PowerPoint Presentation - Darwinian Medicinebio336/Bio336/Lectures08/Ally_Darwinian... · Bio...

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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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•

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


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•

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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•

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?


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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?


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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


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Used frozen flu samples=fossil record

Fitch et al. 1991 PNAS

Bush et al. 1999 Science

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• 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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• 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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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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• 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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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.


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?


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.


Cystic fibrosis

Lao et al. 2003 European Journal of Human Genetics

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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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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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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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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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•

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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•

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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•

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



BsrI

Hinp1I

Hirschhorn

et al. (1996) Nature Genetics

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•

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



BsrI

Hinp1I

Hirschhorn

et al. (1996)

Nature Genetics

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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.

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