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How Genomes Evolve and
Basic Evolution
Jun-Yi Leu (呂俊毅)
Introductory Molecular and
Cellular Biology
1
What is evolution?
2
History of Life
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Why do we care about evolution?
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Evolution Is Relevant to Our Daily Life
•  What is the difference between us and chimpanzee?
(positive selection, drift, trade-off)
•  Why can bird flu infect human beings?
(stabilizing selection, positive selection)
•  Why is it so difficult to cure cancer cells?
(the red queen effect, relaxed selection)
•  Why do we get old?
(relaxed selection, trade-off )
•  ……
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All Life Forms Are Derived from a
Common Ancestor
A
A1
A2
A21
A11
A12
A211
A22
A221
A222
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All Life Forms Are Derived from a
Common Ancestor
A
A1
A2
A21
A11
A12
A211
A22
A221
mutation,
selection,
drift,
…
A222
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Selection
•  How does natural selection work?
–  Genetic variation among individuals creates
differential survival or reproductive success (also
called fitness)
–  This survival (or reproductive) success is conditiondependent (the fittest ones in A condition may not
be the fittest in B condition)
–  Both abiotic and biotic factors may contribute to the
selection (your neighbors are important!!)
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The Genome Sequences of Two Species
Differ in Proportion to the Length of Time
Since They Have Separately Evolved
Q1. Why?
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Phylogenetic Trees Constructed from a
Comparison of DNA Sequences Trace the
Relationships of All Organisms
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No All Organisms Accumulate Changes
over Evolutionary Time
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However, life is more complicated than
this…
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When you look into an individual gene (or
locus)
A
A1
A2
A21
A11
A12
A211
A22
A221
A222
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When you look into an individual gene (or
locus)
A
A1
A2
A21
A11
A12
A211
A22
A221
A222
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When you look into an individual gene (or
locus)
A
A1
A2
A21
A11
A12
A211
A22
A221
A222
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What can we learn from sequence
comparisons?
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Imagining that you just identify a gene in
your favorite organism…
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Messages Carried by the Sequence
Species 1
Species 2
Species 3
AAG CGT CTG GTC CTA TCT CAT ATT
AAA AGA TTA GTA TTG AGC CAC TTT
46% identity
ACG AGC CCA GAC TCA ATG CTT TTT
46% identity
species 1
species 2
species 3
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Messages Carried by the Sequence
Species 1
Lys Arg Leu Val Leu Ser His Ile
AAG CGT CTG GTC CTA TCT CAT ATT
Species 2
Lys Arg Leu Ala Leu Ser His Phe
AAA AGA TTA GTA TTG AGC CAC TTT
88% identity
46% identity
Species 3
Thr Ser Pro Asp Ser Met Leu Phe
ACG AGC CCA GAC TCA ATG CTT TTT
0% identity
46% identity
Species 4
Lys Arg Leu Val Leu Ser His Phe
AAG CGT CTG GTC CTA TCT CAT TTT
88% identity
96% identity
•  How do we integrate the information from both DNA and
protein sequences?
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Distributions of Synonymous and
Nonsynonymous Mutations
•  61 universal codons x 9
substitutions = 549 mutations
AAA
T
G
C
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Distributions of Synonymous and
Nonsynonymous Mutations
•  61 universal codons x 9
substitutions = 549 mutations
•  Synonymous: a base
substitution causing no amino
acid change (silent mutations)
•  Nonsynonymous: a base
substitution causing an amino
acid change (missense or
nonsense mutations)
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Ka/Ks (Synonymous/Nonsynonymous)
•  In the protein coding region, the synonymous and
nonsynonymous substitutions should be treated
differently
•  Why? Most of the synonymous substitutions are neutral
since the protein sequence is not changed. In contrast,
the nonsynonymous substitutions are likely under
selection.
•  Ks: the number of synonymous substitutions per site
Ka: the number of nonsynonymous substitutions per site
•  Ka/Ks: indicator of selective constrains
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When Ka/Ks < 1
•  The gene is under stabilizing selection.
Species 1
Lys Arg Leu Val Leu Ser His Ile
AAG CGT CTG GTC CTA TCT CAT ATT
Low Ka
Species 2
Lys Arg Leu Ala Leu Ser His Phe
AAA AGA TTA GTA TTG AGC CAC TTT
88% identity
46% identity
High Ks
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Stabilizing Selection
•  Selection against genetic diversity (negative or purifying
selection)
•  The most common selection in nature: almost all genes in
the genome are under stabilizing selection.
•  Genes (or sequences) with important functions tend to
under strong stabilizing selection.
⇒ e.g. house keeping genes involved in DNA replication,
metabolic pathways etc.
