Kimura Drift2 skenovat0001
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substitution = replacement of one allele by other (tj. fixation of a new allele)
if an individual do not reproduce, we call it genetic death
J.B.S. Haldane (1957):
advantageous mutation ® fixation and replacement of a deleterious allele
as long as the original allele exists in the population, mean fitness is lower
than maximal fitness
Substitutional load and the cost of natural selection
File:J. B. S. Haldane.jpg
J.B.S. Haldane

File:J. B. S. Haldane.jpg
substitutional load*):   ; when      L = 0
in general
it measures to what extent an average member of the population is less fit
than the best fit genotype
it expresses probability that an average individual dies before his/her
reproduction
*) in general = genetic load; other loads: mutational: emergence of a deleterious allele;
segregational: cost of homozygotes under overdominance

Cost of natural selection:
We can envisage replacement of one allele in a population by another as
a „selective death“ of the original allele
The higher is the strength of selection, the more of the original (less advantageous) alleles are
removed from the population (they „die“)
If the natural selection was too strong it could cause extinction of
the whole population Þ overproduction of the offspring necessary!
eg. if the ratio of non-surviving to surviving alleles is 0,1/0,9, each survivor have to produce by
1/9 more descendants,
but if the ratio is 0,999/0,001 ® by ~1000 more descendants!
Haldane: upper limit of the cost of natural selection » substitution of 1 gene per 300 generations
Þ evolution cannot run too fast, the cost of selection would be too high

http://bio3400.nicerweb.com/Locked/media/ch13/13_07-genetic_code.jpg
64 codons
20 amino acids

likewise M. Grunstein (1976):
evolutionary rate of Histone H4 in 2 sea urchin species
84 bp mtDNA ® 9 of 10 differences synonymous
http://images.gizmag.com/hero/nissans-leather-seats-like-human-skin-4.jpg
https://encrypted-tbn1.gstatic.com/images?q=tbn:ANd9GcSbEXZJ3IFYe5I4_F2mBefY6k4YNaQg7mLIpCn9-5A0Je4
uQKwE http://eatsomethingsexy.com/wordpress/wp-content/uploads/2010/10/seaurchin.jpg
http://www.365daysofdining.com/wp-content/uploads/sea-urchin.jpg
excess of synonymous nucleotide substitutions ® esp. at the 3rd position
M. Kimura (1977): mRNA sequences of humans and rabbits ®
of 53 nucleotide positions 6 differences, of them only 1 nonsynonymous
´ theoretically only 24% of differences should be synonymous

NEUTRAL THEORY OF
MOLECULAR EVOLUTION
Modern Synthesis: selection vs. drift debate
beginning of the 1960s ® amino acid sequences in proteins
1966: protein elektrophoresis
Richard Lewontin and Jack Hubby - Drosophila pseudoobscura;
Harry Harris - humans
® high level of polymorphism

Data gathered till the end of 1960s suggested that:
Rate of molecular evolution is too high
Genetic variation in natural populations is too high
... both would require too high cost of natural selection Þ
polymorphism cannot be maintained by selection
Rate of evolution at the molecular level is constant
Higher evolutionary rate in functionally less important parts of the molecule, in noncoding regions
and pseudogenes

Why so high polymorphism in populations?
Motoo Kimura: because alleles are selectively neutral, it lasts many
generations till a new mutation is fixed – meanwhile the population
must be polymorphic = transient polymorphism
During the process of fixation often a new allele appears by mutation Þ
in a sufficiently large population at each point in time there is a large
amount of variation
Population is in equilibrium between drift
and mutation
M. Kimura (1968)
J.L. King & T.H. Jukes (1969)
neutral theory of
molecular evolution
Kimura
M. Kimura

Mol_sel.tif
fast fixation of a beneficial mutation
neutral allele is fixed randomly
fast extinction of a deleterious mutation
parallel occurrence of several alleles
mostly only 1 allele in the population

