Lecture 22 Human Evolution and Infectious Disease

1. Lecture 22Human Evolution and Infectious Disease Guest Lecture: Joel Wertheim

2. Is infectious disease important in the evolution of humans and their hominid ancestors?What are the most important pathogens in human evolution?

3. Human Genome • >5 % of genes devoted to immune system function (innate and adaptive immunity) • An overrepresentation of these genes are under positive directional selection • Very strong balancing selection is observed for many immunity genes

4. Human Genome Nature 409, 860-921

5. MHC Diversity • MHC-I & MHC-II are the most polymorphic loci in the human genome with 100+ alleles for many genes • High levels of BOTH balancing and directional positive selection How does selection act of these genes?

6. Types of Positive Selection • Directional Selection • Rapid change in amino acid sequence of a gene • Rapid increase in frequency of an allele • Balancing Selection • Increased allelic diversity

7. What is the cause of MHC balancing selection in humans? • Heterozygote Advantage • Frequency Dependant Selection • Fluctuating Levels of Selection

8. Why Pathogens? • Evidence that MHC polymorphism may be related to sexual selection…why? • Correlation found between pathogen richness and increased MHC diversity Could these be related?

9. Heterozygote Advantage • Diverse MHC repertoire could mount a response to more pathogens and be more effective against a single pathogen • Homozygous individuals are more susceptible to Hepatitis B and have a faster progression to AIDS • However, some homozygotes are more resistant to malaria infection • May actually be the result of dominance

10. Frequency Dependant Selection Pathogens become resistant to a common MHC variant and exert selective pressure for rarer alleles Although possible, this phenomenon has not been well documented at the MHC

11. Fluctuating Levels of Selection • Spatial and temporal variation in the pathogen burden • Only requires dominance (heterozyogote only needs to be superior to one of the homozygotes) • Long term studies of ungulate populations have shown reciprocal fluctuations between pathogens and MHC alleles

12. MHC Pre-Speciation Polymorphism Human Allele A Chimpanzee Allele A Human Allele B Chimpanzee Allele B Results from balancing selection

13. Important Pathogens in the Ancestors of Modern Humans • High Levels of Prevalence • Difficult to maintain in small groups • Persistence in small groups • Latency • Reduced Mortality Frank (1975), despite some antiquated vocabulary, outlines characteristics of diseases that may be common in human ancestors

15. Vectored Pathogens

16. Diseases that have likely had a selective impact on human evolution…

17. Mycobacterium tuberculosis • Produces a chronic infection (is difficult to clear even with the contemporary use of antibiotics) • High level of associated mortality • Documented ancient association • Egyptian mummies (5000 years ago) • South American mummies (1000 years ago) • Acquired from cattle (M. bovis) ?

18. Mycobacterium tuberculosis • 15,000-20,000 years old • Predates domestication of cattle (~10 kya) • Cattle may have acquired M. bovis from humans Maintainence of virulence ?

19. Evidence of Selection • Cystic Fibrosis (CF) is the most common single locus genetic disorder • The most common allele (F508) arose ~600 generations ago and may have increased again even more rapidly • Those afflicted with CF cannot produce an enzyme needed by M. tuberculosis • Heterozygotes have a 2% advantage • High levels of F508 in Europeans have been attributed to a 16th century TB epidemic

20. Parasitic Worms • High prevalence and long duration of infection • Although not highly lethal, can decrease the amount of nutrition obtained from food • Specific responses to worm selection have not been identified; likely due to a wide variety of worms, not just one

21. Taenid Worms • Currently, human tapeworms are most closely related to those infecting domesticated animals (e.g. cattle & swine) • Tapeworms were actually acquired from African carnivores just under 1 mya • Likely a tradeoff between nutrition from an omnivorous diet and morbidity

22. Guinea worm • Acquired by drinking water contaminated with fleas that contain the worm larvae • Cause a burning sensation upon penetration through the host skin • Hosts cool the “burn” in water, which allows the release of new larvae. • Schistosoma spp. • Has been infecting humans for over 1 million years (debilitating infection) • River Blindness • Onchocerca volvulus can survive over a decade in humans (sandfly vector)

23. Herpesviruses • Herpes Simplex Virus (HSV 1 & 2) • Varicella Zoster Virus (VZV, Chickenpox) • Epstein Barr Virus (EBV, Mononucleosis and Burikitt’s Lymphoma) All of these viruses go latent and can reemerge in individuals They cause moderate levels morbidity and mortality, often dependant on age of infection

24. Chickenpox/Shingles(not a poxvirus) • VZV phylogeny corresponds to human migratory patterns our of Africa • Increased morbidity in post-adolescents • Reemerges as shingles in adults, therefore is maintained in populations (Frank, 1975) • Has been shown to persist in small populations

25. Epstein-Barr Virus • Goes latent in B-lymphocytes and can cause Burkitt’s Lymphoma, especially in the presence of malarial infection • Modern hygienic practices delay infection until later in life, resulting in Mononucleosis • Positively selected variants of the virus in China and New Guinea are associated with a particular HLA allele

26. Plasmodium falciparum • It has likely been infecting humans since our divergence from chimpanzees • Most adaptive evolution has occurred in the last 10,000 years along with the transition to an agrarian lifestyle • It is unclear whether P. falciparum has become more prevalent, more virulent, or both

27. Evidence of Selection • Heterozygote Advantage • Sickle-cell anemia (HbS mutant) • G6PD A- • Directional Selection • MHC-I alleles increased in West Africa • MHC-II alleles that are rare in Europe These selective forces appear in the last 10,000 years

28. P. vivax • The Duffy blood group (FY) is an antigen found on Red Blood Cells. • P. vivax uses this FY receptor to gain entry into host cells • FY*O, the absence of a surface protein, is very common in sub-Saharan Africa, but is rare in Europe • This selective regime may have begun 60,000 years ago, coinciding with P. vivax infection in humans • FY*O is currently at an elevated level in Papua New Guinea, where P. vivax is also present

29. Retroviruses and Retroelements • >45% of the human genome is composed of retroelements including active and inactive retroviruses • Non-human primates are all infected with many retroviruses, some of which can persist via vertical transmission • Some of the strongest positive selection in the human genome is attributable to these viruses

30. Positive Selection on APOBEC3G APOBEC3G is one of many anti-retroviral proteins in humans, most of which are under extremely strong positive selection Sawyer et al. (2004) PLOS Biol e275

31. Innate Immunity • Not associated with particular pathogens • Balancing selection at CD209 (involved in general immune response to all types of pathogens) • Likely most positive selection (balancing/directional) at these genes due to a myriad of pathogens

32. What about Measles? Westover and Hughes, 2001

33. Measles Virus • Came from Rinderpest, likely around 10,000 years ago accompanying the domestication of cattle • Not sustainable until population reaches 500,000 individuals • No attributable selective impact, yet

34. What about Polio?

35. Hygiene May Have Brought About the Epidemic

36. Summary • MHC are the most polymorphic loci, likely due to pathogen-driven balancing selection • Pathogens that are persistent in the human population (TB, worms, Herpes, Plasmodia, retroviruses) are those most likely to have had a selective impact • Many strategies exist for persistence (lower morbidity/mortality, latency, vector-borne, vertical transmission) • Pathogens that are important today were not necessarily important 100,000+ years ago.