Define Heterozygote Advantage, Random Genetic Drift and Population Stratification

1. Define Heterozygote Advantage, Random Genetic Drift and Population Stratification Alison Skinner RCPath Self Help January 22nd 2009

2. Heterozygote Advantage • Heterozygotes have greater relative fitness compared homozygote wildtype and homozygote for the mutation • Sometimes referred to as overdominance • Maintains 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

3. Sickle Cell Anaemia • Caused by the mutation p.E7V of the β-globin gene (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 it 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 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

4. Sickle Cell anaemia

5. Cystic Fibrosis • It was postulated that people heterozygous for a CF mutation were at an advantage 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 diagnosis 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 Högenauer et al., showed that there was no difference in water loss between normal individuals and CF carriers • It 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 resistance 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 the cell wall, making it more difficult to infect CF carriers

6. 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 • Ochratoxin 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 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 time 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

7. Random Genetic Drift • Random fluctuation of allele frequencies (where neither allele 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 ancestry 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 populations • 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

8. 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 the next generation (0.252+0.252) • If the population size is 5, there is a ~0.002 chance of losing one of the alleles in the next generation (0.255+0.255) • If the population size is 100, there is a ~1.24x10-60 chance of losing one of the alleles in the next generation (0.25100+0.25100) • However although it is unlikely that an allele of 50% frequency is lost from the population in one generation, the frequency will fluctuate slightly between generations eventually drifting to being lost or fixed

9. Random Genetic Drift

10. Population Stratification • A population may become stratified when it is divided into subpopulations • This may be due to migration • Geographical obstacles • The subpopulations generally do not interbreed at a high rate with the rest of the population, therefore the subpopulations diverge

11. Population Stratification • Each subpopulation will eventually have: • Different allele frequencies of variants existing before the split • New variants that get established in that subpopulation will be specific to that subpopulation • If the subpopulations never mix again, speciation can occur as the variation builds up • When subpopulations are merged, the resultant population will be stratified due to the different ancestry of the subpopulations

12. Population Stratification • In a population that contains subpopulations, two markers common to the subpopulation may appear to be linked, even though they are not • If a genetic disease is common to the sub-population, it will be positively correlated with all other markers / conditions that have a high frequency in the sub-population in a sample from the whole population • If the sample is only taken from the sub-population, the disease will only be positively correlated with linked markers

13. Population Stratification • The effect of population stratification skewing statistical results for linked markers becomes more of a problem as the sample gets larger • This is a problem for disease studies which identify loci with low relative risks • Population stratification therefore needs to be either: • Identified by the use of known unlinked markers to the locus in question, if stratification is present the unlinked loci will also show association • Avoided by matching the cases and controls – that is by having equal proportions of each population in the case group and the control group

14. Summary • Heterozygote advantage is not random, and allows alleles that are advantageous in the population to be maintained, but because the homozygous individuals are less fit, the allele does not become fixed in the population • Random genetic drift is the process whereby benign genetic variants drift towards fixation or exclusion from the population • Population stratification is the difference in allele frequencies between subpopulations, which is attributed to different ancestry

15. References • Active intestinal chloride secretion in human carriers of cystic fibrosis mutations: An evaluation of the hypothesis that heterozygotes have subnormal active intestinal chloride secretions • Analysis of human genetic linkage. Jurg Ott (1985) Chaper 8 Evaluating candidate agents of selective pressure for cystic fibrosis. Journal of the Royal Society Interface. (2007) 4 91-98 • Celtic origin of the C282Y mutation of haemochromatosis. Blood Cells, Molecules and Diseases (1998) 433-438 • Further evidence for heterozygote advantage of GJB2 deafness mutations: a link with cell survival. J. Med. Genet. (2004) 41 573-575 • The heterozygote advantage in phenylketonuria. Am J Hum Genet (1986) 38 773-775 • The neutral theory of molecular evolution. Motoo Kimura (1983) p.36-40 (genetic drift) • Use of unlinked genetic markers to detect population stratification in association studies. Am. J. Hum. Genet (1999) 65 220-228 • Pictures from wikimedia commons