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Genomes and Disease. www.womanstats.org India: 933 girls/ 1000 boys Haryana: 834 girls/ 1000 boys China: 837 girls / 1000 boys Genomic data can be.

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Presentation on theme: "Genomes and Disease. www.womanstats.org India: 933 girls/ 1000 boys Haryana: 834 girls/ 1000 boys China: 837 girls / 1000 boys Genomic data can be."— Presentation transcript:

1 Genomes and Disease

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

5 Genomes and Disease 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 How do we translate genome sequence into disease prediction?

6 Development and Disease: Disorders of Human Development

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

8 The eye specification regulatory network

9 Deep conservation of Pax 6 and eye development

10 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

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

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13 Development and Disease: Disorders of Human Development

14 tinman (nkx2.5) mutants lack a heart

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

16 A conserved heart specification network

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

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

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

20 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

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

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

23 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

24 Aging: The Inevitable? Disease Walter Breuning, 114 years old ( ) Record: Jeanne Calment, 122 yrs, 164 days

25 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

26 control Protein oxidation Lifespan Extra SOD and catalase

27 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

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

29 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 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! Can select for long-lived stocks in flies and lifespan mutants in different systems Therefore, lifespan can be genetically programmed Reproduction can be uncoupled from lifespan

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

31 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 Mutants in Dauer Formation Also Show Effects on Lifespan Link between stress resistance and longevity Stress may also increase lifespan: Stress is good!

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

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34 chico Insulin Receptor Pathway Regulates Lifespan in Flies and Mice

35 Nervous System Control Over Aging

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

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

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39 L1Adult 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

40 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 The Germline Signals to Activate Daf-16 in the Intestine

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42 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

43 Lifespan extension also decreases age-related diseases

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45 -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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