Founder Mutations

1. Founder Mutations 0 Current Issues in Biology, Volume 4 Scientific American

2. Founder Mutations Concept Review • A founder mutation is a mutation shared by many individuals because they share a common ancestor. • Founder mutations associated with disease are often recessive and spare individuals who carry only one copy of the mutant gene. • This makes it possible for the mutation to spread from the founder to his or her descendants instead of being eliminated. • Founder mutations provide a window to human migrations.

3. Founder Mutations Concept Review • Mutations arise by random changes to DNA sequences. • Genes can be mutated to cause inherited disease in two general ways: • 1) Different individuals may carry different mutations in the gene associated with the disease. • 2) Precisely the same mutation may be seen again and again in a disease-associated gene.

4. Founder Mutations Concept Review • • A repeatedly observed disease-causing mutation can occur if • - A hotspot for mutation is mutated independently in different individuals. • or • - A mutation occurs in one individual, the founder, and is transmitted to the founder’s descendants.

5. Founder Mutations Concept Review • Everyone who carries the founder mutation also shares nearby sequences of DNA. • This shared DNA region is a haplotype.

6. Founder Mutations Concept Review • Over time, haplotypes become progressively shorter because of recombination between homologous chromosomes. • Therefore, the length of the haplotype provides an estimate of how long ago the founder mutation occurred.

7. Founder Mutations Concept Review • Founder mutations are hundreds to thousands of times more common than typical mutations that cause disease. • Founder mutations reach high frequencies through natural selection because they provide an advantage to individuals who carry only one copy of the mutated gene. • For example, carrying a single copy of the founder mutation that causes hereditary hemochromatosis enhances iron absorption, an advantage when diets are poor in iron.

8. Founder Mutations Concept Review • The frequency of a founder mutation represents a balance between two competing forces – the harm caused by carrying two copies of the mutation weighted against the benefit provided by carrying one copy of the mutation. • This is balancing selection.

9. Founder Mutations Concept Review • PTC Taste Perception and the Out of Africa Hypothesis • About 75% of people worldwide perceive the chemical PTC as extremely bitter; the rest cannot taste it at all. • The inability to taste PTC is due to a founder mutation. • In African populations, there are seven different forms of the gene associated with PTC perception. • Outside of Africa, there is only one major taster and one nontaster form of the gene.

10. Founder Mutations Concept Review • The nontaster mutation is in a very short haplotype, indicating an ancient origin for this mutation. • Two conclusions can be drawn:

11. Founder Mutations Concept Review • The existence of a single nontaster haplotype is consistent with the tenet of the Out of Africa hypothesis that ancestors of modern non-African populations migrated from Africa about 75,000 years ago. These migrants carried one major taster and one nontaster form of the gene. • The single PTC nontaster mutation suggests that migrants from Africa did not interbreed with local populations that almost certainly would have carried their own unique mutations of this gene.

12. Founder Mutations Concept Review • The Hemochromatosis Founder Mutation as a Window to European Migrations • The hemochromatosis founder mutation is found at highest frequencies in Celtic peoples of northwestern Europe and at lower frequencies in other regions of Europe. • The Celts were a dominant group in central Europe 2,000 years ago but were largely displaced north and west by the expanding Roman Empire.

13. Founder Mutations Concept Review • Did the hemochromatosis founder mutation arise in central Europe before Celtic migrations? Or did it originate in today’s Celtic lands and spread southeastward?

14. Founder Mutations Concept Review • The large size of the haplotype that contains the hemochromatosis mutation indicates that it originated recently: 60 to 70 generations ago, or about A.D. 800. • Because this was long after the displacement of the Celts from central Europe, the mutation must have arisen in northwestern Europe and spread southeastward through the founder’s descendants. • Analysis of founder mutations offers insight into where we came from and how we came to inhabit modern homelands.

15. Founder Mutations • Testing Your Comprehension How many copies of a founder mutation are required to cause disease? a) 1 b) 2 c) 4 d) 8

16. Founder Mutations • Testing Your Comprehension How many copies of a founder mutation are required to cause disease? b) 2

17. Founder Mutations • Testing Your Comprehension If two people have the same genetic disease caused by a mutation other than a founder mutation, they usually will have a) exactly the same mutation in the same gene b) different mutations in the same gene c) hotspot mutations in different genes d) markedly different symptoms

18. Founder Mutations • Testing Your Comprehension If two people have the same genetic disease caused by a mutation other than a founder mutation, they usually will have b) different mutations in the same gene

19. Founder Mutations • Testing Your Comprehension Over time, haplotypes become a) shorter b) longer c) more harmful d) less harmful

20. Founder Mutations • Testing Your Comprehension Over time, haplotypes become a) shorter

21. Founder Mutations • Testing Your Comprehension Balancing selection leads to a) elimination of founder mutations b) a continual increase in the frequency of founder mutations c) a stable frequency of a founder mutation d) a fluctuating frequency of a founder mutation

22. Founder Mutations • Testing Your Comprehension Balancing selection leads to c) a stable frequency of a founder mutation

23. Strongly Agree Strongly Disagree A. D. C. B. E. Founder Mutations • Biology and Society The investigation of founder mutations and other markers of human origins shows that human populations are very closely related. If people could be educated about their close degree of kinship, this would help prevent conflicts across the world.

24. Founder Mutations • Thinking About Science The figure shows two sets of DNA sequences obtained from 8 different people. The A shown in red is a disease-causing mutation. Letters in the blue-bordered columns are DNA sequences that may vary, but do not cause the disease. Which set comes from people carrying a founder mutation? a) The top set b) The bottom set

25. Founder Mutations • Thinking About Science The figure shows two sets of DNA sequences obtained from 8 different people. The A shown in red is a disease-causing mutation. Letters in the blue-bordered columns are DNA sequences that may vary, but do not cause the disease. Which set comes from people carrying a founder mutation? b) The bottom set

26. Founder Mutations Interpreting Data and Graphs • DNA sequences of a small part of one gene from a healthy individual and three individuals with genetic disease caused by mutations of this gene are shown in the following table. • Which mutation is likely to cause this disease? • Is this a founder mutation?