Mutation as a source of variation
What is mutation?
Darwin’s theory of natural selection depends
upon genetic variation – source of variation is,
ultimately mutation
Mutation is any heritable change in genomic DNA
– occur at different rates, subject to mutagenic
agents
Most are due to errors in DNA replication –
include: base substitution, base insertion,
inversion length of DNA, duplication/deletion of
a length of DNA
Changes to base sequence have varying
outcomes
Large scale changes to chromosome
content are also possible
- Some chromosomal rearrangements
(eg. inversions) may not have
phenotypic consequences
Types of mutations
Spontaneous Induced
Generally assumed to be random changes Due to natural/artificial agents
in nucleotide sequences Eg. radiation, chemical mutagens
Biochemical alterations to structure of
nitrogenous bases
Loss of function mutations Gain of function mutations
Loss or reduced functionality of wild- Results in new gene product with a new
type gene produce (eg. w eye in function
Drosophila due to lack of pigment May be due to change in amino acid
transporter gene product – typically sequence of the protein or result from
recessive) mutation in regulatory region of gene
Dominant loss of function may result of gene, leading to gene expression at
from a presence of a defective protein an abnormal level, time or place
product that binds to/inhibits action Acquisition of a novel function, often
of normal gene products due to overexpression or
misexpression of a gene product eg.
Drosophila Antennapedia mutation:
antenna leg (Typically dominant)
,Regulatory Mutation Conditional Mutation
Lac operon produces gene product Tay-Sachs, Huntington’s, WD, only
which regulates the transcription of appear at certain points of life cycle
other genes Temperature-sensitive mutations:
Embryonic development: Drosophila permissive temp. survives, restrictive
hedgehog signalling, hierarchal of gap dies
pair-rule, segment-polarity Mutational effect varies with the
environment
Mutation is random
No constraints on what type of mutational event an occur – only constrains on which
can survive consequently (due to physiology or development)
Mutation is random with respect to direction of adaptation
Natural selection, operating over long periods of time, imposes direction of
evolution using undirected variation
Basis of Evolution
Neo-Darwinist View Catastrophist View
Evolution via gradual accumulation of Drivers of speciation are mutations of
advantageous mutations with individually large effect (macromutations) in
small effects on the fitness of carriers regulatory genes cause cascade of changes
on multiple other genes and hence large-
scale phenotypic change
a) What is the rate of mutation?
Variety of estimates:
Rate of base substitution, per replication cycle
Rate at which new mutations occur, at a locus per generation
Rate at which lethal or deleterious mutations accumulate on a chromosome
Rate at which new phenotypic variance is generated by mutations
Detecting rate of visible mutations
- Find rate for designated locus/loci per generation (eg. Multiple locus technique in
mice)
- Reference population females (homozygous for several recessive mutations
affecting coat colour – pallid, leaden, brown) crossed to test population males (wild
type at the coat loci)
, Expect progeny to be wild type – as heterozygotes at marker loci
Any other visible of phenotypes are mutations at one of those loci
- Frequency of mutations – mouse study of >540 000 male F1 and >100 000 female F1
8.4 x 10-4 per locus per male gamete
1.4 x 10-4 per locus per female gamete
Evolutionary Implication of mutation rates
- The mutation rates per locus are very low – but summed over all genes, input of
variation by mutation is considerable
- If a tiny fraction of mutations are advantageous, new material for mutation would
be substantial, especially over thousands/millions of years
b) What are effects of mutation on fitness?
- Mutations vary in their effects on a spectrum ranging from lethal, slightly
deleterious, neutral to advantageous
Mukai, 1972
- Allowed slightly deleterious mutations to accumulate over many generations, at
many loci on chromosomes
- Selection against mutations was minimised
- Examined mutations on the second chromosomes of ~1.7 million flies
Drosophila balancer chromosomes
1. Contain multiple overlapping inversions – which prevent recombination
2. Marked with mutant dominant alleles that alter the appearance of the bearer
(eg. Curly wing)
3. Dominant markers are lethal in homozygous condition
These features enable crosses between a population of interest and a balancer stock to
extract specific chromosomes from test population
Individuals that are heterozygous for a multiply inverted chromosome in effect don’t
produce recombinant progeny can be readily identified
**No recombination in male fruitflies
Mukai’s Design
Made 101 chromosomal lines, using balancers – each line carried an independently
extracted wild-type second chromosome
Maintenance of experimental lines: wild-type chromosomes kept as heterozygotes
with a balancer
In each generation: crossed heterozygotes to reference balancer stock and from
progeny picked out heterozygotes to repeat cross
What is mutation?
