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17/01/2008

What is Population Stratification? Heterozygote Advantage? Random Genetic Drift? What is a Founder Effect? Give Examples, Define Penetrance, Expressivity. 17/01/2008. Random Genetic Drift. aka allelic drift

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17/01/2008

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  1. What is Population Stratification? Heterozygote Advantage? Random Genetic Drift? What is a Founder Effect? Give Examples, Define Penetrance, Expressivity 17/01/2008

  2. Random Genetic Drift • aka allelic drift • Concept first introduced in the 1920s and is now believed to be one of the primary mechanisms of evolution. • www.talkorigins.org ‘The random nature of transmitting alleles from one generation to the next given that only a fraction of all possible zygotes become mature adults. ie If a couple only have a small number of offspring then not all of the parents’ alleles will be passed onto the progeny due to assortment of chromosomes at meiosis.’

  3. Random Genetic Drift (2) • Wikipedia ‘Evolutionary process of change in allele frequencies of a population from one generation to the next, due to the phenomena of probability in which purely chance events determine which alleles within a reproductive population will be carried forward while others disappear.’ • In a large population random genetic drift will not have much of an effect in each generation as the random nature of the process will average out. However, in a small population the effect could be rapid and significant.

  4. Population Stratification • ‘The differences in allele frequencies between cases and controls due to systematic differences in ancestry rather than association of genes with disease.’ • Eg a population contains several genetically distinct subsets. Both the disease and allele A happen to occur frequently in one of the subsets. Lander and Schork (1994) give the example of the association in the San Francsico Bay area between the HLA-A1 allele and the ability to eat with chopsticks. HLA-A1 is more frequent among the Chinese population than Caucasians. HLA-A1 does not confer an ability to eat with chopsticks.

  5. Population Stratification (2) • It is important to control for false positive associations due to population stratification when undertaking genetic association studies. This can be done by genotyping a few dozen unlinked genetic markers and separating the subjects into subgroups, if there is substantial difference in genetic background. The confounding effect of population stratification can then be adjusted for. Small amounts of stratification can exist even in well designed studies.

  6. Heterozygote Advantage • aka overdominance • describes the case in which the heterozygote is fitter than both the homozygous dominant and homozygote recessive genotypes. It can be represented as follows: AA Aa aa 1-s 1 1-t • When heterozygotes are fitter than homozygotes, natural selection will maintain the variant.

  7. Heterozygote Advantage (2) • Eg Cystic Fibrosis • The incidence of CF is significantly higher in the Western population than other populations. 1 in 25 Caucasians are carriers. • Believed that heterozygote CF mutation carriers have an advantage over non-carriers of surviving typhoid fever and/or cholera. Salmonella typhi invade the gastrointestinal cells by attaching to the CFTR protein, and infecting the bloodstream. S. typhi cannot bind to mutant CFTR protein which carries the p.F508del mutation and therefore does not infect the bloodstream of people carrying this mutation so easily. Typhoid fever was widespread across Europe for a long time and the typhoid resistance conferred by the p.F508del mutation could explain its high frequency in the European population today.

  8. Heterozygote Advantage (3) • Also, Vibrio cholerae bacteria produce a toxin which binds to cells in the small intestine causing the transmembrane channels to pump out ~5 gallons of water and chloride ions a day, leading to death. CF carrier mice have been found to secrete only half the amount of water and chloride ions of CF mutation negative mice. Therefore, CF carrier mice have a much higher chance of surviving a cholera infection than non-carriers. But, the advantage of being a mutation carrier has to be weighed up against the unique problems facing individual populations. CF mutations may not have persisted in populations inhabiting hot climates due to a conflicting disadvantage to CF carriers: CF carriers have saltier sweat than those who do not carry a mutation. Therefore in hot climates CF carriers would be more susceptible to dehydration in normal every day life compared to non-carriers, and so the CF mutations have not been maintained at such a high level in such populations.

  9. Founder Effect • Described in 1952 by Ernst Mayr • ‘Loss of variation when a new colony is established by a very small number of individuals (in an extreme case by a single fertilized female) which carry only a small fraction of the total genetic variation of the parental population.’ • As a result of the loss of genetic variation, the new population may be distinctly different (genetically and phenotypically) from the parent population from which it is derived. In extreme cases, the founder effect is thought to lead to speciation and subsequent evolution of new species.

  10. Founder Effect (2) • In addition to founder effects, the new population is often a very small population and so shows increased sensitivity to genetic drift, an increase in inbreeding and relatively low genetic variation. eg gene pool of Quebec where the founder population was 2,600 after 12-16 generations (80 fold growth with minimal gene dilution) • Founder effects can occur as a result of cultural isolation, population bottleneck or naturally as competing genetic lines die out. • An effective founder population consists only of those whose genetic print is identifiable in subsequent generations.

  11. Founder Effect (3) • The Founder effect can have 2 consequences: • An allele may be lost. Eg in the case of alleles A and a. If the founding population are all aa homozygotes, then A will be lost leaving a monomorphic population. In reality founder effect is quite inaffective at reducing genetic variation, even if a founding population is less than 10, it will usually posses both alleles. • In a small sample, the frequencies of alleles may differ from the parental population, leading to higher frequencies of otherwise rare alleles. Examples of founder effects: • 1. Amish population in Unites States. Population grew from a few founders, tend to marry within the community (endogamy). Polydactyly is more common in the Amish population than the general American population.

  12. Founder Effect (4) • 2. South African Muslim population. One notable founder who was a Chinese immigrant who converted to Islam. Cleidocranial dysostosis is common in this population. • 3. Fundamentalist Church of Jesus Christ of Latter Day Saints Community. Sect which practises endogamy and polygamy. Estimated 75-80% of the community are blood relatives of two men-John Y. Barlow and Joseph Smith Jessop. • 4. Tristan da Chuna The population of 250 are mostly descended from one Scottish family who arrived in 1817.

  13. Penetrance • Definition; ‘The proportion of individuals carrying a particular variation of a gene (an allele) that also express its particular trait (phenotype)’ • If 9/10 of individuals carrying an allele express the trait, the trait is 90% penetrant • Penetrance can be age related. Depending on the disease, the penetrance may be 100% if the person lives long enough (eg HD) or, less than 100% where a percentage of people who carry the disease allele will never develop symptoms no matter how long they live (eg familial cancers) • Not to be confused with variable expression!

  14. Expressivity • Definition; ‘variation in allelic expression when the allele is penetrant’ eg Marfan syndrome, affects 1/60,000 live births, symptoms include: skeletal, optical and cardiovascular abnormalities, (arachnodctyly, lengthening of long bones, scoliosis, rib and sternum abnormalities, ectopia lentis, lens dislocation, cardiac aneurysms). Patients may exhibit all of the symptoms or just one. The phenotype therefore shows a range from looking almost normal to severely affected. The phenotype can vary between members of the same family carrying the same mutation, ie. Marfan syndrome shows variable expression.

  15. References • Freedman et al. Nature Genetics 2004, April;36(4):388-393 • Hutchison et al. Psychological Bulletin, 2004, Vol.130, no.1 66-79 • Hao et al. European Journal of Human Genetics, 2004, 12, 1001-1006 • www.blackwellpublishing.com • http://en.wikipedia.org • www.talkorigins.org • www.uic.edu • Human Molecular Genetics, Strachan and Read v.3

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