defective Dauer larvae: alternate developmental “stasis” stage -increased stress tolerance -increased fat storage -decreased metabolism -decreased reproduction Induced by starvation or other high-stress conditions dauer phermone detected by sensory system Link between stress resistance and longevity Stress may also increase lifespan: Stress is good!

  29. daf-16:GFP Some Lifespan Mutants are in the Insulin Signaling Pathway 37 in C. elegans Activation normally decreases lifespan Signaling represses daf-16 Increased Lifespan e.g. Superoxide dismutase Nelson and Padgett, 2003

  30. Insulin Receptor Pathway Regulates Lifespan in Flies and Mice chico

  31. Nervous System Control Over Aging

  32. The Insulin Receptor Pathway is Required in the Nervous System All Neurons All Cells mutant wt transgene Muscle Intestine Note: other data indicates this pathway is also important in the worm intestine and fly fat body--both adipose tissues

  33. BUT, the Nervous System Can Also Negatively Regulate Lifespan Smelling or tasting food may be as detrimental to lifespan as eating it! Mutations affecting sensory neurons can increase lifespan

  34. L1 Adult Z2, Z3 = germline Z1, Z4 = somatic gonad -Germline ablation increases lifespan -Blocking gametogenesis does not - Ablation of both germline and somatic gonad restores normal lifespan -Therefore, increase in lifespan is not directly due to reduced metabolic cost of not reproducing -Lifespan is regulated by SIGNALS from the germline through somatic gonad -Signal appears dependent on germline stem cells

  35. The Germline Signals to Activate Daf-16 in the Intestine Germline ablation causes daf-16 nuclear accumulation in adult intestine/adipose tissue Animals with daf-16 expression only in intestine respond normally to germline ablation Therefore, germline signal likely acts through daf-16 in intestine C. Kenyon and colleagues

  36. Reconciling (somewhat) metabolic and genetic models of aging The same pathways that respond to metabolism can also be regulated genetically and subject to variation and evolution AA sensing Redox sensing Energy sensing Glucose sensing

  37. Lifespan extension also decreases age-related diseases

  38. -4-phenylbutyrate, histone deacetylase inhibitor (Sir2 is deacetylase, so unclear why inhibiting deacetylases would extend life) -Treated flies have normal fecudity and movement -Treated flies are stress resistant (more healthy!) -Previously FDA approved for other uses

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