Evolutionary Medicine

1. Evolutionary Medicine

2. Humans as Recently Evolved, Genetically Diverse Animals • A. Adaptations to Local Environments 1. LCT – locus coding for lactase production - mammals shut down lactase production after weaning - strong selective sweep in Europeans and Africans that drink milk as adults - European sequences: ~ 9000 years old but show spread about ~4000 ya - African sequences ~ 5000 ya, consistent with spread of cattle - convergent evolution of different variants with same effects

3. Humans as Recently Evolved, Genetically Diverse Animals • A. Adaptations to Local Environments 2. Malaria Resistance - Sickle cell (resistance to Plasmodium falciparum malaria)

4. Humans as Recently Evolved, Genetically Diverse Animals • A. Adaptations to Local Environments 2. Malaria Resistance - FY*O allele – Resistance to Plasmodium vivax malaria

5. Humans as Recently Evolved, Genetically Diverse Animals • A. Adaptations to Local Environments 3. High Latitude - Light Pigmentation

6. Greenlandic Inuit show genetic signatures of diet and climate adaptation Matteo Fumagalli, et al. Science 2015. Significant differences in genes for omega-3 fat metabolism (FADS) in Greenland Inuit (GI) compared to Europeans (CEU) and Chinese (CHB). Much higher levels of serum desaturases. TBX15 stimulates adipocytes that burn lipids for heat, and may be an adaptation to cold.

7. Greenlandic Inuit show genetic signatures of diet and climate adaptation Matteo Fumagalli, et al. Science 2015. Significant differences in genes for omega-3 fat metabolism (FADS) in Greenland Inuit (GI) compared to Europeans (CEU) and Chinese (CHB). Much higher levels of serum desaturases. TBX15 stimulates adipocytes that burn lipids for heat, and may be an adaptation to cold. Two other loci associated with decreased height and weight

8. Selection on single genes and polygenic traits in Britons over the last 2000-3000 years Yair Field et al. Science 2016;354:760-764 Published by AAAS

9. Humans as Recently Evolved, Genetically Diverse Animals • A. Adaptations to Local Environments • - Failure to Adapt and ‘Plesiomorphic Traits’ The ‘Hygiene Hypothesis’ of allergies and autoimmune disorders Exposure to weak pathogens is required to stimulate and ‘educate’ the immune system Mice reared in bacteria-free environment develop auto-immune disorders Initial exposure Hylobacter pylori, a stomach bacterium of humans, was ubiquitous in our species before antibiotics. Only 20% of American children have it now. Those who have it are 59% less likely to have asthma, and have lower rates of hay fever and eczema. H. pylori triggers the development of Th17 cells, that regulate responses to bacteria. BUT: increases chance of stomach cancer. acclimatization

10. Humans as Recently Evolved, Genetically Diverse Animals • A. Adaptations to Local Environments • - Failure to Adapt and ‘Plesiomorphic Traits’ Type-2 Diabetes and the ‘Western Diet’ “Thrifty Genotype Hypothesis”: Populations with historically low sugar and fat in the diet have genes to store calories as fat during times of plenty (low insulin production and uptake), to burn during lean times. Now there are no lean times and fat is just stored.

11. Humans as Recently Evolved, Genetically Diverse Animals • A. Adaptations to Local Environments • B. Pair-bonding and Oxytocin Couples who are affectionate (gentle touching) have higher oxytocin levels than couple that don’t. A and B: Childhood stress is negatively associated with oxytocin levels when the grow into adults.

12. Humans as Recently Evolved, Genetically Diverse Animals • A. Adaptations to Local Environments • B. Pair-bonding and Vasopressin • - Prairie voles pair bond, and have high levels of expression for a vasopressin receptor (AVPR1a) in forebrain. • - Male meadow voles are polygamous, and have low levels of expression of AVPR1a in forebrain. • - Inducing expression of meadow vole receptor in males causes pair-bonding… a change in mating system.

