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Sickle Cell and Epistasis

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Sickle Cell and Epistasis. Malaria is the most common and deadly parasitic disease in the world. 300-500 million cases annually.

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Malaria is the most common and deadly parasitic disease in the world. 300-500 million cases annually.


There are 300 million carriers of the sickle cell trait world-wide, and in parts of Africa 40% of the population are carriers. Why doesn't natural selection eliminate the gene?


Epistatic Genes: Effects of one gene override or mask the phenotype of a second gene. Epistasis is not dominance. Compare the definitions:

  • Epistasis
    • One gene masks the expression of a different gene for a different trait
  • Dominance
    • One allele masks the expression of another allele of the same gene

1.-thalassemia carriers (which comprise 20% of African-Americans) These sickle cell patients live longer and have a milder disease than do non-thalassemic patients.

2.Hereditary persistence of fetal hemoglobin (HPFH) Hb F dilutes the Hb S that sickling does not occur or is less prominent. In these people the Hb F gene does not "turn off" in infancy but persists indefinitely.

3.G-6-PD deficiency has been suggested as an ameliorative condition for sickle cell disease.


Adaptation to malarial resulted in a stable polymorphism where 20% of the population is malarial resistant and 80% are malarial susceptible.

The best evolution could do with what it had was to protect 20% of the population and even those individuals still suffer with some degree of sickle cell anemia.

Thus, it turns out that several other loci were affected by this adaptive process, to lessen both the effects of the anemia and malaria.


G-6-PD is controlled by a single, X-linked locus and is involved in the metabolism of glucose in the red blood cells (RBC). It catalyzes the conversion of G-6-phosphate into 6-P-gluconate via an oxidative RXN that is coupled to a reductive conversion of NAPD to NAPDH.


This second, reductive, RXN is what involves the G6PD locus in a malarial resistant adaptation by having it play an indirect role in controlling the amount of met-hemoglobin (met-Hb) in the RBCs.

This helps reduce the impact of anemia by increasing the individual’s ability to carry oxygen.


Sickle cell shows high frequencies in the Mediterranean, Saudia Arabia, and India. However, cases of sickle cell in these regions are much less severe than are those found in Africa. Why is that?


Sickle cell has been in these Near Eastern regions much longer than in Western Africa. The environmental conditions that favored sickle cell genes only arose some 1500 years ago, whereas these conditions have existed in the Near East for far longer. Natural selection has had longer to evolve coadapted complexes, using various other loci, to ameliorate the severity of sickle cell when it is used as a means of malarial resistance.


The Saudi Arabian population shows such a condition where adults have a mixture of both normal and fetal Hb red blood cells.


Duffy protein is an acidic glycoprotein on the surface of blood cells. There are four alleles, five phenotypes and five antigens. It is the receptor for the human malarial parasite Plasmodium vivax, and it binds some chemokines.


Balanced polymorphism: the heterozygote enjoys an advantage that has allowed selection for the gene, making the homozygous condition common. The prime example is sickle cell disease, in which the heterozygote enjoys immunity to malaria. Cystic fibrosis, Tay Sach’s, Gaucher's, and probably others are probably also balanced polymorphisms.


“People who are exposed to HIV but somehow don't become infected may owe their lives to survivors of Europe's bubonic plague epidemic in the 1300s,” according to a report in the May 1998 issue of the American Journal of Human Genetics.


The plague killed between one-quarter and one-third of Europe's population between 1347 and 1350.


About 14% of people of Scandinavian descent have this mutation. However, the defective CCRC 5 mutation is rare in people of African or East Asian ancestry.

Figure source: Scientific American at



Human genetic diversity

HLA blood groups

ABO Blood Groups

Lactose Insufficiency


Antigens Diseases

    • A Syphilis
    • Smallpox
    • B Infantile
    • diarrhea
    • Typhoid fever
    • (not typhus)
    • O Bubonic Plague

The Human Genome Diversity Project (the "HGD Project") is an international project that seeks to understand the diversity and unity of the entire human species.


The definition of a separate human "population" is not precise, but, using language as the primary criterion, there are between 4,000 and 8,000 distinct human populations around the world.


Iceland: A genetically homogeneous population with detailed medical records going back more than 60 years.


“I find it disgusting that people can make such huge amounts of money by breaking ethical rules.” says psychiatrist Peter Hauksson, who is among the 25 percent of Icelanders who object to Stefansson’s plan.