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Population Genetics: The 5 Factors of Evolution

Questions are welcome! Laurence Loewe Laboratory of Genetics Wisconsin Institute of Discovery University of Wisconsin-Madison
Nov, 15, 2013, Biocore 301 PopGen Unit Lecture 2-preB

Population Genetics Unit Overview

Date W Nov 13 F Nov 15 M Nov 17 W Nov 20 F Nov 22 M Nov 25 W Nov 27 Lecture Topic PopGen: science of the future Five factors of evolution Adaptation, selection, fitness landscapes Mutation, selection drift at one locus Multi-locus population genetics Mechanism of speciation Phylogenetic Trees Assignment due Mon Nov 25 email loewe@wisc.edu Office hours Discovery Building at a table near reception desk Thursday, Nov 14, 2-3pm, Thursday, Nov 21, 2-3pm,

5 Factors of Evolution
Modeling Absence of all Presence of Individual Factors Combinations

Evolution as a Unifying Theory

FITNESS ABSTRACTION ALLOWS SEPARATION OF CONCERNS

Summary A Mini-Guide to

Modeling

Math Models

brings Modeling

Renew? or Ruin?
power

responsibility

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maps

to Rea

lity

Math Models

gy o l o i b r o f ant v e l e r l e d e mo h t e tion k s a e m u y Q t i l a a d e oun r a d e ! Links to r p s a k h n i s l e d r o a o for g Links d e d e e n ten f o s c i t s i t Sta

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must simplify well lity

maps to Rea

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Math Models

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Occams Razor Make models as simple as possible, but not simpler.

William of Occam, Franciscan Friar, 1287-1347

Free paraphrase of Albert Einsteins interpretation of Occams Razor http://en.wikipedia.org/wiki/William_of_Ockham

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Question

Wikipedia /File:Ancient_warded_lock_key_transparent.png

Abstration

Wikipedia - ile:English_-_Mortise_Lock_with_Key_-_Walters_52173.jpg

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All models are wrong, but some are useful.

George Box Professor of Statistics, UW-Madison

Wikipedia: Glass-of-water.jpg

must simplify well lity

maps to Rea

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Math Models

must conserve

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Bad Models often Violate a Conservation Principle

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maps to Rea

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Models

must conserve

mus

t ea

rn tr

ust

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You will encounter Models with different levels of maturity

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Life of A Model
Life event Birth Toddler Meaning for a Model First Idea how an answer might even look like Noise about this is heard by more people Model Quality Subconscious Speculation Speculation Conception New Question without a good answer

Wikipedia/File:Learning_to_walk_by_pushing_wheeled_toy.jpg

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Life of A Model
Life event Birth Toddler Teens Twenties Thirties Meaning for a Model First Idea how an answer might even look like Noise about this is heard by more people First Tests using a reasonable Null-Hypothesis First Supporting Evidence and many conflicts 50% Majority Support among key researchers Model Quality Subconscious Speculation Speculation Weak Hypothesis Hypothesis Strong Hypothesis
Wikipedia:Teens_sharing_a_song.jpg

Conception New Question without a good answer

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a Jap dia:

7_S 08.0

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My

tfri bes

end

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Wikipedia:Marine_da_nang.jpg

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Life of A Model
Conception New Question without a good answer Toddler Teens Twenties Thirties Forties >Fifties >Nineties Fossilized Immortal Death
Wikipedia :Lord_Kelvin_photograph.jpg

Subconscious Speculation Speculation Hypothesis Young Theory

Birth

First Idea how an answer might even look like Noise about this is heard by more people First Tests using a reasonable Null-Hypothesis First Supporting Evidence and many conflicts 50% Majority Wikipedia Support among key researchers :Burlington_House_ILN_1873.jpg 80% Majority Support among key researchers, may still be called hypothesis (historic reasons) Doubters lack new evidence; enter textbooks Death of last scientist from era before Death by boredom; all agree; no questions left Now New Discipline: fountain of good questions Death by data: can & does happen any time