1. most allele substitutions in a population are neutral (Þ drift)
skenovat0002
Basic principles of the neutral theory:

fibrinopeptides 8,3
pancreatic ribonuclease 2,1
lysozyme 2,0
alpha-globin 1,2
insulin 0,44
cytochrome c 0,3
histone H4 0,01
2. evolutionary rates in differently important proteins
    are different
skenovat0004
No. AA substitutions per 100 molecules
Time of divergence (millions years)

Eg.: transient receptor potential vanilloid (TRPV) channel protein:
3. diverse evolutionary rate in different parts of proteins
    (binding sites ´ structural areas)
http://www.epernicus.com/figures/1223/zoomed/1223.jpg?1243538696
binding sites are more conserved
ATP molecule

4. different evolutionary rates at individual codone positions
Scan2.TIF


Clock2
5. evolutionary rate of a given protein in various species
    roughly constant
Kimura (1983), vertebrates, a-globin:
Wilson (1977), mammals, 7 proteins:

mostly does not concern morphological, physiological, and behavioural
trais
cannot explain adaptations
many deleterious mutations, however, these rapidly removed by selection
selection acts also at the molecular level but most mutations have only
small effects on fitness Þ important role of drift
Haldane´s cost of selection was overestimated:
selection mostly soft, not hard
frequency-dependent selection rather than overdominance
selection does not affect individual loci independently (epistasis)

Mol_drift.tif
Mean time to fixation of a novel mutation
= 4Ne
moderately sized population: mutations more frequent
small population:
mutations infrequent
Mean interval between fixations
= 1/m
In small populations faster fixations but
longer interval between them:
Theoretical principles of neutral theory:

Mol_drift.tif
Frequency of substitutions (replacements of
one allele by another in populations):
1/(2Ne) ´ 2Nem = m
Þ rate of neutral evolution is
independent of Ne, depends only
on frequency of neutral mutations m !
Mean time to fixation of a novel mutation
= 4Ne
Mean interval between fixations
= 1/m
Theoretical principles of neutral theory:

, where q = 4Nem
mean balanced heterozygosity:
continual emergence of new mutations Þ increase of variation
´ its erosion by drift
Þ continual replacement of one allele by another
Equilibrium between mutation and drift Þ polymorphism
(contrary to the mutation-selection eq.) is transient
Theoretical principles of neutral theory:
larger populations Þ higher heterozygosity

mutace
advantageous
deleterious
Neutral
Rate of neutral mutations:
Zeyl & DeVisser (2001):
yeast Saccharomyces cerevisiae
50 replicated populations,
1 individual in each generation
the experiment does not detect extremely deleterious (lethal) mutations
bimodal distribution of  mutations

Observed heterozygosity lower than predicted by NT
Test of neutral theory: range of heterozygosity
Expected heterozygosity
heterozygosity according to NT

Given the enormous range of population sizes, the range of heterozygosities is too small
Test of neutral theory: range of heterozygosity
Population size (log)

Tomoko Ohta tried to explain the deviations of the observed range of heterozygosity from
predictions:
slightly deleterious mutations (SDM)
Ohta
also substitutions of slightly deleterious alleles
http://authors.library.caltech.edu/5456/1/hrst.mit.edu/hrs/evolution/public/images/TOhta.JPG
in small populations alleles behave as effectively neutral
neutralism
slightly deleterious mutations

Pozn.: protože q = 1/(2N), bude čitatel v rovnici zjednodušen na 1 – e^2s

Fixation probability of neutral,
beneficial, and deleterious mutation:
Eg.:
What is the fixation probability of a mutation in a population of Ne = 1000?
neutral mutation (s = 0): P = 0,05%
advantageous mutation (s = 0,01): P = 20%
advantageous mutation (s = 0,001): P = 2%
deleterious mutation (s = -0,001): P = 0,004%
as s ® 0
higher „neutrality“

Pozn.: protože q = 1/(2N), bude čitatel v rovnici zjednodušen na 1 – e^2s

We can conclude that
1) Not all advantageous mutations may be fixed in
the population
2) Conversely, with low probability also deleterious mutations can be fixed

