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1、Define Heterozygote Advantage, Random Genetic Drift and Population Stratification,Alison Skinner RCPath Self Help January 22nd 2009,Heterozygote Advantage,Heterozygotes have greater relative fitness compared homozygote wildtype and homozygote for the mutation Sometimes referred to as overdominance M
2、aintains genetic variation within a population Most widely known example of this is Sickle cell anaemia, however many other examples exist, including: CFTR GJB2 (CX26) p.C282Y of HFE Phenylketonuria Autoimmune disease susceptibility,Sickle Cell Anaemia,Caused by the mutation p.E7V of the -globin gen
3、e (HbS) In low oxygen conditions HbS polymerises forming fibrous precipitates HbS homozygotes have crises when the red blood cells sickle, obstructing blood flow to an organ These can cause severe damage and may be fatal. The cell sickles when invaded my the malaria parasite Plasmodium, preventing i
4、t from completing its lifecycle HbS homozygotes are resistant to malaria, but are at a fitness disadvantage due to the aforementioned crises HbS heterozygotes (sickle cell trait) generally do not have symptoms (except in extreme situations when they are deprived of oxygen e.g. at high altitude) but
5、are also resistant to malaria Individuals who do not have a copy of HbS are not resistant to malaria Therefore HbS heterozygotes are at an advantage in areas where malaria is prevalent,Sickle Cell anaemia,Cystic Fibrosis,It was postulated that people heterozygous for a CF mutation were at an advanta
6、ge as they lost less water compared to individuals who did not have a CF mutation when they contracted a diarrhoeal infection This meant they were more likely to survive during the outbreaks of cholera Although individuals who have two CF mutations would be likely to lose even less water, the diagno
7、sis of CF usually resulted in infertility, if the individuals survived to reproductive age (which would have been unlikely before the twentieth century) This theory has been questioned as Hgenauer et al., showed that there was no difference in water loss between normal individuals and CF carriers It
8、 was then postulated that CF carriers were at an advantage when exposed to typhoid, as it required wildtype CFTR to enter the submucosa, however the low frequency of CF mutations in areas where typhiod is prevalent has questioned this theory Currently it is thought that CF carriers have some resista
9、nce to tuberculosis and therefore had a selective advantage between 1600 and 1900 when the level of tuberculosis in society was high CF carriers have reduced levels of arylsuphatase B activity Mycobacterium tuberculosis does not have intrinsic arylsulphase activity, yet it requires it for building t
10、he cell wall, making it more difficult to infect CF carriers,Other Cases of Heterozygote Advantage,Phenylketonuria (PKU) Heterozygotes are protected against Ochratoxin A (produced by Aspergillus and Penicillium) which causes a nephropathy and can also can cross the plancenta causing miscarriage Ochr
11、atoxin A is a derivitive of phenylalanine and it competes for the active site of phenylalanine-tRNA-synthetase PKU heterozygotes are protected from ochratoxin A as they have a higher level of phenylalanine in their blood, preventing ochratoxin A from blocking the active site GJB2 (CX26) Nonsyndromic
12、 sensioneural hearing loss Heterozygotes for the common African hearing loss mutation (p.R143W) have a significantly thicker epidermis which is thought to help prevent pathogen invasion Cells containing this mutation have reduced keratinocyte cell death, which extends the terminal differentiation ti
13、me of the keratinocytes resulting in a thicker epidermis HFE (Haemochromatosis p.C282Y mutation) Protects women of a child bearing age from iron deficiency when blood is lost as a result of menstruation and pregnancy,Random Genetic Drift,Random fluctuation of allele frequencies (where neither allele
14、 has a selective advantage) in a population caused by random sampling of gametes during reproduction The amount of fluctuation is inversely proportional to the population size, therefore in a small population there will be greater fluctuation of gene frequencies Founder effects associated with ances
15、try from a small population or from a population bottleneck may have been caused by random genetic drift In small populations, one allele will often disappear (the other allele is fixed in the population) Genetic drift increases genetic variation between populations but reduces variation within popu
16、lations In large populations, allele frequencies are not expected to deviate much between generations and therefore the allele will take many more generations to become fixed,Random Genetic Drift,In the parent population each heterozygous individual has a 50% chance of passing on either allele and a 50% chance of losing an allele (25% per allele) If an allele has a frequency of 50% in the parent population: If the population size is 2, there is a 0.125 chance of losing one of the alleles in
