Evolutionary Medicine I Humans as Recently Evolved Genetically

I. Humans as Recently Evolved, Genetically Diverse Animals A. Adaptations to Local Environments 1.

I. Humans as Recently Evolved, Genetically Diverse Animals A. Adaptations to Local Environments 2.

I. Humans as Recently Evolved, Genetically Diverse Animals A. Adaptations to Local Environments 3.

Greenlandic Inuit show genetic signatures of diet and climate adaptation Matteo Fumagalli, et al.

Selection on single genes and polygenic traits in Britons over the last 2000 -3000

I. Humans as Recently Evolved, Genetically Diverse Animals A. Adaptations to Local Environments -

I. Humans as Recently Evolved, Genetically Diverse Animals A. Adaptations to Local Environments B.

Association between different RS 3 alleles and the Partner Bonding Scale in men Allele

Effect of 0, 1 or 2 334 alleles on male reports on the Partner

Association between 334 alleles in men and their wives' reports of marital qualities (mean)

I. Humans as Recently Evolved, Genetically Diverse Animals II. Evolving Host-Parasite Relationships A. Rapid

Smallpox - Variola major Probably originated ~ 10, 000 bc Oldest possible case: Ramses

“The origin of the Variola virus”. 2015. Viruses 7: 1110 -1112 Camels introduced into

The Ecological Context Lyme Disease: - fragmentation reduces patch size - abundance of predators

West Nile Virus Low Diversity: High Relative Abundance of Hosts High Diversity: Low Relative

I. Humans as Recently Evolved, Genetically Diverse Animals II. Evolving Host-Parasite Relationships III. Antagonistic

III. Antagonistic Pleiotropy A. Cancer B. Other Diseases Examples of antagonistic pleiotropy for genes

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Evolutionary Medicine

I. 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

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

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

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

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. TBX 15 stimulates adipocytes that burn lipids for heat, and may be an adaptation to cold.

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

I. 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 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 Th 17 cells, that regulate responses to bacteria. BUT: increases chance of stomach cancer. Initial exposure acclimatization

I. 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.

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

I. 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 (AVPR 1 a) in forebrain. - Male meadow voles are polygamous, and have low levels of expression of AVPR 1 a in forebrain. - Inducing expression of meadow vole receptor in males causes pair-bonding… a change in mating system.

I. Humans as Recently Evolved, Genetically Diverse Animals A. Adaptations to Local Environments B. Pair-bonding and Vasopressin - Humans (Wahlum et al. 2008). - Humans have AVPR 1 a 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 ( = RS 3) (GATA)14 ( = RS 1) - (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

I. Humans as Recently Evolved, Genetically Diverse Animals A. Adaptations to Local Environments B. Pair-bonding and Vasopressin - Humans (Wahlum et al. 2008). Men Repeat Women df F P GT 25 21, 148 0. 39 0. 99 RS 1 16, 187 1. 03 RS 3 19, 157 2. 48 Effect just for males, as in voles… Repeat df F P GT 25 18, 138 1. 05 0. 41 0. 43 RS 1 15, 197 0. 99 0. 46 0. 001 RS 3 21, 166 1. 19 0. 27

Association between different RS 3 alleles and the Partner Bonding Scale in men Allele Freq Percent Mean df F P 320 21 2. 3 48. 8 (6. 21) 1, 12 1. 52 0. 24 330 92 9. 9 47. 6 (7. 18) 1, 37 0. 21 0. 65 332 128 13. 8 47. 5 (6. 45) 1, 50 0. 06 0. 81 334 371 40. 0 46. 2 (6. 23) 1, 130 16. 35 <0. 0001 336 359 38. 7 47. 6 (6. 35) 1, 133 1. 51 0. 22 338 170 18. 3 48. 3 (6. 21) 1, 77 4. 73 0. 03 340 263 28. 4 47. 5 (6. 56) 1, 106 0. 40 0. 53 342 30 3. 2 47. 0 (4. 49) 1, 12 0. 05 0. 82 344 23 2. 5 45. 6 (6. 43) 1, 8 1. 64 0. 24 346 126 13. 6 46. 7 (6. 87) 1, 60 1. 30 0. 26 348 37 4. 0 47. 9 (8. 47) 1, 16 0. 36 0. 55

