Molecular Evolution

GE3M17

Mario A. Fares

Nothing in biology makes sense except in the light of evolution

Dobzhansky, 1973

Sung  to  the  tune  of  "The  Ba/le  Hymn  of  the  Republic"      My  bones  proclaim  a  story  of  incompetent  design.  My  back  s?ll  hurts,  my  sinus  clogs,  my  teeth  just  won’t  align.  If  I  had  drawn  the  blueprint,  I  would  cer-­‐tain-­‐ly  resign.  Incompetent  Design!  Evo-­‐Evo-­‐Evo-­‐lu?on!  Design  is  but  a  mere  illusion.  Darwin  sparked  our  revolu?on.  Science  SHALL  prevail!  

Don  Wise  

Incompetent  Design!  

Course aims

•  Look at evidence for evolution •  Discuss how to measure evolution •  Describe evolutionary processes

Fossil record

Transi?ons  

Ex?nc?ons  

Sinosauropteryx  

Dromaeosaurid  dinosaur  

Nothing in biology makes sense except in the light of evolution

Dobzhansky, 1973

molecular molecular

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The molecule : DNA

MALVK

gene

genome

protein

Population …. Speciation

Molecules versus Morphology •  Strictly heritable •  Unambiguous

description •  Model of evolution •  More amenable to

mathematical analysis •  Easier homology

assessment •  Distant comparisons •  Abundant

•  Environmental factors •  Classification

differences •  Unclear models

DNA: Material and Markers

•  DNA is both the raw material and the marker of evolution – Genes determine inherited differences, which

is what evolution acts on – Genes change and can be used to measure

evolution

Jean  Bap?ste    de  Lamarck  

Besoin  -­‐  the  need  or  desire  for  change  in    phenotype  

Change  in  phenotype  

Change  in  genotype  

Inherited  Change  in  phenotype  of  offspring  

August  Weismann  

Genotype  unaffected  by  changes  in  phenotype  

Offspring  has  changed  genotype  

Change  in  phenotype  of  offspring  

Spontaneous  and  random  changes  in  

genes  during  reproduc6on  

Weismann  dis6nguished  soma6c  and  germline  muta6on  

Descent with modification

•  Charles Darwin •  For evolution to happen, must have

heredity and variation

Natural  Selec?on:  Survival  of  the  Fi/est  

“In  the  struggle  for  survival,  the  fi/est  win  out  at  the  expense  of  their  rivals  because  they  succeed  in  adap?ng  themselves  best  to  their  environment”  

Variation by DNA mutation •  Nucleotide substitution

–  Replication error –  Chemical reaction

•  Insertions or deletions (indels) –  single base indels –  Unequal crossing over

•  Consequences  of  point  muta?ons  within  genes  Figure 15-2

•  Point  muta?ons  can  alter  mRNA  splicing  

Measuring evolution ...

•  DNA sequences change very slowly •  Cannot directly observe evolution •  Compare two or more homologous sequences •  Homologous = descended from a common

ancestor (= related)

•  Analysis requires statistical models –  See later

“Evolu6on  has  been  observed.  It’s  just  it  has  not  been  observed  while  it’s  happening”      

Natural  Selec?on:  adap?ve  Evolu?on  and  Fitness  Traps  

Fitness  

Fitness  traps  preclude  innova?on  leaps  

FITNESS  

(a)  

(b)  

•  Stable  systems  navigate  landscapes  of  low  complexity  with  smooth  and  densely  populated  adap?ve  picks  and  lowly  populated  deleterious  valleys  

•  Non-­‐robust  systems  present  more  complex  landscapes  with  very  dense  deleterious  valleys  in  genotypes  

Observing  Evolu?on  of  Novel  Func?ons  while  it’s  Happening  

Two  stages  for  observing  evolu?on:  1) Describe  what  we  observe  2)  Iden?fy  the  mechanism  underlying  that  we  observe  

Gener.  440  

Gener.  660  

Gener.  1100  

Gener.  1,540  

Gener.  1,980  Gener.  2,200  

Evolutionary models

•  Neo-Darwinian (Pan-selectionist) – positive selection only

•  Mutationist – mutation and random drift

•  Neutralist – mutation, random drift, and negative selection

Positive selection

•  A new allele (mutant) confers some increase in the fitness of the organism

•  Selection acts to favour this allele

•  Also called adaptive evolution

NOTE: Fitness = ability to survive and reproduce

Advantageous allele

Herbicide resistance gene in nightshade plant

Negative selection

•  A new allele (mutant) confers some decrease in the fitness of the organism

•  Selection acts to remove this allele

•  Also called purifying selection

Deleterious allele Human breast cancer gene, BRCA2

Normal (wild type) allele

Mutant allele (Montreal 440 Family)

4 base pair deletion Causes frameshift

Stop codon

5% of breast cancer cases are familial Mutations in BRCA2 account for 20% of familial cases

Neutral mutations

•  Neither advantageous nor disadvantageous

•  Invisible to selection (no selection) •  Frequency subject to ‘drift’ in the

population •  Random drift – random changes in small

populations

Frequency of ABO Blood Group B-allele

0.4  2  

13  

3  

9  

19  

18  

24  

20  

13  

12  

14  

14  

8  7  

Neo-Darwinian Model

•  Mutation is recognised as the origin of variation

•  Gene substitution (new allele replacing old) occurs by positive selection only

•  Polymorphism (multiple alleles co-existing) caused by balancing selection

Large variation unexplained by Natural selection

•  Zuckerkandel & Pauling – 1960s

•  Electrophoretic gel separation of proteins

•  Proteins travel at different speeds according biochemical properties or molecular weight

•  15-50% of genes have 2 or more electrophoretic alleles

•  Consequences  of  point  muta?ons  on  gene  products  

Unexplained variation

•  Too much polymorphism to be explained by mutation and positive selection alone (NeoDarwinian model)

•  Why so much?

Neutral Theory

•  Neutral Theory of Molecular Evolution – Motoo Kimura, 1968

•  Most polymorphism is selectively neutral •  Majority of evolutionary changes caused

by random genetic drift of selectively neutral (or almost neutral) alleles

•  Still allows for some selection

Motoo  Kimura  (1924-­‐94)  

Genetic Drift

Random Genetic Drift Selection A

llele

freq

uenc

y

0

100

advantageous

disadvantageous

Genetic Drift •  Each new allele (mutant) has a

chance of being fixed (= present in all individuals) in the population

•  Probability is proportional to frequency

•  Selection (positive or negative) also affects rate and likelihood

•  Neutral alleles have no selection

•  May ‘drift’ to fixation or extinction

•  Under genetic drift the probability of fixation is simply equal to freq.

Rate of Neutral Evolution

µ =  neutral  muta6on  rate  per  allele  

Neutral  muta6on  

New  allele  Frequency  of  1/2N  

Popula?on  of  N  diploid  individuals  Containing  2N  alleles  (2  per  individual)  

Probability  of  being  fixed  

2Nµ  =  number  of  new  muta?ons  in  a  popula?on  of  N  

Muta?on  Rate  

Rate  of  neutral  evolu?on  =  rate  of  muta?on  X  probability  of  muta?on  being  fixed  

=  2Nµ  X  1/2N  

=  µ  

Under  the  neutral  theory,  the  rate  of  subs:tu:on  =  rate  of  muta:on  

Molecular clock

But …

•  Molecular clock does not always hold

•  Still is a useful concept

•  … more details later …