Weak Hypothesis Strong Hypothesis

Theory,Principle, Law, Dogma, ... Everybody knows Institutionalized Case for history

Wikipedia :Charles_Darwin_by_Julia_Margaret_Cameron_2.jpg

Life event

Meaning for a Model

Model Quality

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Life of A Model
Life event Birth Toddler Teens Twenties Thirties Forties >Fifties >Nineties Fossilized Immortal Data Meaning for a Model First Idea how an answer might even look like Noise about this is heard by more people First Tests using a reasonable Null-Hypothesis Model Quality Subconscious Speculation Speculation Weak Hypothesis Hypothesis Strong Hypothesis Young Theory Theory,Principle, Law, Dogma, ... Everybody knows Institutionalized Case for history Conception New Question without a good answer

Improving First Supporting Evidence and many conflicts Quality

50% Majority Support among key researchers 80% Majority Support among key researchers, may still be called hypothesis (historic reasons)

of enter textbooks Doubters lack new evidence; Models Death of last scientist from era before
Death by boredom; all agree; no questions left Now New Discipline: fountain of good questions Death by data: can & does happen any time

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It can happen ...

... any time ...

... to any model ...

Death by Data
... especially if the data is ... ... easier to understand ... ... in a simpler model...

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Model Reliability is Variable

Speculation Facts
Science fiction Hard problems in basic research Applied science

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Before you believe anything in science ... ... and also after you do ... ... dont forget to:

Evaluate the evidence.

... but how?

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Intuition Real Life in natura

All Approaches need to work together!

Test Tube in vitro Bloody Statistics in estimo Shoulders of Giants
by Brian Pelletier!

Controlled Lab in vivo Hard Dry Math in ratio Meaty Simulations in silico

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You need a bit of modeling background for appreciating:

Evolution = Map* to how populations change

* Map under construction: you can hurt yourself & others if you get this wrong!

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Evolution as a Unifying Theory

FITNESS ABSTRACTION ALLOWS SEPARATION OF CONCERNS

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5 Factors of Evolution
Modeling Absence of all Presence of Individual Factors Combinations

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Who?

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What is a

Null-Model ?
0 0 0
0 0 00 0

0 0

Null Model

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Mini-guide to constructing Null-Models:

What is the most BORING thing that could possibly happen?

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The Big Null Model In Evolution:

Nothing interesting ever happens in evolution.

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Evolution needs change in allele frequencies. What is the most boring thing that could happen to a collection of alleles?
You tell me...

Null Model

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Big Null Model In Evolution

There is no evolution Allele frequencies do not change

Null Model

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Big Null Model In Evolution

There is no evolution Allele frequencies uch m y r e v do not change at the

mo

t s o alm

t n me

Null Model

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Lets find a good abstraction!

Assume only counts of different alleles matter

" Track identity of allele types, ignore structure, function... " 1 allele could be like 1 bean " population = bean-bag !" inheritance by sampling " simplest diploids: 1 locus, 2 alleles

Bean Bag Genetics

Abstraction

Hardy-Weinberg Principle:

Conservation Law of Evolution

Alleles do not appear or disappear in a population unless some evolutionary factor is operating on the population. Remember: Evolution means change in allele frequencies

Conservation

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How does that work?

Lets do a very small simulation! Ideal diploid population: 1 locus, 2 alleles Question: How do genotypes and alleles change over time?
See Movie

Conservation

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Hardy-Weinberg Ratios

A Mendelian diploid locus with 2 alleles has the equilibrium genotype frequencies

p2 + 2pq + q2 = 1
that can be predicted from allele frequencies p+ q = 1 ... but only if evolutionary factors are absent!

Results

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Please close your laptops!

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CleanerX
t n e g r y e r t t e n d u o ec new h t c t i t n n i s e a g $ t r n te e lion l d i b y " Fa r 1 nd .4 u 2 a l e r u fo en e v r e a r l h ts ua e n k n r A a m " n i e s rea c n i % " 3 5

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Hardy-Weinberg-The-Movie Have you seen it?

