genomes and disease. india: 933 girls/ 1000 boys haryana: 834 girls/ 1000 boys china: 837 girls /...
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www.womanstats.orgIndia: 933 girls/ 1000 boys Haryana: 834 girls/ 1000 boysChina: 837 girls / 1000 boys
Genomic data can be used for good or bad
Exclusion from insurance coverage for “pre-existing” genotypesGenetic discriminationEugenics
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?
eyeless
Wild type
antennae wing
antennae leg
eyeless/Pax6 is necessary and sufficient for eye formation
Ectopic expression of eyeless/Pax6
Walter Gehring and colleagues
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
Pax 6 mutants lead to congenital eye defects in humans
Pax6 +/- mutant leads to loss of iris (aniridia) along with other eye defects
Mutations in Nkx2.5 cause congenital heart defectsPatients heterozygous for mutations exhibit a range of defects
National Vital Statistics Report May 2010 on data for 2007
Leading Causes of Death, United States 2007
Nkx2.5 is expressed in the adult mouse heart
The genes that control organ development can also control adult function and homeostasis
Nkx2.5 function is still required post-natally
PMID:18689573
CRE-ER to delete Nkx2.5 at birth
Heart contraction defects Reduced ion channel expression
Also showed direct Nkx2.5 regulation of ion channel genes50% mortality after 3 weeks
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
Disrupted lipid metabolism
aging
The Fly as a surprising model for adult heart physiology, disease and aging
ion channel disruption
National Vital Statistics Report May 2010 on data for 2007
Leading Causes of Death, United States 2007
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
Aging: The Inevitable? Disease
Walter Breuning, 114 years old (1896-2001)
Record: Jeanne Calment, 122 yrs, 164 days
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
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
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
BUT, Metabolic Potential Can’t be the Whole StoryCellular 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 yrsSquirrels live 25 yrsBats 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!
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
daf-2age-1
2-3 fold increase in lifespan (=150-200 yrs old for human)
daf-16daf-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
daf = dauer formation defectiveDauer larvae: alternate developmental “stasis” stage
-increased stress tolerance-increased fat storage-decreased metabolism-decreased reproduction
Induced by starvation or other high-stress conditionsdauer phermone detected by sensory system
Mutants in Dauer Formation Also Show Effects on Lifespan
Link between stress resistance and longevityStress may also increase lifespan: Stress is good!
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 Lifespane.g. Superoxide dismutase
daf-16:GFP
wt mutanttransgene
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
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!
L1 Adult
Z2, Z3 = germlineZ1, 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
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
Reconciling (somewhat) metabolic and genetic models of agingThe same pathways that respond to metabolism can also be regulated genetically and subject to variation and evolution
AAsensing
Redoxsensing
Energysensing
Glucosesensing