Definitions/questions

Mechanisms

  • active defense (plastic or facultative defenses): recognition systems and effectors
    • recognition systems are the qualitative component of host defense: does the host recognize that the parasite (specifically, a parasite antigen) is present? These will typically evolve by Red Queen dynamics (i.e., via an inverse matching allele model). In vertebrates: antibodies
    • must be specific (self/non-self recognition), trigger proportionate response
    • coded by the major histocompatibility complex (self/non-self recognition), somatic recombination, deletion of host-specific antigens (Borghans, Beltman, and De Boer 2004; Acevedo-Whitehouse and Cunningham 2006; Rauch, Kalbe, and Reusch 2006; Spurgin and Richardson 2010)
    • effectors: what does the host do once the parasite is detected?
  • passive/always-on defense: constitutive
    • changing cell surface receptors (e.g. CCR5-\(\Delta 32\) (HIV, Hummel et al. (2005)); matching-allele model
  • parasite countermeasures (immune evasion [trypanosomes], immune suppression [measles, anthrax, …]) (Schmid-Hempel 2009)

Costs and tradeoffs

What are the costs of resistance and tolerance? (= Why aren’t all hosts tolerant/resistant to all parasites?)

(Klemme, Hyvärinen, and Karvonen 2020)

  • cost of maintaining recognition mechanisms
  • cost of choosing different habitats
  • tradeoffs (RQ-related or ?)

Population-level evolution (eco-evolution)

Stahl et al. (1999); Roy and Kirchner (2000)

  • resistance lowers prevalence - selects against itself; expect polymorphism
  • tolerance increases prevalence - selects for itself (apparent competition with non-tolerant genotypes); expect fixation. (Is tolerance evolution-proof? (Schneider and Ayres 2008))

Measuring quantitative resistance/tolerance

  • tolerance: loss of fitness per unit parasite load
  • resistance: level of parasite load

(Raberg, Sim, and Read 2007; Råberg, Graham, and Read 2009)
!

Disentangling the history/origin of deleterious recessive Mendelian alleles

  • Genetic polymorphisms are interesting; why haven’t they been eliminated or fixed?

hypotheses

  • genetic drift (null)
    • historic size of populations? (historical records, population genetics [coalescents])
    • strength of selection/maintenance in large populations?
  • heterozygote advantage
  • frequency-dependent selection (RQ vs. arms race)

Tay-Sachs disease

  • Lethal abnormality in hexosaminidase A (lipid metabolism); early (infant/toddler) death
  • Mendelian, recessive lethal (\(s=1\))
  • allele frequency \(\approx\) 1/300 in US population, 1/30 in Ashkenazi (E. European) Jews: also high in French Canadians, Cajuns, Pennsylvania Dutch …
  • Population-genetic evidence suggests drift
  • (Terrible!) speculation about overdominance or heterozygote advantage: Tb resistance, intelligence: ???
    (Spyropoulos 1988; Frost 2012; Frisch et al. 2004)

phenylketonuria (PKU)

  • metabolic disorder (phenylalanine)
  • many different mutations
  • homozygous PKU historically lethal (selection coefficient = 1)
  • PKU alleles are old

PKU incidence (Hillert et al. 2020)

PKU genetics

why not drift? (Krawczak and Zschocke 2003)

  • many different mutations
  • present across many populations
  • populations without history of being small
    • e.g. Irish gene pool from \(\approx\) 2500 BC
    • population size was 100K-200K
    • current expected frequency 0.6% is twice as high as expected

PKU genetics: conclusion

  • calculation from genetic models
  • heterozygote advantage probably \(\approx\) 1.5%
  • hard to measure directly!
  • probably due to higher phenylalanine levels in heterozygotes
  • phenotypic effects?
    • higher birth weight
    • mycotoxin resistance?
    • starvation resistance?

Sickle-cell

  • overdominance
    (heterozygote advantage)
  • selection for falciparum malaria resistance
  • geographic patterns;
    consistency with malaria distribution Esoh and Wonkam (2021)
  • mechanistic basis for protection
  • evidence for positive selection (age??)