Darwin’s theory of natural selection depends
upon genetic variation – source of variation is,
ultimately mutation
Mutation is any heritable change in genomic DNA
– occur at different rates, subject to mutagenic
agents
Most are due to errors in DNA replication –
include: base substitution, base insertion,
inversion length of DNA, duplication/deletion of
a length of DNA
Changes to base sequence have varying
outcomes
Large scale changes to chromosome
content are also possible
- Some chromosomal rearrangements
(eg. inversions) may not have
phenotypic consequences
Types of mutations
Spontaneous Induced
Generally assumed to be random changes Due to natural/artificial agents
in nucleotide sequences Eg. radiation, chemical mutagens
Biochemical alterations to structure of
nitrogenous bases
Loss of function mutations Gain of function mutations
Loss or reduced functionality of wild- Results in new gene product with a new
type gene produce (eg. w eye in function
Drosophila due to lack of pigment May be due to change in amino acid
transporter gene product – typically sequence of the protein or result from
recessive) mutation in regulatory region of gene
Dominant loss of function may result of gene, leading to gene expression at
from a presence of a defective protein an abnormal level, time or place
product that binds to/inhibits action Acquisition of a novel function, often
of normal gene products due to overexpression or
misexpression of a gene product eg.
Drosophila Antennapedia mutation:
antenna leg (Typically dominant)
,Regulatory Mutation Conditional Mutation
Lac operon produces gene product Tay-Sachs, Huntington’s, WD, only
which regulates the transcription of appear at certain points of life cycle
other genes Temperature-sensitive mutations:
Embryonic development: Drosophila permissive temp. survives, restrictive
hedgehog signalling, hierarchal of gap dies
pair-rule, segment-polarity Mutational effect varies with the
environment
Mutation is random
No constraints on what type of mutational event an occur – only constrains on which
can survive consequently (due to physiology or development)
Mutation is random with respect to direction of adaptation
Natural selection, operating over long periods of time, imposes direction of
evolution using undirected variation
Basis of Evolution
Neo-Darwinist View Catastrophist View
Evolution via gradual accumulation of Drivers of speciation are mutations of
advantageous mutations with individually large effect (macromutations) in
small effects on the fitness of carriers regulatory genes cause cascade of changes
on multiple other genes and hence large-
scale phenotypic change
a) What is the rate of mutation?
Variety of estimates:
Rate of base substitution, per replication cycle
Rate at which new mutations occur, at a locus per generation
Rate at which lethal or deleterious mutations accumulate on a chromosome
Rate at which new phenotypic variance is generated by mutations
Detecting rate of visible mutations
- Find rate for designated locus/loci per generation (eg. Multiple locus technique in
mice)
- Reference population females (homozygous for several recessive mutations
affecting coat colour – pallid, leaden, brown) crossed to test population males (wild
type at the coat loci)
, Expect progeny to be wild type – as heterozygotes at marker loci
Any other visible of phenotypes are mutations at one of those loci
- Frequency of mutations – mouse study of >540 000 male F1 and >100 000 female F1
8.4 x 10-4 per locus per male gamete
1.4 x 10-4 per locus per female gamete
Evolutionary Implication of mutation rates
- The mutation rates per locus are very low – but summed over all genes, input of
variation by mutation is considerable
- If a tiny fraction of mutations are advantageous, new material for mutation would
be substantial, especially over thousands/millions of years
b) What are effects of mutation on fitness?
- Mutations vary in their effects on a spectrum ranging from lethal, slightly
deleterious, neutral to advantageous
Mukai, 1972
- Allowed slightly deleterious mutations to accumulate over many generations, at
many loci on chromosomes
- Selection against mutations was minimised
- Examined mutations on the second chromosomes of ~1.7 million flies
Drosophila balancer chromosomes
1. Contain multiple overlapping inversions – which prevent recombination
2. Marked with mutant dominant alleles that alter the appearance of the bearer
(eg. Curly wing)
3. Dominant markers are lethal in homozygous condition
These features enable crosses between a population of interest and a balancer stock to
extract specific chromosomes from test population
Individuals that are heterozygous for a multiply inverted chromosome in effect don’t
produce recombinant progeny can be readily identified
**No recombination in male fruitflies
Mukai’s Design
Made 101 chromosomal lines, using balancers – each line carried an independently
extracted wild-type second chromosome
Maintenance of experimental lines: wild-type chromosomes kept as heterozygotes
with a balancer
In each generation: crossed heterozygotes to reference balancer stock and from
progeny picked out heterozygotes to repeat cross
