Upload
tea
View
20
Download
0
Tags:
Embed Size (px)
DESCRIPTION
The Red Death Meets the Abdominal Bristle: Polygenic Mutation for Susceptibility to a Bacterial Pathogen in Caenorhabditis elegans. Veronique Etienne 1 , Erik C. Andersen 2 , Jose Miguel Ponciano 1 , and Charles F. Baer 1 1- Dept. of Biology, University of Florida, Gainesville, FL - PowerPoint PPT Presentation
Citation preview
The Red Death Meets the Abdominal Bristle: Polygenic Mutation for Susceptibility to a
Bacterial Pathogen in Caenorhabditis elegans
Image by Alison Larsen
Veronique Etienne1, Erik C. Andersen2, Jose Miguel Ponciano1, and Charles F. Baer1
1- Dept. of Biology, University of Florida, Gainesville, FL2- Dept. of Molecular Biosciences, Northwestern University, Evanston, IL
Question (Age-old):
• When “something is going around”, why do some individuals become deathly ill, other individuals only get mildly sick and other individuals don’t get sick at all?
Question (Age-old):
• When “something is going around”, why do some individuals become deathly ill, other individuals only get mildly sick and other individuals don’t get sick at all?
• That is, what are the sources of variation in the response to exposure to pathogens?
Point of departure:
• Variation in the response to pathogen(s) often has a genetic basis
– In some cases one or a few loci of large effect underlie variation (e.g., β-globin/sickle cell/malaria)
– In other cases the variation appears to be polygenic
Quantitative Genetics of Pathogen Susceptibility in C. elegans
1. How much genetic variance is introduced by mutation?• VM = UQα2
• VM = per-generation increase in genetic variance due to new mutations (“mutational variance”)• U = genome-wide mutation rate• Q = fraction of genome that can affect the trait
(“mutational target”)• α = average effect of a mutation on the trait
The Mutation Accumulation (MA) Process
N=1 N=1 N=1
Evolution under MA conditions
Generations of MA0
0
1
Genetic Variance (slope=VM)
Fitness
Evolution under MA conditions: Mutational Bias (ΔM)
Generations of MA0
0
1
Fitness
Trait X (e.g., size at maturity)
Trait Y (e.g., time to maturity)
The Phenotype: Susceptibility of C. elegans to the pathogenic effects of Pseudomonas aeruginosa
1. Inoculate a 35 mm plate w/ 5 ul of saturated P. aeruginosa (PA14)
2. Introduce ~30 L4-stage juvenile C. elegans
3. Record mortality at 12 hr intervals for 128 hrs
4. Median time of death (LT50) is the measure of susceptibility to the pathogen
Results (1): Mutational Variance, compared with other traits measured in these C. elegans MA lines
10
5
10
15
20
25
30
LT50PaLT50MAW(25)WsortSurvSize
VM (C
V^2
x 1E
5)
Results (2): LT50Pa vs. the Dmel Bristle
10
5
10
15
20
25
30
LT50PaDmel bristles
VM (C
V^2
x 10
x1E
5)
Results (3): Mutational Heritability (VM/VE), compared with other traits in C. elegans
10
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
LT50PaLT50MAW25WsortSurvSizeDmel bristles
h2m
(x 1
E3)
0 50 100 150 200 250 3000.6
0.65
0.7
0.75
0.8
0.85
0.9
0.95
1
LT50PaLinear (LT50Pa)LT50MaLinear (LT50Ma)W25Linear (W25)WsortLinear (Wsort)SurvLinear (Surv)SizeLinear (Size)Generations of MA
Trait
Mean
Results (4): Mutational Bias (ΔM)
Results (5): Selection Gradient – LT50Pa is under asymmetric stabilizing selection
0.00001 0.0001 0.001 0.010.00001
0.0001
0.001
0.01
0.1
1
10
100
1000
VM
VGNeutral TraitNeutral Trait
4NeVM
s=.001
s=1s=.1s=.01
Neutral Trait
Dominant Lethal
Results (6): Comparison with standing genetic variation; at MSB, VM/VG ~ s
VM x 105
VG x
105
Results (7): Distribution of Mutational Effects: Large Target (Q≥0.5%), Modest Effects (|α|~ “a few percent”)
Conclusions:1. Susceptibility to this pathogen (the PA14 strain of P.
aeruginosa) of this host (the PB306 strain of C. elegans) as quantified in this way (LT50) is a typical quantitative trait
2. Mutations that affect susceptibility to P. aeruginosa are under asymmetric stabilizing selection of a few tenths of a percent.
3. A model of large target/small-to-modest effects fits the data better than a model with a small mutational target and large effects.
Thanks!• Joanna Chan• Sarah Eaton • Nick Martinez• Andy Mills• Joanna Tran-Nguyen• Matt Vasquez
• NIH R01GM072639 (CFB)• Ruth Kirschstein NRSA F32-
GM089007 (ECA)• NCI Training Grant T32-
CA009528 (ECA)
Postdoc Wanted!