A Yes. I easily followed the explanations B Yes. I worked through the explanations and got it not easy C Yes, I tried, but that was too hard D Parts, I didnt have time for it all E No, I have not yet watched it

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What is the annual revenue of CleanerX? Which value comes closest?

A 2.1 million $ B 2.4 million $ C 3.5 million $ D 2.5 trillion $ E 1.9 billion $

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Hardy-Weinberg-The-Movie What are the main results of the study?

A The twiddle-dee population is not in Hardy Weinberg Equilibrium. On these grounds they get the company to change. B The population is in Hardy-Weinberg Equilibrium. C The data shows that recessive alleles at SweetLocus1 decrease in the orchard. That is why pollination declines in the movie. D I dont know. E No, I have not yet watched it.

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Hardy-Weinberg-The-Movie What are the main results of the study?

A Frank & Rose find the population is not in Hardy Weinberg Equilibrium. On these grounds they get the company to change. B The population is in Hardy-Weinberg Equilibrium. C The data shows that recessive alleles at SweetLocus1 decrease in the orchard. That is why pollination declines in the movie. D I dont know. E No, I have not yet watched it.

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CleanerX
t n e g r y e r t t e n d u o ec new h t c t i t n n i s e a g $ t r n te e lion l d i b y " Fa r 1 nd .4 u 2 a l e r u fo en e v r e a r l h ts ua e n k n r A a m " n i e s rea c n i % " 3 5

...illions

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You can open your laptops again ...

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1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 2012 2013 0.16 0.25 0.48 0.5 Aa (heterozygotes dominant likes CleanerX) aa (pollinates recessive) 0.36 0.25 AA (dominant likes CleanerX)

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Hardy-Weinberg-The-Movie What are the main results of the study?

A Frank & Rose find the population is not in Hardy Weinberg Equilibrium. On these grounds they get the company to change. B The population is in Hardy-Weinberg Equilibrium. C The data shows that recessive alleles at SweetLocus1 decrease in the orchard. That is why pollination declines in the movie. D I dont know. E No, I have not yet watched it.

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It can happen ...

... any time ...

... to any model ...

Death by Data
... especially if the data is ... ... easier to understand ... ... in a simpler model...

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What did we not test yet? Were all tests done rigorously?

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There was this talk by Prof. Karl Broman...

2013, BMI, UW-Madison

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Lets do a classical Hardy-Weinberg Test for 2013

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Hypothesis: CleanerX kills Alleles that Pollinate

(If not, then CleanerX removes only alleles that would not have pollinated anyway!)

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Computing Hardy-Weinberg Equilibrium

1. Observe genotype counts (co-dominance needed, if using phenotype)
Genotype Observed Expected Genotype Genotype Equations = Freq * ! = Count Count / ! = Freq 7000 2800 200 p2 2pq p2 p2+2pq +q2 ObservedExpected Count "2

AA Aa aa Total !

Allele A a

Symbol for allele frequency p q

Allele Counts from Genotype Counts 2AA + Aa = 2aa + Aa =

Allele frequency

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Computing Hardy-Weinberg Equilibrium

2. Compute sum of genotypes
Genotype Observed Expected Genotype Genotype Equations = Freq * ! = Count Count / ! = Freq 7000 2800 200 10000 p2 2pq p2 p2+2pq +q2 ObservedExpected Count "2

AA Aa aa Total !

Allele A a

Symbol for allele frequency p q

Allele Counts from Genotype Counts 2AA + Aa = 2aa + Aa =

Allele frequency

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Computing Hardy-Weinberg Equilibrium

3. Compute observed genotype frequencies
Genotype Observed Expected Genotype Genotype Equations = Freq * ! = Count Count / ! = Freq 7000 2800 200 10000 0.70 0.28 0.02 1 p2 2pq p2 p2+2pq +q2 ObservedExpected Count "2

AA Aa aa Total !

