Transcript Mutation

UST 1st Molecular evolution
Bioinformatics and Molecular Evolution
Paul G. Higgs and Teresa K. Attwood
Jeong, Da Geum
Chapter 3
Molecular evolution and population genetics
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- mutation
- natural selection
- random drift
- Coalescence theory
- Fixation of new mutations in a population
- Fixation probability
- Adaptationist and Neutralist
Chapter 3
Molecular evolution and population genetics
3.1 What is Evolution?
Evolution
Biology
Life
Life is a self-sustained chemical system capable of undergoing Darwinian evolution
Evolution
- “Survival of the fittest”
- “Change in frequency of genes in a population”
- “Heritable changes in a population over many generations”
The Essential factors that define evolution
i) error-prone self-replication
ii) variation in success at self-replication
Molecular evolution and population genetics
3.1 What is Evolution?
Point i) error-prone self-replication
“Self-replication” – The ability to make copies of itself
Dawkins(1976) – “replicator” – a thing that can self-replicate.
fundmental replicator-> gene rather than organisms
“Error-prone” – Copies are not always identical to the originals.
Error is essential for evolution.
If there are too many errors, there will be no heredity.
Molecular evolution and population genetics
3.1 What is Evolution?
Point ii) variation in success at self-replication
Limited size of population
Possibility of some aspects occurring
-Natural selection:
Variants with higher fitness will increase
in number relative to those with lower fitness
-Random drift (chance fluctuation):
Change in gene frequency owing to chance effects
in a finite sized population rather than to natural selection
-Neutral evolution:
a mutation whose fitness is equal or close to the fitness of
the original sequence that the fate of the mutation is determined
by random drift
How do gene sequences evolve?
Molecular evolution and population genetics
3.2 MUTATIONS
Introduce some genetic terminology
Locus: A particular position on a chromosome
a gene, a molecular marker
Alleles: Alternative sequence variants that occur at the same locus
polymorphism: having multiple alleles present in the population
at a significant frequency ( usually <99%)
Haploid: Have a single copy of each locus( most prokaryotic organisms)
Diploid: Have two copies of each locus( most eukaryotic organisms)
Molecular evolution and population genetics
3.2 MUTATIONS
reference:www.geneticsandhealth.com/wp-content/allele.jpg
Introduce some genetic terminology
Homozygous : individual same allele at a locus
Heterozygous: individual with different alleles
Mutation: Any change in a gene sequence
that can be passed on to offspring
(Result of some damages: ex. radiation)
DNABASE: A,G : purines C,T/U : pyrimidines
Transition: purine -> purine (A<->G)
pyrimidine -> pyrimidine(C<->T)
Transversion: purine <-> pyrimidine ( A,G <-> C, T)
Molecular evolution and population genetics
3.2 MUTATIONS
Introduce some genetic terminology
Point mutation : A type of mutation that causes the replacement
of a single base nucleotide with another nucleotide.
synonymous: a substitution at nucleic level that does not lead to change of
the amino acid sequence of the protein
ex) UUC(F) -> UUU(F)
nonsynonymous: one that does change the amino acid
missense mutation: code for a different amino acid, vs silent mutation
ex)AUA(I) -> AUG(M)
nonsense mutation: code for a stop, which can truncate the protein
ex) TGG( trp) -> TAG ( stop)
Molecular evolution and population genetics
3.2 MUTATIONS
Introduce some genetic terminology
Indels: insertions and deletions
Microsatellites : part of ’junk’ DNA. Also known as short sequence repeats,
e.g. GCGCGCGCGC
Frameshift: insertion of deletion can distrupt the grouping of the codons.
Inverted: section of DNA can be reversed in direction.
Translocated: cut out from one part of a genome and inserted into another
Molecular evolution and population genetics
3.3 SEQUENCE VARIATION WITHIN AND BETWEEN SPECIES
Patterns of sequence variation
gene BRCA1(408 mutations)
1/3 mutations: single nucleotide substitutions. small deletions
splice-site mutations
Deleterious:
a mutation that causes the fitness of a gene
to be reduced with respect to the original sequence
Advantageous:
a mutation that increase the fitness of the sequence
Cytogenetic Location: 17q21
Molecular Location on chromosome 17:
base pairs 38,449,839 to 38,530,993
A group of species
known as Afrotheria
Synonymous change
fig. 3.1: Part of the alignment of
the DNA sequences of the BRCA1 gene
conservative:
between a.a of similar chemical properties
tend to be more frequent
transition -> transition (easy)
transition -> transversion (difficult)
fig. 3.2 Alignment of the BRCA1 protein sequence for the same region of the gene as Fig. 3.1
Molecular evolution and population genetics
3.4 GENEALOGICAL TREES AND COALESCENCE
3.4.1 Adam and Eve
Fig3.3 Illustration of the coalescence process.