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Multispecies Sequence Comparisons Identify
Conserved DNA Sequences with Specific
Functions
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Messages Carried by the Sequence
Species 1
Lys Arg Leu Val Leu Ser His Ile
AAG CGT CTG GTC CTA TCT CAT ATT
Species 2
Lys Arg Leu Ala Leu Ser His Phe
AAA AGA TTA GTA TTG AGC CAC TTT
88% identity
46% identity
What does the sequence comparison tell us?
Species 4
Lys Arg Leu Val Leu Ser His Phe
AAG CGT CTG GTC CTA TCT CAT TTT
88% identity
96% identity
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When Ka/Ks > 1
•  The gene is under positive selection.
Species 1
Lys Arg Leu Val Leu Ser His Ile
AAG CGT CTG GTC CTA TCT CAT ATT
Species 2
Thr Ser Pro Asp Ser Met Leu Phe
ACG AGC CCA GAC TCA ATG CTT TTT
0% identity
46% identity
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Positive Selection
•  Selection for increasing genetic diversity (that involves
multiple rounds of selection)
•  Not very common in most of the genome
⇒ often driven by host-pathogen interactions (the red
queen effect) or sexual selection.
•  Changes in previously conserved sequences can help
decipher critical steps in evolution
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The Red Queen Effect
•  Constant evolutionary arms races
•  between different species: host-parasite
•  between different cellular components: nucleusmitochondrion
•  between different genetic components: genomeselfish gene
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selfish mitochondrial DNA
lower fitness
counteracting
mitochondrial
mutation
counteracting
nuclear mutation
high fitness
complementary
nuclear mutation
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Host-Virus Arms Race
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Sexual Selection
•  first described by Darwin as a mechanism that leads
to sexual dimorphism in a species. It is caused by
mate choice - a big puzzle in evolutionary biology.
•  the major difference between sexual selection and
other types of selection is that under sexual selection
the survival rate of the organism is not
improved.
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Q2. using the peacock’s tail as an
example, explain why peahens want to
choose males with a more flamboyant tail.
Q3. please provide other examples of
sexual selection.
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How does sexual selection drive gene
evolution?
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Q4: What is the adaptive advantage of
sex?
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x
x
➔
➔
x
x
➔
➔
➔
➔
➔
The Cost of Sex
x
x
x
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Q5: Why is the male/female ratio close
to one in many organisms?
Q6: Why are there only two sexes in
most higher eukaryotes?
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Positive Selection
•  Selection for increasing genetic diversity (that involves
multiple rounds of selection)
•  Changes in previously conserved sequences can help
decipher critical steps in evolution
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Mutations in the DNA Sequences That
Control Gene Expression Have Driven Many
of the Evolutionary Changes in Vertebrates
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When Ka/Ks ~ 1
•  The gene is under relaxed selection (no selection).
•  Genes (or sequences) that have lost their functions or are
newly duplicated.
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Gene Duplication Provides an Important
Source of Genetic Novelty During Evolution
•  The evolution of the
globin gene family
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The Evolution of the Globin Gene Family
Shows How DNA Duplications Contribute to
the Evolution of Organisms
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Polyploid Organisms Occur Commonly in
Nature or during Evolution
fungi
plants
animals
•  Polyploidy: organisms contain more than two sets of genomes.
But,…
how can a neutral mutation become fixed in
a population?
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Fixation: an allele spreads into the whole
population
beneficial mutations
deleterious mutations
neutral mutations
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Fixation of an Allele by Genetic Drift
•  Expected time for an allele to be fixed by chance: 2Ne
generations (Ne = effective population size)
•  A very slow process in general!
•  Effective population size Ne: a simplified and idealized
population size that can represent the actual population
size in a complicated population or during a long term
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Genetic Drift
•  Genetic drift: random
fluctuation of gene
frequencies in
populations
•  Very sensitive to
population size
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Computer Simulation: A Powerful Tool
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Fixation of an Allele by Genetic Drift
•  Expected time for an allele to be fixed by chance: 2Ne
generations (Ne = effective population size)
•  A very slow process in general!
Example:
If the population size is 1000, it takes 2 x 1000 = 2000
generations to fix a mutation by drift.
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Beneficial Mutations Spread More Quickly
•  Example
Genotype: wild type
Fitness:
1
If s = 1, m =1
mutant
1+s
m = (1 + 1)
m = (1+1)(1+1)
after N generations,
m = (1+s)N
•  If the population size is 1000 and the beneficial mutation
increases 10% of fitness (s = 0.1), how many generations
does it take to fix the mutation?
(1.1)N/1000 = 1
(1.1)N = 1000
ln(1.1)N = ln(1000)
N x ln(1.1) = ln(1000)
N = 72.5
ln(1.1) = 0.0953, ln(1000) = 6.9078
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Fixation of an Allele by Genetic Drift
•  Expected time for an allele to be fixed by chance: 2Ne
generations (Ne = effective population size)
•  A very slow process in general!
