Introduction to Cystic Fibrosiso Single gene Mendelian disorder

o Gene codes for the Cystic Fibrosis Transmembrane Conductance Regulator protein (CFTR)

Daniel R. Taub and Joshua Page. Cystic Fibrosis: Exploration of evolutionary explanations for the high frequency of a common genetic disorder.

Daniel R. Taub and Joshua Page. Cystic Fibrosis: Exploration of evolutionary explanations for the high frequency of a common genetic disorder.

CFTRo

Transmembrane Cl- channel protein

o Gene located on human chromosome seven

o More than 1400 alleles with diminished function

o Most common CF disorder allele is 508D

Daniel R. Taub and Joshua Page. Cystic Fibrosis: Exploration of evolutionary explanations for the high frequency of a common genetic disorder.

oWhat would the 508 D allele be considered to be?

A: A dominant allele

B: A recessive allele

C: Neither dominant nor recessive

Daniel R. Taub and Joshua Page. Cystic Fibrosis: Exploration of evolutionary explanations for the high frequency of a common genetic disorder.

What would be the expected phenotype of an individual heterozygous for two different non-functional CFTR alleles?

A: They would have cystic fibrosis

B: They would not have cystic fibrosis

Daniel R. Taub and Joshua Page. Cystic Fibrosis: Exploration of evolutionary explanations for the high frequency of a common genetic disorder.

Medical aspects of Cystic Fibrosis

o Impaired lung clearance of mucous

o Recurrent lung infection and inflammation o Pancreatic damage

oImpaired digestion

Daniel R. Taub and Joshua Page. Cystic Fibrosis: Exploration of evolutionary explanations for the high frequency of a common genetic disorder.

Clinical outcomes of CF

o Historically, most CF individuals would die in early childhood

o Improved medical care has raised median lifespan into the fifth decade.

Daniel R. Taub and Joshua Page. Cystic Fibrosis: Exploration of evolutionary explanations for the high frequency of a common genetic disorder.

In Europe, approximately 1 in 2500 live births is an individual with CF. What do we expect to be the frequency of loss-of-function alleles of CFTR in the gene pool?

Daniel R. Taub and Joshua Page. Cystic Fibrosis: Exploration of evolutionary explanations for the high frequency of a common genetic disorder.

What proportion of Europeans do we expect to be carriers for CF?

Daniel R. Taub and Joshua Page. Cystic Fibrosis: Exploration of evolutionary explanations for the high frequency of a common genetic disorder.

With your group, come up with a list of the major evolutionary processes.

Daniel R. Taub and Joshua Page. Cystic Fibrosis: Exploration of evolutionary explanations for the high frequency of a common genetic disorder.

In your groups, develop hypotheses for how the high frequency of CF in Europe could be the result of:MutationGenetic driftNatural Selection

Assess how plausible each of your explanations is.

Daniel R. Taub and Joshua Page. Cystic Fibrosis: Exploration of evolutionary explanations for the high frequency of a common genetic disorder.

What would be the maximum possible frequency of a lethal recessive allele in a population?

Daniel R. Taub and Joshua Page. Cystic Fibrosis: Exploration of evolutionary explanations for the high frequency of a common genetic disorder.

What would be the most convincing evidence that a particular infectious disease acts as a selective agent for CFTR heterozygote advantage?

Daniel R. Taub and Joshua Page. Cystic Fibrosis: Exploration of evolutionary explanations for the high frequency of a common genetic disorder.

What other forms of evidence might support one particular infectious disease as the selective agent that has (through heterozygote advantage) produced the high frequency of CF in Europe?

Daniel R. Taub and Joshua Page. Cystic Fibrosis: Exploration of evolutionary explanations for the high frequency of a common genetic disorder.

With your group, write a one or two sentence summary of what the evidence suggests is the most likely explanation for the high frequency of CF in European populations.