Supplement 9-1

1
Supplement 9-1
The following slides present data which supports
the views taken in Figures 9-4 and 9-6 of the
textbook. These data present empirical evidence
supporting 1) the existence of modifier or minor
effect genes, 2) the fact that they outnumber the
major effect genes, and 3) the important role
they play in modulating the action of the major
effect genes. They also illustrate the
synergistic negative effect that low levels of
abnormal proteins may have on the individual
organism via their acting at the
post-translational level to disrupt protein
folding, clog up the protein disposal systems,
and generally raise havoc with many of the cells
mechanisms. The result is a loss of cell function
and eventual death.
2
Let us start with the evidence for hsp
involvement in longevity
Both HSF ISP are required for extended longevity
3
hsf in muscle tissue extends life span
hsf in neural or intestinal tissue also extends
life span
4
Ex. 2
ts Mutations With Low Effect Act As Significant
Modifiers of PolyQ Genes in
Caenorhabiditis
Pre-existing abnormal proteins synergistically
enhance the effects of other abnormal proteins,
accelerate onset of senescence
From Gidalevitz et al. Science 3111471, 2006
5
MnSOD Deficiency in Mice is a Monogenic Trait
Significantly Modified by Other Genes
Survival of short lived strain 1 QTL from long
lived strain (116.1 on next slide)
Survival of short-lived strain
Survival of F1 hybrid strain
Huang et al, Hum. Mol. Gen. 151187, 2006
6
MnSOD Effects Are Modified By The mt-NNT Gene on
the Same Chromosome

7
Huang et al, Hum. Mol. Gen. 151187, 2006
NNT is postulated to modify the effects of MnSOD
deficiency due to NNTs ability to decrease the
internal ROS levels in the mitochondria, and thus
decrease the rate of increase of mt ROS.
NNT nicotinamide nucleotide transhydrogenase
8
MnSOD Deficiency in Mice is a Monogenic Trait
Significantly Modified by Other Genes
Ex. 1
But these data only explain the C57BL/6J DBA/2J
difference in this one QTL. They do NOT explain
the extra difference between DBA/2J and B6D2F1.
To explain those differences, you must postulate
the existence of additional modifier genes. Thus
the number of modifier genes is at least 2 (and
probably 5). Thus the of modifier genes gt of
major genes.
What does that inequality mean from the viewpoint
of genetic architecture?
Huang et al, Hum. Mol. Gen. 151187, 2006
9
What does that inequality mean from the viewpoint
of genetic architecture?
It means that modifier genes exist for both the
ADS genes for hsps. There are more modifier
genes than major genes. The modifier genes can
cause synergistic effects in enhancing or
decreasing cell function.
BUT, if the modifier genes are so potent, then
how is it that certain Tx can bring about
systemic effects?
10
Reducing I-IGF /or dFOXO Signaling Halts
Cardiac Aging in Flies
heart rate
heart failure rate
But Cardiac Aging Can Be Restarted by Excess
JH which is itself regulated by dFOXO
from Wessels et al., Nature Genetics 361275, 2004
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FOXO3a Levels Senescence Are Causally Connected
in Human Fibroblasts in vitro
from Kim et al., JGBS 60A4-9, 2005
12
Drug Interventions Extend Longevity in Flies
HDAc-Inhibitors Work in Flies
The HDAcs specifically induce many
stress-resistance genes.
The Drug Activates the Flys Stress
Resistance Genes
Glucoregulatory drugs extend longevity in rats.
(Spindler et al., 2004)
from Kang et al., PNAS 99 (2)838, 2002
13
Old Animals Have Lower Levels of Signals Than Do
Young AnimalsBut Their Cells Are Still
Responsive
Cells from Old Animals Put in Culture and Bathed
with Sera from Young Animals Have Higher
Incidence of Activated Regenerating Cells Than Do
Old Cells in Old Sera.
Pair Old or Young Animals via Common Circulatory
System.. Measure Their Ability to Regenerate
Damaged Muscle.
Old Animals Regenerate Better When They Have
Young Blood Circulating!
Old Cells Are Activated to Regenerate By Sera
From Young Animals!
Aging May Be A Software Problem Not A
Hardware Problem!
from Conboy et al., Nature 433760, 2005
14
The Transition from Health to Senescence is
Regulated by Major Minor Genes Acting at the
Cell Level
And what about the minor effect genes, what do
they have to do with a gene interaction network?
JH ---------l
from Arking, 2005, based on work from the
Morimoto lab
15
Senescence May Start With the Degradation of the
Gene Interaction Network
1
2

hubs spokes
4
3
6
5
 
after Giot et al, 2003