•  Effective population size Ne: a simplified and idealized
population size that can represent the actual population
size in a complicated population or during a long term
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Examples
•  Complicated populations: In a population of size N, all the
females (N/2) and only a few alpha males take part in the
reproductive process. What is the effective population
size?
•  Fluctuating populations: If a population size fluctuates
during the time of 10 generations and their actual
population sizes are N1~N6 = 100 ; N7~N8 = 10 ; N9~N10 =
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1000, what is the effective population size?
Factors that can Enhance the Effect of
Random Genetic Drift
•  Bottleneck effect:
population size is
reduced by external
factors
–  e.g., Northern
Elephant Seal
populations depleted
by overhunting,
exacerbated by harem
system of mating,
leads to lack of
genetic variation in
today's population
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Factors that can Enhance the Effect of
Random Genetic Drift
•  Founder effect: small sample of population leaves and
colonizes a new area (population migration)
–  e.g., Human populations on Islands of Tristan de
Cunha - founded by 15 individuals - high incidence
of retinitis pigmentosa (a genetic disease leads to
blindness)
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Neutral Mutations Often Spread to Become
Fixed in a Population, with a Probability That
Depends on Population Size
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A Great Deal Can Be Learned from Analyses
of the Variation Among Humans
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Q7: What problems will a population
face when it has experienced a small
bottleneck?
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Is genetic drift the only way to spread a
bad (or disease-related) mutation?
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Fixation: an allele spreads into the whole
population
beneficial mutations
deleterious mutations
neutral mutations
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Sickle Cell Allele Is Under Stabilizing
Selection in Malaria-Prevailing Areas
susceptible to malaria
resistant to malaria
very sick
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Balancing Selection
•  Selection against extreme individuals and for the average
phenotype
•  Overdominant (heterozygote advantage): heterozygote
has the highest fitness (s1 > s2) ⇒ e.g. sickle cell trait
Genotype: A1A1
Fitness:
1
A1A2 A2A2
1 + s1 1 +s2
•  Frequency dependent selection
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Q8: other examples of balancing
selection?
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Chromosomal Mutation
•  Mutations at chromosomal
levels
–  Deletion or duplication
–  Inversion
–  Translocation
–  Aneuploidy: loss or
addition of
chromosomes
–  Whole genome
duplication (WGD)
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Chromosomal Mutation
•  Mutations at chromosomal
levels
•  Consequences:
–  Change gene copy
numbers
–  Create new genes or
new gene expression
patterns
–  Create genome
instability
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Chromosomal Mutation
•  Mutations at chromosomal levels
–  Deletion: Jacobsen syndrome
–  Duplication: Copper resistance in yeast
–  Inversion: reduced fertility
–  Translocation: some antibiotic resistance genes and
oncogenes
–  Aneuploidy: Down syndrome
–  Whole genome duplication: yeast, fish and mammal
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A Comparison of Human and Mouse
Chromosomes Shows How the Structures of
Genomes Diverge
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The Genome Size Can Differ
Dramatically between Species
•  Genome size:
–  E. coli: 4.6 x 106 bp (1X); 4288 genes (1X)
–  Yeast: 1.2 x 107 bp (~3X); 6294 genes (~1.5X)
–  Fruit fly: 1.7 x 108 bp (~40X); 13600 genes (~3.2X)
–  Human: 3.2 x 109 bp (~700X); 20251 genes (~4.7X)
•  Most of large genomes are made up of non-coding
or repetitive sequences.
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The Genome Size Can Differ
Dramatically between Species
•  Genome size:
–  Human: 3.2 x 109 bp (~8X); 20251 genes
–  Puffer fish (Fugu): 3.9 x 108 bp (1x); ~22000 genes
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Q9: Why do different organisms have
different numbers of genes?
Q10: Do you think that most of the noncoding or repetitive sequences in the
expanded genomes are neutral? How
can they be maintained?
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What is evolution?
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Are we getting better, and better?
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The Red Queen Effect
selfish mitochondrial DNA
lower fitness
counteracting
mitochondrial
mutation
counteracting
nuclear mutation
high fitness
complementary
nuclear mutation
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The Trade-off Hypothesis
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Do you know how
smart I am?
There is no writing
exam here :(
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Recent Advances in Evolutionary Biology
•  Genome projects:
–  Whole genome sequences allow us to do more
comprehensive comparisons, e.g., promoter
sequences or disease allele
–  Genomic tools allow us to compare the model
organisms with their relative species, e.g., S.
cerevisiae and S. paradoxus
•  Experimental evolution:
–  We can examine evolutionary hypotheses directly
–  By analyzing the evolved product, we can understand
how cells evolve
•  Systems biology:
–  Combining computer modeling, physics and genomics
to identify the critical parameters of evolution
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