Download evolution of mutability

The capacity to blunder slightly is
the real marvel of DNA.
Without this special attribute, we
would still be anaerobic bacteria and
there would be no music.
Lewis Thomas, 1979
The Medusa and the Snail
When Darwin wrote the Origin, he imagined that . . .
A grand and almost untrodden field of
inquiry will be opened, on the causes and
laws of variation.
Charles Darwin, 1859
On the Origin of Species
Today we shall visit that field of inquiry.
Why do mutations
happen?
There are two classical answers.
1.
2.
There are two classical answers.
1. Mutations are accidents, and
“accidents will happen.”
2.
There are two classical answers.
1. Mutations are accidents, and
“accidents will happen.”
2. Mutations are necessary,
“for the good of
the species.”
Here are the basic facts.
●
●
●
●
Here are the basic facts.
● Most mutations are deleterious.
●
●
●
Here are the basic facts.
● Most mutations are deleterious.
● Organisms differ widely, in their
susceptibility to mutation.
●
●
Here are the basic facts.
● Most mutations are deleterious.
● Organisms differ widely, in their
susceptibility to mutation.
● Genes coding enzymes for
DNA replication, proofreading,
and correction come in various
alleles, with varying degrees of accuracy.
●
Here are the basic facts.
● Most mutations are deleterious.
● Organisms differ widely, in their
susceptibility to mutation.
● Genes coding enzymes for
DNA replication, proofreading,
and correction come in various
alleles, with varying degrees of accuracy.
● Mutation rates could be much lower
than they are.
Why has natural selection not
reduced the mutation rate even more?
Why are mutation rates not
much lower?
Natural selection usually involves
compromise.
What advantages and costs are
being compromised?
Why are mutation rates not
much lower?
Is the advantage of accurate replication
being balanced by selection . . .
●
●
Why are mutation rates not
much lower?
Is the advantage of accurate replication
being balanced by selection . . .
● against the immediate expense of accurate replication?
●
Why are mutation rates not
much lower?
Is the advantage of accurate replication
being balanced by selection . . .
● against the immediate expense of accurate replication?
or
● against the occasional benefit of inaccurate replication?
Two hypotheses . . .
1.
2.
Two hypotheses . . .
1. “Accidents will happen.”
Error-free reproduction is simply
too expensive to be practical.
2.
Two hypotheses . . .
1. “Accidents will happen.”
Error-free reproduction is simply
too expensive to be practical.
2. “For the good of the species.”
A low level of mutation must be maintained
as a hedge against extinction.
Is the immediate hazard of mutation
balanced by . . .
Immediate expense
of accuracy?
__________
OR
Long-term benefit for
adaptation?
__________
Is the immediate hazard of mutation
balanced by . . .
Immediate expense
of accuracy?
__________
Long-term benefit for
adaptation?
__________
Do mutations happen
only as accidental
errors?
Is a low but positive
mutation rate selected
because some mutations
will be beneficial?
OR
Is a low but positive
rate of mutation . . .
Accidental?
OR
Selected?
Accidental?
Mutations are accidents,
and accidents will happen.
A.H. Sturtevant, 1937
Mistakes in the copying
of genetic information
produce mutations.
D. Futuyma, 1979
Evolutionary Biology
(Classic textbook)
Selected?
Accidental?
. . . The cost of fidelity is the generally
accepted explanation for non-zero
mutation rates in multicellular eukaryotes.
Direct selection almost always favours a
decrease in the mutation rate to reduce
the frequency of deleterious mutations.
However, selection to reduce the cellular
resources that are devoted to maintaining
replication fidelity and/or selection to
increase the speed of replication lead to
indirect selection to increase the mutation
rate.
The optimum is established when the
cumulative direct and indirect effects
cancel each other out.
C.F. Baer, et al. 2007
Nature Reviews Genetics
Selected?
Cells have evolved several
enzymatic systems that either
prevent mutations from
forming or eliminate those
that do.
These safeguards enable
organisms to keep mutations
to a low level that balances
their need to evolve with
their need to avoid damage
to their genomes.
L.H. Hartwell, et al., 2008
Genetics: From Genes to Organisms
(current textbook for ZOOL 305)
Accidental?
Selected?
Mutations are accidents,
and accidents will happen.
Cells have evolved several
enzymatic systems that either
prevent mutations from
forming or eliminate those
that do.
A.H. Sturtevant, 1937
Mistakes in the copying
of genetic information
produce mutations.
D. Futuyma, 1979
Evolutionary Biology
(Classic textbook)
These safeguards enable
organisms to keep mutations
to a low level that balances
their need to evolve with
their need to avoid damage
to their genomes.
L.H. Hartwell, et al., 2008
Genetics: From Genes to Organisms
(current textbook for ZOOL 305)
Mutations are accidents.
