Molecular evolution:
This presentation is the property of its rightful owner.
Sponsored Links
1 / 46

how do we explain the patterns of variation observed in DNA sequences? PowerPoint PPT Presentation


  • 80 Views
  • Uploaded on
  • Presentation posted in: General

Molecular evolution: . how do we explain the patterns of variation observed in DNA sequences? how do we detect selection by comparing silent site substitutions to replacement substitutions?

Download Presentation

how do we explain the patterns of variation observed in DNA sequences?

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


How do we explain the patterns of variation observed in dna sequences

Molecular evolution:

how do we explain the patterns of variation observed in DNA sequences?

how do we detect selection by comparing silent site substitutions to replacement substitutions?

how do we detect selection by comparing fixed differences between species to polymorphisms within species?

how do we detect selection by using hitchhiking?

Goal: understand the logic behind key tests.


Neutralist vs selectionist view

Neutralist vs. selectionist view

Are most substitutions due to drift or natural selection?

“Neutralist” vs. “selectionist”

Agree that:

Most mutations are deleterious and are removed.

Some mutations are favourable and are fixed.

Dispute:

Are most replacement mutations that fix beneficial or neutral?

Is observed polymorphism due to selection or drift?


Reminder substitution vs polymorphism

Reminder: substitution vs. polymorphism

What happen after a mutation changes a nucleotide in a locus

Polymorphism: mutant allele is one of several present in population

Substitution: the mutant allele fixes in the population. (New mutations at other nucleotides may occur later.)


Substitution schematic

Substitution schematic

Individual 1 2 3 4 5 6 7

Time 0: aaat aaat aaat aaat aaat aaat aaat

Time 10: aaat aaat aaat aaat acat aaat aaat

Time 20: aaat aaat acat aaat acat acat acat

Time 30: acat acat acat acat acat acat acat

Time 40: acat acat actt acat acat acat acat

Times 10-29: polymorphism

Time 30: mutation fixed -> substitution

Time 40: new mutation: polymorphism


Reminder substitution rates for neutral mutations

Reminder: substitution rates for neutral mutations

Most neutralmutations are lost

Only 1 out of 2N fix

Most that are lost go quickly (< 20 generations for population sizes from 100 - 2000)

Most replacementmutations are lost since deleterious: rate of loss is faster than neutral


Data in favor of neutrality

Data in favor of neutrality

  • Substitutions in DNA appear to be clock-like

Figure 6.21


Drift model pseudocode

Drift model pseudocode

Population with 2N – 1 copies of allele A, 1 of allele a

For each generation, draw from prior generation alleles.

-> generate a random number. If less than f(A), new allele = A. Otherwise, allele = a.

-> repeat until 2N alleles drawn

Check to see outcome of drift

->If a is lost, start over.

->If a has fixed, note the number of years

->Otherwise, next year with the new allele frequencies

Repeat 100x per population size

Test populations of 100, 500, 1000, 1500, and 2000


Times to fix for neutral alleles only 1 2n fix how long do they take

Times to fix for neutral alleles(Only 1/2N fix: how long do they take?)

Estimated formula: fixation time = 4.07 * N – 57

Theoretical formula: fixation time = 4N


Puzzle for neutrality

Expected pattern

Actual pattern

rabbits

rabbits

Substitutions

Substitutions

elephants

elephants

Years

Years

Puzzle for neutrality

  • Rates of substitution are clock-like per year, not per generation.


Revised theory the nearly neutral theory

Revised theory: the nearly – neutral theory

Figure 6.22


Can we distinguish selection from drift using sequence data

Can we distinguish selection from drift using sequence data?

  • Compare two species: infer where substitutions have occurred.

  • Silent site substitutions should be neutral (dS)

  • Non-synonymous substitutions are expected to be deleterious (usually) (dN)

  • so, expect < 1

    Translation: rate of non-synonymous (dN) is less than the rate of synonymous substitutions (dS)


How do we explain the patterns of variation observed in dna sequences

and inferences about selection

< 1: replacements are deleterious

= 1: replacements are neutral

> 1: replacements are beneficial


What happens to fixation time with selection model pseudocode

What happens to fixation time with selection? Model pseudocode

Population with 2N – 1 copies of allele A, 1 of allele a

WA = 1 + s; Wa = 1

For each generation, draw from prior generation alleles.

