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Darwinian Medicine
Learning objectives:
1.
Defining proximate vs. evolutionary mechanisms and questions.
2.
Identifying the targets: universal traits or genes, pathogens, cells.
3.
Cool examples of evolution applied to human health.
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Darwinian medicine
Definition:
The application of Darwinian concepts like phylogeny, natural selection, etc. to medical problems and treatments.
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Darwinian medicineDistinction between evolutionary and proximate questions:
Proximate:How does the mechanism work?What is the ontogeny of the mechanism?
Evolutionary:Does this mechanism provide a selective advantage?What is the evolutionary history of this trait?
Tinbergen(1963) Zeitschrift für Tierpsychologie
Nesse
and Stearns 2007 Evolutionary Applications
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Darwinian medicineDistinction between evolutionary and proximate questions:
•
Bilirubin
is a yellow breakdown product of heme
catabolism
•
Accumulates when there is liver failure resulting in jaundice
•
Excreted via bile after it is made water soluble in the liver = proximate
Biliverdin
Bilirubin
+Glucuronic
acid Bile(liver)
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Why does the body go to the trouble of making a difficult-to- excrete toxin?
= evolutionary question
Darwinian medicineDistinction between evolutionary and proximate questions:
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Darwinian medicineDistinction between evolutionary and proximate questions:
•
Low density lipoproteins (LDLs) transport cholesterol to the arteries and when LDL is oxidized it is retained by the arteries creating plaques -
atherosclerosis-
> heart disease
•
One risk factor for heart disease = elevated levels of LDH•
The oxidation of LDH can be prevented by water and lipid soluble
anti-oxidants•
Bilirubin
is a molecule that protects against oxidative damage.
http://www.cardioconnection.org/images/
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Darwinian medicineDistinction between evolutionary and proximate questions:
•
Do higher levels of bilirubin
protect against heart attack?•
Schwertner
et al. 1994; Breimer
et al 1995, Vitek
et al. 2002
Group Bilirubin
(µmol/l)
Anti-oxidant status (nmol/l)
LDL cholesterol (nmol/l)
HDL cholesterol (nmol/l)
Gilbert patients
32.6±13.5 1.433 ±0.14 3.5 ±
0.9 1.5 ±0.5
Heart disease patients
9.0 ±2.7 1.296 ±0.14 3.7 ±1.0 1.1 ±0.2
Control 9.1 ±2.7 1.323 ±0.13 3.3 ±0.6 1.3±0.3
Modified from Vitek
et al. 2002 Atheroscelerosis
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Darwinian medicineDistinction within evolutionary questions:
Evolutionary:
What is the evolutionary history of a trait?
What is the adaptive significance of this trait ? Is there a selective advantage to this trait?
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Darwinian medicineDistinguishing among the targets of our evolutionary questions
Why are our bodies the way they are? Object = a universal trait or gene (e.g. bilirubin)
Why are pathogens the way they are? Object = bacteria, viruses, worms, etc.
Why are cells within the body the way they are ?Object = cell lineages
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Darwinian medicine
What is the evolutionary history of the flu?
Using phylogenetic methods, can we make predictions about the course of future human influenza strains?
Object = viruses
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Darwinian medicineInfluenza: from phylogeny to prediction
http://en.wikipedia.org/wiki/Influenza
• RNA virus: 8 RNA strands encode 11 proteins
•
Hemagglutinin
(HA) is a viral coat protein (spike) used to bind to the cells of the nose, throat, and lungs
•
HA is the primary protein recognized, attacked, and remembered by the host immune system = antigenic sites.
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Darwinian medicine
Influenza: from phylogeny to prediction
• Lacks RNA proof-reading enzymes. Error rate of RNA transcriptase high
• Every newly synthesized influenza virus is a mutant
• Virus avoids detection by the immune system because mutations change the HA molecule and is no longer recognized by immune system
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Darwinian medicine
http://en.wikipedia.org/wiki/Influenz•
As a result of the mutations antibodies no longer recognize the virus allowing it to replicate.
•
Vaccines lose their efficacy and thus new ones must be made
•
But which of today’s strains is the progenitor of next years strains?
Influenza: from phylogeny to prediction
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Darwinian medicine
Does knowledge of the evolutionary history of the HA gene help to predict which strains should be
included for next years vaccine?
Influenza: from phylogeny to prediction
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Darwinian medicine
Phylogenetic
relationship of the full-
length genome of HIV-1 subtype C sequences.
Novitsky
et al. 2002 J. Virology
Influenza: from phylogeny to prediction
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Darwinian medicineInfluenza: from phylogeny to prediction
Used frozen flu samples=fossil record
Fitch et al. 1991 PNAS
Bush et al. 1999 Science
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Darwinian medicineInfluenza: from phylogeny to prediction
• Most frozen flu samples represented extinct side of the phylogeny
• Flu lineages that persisted into to 1980s were not a diverse assembly of strains from the 1960s and 70s
• Instead -
strains alive in 1980 were closely related and descended from a single one of the late 1960 strain
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Darwinian medicineInfluenza: from phylogeny to prediction
• Flu strains accumulate nucleotide substitutions in their hemagglutinin
genes at a rate of 5.7x10-3
per nucleotide per year (6.7 x10-3
in Freeman and Herron 2007 -see textbook for a figure that shows 1968s to 80s)
Fitch et al. 1991 PNAS
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Darwinian medicineInfluenza: from phylogeny to prediction
Lineage type In antigenic sites In non-antigenic sites
Surviving lineage 33 10Extinct lineage 31 35
• What was special about the surviving lineage?
