Lecture 22Lecture 22

Human Evolution and Human Evolution and Infectious DiseaseInfectious Disease

Guest Lecture:Guest Lecture:

Joel WertheimJoel Wertheim

Is infectious disease important Is infectious disease important in the evolution of humans and in the evolution of humans and

their hominid ancestors?their hominid ancestors?

What are the most important What are the most important pathogens in human evolution?pathogens in human evolution?

Human GenomeHuman 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

Human GenomeHuman Genome

Nature 409, 860-921

MHC DiversityMHC 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?

Types of Positive Types of Positive SelectionSelection

• Directional Selection– Rapid change in amino acid sequence of a

gene– Rapid increase in frequency of an allele

• Balancing Selection– Increased allelic diversity

What is the cause of MHC What is the cause of MHC balancing selection in balancing selection in

humans?humans?

1. Heterozygote Advantage

2. Frequency Dependant Selection

3. Fluctuating Levels of Selection

Why Pathogens?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?

Heterozygote AdvantageHeterozygote 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

Frequency Dependant Frequency Dependant SelectionSelection

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

Fluctuating Levels of Fluctuating Levels of SelectionSelection

• 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

MHC Pre-Speciation MHC Pre-Speciation PolymorphismPolymorphism

Human Allele A

Human Allele B

Chimpanzee Allele A

Chimpanzee Allele B

Results from balancing selection

Important Pathogens in the Important Pathogens in the Ancestors of Modern HumansAncestors 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

Vectored PathogensVectored Pathogens

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

Mycobacterium tuberculosisMycobacterium 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) ?

Mycobacterium tuberculosisMycobacterium tuberculosis

• 15,000-20,000 years old• Predates domestication of

cattle (~10 kya)• Cattle may have acquired

M. bovis from humans

Maintainence of virulence ?

Evidence of SelectionEvidence 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

Parasitic WormsParasitic 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

Taenid WormsTaenid 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

• 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)

HerpesvirusesHerpesviruses

• 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

Chickenpox/ShinglesChickenpox/Shingles (not a poxvirus)(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

Epstein-Barr VirusEpstein-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

Plasmodium falciparumPlasmodium 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

Evidence of SelectionEvidence 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

P. vivaxP. 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

Retroviruses and Retroviruses and RetroelementsRetroelements

• >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

Positive Selection on Positive Selection on APOBEC3GAPOBEC3G

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

Innate ImmunityInnate 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

What about Measles?What about Measles?

Westover and Hughes, 2001

Measles VirusMeasles 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

What about Polio?What about Polio?

Hygiene May Have Brought Hygiene May Have Brought About the EpidemicAbout the Epidemic

SummarySummary• 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.