Supplement 9

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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 cell’s
mechanisms. The result is a loss of cell function and
eventual death.
Let us start with the evidence for hsp involvement in
longevity
Both HSF & ISP are required for extended longevity
hsf in muscle tissue extends life span
hsf in neural or intestinal tissue also
extends life span
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 311:1471, 2006
MnSOD Deficiency in Mice is a Monogenic Trait
Significantly Modified by Other Genes
Survival of
short-lived
strain
Survival of short lived
strain + 1 QTL from
long lived strain
(#116.1 on next
slide)
Survival of F1
hybrid strain
Huang et al, Hum. Mol. Gen. 15:1187, 2006
MnSOD Effects Are Modified By The mt-NNT Gene
on the Same Chromosome
*
Huang et al, Hum. Mol. Gen. 15:1187, 2006
NNT is postulated to modify the effects of MnSOD deficiency due to
NNT’s ability to decrease the internal ROS levels in the mitochondria,
and thus decrease the rate of increase of mt ROS.
NNT = nicotinamide nucleotide transhydrogenase
Ex. 1
MnSOD Deficiency in Mice is a Monogenic Trait
Significantly Modified by Other Genes
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.
What does that inequality mean
from the viewpoint of genetic
architecture?
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 >
# of major genes.
Huang et al, Hum. Mol. Gen. 15:1187, 2006
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?
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 36:1275, 2004
FOXO3a Levels & Senescence Are Causally
Connected in Human Fibroblasts in vitro
from Kim et al., JGBS 60A:4-9, 2005
HDAc-Inhibitors
Work
in Flies in Flies
Drug Interventions
Extend
Longevity
The HDAcs
specifically
many
stress-resistance
The Drug
Activatesinduce
the Fly’s
Stress
Resistance Genesgenes.
Glucoregulatory drugs extend
from Kang et al., PNAS 99 (2):838, 2002
longevity in rats. (Spindler et al., 2004)
Old Animals Have Lower Levels of Signals Than Do
Young Animals…But Their Cells Are Still Responsive
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!
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.
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 433:760, 2005
The Transition from Health to Senescence is Regulated
by Major & Minor Genes Acting at the Cell Level
JH ---------l
And what
about the
minor effect
genes, &
what do
they have to
do with a
“gene
interaction
network”?
from Arking, 2005, based on work from the Morimoto lab
Senescence May Start With the Degradation of
the Gene Interaction Network
1
2
hubs & spokes
4
3
6
5
after Giot et al, 2003
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