This is the most widely accepted answer to the question,
“Why do mutations happen.”
_________________________
Mutations are the unavoidable side effect of
compromising accuracy with speed and efficiency.
A strong argument supports this position.
Mutations are accidents.
This is the most widely accepted answer to the question,
“Why do mutations happen.”
_________________________
Mutations are the unavoidable side effect of
compromising accuracy with speed and efficiency.
A strong argument supports this position.
Mutations are accidents.
_________________________
Point mutation rates are governed by genes that make enzymes
which replicate, proofread, and correct DNA. Allelic variation
in these genes determines replication speed and fidelity.
Mutations are accidents.
_________________________
Point mutation rates are governed by genes that make enzymes
which replicate, proofread, and correct DNA. Allelic variation
in these genes determines replication speed and fidelity.
Since most point mutations are deleterious, “mutator” alleles which
decrease replication fidelity will be selected against (unless there
is a compensating increase in replication rate).
Mutations are accidents.
_________________________
Point mutation rates are governed by genes that make enzymes
which replicate, proofread, and correct DNA. Allelic variation
in these genes determines replication speed and fidelity.
Since most point mutations are deleterious, “mutator” alleles which
decrease replication fidelity will be selected against (unless there
is a compensating increase in replication rate).
A “mutator” allele might hitchhike by linkage with a
(rare) beneficial allele, but recombination will
eventually separate the two.
Mutations are accidents.
_________________________
Natural selection cannot be caused
by a “need to evolve.”
Mutations are accidents.
_________________________
Natural selection cannot be caused
by a “need to evolve.”
Selection cannot see into the future.
Mutations are accidents.
_________________________
Natural selection cannot be caused
by a “need to evolve.”
Selection cannot see into the future.
Selection is blind to “the good of the species.”
This argument supports a strong conclusion:
Natural selection of mutation rates has
only one possible direction, that of
reducing the frequency of mutation to zero.
That mutations should continue to occur . . .
is merely a reflection of the unquestionable
principle that natural selection can often
produce mechanisms of extreme precision,
but never of perfection.
George Williams, 1966
Adaptation and Natural Selection
The cost of fidelity is the generally accepted
explanation for non-zero mutation rates in
multicellular eukaryotes.
C.F. Baer, et al. 2007
Nature Reviews Genetics
Evolution has probably reduced the mutation
rates to far below species optima, as the
result of unrelenting selection for zero
mutation rate in every population.
Mutation is, of course, a necessary
precondition to continued evolutionary
change.
So evolution takes place, not so much
because of natural selection, but to a
large degree in spite of it.
George Williams, 1966
Adaptation and Natural Selection
A low but positive
rate of mutation is . . .
Accidental.
OR
Selected?
A low but positive
rate of mutation is . . .
Accidental.
Mutations are the errors
which remain after
selection has optimized
replication fidelity against
metabolic cost and
speed of replication.
OR
Selected?
The preceding argument that
“mutations are accidents” is
based on our understanding of
point mutations within classical
genes.
This argument is probably correct regarding point mutations in
protein-coding sequences.
● Point mutations probably are mostly deleterious
● Point mutations probably do occur at random
sites within genomes.
● Rates for point mutation probably are determined
by genes for replication fidelity.
● If these are true, the conclusion does follow:
Mutations are accidents.
The preceding argument that
“mutations are accidents” is
based on our understanding of
point mutations within classical
genes.
This argument is probably correct regarding point mutations in
protein-coding sequences.
● Point mutations probably are mostly deleterious.
● Point mutations probably do occur at random
sites within genomes.
● Rates for point mutation probably are determined
by genes for replication fidelity.
● If these are true, the conclusion does follow:
Mutations are accidents.
The preceding argument that
“mutations are accidents” is
based on our understanding of
point mutations within classical
genes.
This argument is probably correct regarding point mutations in
protein-coding sequences.
● Point mutations probably are mostly deleterious.
● Point mutations probably do occur at random
sites within genomes.
● Rates for point mutation probably are determined
by genes for replication fidelity.
● If these are true, the conclusion does follow:
Mutations are accidents.
The preceding argument that
“mutations are accidents” is
based on our understanding of
point mutations within classical
genes.
This argument is probably correct regarding point mutations in
protein-coding sequences.
● Point mutations probably are mostly deleterious.
● Point mutations probably do occur at random
sites within genomes.
● Rates for point mutation probably are determined
by genes for replication fidelity.
● If these are true, the conclusion does follow:
Mutations are accidents.
The preceding argument that
“mutations are accidents” is
based on our understanding of
point mutations within classical
genes.
This argument is probably correct regarding point mutations in
protein-coding sequences.
● Point mutations probably are mostly deleterious.
● Point mutations probably do occur at random
sites within genomes.
