Transcript Lecture 22 Human Evolution and Infectious Disease

Lecture 22
Human Evolution and
Infectious Disease
Guest Lecture:
Joel Wertheim
Is infectious disease important
in the evolution of humans and
their hominid ancestors?
What are the most important
pathogens in human evolution?
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
Human Genome
Nature 409, 860-921
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?
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
What is the cause of MHC
balancing selection in
humans?
1. Heterozygote Advantage
2. Frequency Dependant
Selection
3. Fluctuating Levels of Selection
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 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
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
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
MHC Pre-Speciation
Polymorphism
Human Allele A
Chimpanzee Allele A
Human Allele B
Chimpanzee Allele B
Results from balancing selection
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
Vectored Pathogens
Diseases that have likely
had a selective impact
on human evolution…
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) ?
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 ?
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
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
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
• 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)
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
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
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
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
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
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
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
Positive Selection on
APOBEC3G
APOBEC3G is one
of many antiretroviral proteins in
humans, most of
which are under
extremely strong
positive selection
Sawyer et al. (2004) PLOS Biol e275
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
What about Measles?
Westover and Hughes, 2001
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
What about Polio?
Hygiene May Have Brought
About the Epidemic
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.