Population Genetics: Its Mathematical Principles …manabe/ppt/tomokoohta.pdfPopulation Genetics...
Transcript of Population Genetics: Its Mathematical Principles …manabe/ppt/tomokoohta.pdfPopulation Genetics...
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Population Genetics: Its Mathematical Principles and Some Recent Trends
Tomoko Ohta, Ph.D.National Institute of Genetics
Mishima, Japan
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Population Genetics
• Darwin + Mendel
• Population consequences of Mendelian Inheritance worked out in 1930s
R. A. Fisher, J. B. S. Haldane and S. Wright
Change of gene frequencies in populations by natural selection, random genetic drift, mutation and migration
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Change in gene frequency
Natural selection
Deterministic: Necessity
selection coefficient: s
Genetic drift
Erratic movement of gene frequency
Stochastic: Chance
Mainly by random sampling of gametes at reproduction
Effective population size: N
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Random sampling
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Beginning ofPopulation Genetics + Molecular Evolution
• 1960s
• Application of data on genetic variation and evolution to population genetic models
• Stochastic processes becoming more applicable.
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1960s
Kimura: Population genetics + Molecular biology
Zuckerkandl-Pauling: Molecular clock (1965)
Kimura: Neutral theory (1968)
King-Jukes: Non-Darwinian evolution (1969)
Ohno: Evolution by gene duplication (1970)
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Protein polymorphisms by electrophoresis
Lewontin-Hubby 1966
Kimura-Crow model 1964
Infinite-site model 1969
Step-mutation model 1973
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Three Problems
• What are borderline mutations between the selected and the neutral?
• Molecular clock: year or generation-time dependent?
• Narrow range of heterozygosity?
Ohta: Slightly deleterious mutation theory 1973
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Step-mutation model
• Rare Common Rare
• Slightly deleterious mutation
• Used in probability theory by JFC Kingman
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• Prediction of the Neutral Theory
Evolutionary rate = Neutral mutation rate
• Prediction of the Nearly Neutral Theory
Negative correlation between the population size and evolutionary rate
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Early support of rapid evolution of small populations
• Endosymbiotic bacteria
Moran 1996
• Island species of birds
Johnson and Seger 2001
Woolfit and Bronham 2005
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dN/dS
Human > Pig > Mouse
Jorgensen et al. 2005
Human > Dog > Mouse
Lindblad-Toh et al. 2005
Hominid > Rodent
The Chimpanzee Sequencing Consortium 2005
Yeast laboratory strain > Yeast wild strain
Gu et al. 2005
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Polymorphism
Human SNPs : Abundant rare alleles
Bacteria 84 species Tajima’s D
Dnon 68% negative
Dsyn 70% positive
Hughes 2005
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Protein Folding and Proteostasis
• Aberrant folding and aggregation - Toxic
Peak and valley of free-energy landscape
• Chaperones - Dynamics
F U Hartl et al. 2011
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Intrinsically Disordered Protein
• Signaling and regulatory functions:
tightly regulated but provide versatility
via post-translational modification
Babu et al. 2011
Examples:
Histone tail for chromatin function
Tissue specific splicing disordered segment
for protein interaction network
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Evolution of Complex Gene Regulatory Systems
Phenotype, especially morphology, changes:
mainly coming from gene regulatory changes
Gene expression: Time and Space
Expression quantity
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Robustness of gene regulatory network
Gene redundancy
Gene degeneracy
J. M. Whitacre
Distributed robustness: flexible regulatory network
A. Wagner
Robustness→ Increase of nearly neutral mutations
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• Ratio of gene expression divergence between species to gene expression diversity within species
– About equal in the brain, heart, kidney, liver but three fold higher in the testes
Brain: Ratio of the change of the human lineage to that of chimpanzee is larger than the same ratio in the liver or heart
Khaitovich et al. 2006
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Weak stabilizing selection on gene expression
• Divergence of gene expression among Drosophila species initially increases with time, but eventually saturates.
• The strength of stabilizing selection is estimated to be very weak, i. e., nearly neutral.
Bedford- Hartl, 2009
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The ENCODE project
• Many transcripts with unknown function and/or without constraint exist in human cells
• Neutral or nearly neutral
• Provide opportunities for new regulatory systems
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Genome Accessibility
• Nucleosome packaging and positioning
DNA wrapped around a octamer: H3,H4,H2A,H2B
Linker histone between nucleosomes: H1
• DNA sequence and chromatin remodeling
O. Bell et al. 2011
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Linker Histone Variability
• H1 family: subtypes
• differential expression, mobile,
non-random distribution on chromatin regions
Polymorphic: physiological traits
Intrinsically disordered region for signaling system
AS. Kowalsky and J. Palyga 22012
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Chromatin Modifying Enzymes
readers, writers, erasers
histone tails (intrinsically disordered)
acetylation, methylaton, phosphorilaton etc
histone mimick sequences of nuclear proteins
Digital to analog transformation
A. I. Badeaux and Y. Shi 2013
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Protein kinases
Phosphorylation sites in orthologous proteins of different species, not conservative
human vs mouse: 12% of phosphoserine
15% of phosphothreonine
Lienhard, 2008
~500 protein kinases in human
10%: pseudokinases
Taylor and Kornev 2010
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Near-neutralityGenotype
Epigenetics RobustnessChromatin structure Extra-activity of genome
DNA methylation and others Cooption in gene regulation
Stochastic variation → Modification ofof gene expression ← gene network
↑environment
PhenotypeDarwinian selection
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Environment -> Gene Expressionendogenous
Ligand Receptor
exogenous
steroid nuclear-receptor superfamily
retinoid
vitamin D flexible
thyroid hormone
hormone response elements: numerous and often weak-binding
Ligand-dependent transcription
Evans and Mangelsdorf 2014
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Attractors and Democratic Dynamics in Gene Regulation
• Autocratic: master gene
• Intermediate: common in real regulation
• Democratic: all genes interact
attractors, self-organization
Bar-Yam t al. 2009
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Evolution of complex systems
• Epigenetics
• Genetic Drift Work together
• Natural selection