We expect selection to keep lethal recessive alleles low in frequency What explains these exceptions? lethal recessive disease frequency in general population PKU 1/200,000 Tay Sachs 1/360,000 Sickle Cell 1/125,000 sub-population frequency Caucasian 1/10,000 Ashkenazi Jewish 1/3,600 African Americans 1/5000 Reproductive isolation Founders effect heterozygote advantage

Tay Sachs due to Founders Effect parent population founders of new population FF FF FF FF FF FF FF FF FF FF Ff FF Ff Ff = 2/12 = 0.16 Ff = 2/3 = 0.67

Sickle cell trait due to Heterozyote Advantage aa Aa AA aa Aa AA What type of selection?

The sickle cell allele results from a single point mutation in the gene coding for hemoglobin dominant Negatively charged recessive Hydrophobic

With the changed amino acid, in low O2 situations the behavior of the molecule changes Normal Hb Mutant Hb Bonding forms chains Valine is hydrophobic, so it is ‘pushed’ to other HB molecules, creating chains. These are most problematic when the molecule is carrying little O2. Polymerization occurs only after red blood cells have released the oxygen molecules that they carry to various tissues throughout the body. Once red blood cells return to the lungs where hemoglobin can bind oxygen, the long fibers of Hb S molecules depolymerize or break apart into single molecules. Cycling between polymerization and depolymerization causes red blood cell membranes to become rigid. The rigidity of these red blood cells and their distorted shape when they are not carrying oxygen can result in blockage of small blood vessels. This blockage can cause episodes of pain and can damage organs.

Sickled RBC Are more likely to burst Cause flow problems

Heterozygote Advantage Heterozygotes maintain a deleterious allele in a population These carriers typically do not express the disease Who are carriers? Which offspring has the disease?

Observed: tropical Africa harbors malaria Most common in Africa: 225million cases 781,000 deaths Mostly children, under the age of five. Fact Sheet. Us Global Health Policy. March 2011

The distribution of the sickle cell allele and the incidence of malaria are correlated Yellow = malaria zone Striped = sickle cell in high frequency Experiments carried out in vitro with sickle trait red cells showed that under low oxygen tension, cells infected with P. falciparum parasites sickle much more readily than do uninfected cells (Roth Jr., et al., 1978). Since sickle cells are removed from the circulation and destroyed in the spleen, selective sickling of infected sickle trait red cells would reduce the parasite burden in people with sickle trait. These people would be more likely to survive acute malarial infections.

Infected cells more readily sickle Aa aa AA Likely to die from malaria Dies from sickle cell disease Infected cells more readily sickle Sickling kills the parasite (low K+) Sickled cells removed in immune response Experiments carried out in vitro with sickle trait red cells showed that under low oxygen tension, cells infected with P. falciparum parasites sickle much more readily than do uninfected cells (Roth Jr., et al., 1978). Since sickle cells are removed from the circulation and destroyed in the spleen, selective sickling of infected sickle trait red cells would reduce the parasite burden in people with sickle trait. These people would be more likely to survive acute malarial infections.

Both AA and aa children high risk of death; Aa beats both diseases

Sickle Cell trait (Aa) results in greater malaria survival – fewer infected cells, fewer sickled cells

Heterozygous Homozygous normal RBC Homozygous sickled

PRACTICE If 9% of an African population is born with sickle-cell disease (ss), what percentage of the population will be more resistant to malaria because they are heterozygous (Ss) for the sickle-cell gene? Use q2 approach

Practice If 9% of an African population is born with sickle-cell disease (ss), what percentage of the population will be more resistant to malaria because they are heterozygous (Ss) for the sickle-cell gene? q2= .09 q = .3 p = .7 2pq = 2(.7)(.3) = .42

Parasite • Vector • Host 4 species of Plasmodium Impacts mostly children, under the age of five. Anopheles mosquito 40 species transmit malaria

Global Malaria Eradication Program WHO 1955 • DDT already available as an agricultural pesticide • Success dependent upon, temperate climate, seasonal malaria cycle, good healthcare • Successful eradication on islands : Taiwan, Jamaica

Problem : Natural selection • Reduction often followed by resurgence of now- resistant Anopheles populations Resistant Anopheles selected for

Evidence Conclusion Not possible to eradicate malaria In tropical areas A sample of mosquitos was captured at each time indicated The number killed by a standard dose of DDT in the laboratory was measured. From Curtis et al. (1978) how quickly the population evolves!