Balanced polymorphisms

  • Sickle-cell (and all cases of overdominance) depends on genetic makeup of the population
  • chance of mating with a carrier is higher when allele is more common
  • easier to do the math at the level of alleles

Selective sweeps

  • strong selection on an allele
  • individuals carrying that allele have high fitness
  • lower (gene-specific) effective population size
  • neighbouring loci carried along as haplotypes: hitchhiking
  • haplotypes gradually erode (narrow) by recombination
  • e.g. MHC class I variability in chimpanzees decreased ~ 2-3 mya (Groot et al. 2002)

Selective sweep: chromosome pattern

(Nair et al. 2003)

Other malaria-protective variation

  • hemoglobin variants:
    • blood groups, Rh-negativity
      (older than malaria)
    • thalassemia
  • enzyme variants:
    • GP6D deficiency/favism
      • Mediterranean populations
      • X-linked
      • arose 5-10K years ago: agriculture?
  • Duffy antigens (protection against vivax malaria)

Wikipedia

Cystic fibrosis

  • Lethal lung disease: mucus build-up
    (1/4 chance of death before 30, previously much higher)
  • 4% carriers in European whites (1/2500 diseased: \(2pq=0.04 \to q^2=0.0004\))
  • Mutated cftr gene, changes chloride metabolism;
    age approx. 50 KYA
  • Protection from cholera? (First European cholera epidemic 1817) Dehydrating intestinal diseases? Typhoid?
  • Pleiotropy (multiple effects from one gene)

HIV

From Galvani and Novembre (2005):

  • where does CCR5-\(\Delta 32\) come from?
  • homozygous individuals are healthy …
  • at least 5000 years old; Hummel et al. (2005); Novembre, Galvani, and Slatkin (2005); Galvani and Novembre (2005); Lidén, Linderholm, and Götherström (2006)
    • “If \(\Delta 32\) were neutral, population genetics theory predicts it would have to be much older given its frequency.”
  • high dispersal, sustained strong selection (\(s > 0.1\)); what selective agent? plague? smallpox?

Summary: variation in Mendelian traits

  • (relatively) simple inheritance
    • recessive/dominant, autosomal/X/Y-linked
  • mechanisms
    • drift
    • heterozygote advantage
    • balancing selection/tradeoffs; gene × environment interaction
  • evidence
    • ancient DNA
    • phylogenetic patterns/coalescent methods to estimate origin times/places
    • biogeography/history of disease/environment
    • mechanism
    • population history

more examples

Domínguez-Andrés and Netea (2019)

GWAS

Mboowa et al. (2018)

References

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Borghans, J. A. M, J. B Beltman, and R. J De Boer. 2004. “MHC Polymorphism Under Host-Pathogen Coevolution.” Immunogenetics 55 (11): 732–39.
Domínguez-Andrés, Jorge, and Mihai G. Netea. 2019. “Impact of Historic Migrations and Evolutionary Processes on Human Immunity.” Trends in Immunology 40 (12): 1105–19. https://doi.org/10.1016/j.it.2019.10.001.
Esoh, Kevin, and Ambroise Wonkam. 2021. “Evolutionary History of Sickle-Cell Mutation: Implications for Global Genetic Medicine.” Human Molecular Genetics 30 (R1): R119–28. https://doi.org/10.1093/hmg/ddab004.
Frisch, Amos, Roberto Colombo, Elena Michaelovsky, Mazal Karpati, Boleslaw Goldman, and Leah Peleg. 2004. “Origin and Spread of the 1278insTATC Mutation Causing Tay-Sachs Disease in Ashkenazi Jews: Genetic Drift as a Robust and Parsimonious Hypothesis.” Human Genetics 114 (4): 366–76. https://doi.org/10.1007/s00439-003-1072-8.
Frost, Peter. 2012. “Tay-Sachs and French Canadians: A Case of Gene-Culture Co-Evolution?” Advances in Anthropology 02 (03): 132–38. https://doi.org/10.4236/aa.2012.23016.
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Hillert, Alicia, Yair Anikster, Amaya Belanger-Quintana, Alberto Burlina, Barbara K. Burton, Carla Carducci, Ana E. Chiesa, et al. 2020. “The Genetic Landscape and Epidemiology of Phenylketonuria.” The American Journal of Human Genetics 107 (2): 234–50. https://doi.org/10.1016/j.ajhg.2020.06.006.
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Last updated: 2023-10-30 12:17:56.281281