-> generate a random number. If greater than f(A), new alleel = a. Otherwise, test fitness: if random < WA, new allele = A.

-> repeat until 2N alleles drawn

Check to see outcome of drift

->If a is lost, start over.

->If a has fixed, note the number of years

->Otherwise, next year with the new allele frequencies

Repeat 100x per fitness

Test populations of 100


Time to fix favourable allele

Time to fix favourable allele


Time to fix neutral vs favourable

Time to fix: neutral vs. favourable

Simulation results: black – neutral mutations; red – favourable mutations


Time to fixation drift is slow

Time to fixation: drift is slow

Neutral:

New mutations per generation: 2Neu

Probability of fixing a new mutation: 1 / 2Ne

Fixations per generation: = 2Neu * 1 / 2Ne = u

Time to fix: 4Ne

Favored by selection

New mutations per generation: 2Neu (but how many favourable??)

Favored mutation probability of fixing: 2|s|

Fixations per generation: 2Neu * 2|s| * prob. favourable

Time to fix: 2 ln (2Ne) / |s|

2 ln (2Ne) / |s| << 4Ne

Shorter time to fixation

Derivations of these results are tough! See Kimura (1962) and Kimutra and Ohta (1969).


Time to fixation favourable and neutral

Time to fixation: favourable and neutral


Dn ds data brca1

dN / dS data: BRCA1

> 1

< 1

Figure 6.21


Molecular evidence of selection ii mcdonald kreitman test

Molecular evidence of selection II: McDonald-Kreitman Test

is very conservative: many selective events may be missed.

Example: immunoglobins.

= 0.37 overall

We suspect selection favoring new combinations at key sites. Antigen recognition sites:

> 3.0


Evidence of selection ii mcdonald kreitman test

Evidence of selection II: McDonald-Kreitman test

v

v


Mcdonald kreitman test iii

McDonald-Kreitman test III

If evolution of protein is neutral, the percentage of mutations that alter amino acids should be the same along any branch

If all mutations are neutral, all should have the same probability of persisting

So: dN / dS among polymorphisms should be the same as within fixed differences


Mcdonald kreitman logic

McDonald-Kreitman logic

  • Silent sites

    - always neutral

    - fix slowly

    - contribute to polymorphism

  • Replacement sites

    • mainly unfavourable

    • if neutral, fix at same rate as silent and contribute to polymorphism

    • proportion of replacement mutations that are neutral determines dN / dS for polymorphism

    • if favourable, fix quickly and do not contribute to polymorphism: higher dN / dS for fixed differences, lower rate for polymorphism


How do we explain the patterns of variation observed in dna sequences

Time to fixation: favourable and neutral


Polymorphism and fixation

Polymorphism and fixation

Neutral

Deleterious

Silent

Replacement

1 / 2N neutral mutations fix


Polymorphism and fixation1

Polymorphism and fixation

Neutral

Deleterious

Favourable

Silent

Replacement

1 / 2N neutral mutations fix

- slow

2|s| fix

-fast

Neutral

Favourable


Dn ds for neutral and favourable

dN / dS for neutral and favourable

Neutral

Favourable

Polymorphism

dN

dN

dS

dS

Fixation

dN

dN

dS

dS

=

<

poly

fixed

poly

fixed


Mcdonald kreitman hypotheses

McDonald-Kreitman hypotheses

H0: All mutations are neutral.