● Rates for point mutation probably are determined
by genes for replication fidelity.
● If these assumptions are true, the conclusion does
follow: Mutations are accidents.
However . . .
This argument is also fundamentally misleading.
Several other styles of mutation are also known,
besides point mutations.
Several other styles of mutation are also known,
besides point mutations.
● programmed gene rearrangements
● transposable elements
● gene duplications
● repeat-based mutability
Several other styles of mutation are also known,
besides point mutations.
● programmed gene rearrangements
● transposable elements
● gene duplications
● repeat-based mutability
All of these were unexpected when first discovered.
Although some of these are commonly dismissed as “selfish” or
“junk” DNA, their implications have yet to be fully integrated into
evolutionary theory.
Can unconventional mutational mechanisms
be positively selected?
My answer is Yes,
but . . .
I by no means expect to convince
experienced naturalists whose minds
are stocked with a multitude of facts
all viewed, during a long course of
years, from a point of view directly
opposite to mine.
Charles Darwin, 1859
On the Origin of Species
It is common sense that most mutations
that alter fitness at all will lower it.
John Maynard Smith, 1989
Evolutionary Genetics
Is this familiar assertion true?
It is common sense that most mutations
that alter fitness at all will lower it.
John Maynard Smith, 1989
Evolutionary Genetics
Are there any modes of mutation which are
frequently beneficial?
It is common sense that most mutations
that alter fitness at all will lower it.
John Maynard Smith, 1989
Evolutionary Genetics
Are there any modes of mutation which are
frequently beneficial?
● immune system
hypermutation
● programmed gene
rearrangements
● “mutations of small effect”
It is common sense that most mutations
that alter fitness at all will lower it.
John Maynard Smith, 1989
Evolutionary Genetics
Are there any modes of mutation which are
frequently beneficial?
● immune system
hypermutation
● programmed gene
rearrangements
● “mutations of small effect”
It is common sense that most mutations
that alter fitness at all will lower it.
John Maynard Smith, 1989
Evolutionary Genetics
Are there any modes of mutation which are
frequently beneficial?
● immune system
hypermutation
● programmed gene
rearrangements
● “mutations of small effect”
Mutations are chance occurrences
modifying the genome at random.
L.H. Hartwell, et al., 2008
Genetics: From Genes to Organisms
(current textbook for ZOOL 305)
Mutations are chance occurrences
modifying the genome at random.
L.H. Hartwell, et al., 2008
Genetics: From Genes to Organisms
(current textbook for ZOOL 305)
Are there any particular modes of mutation
which are site-specific
(non-random)?
Here is one example:
Mutations based on SIMPLE SEQUENCE REPEATS
are site-specific and remarkably benign.
Mutations based on SIMPLE SEQUENCE REPEATS
are site-specific and remarkably benign.
Simple Sequence Repeats (SSRs) are also called
MICROSATELLITES and MINISATELLITES.
Mutations based on SIMPLE SEQUENCE REPEATS
are site-specific and remarkably benign.
Simple Sequence Repeats are also called
MICROSATELLITES and MINISATELLITES.
Simple Sequence Repeats are DNA tracts
in which a relatively short “motif” is repeated
over and over in tandem.
SIMPLE SEQUENCE REPEATS have several
remarkable properties.
● SSRs experience frequent, reversible,
site-specific mutations which add or subtract
motif units.
● SSRs are located within functional regions of many genes, in
exons, introns, upstream and downstream regulatory sites.
● The number of motif repetitions can influence practically any
aspect of gene function.
SIMPLE SEQUENCE REPEATS have several
remarkable properties.
● SSRs experience frequent, reversible,
site-specific mutations which add or subtract
motif units.
● SSRs are located within functional regions of many genes, in
exons, introns, upstream and downstream regulatory sites.
● The number of motif repetitions can influence practically any
aspect of gene function.
SIMPLE SEQUENCE REPEATS have several
remarkable properties.
● SSRs experience frequent, reversible,
site-specific mutations which add or subtract
motif units.
● SSRs are located within functional regions of many genes, in
exons, introns, upstream and downstream regulatory sites.
● The number of motif repetitions can influence practically any
aspect of gene function.
SIMPLE SEQUENCE REPEATS have several
remarkable properties.
● SSRs experience frequent, reversible,
site-specific mutations which add or subtract
motif units.
● SSRs are located within functional regions of many genes, in
exons, introns, upstream and downstream regulatory sites.
● The number of motif repetitions can influence practically any
aspect of gene function.
Repeat-number Mutations vs. Classical Point Mutations
____________________
___________________
●
●
●
●
●
●
●
●
●
●
Repeat-number Mutations vs. Classical Point Mutations
____________________
___________________
● add or subtract repeating
motifs.