• Higher fraction of amino acid replacements in the antigenic sites.
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Darwinian medicineInfluenza: from phylogeny to prediction
• 18 codons
in the hemagglutinin
gene -
replacement > silent ones
• Evidence for positive selection
• Flu strains are more likely to survive if they have novel amino acid sequences.
• Progenitor strain is the one with the most mutations in the 18 codons.
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Darwinian medicine
Why are our bodies the way they are? Object = human trait or gene
What evolutionary forces have maintained the frequency of disease-causing alleles?
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•
HbS
allele of ß-globin
gene is responsible for sickle cell anemia.
•
Mainly homozygotes have the disease but incomplete recessivity causes carriers to have a few sickle red blood cells at all times.
•
Produces misshapen red blood cells but also late-
onset stroke, sudden unexplained death and acute chest syndrome.
•
No significant reduction in fertility.
Darwinian medicineRole of selection in maintaining disease alleles:
Sickle cell anemia and Malaria
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Darwinian medicine
Dean et al. 2002
HbA/HbS
HbA/HbS
HbS/HbSDEAD
HbA/HbA HbA/HbS
HbA/HbS
Role of selection in maintaining disease alleles: Sickle cell anemia and Malaria
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Darwinian medicineRole of selection in maintaining disease alleles:
Sickle cell anemia and Malaria
Distribution of sickle cell anemia
Distribution of malaria
http://en.wikipedia.org/wiki/Sickle-cell_disease#Genetics
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•
Autosomal
recessive disease occuring
at frequency of 1/1600, carrier frequency is 1/20.
•
Results in infertility in both males and females, poor growth (enlarged fingers), lung infections, shortened life span.
•
CFTR gene encodes a chloride ion channel important in regulation of exocrine secretions.
•
Mutation in the CFTR protein ∆F508 causes the protein to fold improperly and thus be degraded in the cell.
Darwinian medicineRole of selection in maintaining disease alleles:
Cystic fibrosis
http://en.wikipedia.org/wiki/Cystic_fibrosis
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•
∆F508 mutation is estimated to be 52, 000 years old
•
If it is so lethal, why has it persisted and spread in the human population?
•
Is there a similar selective advantage as is found in carriers for sickle cell anemia?
Darwinian medicineRole of selection in maintaining disease alleles:
Cystic fibrosis
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•
First line of evidence for selection:
Geographical differences in the frequency of the disease.
Frequency of CF is highest in Northern Europe and declines in both the South and East
∆F508 (major allele) accounts for 70-
80% of the CF alleles in Britain but only 40-50% of the CF alleles in Greece and Russia.
Darwinian medicineRole of selection in maintaining disease alleles:
Cystic fibrosis
Lao et al. 2003 European Journal of Human Genetics
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Darwinian medicineRole of selection in maintaining disease alleles:
Cystic fibrosis
•
Second line of evidence for selection is associative:
Bacterial toxins (from cholera and E.coli) cause increased fluid flow in the intestine -> diarrhea
CF homozgyotes
fail to secrete chloride ions in response to bacterial toxins.
Heterozygote mice (for CFTR mutant alleles) show reduced intestinal fluid secretion in response to cholera toxin.
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Darwinian medicineRole of selection in maintaining disease alleles:
Cystic fibrosis
•
Second line of evidence for selection is associative:
ALTERNATIVELY,
CFTR is involved in resistance to typhoid fever caused by Salmonella typhimurium.
The related bacteria Salmonella typhi uses CFTR to enter epithelial cells
Heterozygous mice for ∆F508 showed an 86% reduction (relative to WT) in the amount of S.typhi in their gastrointestinal tract.
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Darwinian medicine
Why are cells in our bodies the way they are? Object = cells
Is there natural selection among cell lineages within the human body ?
Tissues as evolving populations of cells
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Darwinian medicineTissues as evolving populations of cells
•
All cells in an individual’s body are descended from a common ancestor.
•
A mutation that occurs in a dividing cell will pass on its change to its descendant cells.
•
If the blue cell is capable of increased cell survival or faster reproduction, then it will leave more descendants than other cells.
•
Heritable variation and fitness differences -
> evolution by natural selection can operate within cells in the body.
mutation
Dividing cells
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Darwinian medicineTissues as evolving populations of cells
mutation
•
Adenosine deaminase
(ADA) is a housekeeping enzyme found in all cells of the body -
recycles purines
•
Cells that lack ADA accumulate poisonous metabolites.