Effect of 0, 1 or 2 334 alleles on male reports on the Partner Bonding Scale, marital crisis, and marital status Number of 334 alleles Measure LOWER PBS 0 1 2 df F P 8. 40 0. 0004 Mean score for the Partner Bonding Scale in the three groups Partner Bonding Scale 48. 0 (6. 50) 46. 3 (6. 16) 45. 5 (6. 71) 2, 143 Frequency and column-wise percentage of subjects reporting marital crisis/threat of divorce in the three groups Have you experienced marital crisis or threat of divorce during the last year? More Marital No Yes Crisis 469 (85%) 277 (84%) 27 (66%) 81 (15%) 51 (16%) 14 (34%) 2, 143 5. 00 0. 008 Frequency and column-wise percentage of subjects being married or cohabiting in the three groups Marital status Less Marriage Marrie d 457 (83%) 275 (84%) 28 (68%) Cohabi ting 96 (17%) 52 (16%) 13 (32%) 2, 143 4. 36 0. 01

Association between 334 alleles in men and their wives' reports of marital qualities (mean) β Unadjusted 18. 0 (2. 99) 17. 4 (2. 92) Adjusted — Unadjusted Quality Affectional expression Dyadic consensus Dyadic cohesion Dyadic satisfaction One or two 334 No 334 (mean) df F P − 0. 64 1, 113 10. 08 0. 002 — − 0. 39 1, 111 4. 30 0. 04 65. 4 (8. 11) 63. 9 (8. 57) − 1. 46 1, 117 6. 92 0. 01 Adjusted — — − 0. 82 1, 115 2. 46 0. 12 Unadjusted 19. 5 (4. 34) 18. 9 (4. 10) − 0. 60 1, 116 4. 27 0. 04 Adjusted — — − 0. 20 1, 114 0. 53 0. 47 Unadjusted 43. 3 (3. 14) 43. 2 (2. 92) − 0. 12 1, 111 0. 49 334 allele associated with increased hippocampal m-RNA, amygdala activity, and overexpression in autism

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

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

I. 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

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

I. 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 3 rd molar

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

I. Humans as Recently Evolved, Genetically Diverse Animals II. 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

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

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

Smallpox - Variola major Probably originated ~ 10, 000 bc Oldest possible case: Ramses V (~1150 bce) Likely in India bce; China in 3 rd 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 20 th century 1950’s – global eradication program began 1979 – WHO declares smallpox eradicated Ramses V

“The origin of the Variola virus”. 2015. Viruses 7: 1110 -1112 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). Human smallpox (specific) (2000 bc) Ramses V (1150 bc) Naked soil gerbil (specific) Camelpox (specific) Monkeypox Cowpox Rodent Reservoir Also infect humans

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.

West Nile Virus Low Diversity: High Relative Abundance of Hosts High Diversity: Low Relative Abundance of Hosts Swaddle and Carlos, 2008. PLo. S one 3: e 2488

I. Humans as Recently Evolved, Genetically Diverse Animals II. 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.

I. Humans as Recently Evolved, Genetically Diverse Animals II. Evolving Host-Parasite Relationships III. 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

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

III. Antagonistic Pleiotropy A. Cancer B. Other Diseases Examples of antagonistic pleiotropy for genes that increase risk or severity of chronic inflammatory diseases Genes HLA DR 4 (DRB 1*04) HLA B 27 PTPN 22 1858 C>T* CTLA 4 49 A>G Evolutionary medicine and chronic inflammatory state—known and new concepts in pathophysiology. J. Mol. Med. 2012. NOD 2/CARD 15 Chronic inflammatory disease Pleiotropic meaning outside of chronic inflammatory diseases (with selection advantage) Decrease of risk of dengue Rheumatoid arthritis and hemorrhagic fever (defense other autoimmune diseases against infectious agents) Ankylosing spondylitis and Decrease of viral infection other axial forms of (defense against infectious spondyloarthritis agents) Higher body mass index, higher Many autoimmune diseases waist-to-hip ratio in women (storage of energy-rich fuels) Better defense against hepatitis B virus and Helicobacter pylori Many autoimmune diseases (defense against infectious agents) Crohn’s disease Hypertension (activation of the sympathetic nervous system) Refs. [21] [57, 58] [59] [60, 61] [62]