What is the fixation probability of a mutation in a population of Ne = 10 000?
neutral mutation (s = 0): P = 0,005%
advantageous mutation (s = 0,01): P = 20%
advantageous mutation (s = 0,001): P = 2%
deleterious mutation (s = -0,001): P = 2.10-17%
in a large population P of an advantegous allele is the same as in a small one but for a
deleterious allele P ® 0

Conclusions:
1) In large populations selection plays a much more important role; conversely, with decreasing
population size the role of drift is increasing
2) Harmfulness of a mutation is inversely proportional to population size: the more it approaches
zero, the larger the population may be for allele fixation (drift exceeds negative selection) and
vice versa: the stronger selection against an allele, the smaller the population must be to allow
drift to play a substantial role
3) This means that in small populations slightly deleterious mutations behave as effectively
neutral

Clock2
MOLECULAR CLOCK
Zuckerkandl & Pauling (1962-65)
AA and/or nucleotide substitution rate is constant
effect of generation time:
  dependency on absolute or
  generation time?

AA sequences of the a-chain of hemoglobin of 6 vertebrate species:
XY = XZ
despite being morphologically more similar, the distance of the shark from humans is the same as
from the carp
Þ AA differences are cumulating constantly in time regardless of the phenotypic evolution
http://static.squarespace.com/static/5181d5b7e4b07b8c66ed5614/t/528eeee2e4b0fc15797f8ebf/1385098979
427/chicken.jpg http://images.yourdictionary.com/images/definitions/lg/house-mouse.jpg
http://www.warrenphotographic.co.uk/photography/bigs/04804-Common-Newt-white-background.jpg
http://www.dpi.nsw.gov.au/__data/assets/image/0015/318300/Common-carp-Pat-Tully.jpg
http://interactivemedia.seancohen.com/fa2012/Lam_Joan/web2/assignment6/sliding-horizontal-parallax/
images/shark.png http://pixabay.com/static/uploads/photo/2014/02/20/08/45/man-270415_640.png
the same distance between the human or mouse from the shark as between the carp and shark Þ no
generation time effect

both dating methods show almost constant rate independent of generation time
Generation or absolute time?
Accumulation of neutral substitutions in placental mammals:

species with larger populations tend to have shorter generation times
Population size and generation time:
Þ potential explanation of absolute time dependence: in smaller
     populations also slightly deleterious alleles are fixed

http://upload.wikimedia.org/wikipedia/commons/thumb/7/7e/SNP_saturation.PNG/300px-SNP_saturation.PN
G Scan20001.TIF
But molecular clock does not „tick“ with the same pace
   in different groups
eg. cetaceans < „artiodactyls“< primates < murine rodents
in primates Old World monkeys > „apes“ > humans
Problem of sequence saturation:
® using an appropriate evolutionary model („straightening“ of the curve)
relaxed molecular clock method

CONCERTED EVOLUTION AND MOLECULAR DRIVE
ribosomal DNA
globin genes
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current genes have emerged through a series of duplications
the ape species pairs differ by ~ 2,5 AA substitutions in the a1 i a2 gene ...
... only few differences accumulated between the a1 a a2 gene ...
... in fact this duplication is older than 300 million years
Þ molecular clock is invalid in this case, the genes do not
    evolve independently – the evolution is concerted

Mechanisms of concerted evolution:
Gabriel Dover (1982): Molecular drive
mechanism different from selection and drift
1. unequal crossing-over
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copy loss
copy gain
´
´
´
gain of a mutant copy
loss of a
normal copy
gain of a mutant copy
... etc. ...

2. replication slippage
http://web.stanford.edu/group/hopes/cgi-bin/hopes_test/wp-content/uploads/2011/02/f_q05slippage.gif
Výsledek obrázku pro polymeraseslippage image

3. gene conversion
File:Conversion and crossover.jpg
Conclusions:
a consequence of unequal crossing-over and slippage =
   change of a copy number
a consequence of unequal c-o and gene conversion =
   sequence homogenization