Then, dN / dS for polymorphic sites should equal dN / dS for fixed differences

H1: replacements are favoured. Favoured mutations fix rapidly, so dN / dS for polymorphic < dN / dS fixed


Example of mk test adh in drosophilia

Example of MK test: ADH in Drosophilia

Compare sequences of D. simulans and D. yakuba for ADH (alcohol dehydrogenase)

Significance? Use χ2 test for independence


Evidence of selection iii selective sweeps

Evidence of selection III: selective sweeps

  • Imagine a new mutation that is strongly favored (e.g. insecticide resistance in mosquitoes)


Detecting selection using linkage g6pd in humans

Detecting selection using linkage: G6PD in humans

Natural history:

  • Located on X chromosome

  • encodes glucose-6-phosphate dehydrogenase

  • Red blood cells lack mitochondria

  • Glycolysis only

  • NADPH only via pentose-phosphate shunt –requires G6PD

  • NADPH needed for glutathione, which protects against oxidation


G6pd and malaria

G6PD and malaria

  • Malaria (Plasmodium falciparum) infects red blood cells

  • Has limited G6PD function typically (but can produce the enzyme)

  • Uses NADPH from red blood cell

  • In G6PD deficient individuals?


G6pd mutants

G6PD mutants

  • Different mutants result in different levels of enzymatic activity

  • Severe mutants result in destruction of red blood cells and anemia

  • Most common mutant: G6PD-202A

  • Usually mild effects: may increase risk of miscarriage

  • Prediction: G6PD and malaria?


Frequency of g6pd deficiency

Frequency of G6PD deficiency


Has g6pd 202a been selected

Has G6PD-202A been selected?

  • 14 markers up to 413,000 bp from G6PD

  • LD?

  • Long distance LD implies strong, recent selection


Has g6pd 202a been selected1

Has G6PD-202A been selected?

Fig 7.14

Linkage disquilibrium

kb from core region


Alternative hypothesis drift caused linkage disequilibrium

Alternative hypothesis: drift caused linkage disequilibrium

G6PD-202A

Allele frequency

Figure 7.14b


Detecting selection ii ccr5 32

Detecting selection II: CCR532


Detecting selection ii ccr5 321

Detecting selection II: CCR5Δ32

  • Stephens (1998) found strong disequilibrium between CCR5-Δ32 and nearby markers

  • Implies recent origin (< 2000 years): recombination breaks down linkage

  • Implies selected


Detecting selection ii ccr5 322

Detecting selection II: CCR5Δ32

  • But: new data – November 2005.

  • Better map:


Detecting selection summary

Detecting selection: summary

  • Several approaches to detecting selection

    • dN / dS

    • McDonald-Kreitman test

    • using hitchhiking

      Challenges of each method?


Other uses of molecular data the coalescent

Other uses of molecular data: the coalescent

Any two alleles in a population share a common ancestor in the last generation

1 / 2Ne

Therefore, going backwards in time, the expected time to find the common ancestor is 1 / (1 / 2Ne) = 2Ne


Coalescent ii

Coalescent II


Coalescent and sequences

Coalescent and sequences

Imagine that you have two sequences at a locus.

They shared a common ancestor 2Ne generations ago.

They accumulate mutations at rate u per generation per basepair.

2Ne generations / lineage * 2 lineages * u =

4Neu differences per basepair between the two sequences.


Coalescent example

Coalescent example

We sequence 1000 base pairs from two sequences, and find 16 base pair differences, how large is the population/

Assume u = 2 x 10-8.

4Neu * 1000 = 16; 8 x 10-5 * Ne = 16;

Ne * 10-5 = 2; Ne = 200,000


Neutral theory as a null model

Neutral theory as a null model


Additional readings

Additional readings

Eyre-Walker (2006) The genomic rate of adaptive evolution. Trends in Ecology and Evolution 29:569-575. (Well-written review)

Gillespie (2004). Population genetics: a concise guide. John Hopkins: Baltimore, MD. (Very short, clear, but dense!)

Graur and Li (2000) Fundamentals of molecular evolution. Sinauer: Sunderland, MA. (Very clear)

Kimura (1962) On the probability of fixation of mutant genes in populations. Genetics 47:713-719. (If you really want the derivation)

Kimura and Ohta (1969) The average number of generations until fixation of a mutant gene in a finite population. Genetics 61:763-771. (If you really want the derivation)

Sabeti et al (2006) The case for selection at CCR5-32. PLoS Biology 3:1963-1969.

Questions: 1. Explain why clock-like rates of substitutions per year did not fit with the neutral theory.

See posted molecular evolution practice questions: highly recommended!


  • Login