Each circle represents one gene copy.
Bold lines show the lines of descent of
genes in the current generation.
Thin lines show lines of descent
that do not lead to the current generation.
Shaded circles show the inheritance
of two different mutation
Coalescence : the merging of lineages in backwards time
– To trace the lines of descent of a gene back through the generation
mitochondrial DNA: is inherited through the maternal line (all)
-mitochondria eve, 200000 years ago,
-non african sequence : 52000 +/- 27000
-“out of Africa” hypothesis: all descended from an African population
-plate 3.1
Y chromosome DNA: is inherited through the paternal line (male)
-“Y-chromosome Adam”, 59000 years ago Thompson et al.(2000)
No reason why Adam and Eve should have existed in the same time and same place
Patterns of migration of men and women over time may also have been different
Molecular evolution and population genetics
3.4 GENEALOGICAL TREES AND COALESCENCE
3.4.2 A model of the coalescence process _
P(T) = (1-1/N)T-1 * 1/N
P(T) = 1/N *
–T/N
Molecular evolution and population genetics
3.5 THE SPREAD OF NEW MUTATIONS
3.5.1 Fixation of neutral mutations
P fix = 1/N
U fix = Nu * P fix = u
Molecular evolution and population genetics
3.5 THE SPREAD OF NEW MUTATIONS
3.5.2 Simulation of random drift and fixation
P(n) = CnN an(1-a) N-n
The probability of fixation is 1/N
Fig. 3.4 Simulation of the spread of neutral mutations
through a population under the influence of random drift
Molecular evolution and population genetics
3.5 THE SPREAD OF NEW MUTATIONS
3.5.3 Introducing selection
s = selection coefficient
Fig. 3.5 Simulation of the spread of advantageous mutations through
a population (a) For selection coefficient s = 0.05
both selection and random drift are important.
(b) For s = 0.2 selection dominates random drift.
The dashed lines show the predictions of the deterministic theory
in Box 3.2
Molecular evolution and population genetics
3.6 NEUTRAL EVOLUTION AND ADAPTATION
Extremely advantageous
s >>1 pfix ≒ 1
slightly advantageous mutation
s<<1, Ns>>1
Nearly neutral mutation
Ns<<1
Fig.3.6 Fixation probability in a population of N = 200 as a function of
selection coefficent s, for both advantageous and deleterious mutations.
When Ns<<1, both types of mutation behave as nearly neutral mutations.
Molecular evolution and population genetics
3.6 NEUTRAL EVOLUTION AND ADAPTATION
Natural selection – Positive selection (due to select new variants)
-Adaptations at the sequence level
Adaptationists – people who argue that positive selection is
the major driving force in molecular evolution
Neutralists – neutral evolution is a major role
Molecular evolution and population genetics
3.6 NEUTRAL EVOLUTION AND ADAPTATION
NEW Technique for selection test
Allozymes:
Variant forms of an enzyme that are coded for
by different alleles at the same locus
-many protein loci are polymorphic
-only detects a fraction of the sequence variation
that is present
RFLPs (Restriction fragment length polymorphisms):
Restriction enzymes will cut a long section of DNA into fragments
that can be separated by electrophoresis
-mitochondrial DNA
-difference in fragment lengths: polymorphism in the DNA
Recent: DNA Sequencing
Molecular evolution and population genetics
3.6 NEUTRAL EVOLUTION AND ADAPTATION
Adaptationists:
Positive selection removes deleterious alleles,
hence reduces the number of polymorphic loci
Selective scenarios for maintenance of polymorphisms
1. advantageous and disadvantageous( maintenance of both alleles)
2. Heterozygotes have a higher fitness than homozygotes
Molecular evolution and population genetics
3.6 NEUTRAL EVOLUTION AND ADAPTATION
Neutralist:
polymorphism is a constant process of
- creation of new alleles by mutation
- loss of old alleles due to random drift
- measure of variability : heterozygosity
average heterozygosity: Nu
N: populatio size
u: mutation rate
Nu>= 1:
mean heterozygosity will be large
and most loci will be polymorphic
Nu<<1
mean heterozygosity will be low
few polymorphic loci
Features of neutral theory
-calculation using null hypothesis (selection or not)
-large fluctuation in quantities
Molecular evolution and population genetics
3.6 NEUTRAL EVOLUTION AND ADAPTATION
A selective sweep: the reduction or elimination of variation
among the nucleotides in neighbouring DNA of a mutation
as the result of recent and strong natural selection.
stabilizing selection (purifying selection) : ①
genetic diversity decreases as the population stabilizes
on a particular trait value
Codon bias: Codon usage
because of codon redundancy all but two amino acids are coded for
by more than one triplet.
Different organisms often show particular preferences
for one of the several codons
that encode the same given amino acid.
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