13. Humans as Recently Evolved, Genetically Diverse Animals • A. Adaptations to Local Environments • B. Pair-bonding and Vasopressin • - Humans (Wahlum et al. 2008). • - Humans have AVPR1a on Chromosome 12. • - there is a polymorphic flanking region with three repeat sequences that are polymorphic: • (GT)25 dinucleotide repeat ( = GT) • (CT)4-TT-(CT)8-(GT)24 repeat ( = RS3) • (GATA)14 ( = RS1) • - (variants may be associated with autism, age of first intercourse, and altruism) • Wahlum et al. (2008) used Swedish twin database (552 same-sex twins) • - genotypes twins and scored their relationships on a “Pair-Bonding Scale” used for other primates

14. Humans as Recently Evolved, Genetically Diverse Animals • A. Adaptations to Local Environments • B. Pair-bonding and Vasopressin • - Humans (Wahlum et al. 2008). Effect just for males, as in voles…

15. Association between different RS3 alleles and the Partner Bonding Scale in men

16. Effect of 0, 1 or 2 334 alleles on male reports on the Partner Bonding Scale, marital crisis, and marital status LOWER PBS More Marital Crisis Less Marriage

17. Association between 334 alleles in men and their wives' reports of marital qualities 334 allele associated with increased hippocampal m-RNA, amygdala activity, and overexpression in autism

18. Humans as Recently Evolved, Genetically Diverse Animals • A. Adaptations to Local Environments • B. Pair-bonding and Vasopressin • C. Kin Selection / Infanticide

19. Humans as Recently Evolved, Genetically Diverse Animals • A. Adaptations to Local Environments • B. Pair-bonding and Vasopressin • C. Kin Selection / Infanticide • D. Physical Ailments

20. Humans as Recently Evolved, Genetically Diverse Animals • A. Adaptations to Local Environments • B. Pair-bonding and Vasopressin • C. Kin Selection / Infanticide • D. Physical Ailments

21. Humans as Recently Evolved, Genetically Diverse Animals • A. Adaptations to Local Environments • B. Pair-bonding and Vasopressin • C. Kin Selection / Infanticide • D. Physical Ailments “hunch” back ‘sway’ back scoliosis

22. Humans as Recently Evolved, Genetically Diverse Animals • A. Adaptations to Local Environments • B. Pair-bonding and Vasopressin • C. Kin Selection / Infanticide • D. Physical Ailments Pregnancy and lower back pain from lordosis

23. Humans as Recently Evolved, Genetically Diverse Animals • A. Adaptations to Local Environments • B. Pair-bonding and Vasopressin • C. Kin Selection / Infanticide • D. Physical Ailments male female Men: Kyphotic at 1 and 2 lordotic at 4 and 5 Women: kyphotic at 1 lordotic at 3-5

24. Humans as Recently Evolved, Genetically Diverse Animals • A. Adaptations to Local Environments • B. Pair-bonding and Vasopressin • C. Kin Selection / Infanticide • D. Physical Ailments

25. Humans as Recently Evolved, Genetically Diverse Animals • A. Adaptations to Local Environments • B. Pair-bonding and Vasopressin • C. Kin Selection / Infanticide • D. Medical Ailments Impacted 3rd molar

26. Humans as Recently Evolved, Genetically Diverse Animals • A. Adaptations to Local Environments • B. Pair-bonding and Vasopressin • C. Kin Selection / Infanticide • D. Medical Ailments Impacted 3rd molar

27. Humans as Recently Evolved, Genetically Diverse Animals • Evolving Host-Parasite Relationships • A. Rapid Within-Host Evolution • - mutation rates high • - reproduction is rapid Variation and Rapid Response to Selection by Immune system Increased Energy use + virulence HIV

28. Humans as Recently Evolved, Genetically Diverse Animals • Evolving Host-Parasite Relationships • A. Rapid Within-Host Evolution • B. Balanced by Transmission Rate and “between host” evolution • - if transmission rate is high, virulence and “within-host” evolution dominates • - if transmission rates are low, selection favors strains that do not kill their host

29. Humans as Recently Evolved, Genetically Diverse Animals • Evolving Host-Parasite Relationships • A. Rapid Within-Host Evolution • B. Between-Host Evolution • C. Response to Antibiotics

