Sickle Cell and EpistasisSickle Cell and Epistasis

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

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 Epistasis One gene masks the expression of a different gene for a different trait

DominanceDominance 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.

http://web2.iadfw.net/uthman/hemoglobinopathy/hemoglobinopathy.html

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.

http://bioag.byu.edu/zoology/zool510/POPGEN017.htm

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

Having a G6PD deficiency, also tends to give some level of protection against malaria.

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 Hbfetal 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.

How do disease-causing mutations arise and how are they maintained in populations?

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 diseasesickle cell disease, in which the heterozygote enjoys immunity to malaria. Cystic Cystic fibrosisfibrosis, Tay Sach’sTay Sach’s, Gaucher'sGaucher'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.

The HIV resistance mutation disables the CCR5 receptor.

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 athttp://www.sciam.com/0997issue/0997obrienbox5.html

Human genetic diversityHuman genetic diversity

HLA blood groups

ABO Blood GroupsABO Blood Groups

Lactose InsufficiencyLactose Insufficiency

Antigens DiseasesAntigens 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.

deCODE´s research on the origin of Icelanders

“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.