•
Cells most susceptible to these poisons are lymphocytes (T cells and B cells)
•
Individuals who inherit loss-of-function mutations in both copies of the ADA gene have no T cells and B cells are non-
functional or absent
•
These individuals usually die at a very early age.
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Darwinian medicineTissues as evolving populations of cells
Dead (age 2)(From age 0-5)
(Age 5-8 no disease)
•
Two carriers had two sons. Carriers for different loss-of-function alleles.
•
First son inherited two loss-of-function alleles, made no ADA and died
•
The second son inherited both parents’
mutant alleles and in the first five years suffered recurrent infections.
•
Between the ages of 5-8 he recovered mysteriously. Why?
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Darwinian medicineTissues as evolving populations of cells
•
Both parents have point mutations where an A
substitutes for a G
•
Dad’s point mutation occurs in an intron/exon
splice site -
deletion of the entire exon
from the ADA transcript. Mutant allele eliminates the BsrI cut site
•
Mom’s point mutation results in the substitution of one amino acid for another -
no enzymatic activity. Mutant allele eliminates the Hinp1I cut site
WT: GCGCCACCAGCCCAGT
Dad: GCGCCACCAGCCCAAT
Mom: GCACCACCAGCCCAGT
Hinp1I BsrI
Hinp11 and BsrI are restriction enzymes
Freeman and Herron (2007) Box 14.1
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Darwinian medicineTissues as evolving populations of cells
•
BsrI
cut site in:
–
The WT sequence results in a 182bp and a 72bp fragment
–
Mom’s: both her WT and mutant allele result in proper digestion and thus results only in a 182bp and 72bp fragment.
–
Dad’s: his WT allele results in two fragments 182 and 72bp but his mutant allele is not digested, it shows up as a 254bp fragment.
D M
D M
PBL=peripheral leukocytes
LL= lymphoid B cells
BsrI
Hinp1I
Hirschhorn
et al.
(1996) Nature Genetics
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Darwinian medicineTissues as evolving populations of cells
•
Hinp1I cut site in:
–
The WT sequence results in a 174bp and a 83bp fragment
–
Dad’s: both his WT and mutant allele result in proper digestion and thus results only in a 174bp and 83bp fragment.
–
Mom’s: her WT allele results in two fragments 174bp and 83bp but her mutant allele is not digested, it shows up as a 254bp fragment.
D M
D M
PBL=peripheral leukocytes
LL= lymphoid B cells
BsrI
Hinp1I
Hirschhorn
et al. (1996) Nature Genetics
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Darwinian medicineTissues as evolving populations of cells
•
Now look at the son’s DNA:
–
For the BsrI: The son has three bands: 254, 182, and 72bp suggesting he carries his father’s allele in both peripheral leukocytes and lymphoid B cells
–
For Hinp1I the son carries his mom’s in peripheral leukocytes but not in most lymphoid B cells (254bp band).
•
Mom also had a neutral marker that was found in the son’s lymphoid B cell lines.
D M
D M
PBL=peripheral leukocytes
LL= lymphoid B cells
BsrI
Hinp1I
Hirschhorn
et al. (1996)
Nature Genetics
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Darwinian medicineTissues as evolving populations of cells
Reversion
•
The cell ancestral to most of the boy’s existing lymphoid B cells had acquired a back mutation in the allele inherited from Mom -> WT
•
Over time the descendants of this reverted cell line became more abundant.
•
The cells made and released enough ADA that the boy’s clinical symptoms disappeared.
•
Was it natural selection or was it drift?
Lymphoid B cells
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Darwinian medicineAn evolutionary perspective can help medicine develop
hypotheses about physiological function.
To take aspririn or not?
•
Muller (1948), Kluger
(1979) suggested that fever was an adaptive defense against disease.
•
Fever is the manipulation of the host by the pathogen
What experiment(s) would you do to distinguish between the two?
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Darwinian medicineOther topics include:
•
Genetic conflicts (Host pathogen conflicts and virulence evolution)
•
Aging
•
Nutrition and development
•
Reproductive medicine (miscarriages, menopause, etc.)
•
Mental disorders
•
Cancer
•
Epidemiology
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Darwinian medicine: BibliographyThis lecture was largely based on the perspective articles by :Nesse
and Stearns (2008). The great opportunity: Evolutionary applications to medicine and public health. Evolutionary Applications 1:28-48.Williams and Nesse
(1991). The dawn of Darwinian medicine. Quarterly Review of Biology. 66: 1-22.
Other references include:Dean et al. (2002). Balanced polymorphism selected by genetic versus infectious human disease. Ann. Rev. Genomics and Human Genetics 3:263-292Fitch et al. (1997). Long term trends in the evolution of H(3) HA1 human influenza type A. PNAS 94: 7712-7718.Bush et al. (1999). Predicting the evolution of human influenza
A. Science 286: 1921.Hirschhorn
et al. (1996). Spontaneous in vivo reversion to normal of an inherited mutation in a patient with adenosine deaminase
deficiency. Nature Genetics 13: 290-295.
From your textbook, you can read:Freemon
and Herron (2007). Evolutionary Analysis. Chapter 14: pp532-534, 546-547, 556-560.