Allele A a

Symbol for allele frequency p q

Allele Counts from Genotype Counts 2AA + Aa = 2aa + Aa =

Allele frequency

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Computing Hardy-Weinberg Equilibrium

4. Compute observed allele frequencies
Genotype Observed Expected Genotype Genotype Equations = Freq * ! = Count Count / ! = Freq 7000 2800 200 10000 0.70 0.28 0.02 1 p2 2pq p2 p2+2pq +q2 ObservedExpected Count "2

AA Aa aa Total !

Allele A a

Symbol for allele frequency p q

Allele Counts from Genotype Counts 2AA + Aa = 16800 2aa + Aa = 3200

Allele frequency 16800 /(2! ) = 0.84 3200 /(2!) = 0.16

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Computing Hardy-Weinberg Equilibrium

5. If at HWE: Compute expected genotype frequencies
Genotype Observed Expected Genotype Genotype Equations = Freq * ! = Count Count / ! = Freq 7000 2800 200 10000 0.70 0.28 0.02 1 p2 2pq p2 p2+2pq +q2 0.705 0.269 0.026 1 ObservedExpected Count "2

AA Aa aa Total !

Allele A a

Symbol for allele frequency p q

Allele Counts from Genotype Counts 2AA + Aa = 16800 2aa + Aa = 3200

Allele frequency 16800 /(2! ) = 0.84 3200 /(2!) = 0.16

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Computing Hardy-Weinberg Equilibrium

6. Compute expected genotype counts
Genotype Observed Expected Genotype Genotype Equations = Freq * ! = Count Count / ! = Freq 7000 2800 200 10000 0.70 0.28 0.02 1 p2 2pq p2 p2+2pq +q2 0.705 0.269 0.026 1 7050 2690 260 10000 ObservedExpected Count "2

AA Aa aa Total !

Allele A a

Symbol for allele frequency p q

Allele Counts from Genotype Counts 2AA + Aa = 16800 2aa + Aa = 3200

Allele frequency 16800 /(2! ) = 0.84 3200 /(2!) = 0.16

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Computing Hardy-Weinberg Equilibrium

7. Compute "2 test statistic
Genotype Observed Expected Genotype Genotype Equations = Freq * ! = Count Count / ! = Freq 7000 2800 200 10000 0.70 0.28 0.02 1 p2 2pq p2 p2+2pq +q2 0.705 0.269 0.026 1 7050 2690 260 10000 ObservedExpected Count "2 -50 110 -60 0.35 4.5 13.8 18.6

AA Aa aa Total !

Allele A a

Symbol for allele frequency p q

Allele Counts from Genotype Counts 2AA + Aa = 16800 2aa + Aa = 3200

Allele frequency 16800 /(2! ) = 0.84 3200 /(2!) = 0.16

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Chi-Square Significance Test

1. Compute test statistic "2 = 18.6

! ="
2 all

(Obs ! Exp)
Exp

2." Determine probability that null hypotheses explains the data (P-Value): "2 Table lookup, 1 degree of freedom: P # 5% "2 $ 3.84 (P value # 5% for test statistic "2 $ 3.84) P # 0.1% "2 $ 10.83 P = 1.6*10-5
(computed by R command: pchisq(q=18.6,df=1,lower.tail=FALSE)

It is very unlikely that this population is in Hardy-Weinberg Equilibrium. !" Practical Conclusion: No equilibrium Interpretation: The hypothesis is back, but we still need to check if this generation is indeed special (i.e. something else could be going on).

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Summary How to test for Hardy Weinberg Equilibrium

1." Observe genotype counts (co-dominance needed, if using phenotype) 2." Compute sum of genotypes 3." Compute observed genotype frequencies
(Divide each genotype count by !G to get its frequency.)

4." Compute observed allele frequencies

For the first allele add the homozygous genotype frequency to half of the heterozygote frequency. For the next, just use the relationship p + q = 1 for loci with 2 alleles.

5.! If at HWE: Compute expected genotype frequencies

Use the Hardy-Weinberg relations : p2 + 2pq + q2 = 1

6." Compute expected genotype counts 7." Compute "2 test statistic. Here chsquare% 8." Convert the test statistic to a P value%

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5 Factors of Evolution
Modeling Absence of all Presence of Individual Factors Combinations