human genetics evolutionary genetics

Evolutionary GeneticsHuman Genetics

http://slideshare.net/[email protected]

March 7th, 2016Dr. Dan Gaston

http://slideshare.net/dangaston

"Nothing in Biology Makes Sense Except in the Light of Evolution"

-- Theodosius Dobzhansky

Evolutionary Genetics

Genetics Evolution

Evolutionary Genetics

Population Genetics Evolution

Evolutionary Genetics: Darwinian Origins

Voyage of The Beagle: 1831-1836Origin of Species: November 24th, 1859

Evolutionary Genetics: Mendel and Genetics

• Gregor Mendel's experiments: 1856-1865

• Mendel's rediscovery and early modern genetics (de Vries, Bateson, Morgan, Punnet): Early 1900’s

The Forces of Evolution

•Mutation•Genetic Drift

•Selection

Mutation

Genetic Drift

Selection• W = 1 – s

• W: Fitness• s: Selection Coefficient

• s = 1 (Lethal)• s = 0 (No difference in fitness)

Evolutionary Debates of the early-mid 20th century• Primarily differences in view and opinion on relative importance of

different forces:• "The Mendelians": Geneticists who generally asserted the primacy

of mutation to greater or lesser degrees

• "The Naturalists": Field Biologists who generally asserted the importance of natural selection

Evolutionary Genetics: Modern Synthesis• The foundation of Evolutionary Genetics is the foundation of Population Genetics (1918-1939):

• RA Fisher• JBS Haldane• Sewall Wright

• The naturalists (1940s):• Theodosius Dobzhansky• EB Ford• Ernst Mayr• George Simpson• Julian Huxley

"Natural selection is a mechanism for generating an exceedingly high degree of improbability." - RA Fisher

Neutral and Nearly Neutral Theory of Evolution• Kimura (1968) and King and Jukes (1969) (Neutral Theory)• Most genetic differences between organisms selectively neutral

• Synonymous mutations

• Molecular level dominated by neutral mutations and genetic drift• Phenotypic level differences dominated by selection• Expanded on By Tomoko Ohta and Kimura in 1973 (Nearly Neutral

Theory)• In addition to neutral, beneficial, and deleterious mutations there are also

nearly neural mutations. Slightly deleterious and slightly advantageous

Evidence for Near Neutrality• Prediction: Fixation of Neutral sites will occur at the rate of mutation

(or nearly so for near neutrality)

Evidence for Near Neutrality• Prediction: Fixation of Neutral sites will occur at the rate of mutation

(or nearly so for near neutrality)• Evidence:

• Synonymous sites• Introns• Intergenic DNA• Pseudogenes

Nearly Neutral Theory of Evolution

Neutral Evolution becomes the Null Hypothesis in Evolutionary Biology. It is the default assumption in the absence of evidence of selection

Mutation

Phylogenetic Trees and Models of Evolution

Phylogenetic Trees

Phylogenetic Trees and Evolutionary Genetics: Molecular Evolution• Theoretical Framework in the 1960’s: Zuckerkandl, Pauling, Margoliash, Fitch• Originally based on comparing proteins based on electrophoresis and later

DNA via DNA-DNA hybridization experiments• Sanger sequencing (1977) ushers in DNA sequencing• A variety of techniques and statistical algorithms have been developed over

the decades: • Maximum Parsimony• Maximum Likelihood• Bayesian Inference• Distance Methods• Neighbour-Joining

Maximum Parsimony

Maximum Parsimony

Minimize the amount of change necessary to describe therelationship between organisms/sequences

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Maximum Parsimony: Informative and Non-Informative Sites

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Maximum Parsimony: Challenges• Enumerating the minimum number of changes on a tree gets

inefficient as the number of leaf nodes increases (Easy)• Fitch Algorithm Solution

• Evaluating all possible trees becomes impossible as the number of leaf nodes increases (Hard)

• Number of unrooted trees for N leaf nodes:• π(i=3 ...n) (2i – 5) (10 Nodes = > 2 million trees)

• Number of rooted trees for N leaf nodes: • π(i=3 ...n) (2i – 3) (10 Nodes = >34 million trees)

Phylogenetic Trees and Evolutionary Genetics• Performed on Amino Acid or Nucleotide sequences• Performed on basis of single-genes, multiple genes, or whole

genomes• Typically rely on:

• Multiple sequence alignment• Model of evolution

• Amino acid or nucleic acid exchange probabilities• Rates of substitution• Site classes

Interesting Deviations

Horizontal Gene Transfer

Horizontal Gene Transfer in Animals

Horizontal Gene Transfer and Mammalian Reproduction

Horizontal Gene Transfer and Mammalian Reproduction

• Multiple Independent acquisitions of Syncytin genes

• Syncytin gene acquisition primarily in lineages with moderate to highly invasive placental type

• Cell fusion and immunosuppresion

Human Evolution

Human Population Movement

Human Evolution: Neanderthal and Denisovan Interbreeding

Recent Human Evolution and Population Movements

Recent Human Evolution: Agriculture and Immunology• Evolution hasn’t stopped in humans, although modern medicine and society

has shifted selection pressures• SLC22A4: Ergothioneine absorption. Variant with enhanced activity arises

and spreads in Neolithic Europe with the rise of agriculture and shift to wheat consumption

• Lactase persistence arises in multiple populations around the world• Lighter skin of Europeans relatively recent. First with arrival of migrants

from Turkey <9,000 years ago, then with a second mutations sometime more recently

• Height (Particularly linked to Yamnaya introgression in Northern Europeans)

"Nothing in Biology Makes Sense Except in the Light of Evolution"

-- Theodosius Dobzhansky

human genetics evolutionary genetics

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