30. Humans as Recently Evolved, Genetically Diverse Animals • Evolving Host-Parasite Relationships • A. Rapid Within-Host Evolution • B. Between-Host Evolution • C. Response to Antibiotics

31. Humans as Recently Evolved, Genetically Diverse Animals • Evolving Host-Parasite Relationships • A. Rapid Within-Host Evolution • B. Between-Host Evolution • C. Response to Antibiotics • D. The Evolution of ‘Old’ Diseases Herpesvirus 5 only infects humans, but it’s relatives infect other primates and radiated with primate evolution

32. Humans as Recently Evolved, Genetically Diverse Animals • Evolving Host-Parasite Relationships • A. Rapid Within-Host Evolution • B. Between-Host Evolution • C. Response to Antibiotics • D. The Evolution of ‘Old’ Diseases • E. The Evolution of ‘New’ Diseases Human infections 2012 – Saudis began dying of “Middle Eastern Respiratory Syndrome” (30% fatality rate)

33. Smallpox - Variola major Probably originated ~ 10,000 bc Oldest possible case: Ramses V (~1150 bce) Likely in India bce; China in 3rd century ce Needs large population of susceptible hosts (children) Probably a ‘new’ virus, needing pop of 200-300,000. Many epidemics in Africa, Asia, and Europe In late 1700’s – killed 400,000/year in Europe Average mortality rate in Europe of 30-35% In Western Hemisphere/Australia, mortality of 90% ‘Variolation’ was used to inoculate – 2% mortality rate 1796 - Edward Jenner used cowpox pus to vaccinate James Phipps (8 yr old son of his gardener). Word spread and vaccinations (with Vaccinia) became common in Europe. Killed 300-500 million people in 20th century 1950’s – global eradication program began 1979 – WHO declares smallpox eradicated Ramses V

34. “The origin of the Variola virus”. 2015. Viruses 7: 1110-1112 Human smallpox (specific) (2000 bc) Ramses V (1150 bc) Camels introduced into East Africa about 2500 bc, and a period of dramatic climate change may have stimulated the jump of CPXV to new hosts (camels, rodent, human). Naked soil gerbil (specific) Camelpox (specific) Cowpox Monkeypox Rodent Reservoir Also infect humans

35. Humans as Recently Evolved, Genetically Diverse Animals • Evolving Host-Parasite Relationships • A. Rapid Within-Host Evolution • B. Between-Host Evolution • C. Response to Antibiotics • D. The Evolution of ‘Old’ Diseases • E. The Evolution of ‘New’ Diseases

36. The Ecological Context Lyme Disease: - fragmentation reduces patch size - abundance of predators like fox declined - white-footed mice (host of Borrela burgdorferi bacterium) increase. - increase host density, increase infection rate of ticks.

37. West Nile Virus Low Diversity: High Relative Abundance of Hosts High Diversity: Low Relative Abundance of Hosts Swaddle and Carlos, 2008. PLoS one 3:e2488

38. Humans as Recently Evolved, Genetically Diverse Animals • Evolving Host-Parasite Relationships • A. Rapid Within-Host Evolution • B. Between-Host Evolution • C. Response to Antibiotics • D. The Evolution of ‘Old’ Diseases • E. The Evolution of ‘New’ Diseases • F. Attenuated Viruses Infect non-human primates and continually transfer them between new individuals, adapting the virus to the new host. When presented to humans, it still elicits an immune response but does not infect human cells and cause disease.

39. Humans as Recently Evolved, Genetically Diverse Animals • Evolving Host-Parasite Relationships • Antagonistic Pleiotropy • A. Cancer • - The benefits of cell division and healing when young increase mutation rates that cause cancer later. • - Children, with rapidly dividing cells, are more susceptible to environmental mutagens

40. Humans as Recently Evolved, Genetically Diverse Animals • Evolving Host-Parasite Relationships • Antagonistic Pleiotropy • A. Cancer • B. Other Diseases

41. Antagonistic Pleiotropy • A. Cancer • B. Other Diseases Examples of antagonistic pleiotropy for genes that increase risk or severity of chronic inflammatory diseases Evolutionary medicine and chronic inflammatory state—known and new concepts in pathophysiology. J. Mol. Med. 2012.