●
●
●
●
●
●
●
●
●
Repeat-number Mutations vs. Classical Point Mutations
____________________
___________________
● add or subtract repeating
motifs.
● involve assorted substitutions,
●
●
●
●
insertions, and deletions.
●
●
●
●
Repeat-number Mutations vs. Classical Point Mutations
____________________
___________________
● add or subtract repeating
motifs.
● involve assorted substitutions,
● yield small, quantitative effects
with fair likelihood of adaptive
advantage.
●
●
●
insertions, and deletions.
●
●
●
●
Repeat-number Mutations vs. Classical Point Mutations
____________________
___________________
● add or subtract repeating
motifs.
● involve assorted substitutions,
● yield small, quantitative effects
with fair likelihood of adaptive
advantage.
● effects range from neutral
to lethal, with beneficial effects
occurring only rarely.
●
●
insertions, and deletions.
●
●
●
●
Repeat-number Mutations vs. Classical Point Mutations
____________________
___________________
● add or subtract repeating
motifs.
● involve assorted substitutions,
● yield small, quantitative effects
with fair likelihood of adaptive
advantage.
● effects range from neutral
to lethal, with beneficial effects
occurring only rarely.
● can be readily reversed.
●
insertions, and deletions.
●
●
●
●
Repeat-number Mutations vs. Classical Point Mutations
____________________
___________________
● add or subtract repeating
motifs.
● involve assorted substitutions,
● yield small, quantitative effects
with fair likelihood of adaptive
advantage.
● effects range from neutral
to lethal, with beneficial effects
occurring only rarely.
● can be readily reversed.
● are reversible only with very low
probability.
insertions, and deletions.
●
●
●
●
Repeat-number Mutations vs. Classical Point Mutations
____________________
___________________
● add or subtract repeating
motifs.
● involve assorted substitutions,
● yield small, quantitative effects
with fair likelihood of adaptive
advantage.
● effects range from neutral
to lethal, with beneficial effects
occurring only rarely.
● can be readily reversed.
● are reversible only with very low
probability.
insertions, and deletions.
● are inextricably linked to
mutable sites.
●
●
●
Repeat-number Mutations vs. Classical Point Mutations
____________________
___________________
● add or subtract repeating
motifs.
● involve assorted substitutions,
● yield small, quantitative effects
with fair likelihood of adaptive
advantage.
● effects range from neutral
to lethal, with beneficial effects
occurring only rarely.
● can be readily reversed.
● are reversible only with very low
probability.
insertions, and deletions.
● are inextricably linked to
mutable sites.
● may happen anywhere.
●
●
Repeat-number Mutations vs. Classical Point Mutations
____________________
___________________
● add or subtract repeating
motifs.
● involve assorted substitutions,
● yield small, quantitative effects
with fair likelihood of adaptive
advantage.
● effects range from neutral
to lethal, with beneficial effects
occurring only rarely.
● can be readily reversed.
● are reversible only with very low
probability.
● are inextricably linked to
repeat sites.
● occur at rates orders of
magnitude greater than
point mutations.
insertions, and deletions.
● may happen anywhere.
●
Repeat-number Mutations vs. Classical Point Mutations
____________________
___________________
● add or subtract repeating
motifs.
● involve assorted substitutions,
● yield small, quantitative effects
with fair likelihood of adaptive
advantage.
● effects range from neutral
to lethal, with beneficial effects
occurring only rarely.
● can be readily reversed.
● are reversible only with very low
probability.
● are inextricably linked to
mutable sites.
● occur at rates orders of
magnitude greater than
point mutations.
insertions, and deletions.
● may happen anywhere.
● occur at extremely low rates.
Repeat-number Mutations
____________________
● Small, quantitative effects
with fair likelihood of adaptive
advantage.
●
●
Repeat-number Mutations
____________________
● Small, quantitative effects
with fair likelihood of adaptive
advantage.
●
●
This contravenes the assumption
that most mutations which affect
fitness will be deleterious.
Repeat-number Mutations
____________________
● Small, quantitative effects
with fair likelihood of adaptive
advantage.
● Inextricably linked to
mutable sites.
●
This contravenes the assumption
that most mutations which affect
fitness will be deleterious.
Repeat-number Mutations
____________________
● Small, quantitative effects
with fair likelihood of adaptive
advantage.
This contravenes the assumption
that most mutations which affect
fitness will be deleterious.
● Inextricably linked to
mutable sites.
This contravenes the assumption
that “mutation-rate” genes cannot
consistently hitchhike with
beneficial mutations.
●
Repeat-number Mutations
____________________
● Small, quantitative effects
with fair likelihood of adaptive
advantage.
This contravenes the assumption
that most mutations which affect
fitness will be deleterious.
● Inextricably linked to
mutable sites.
This contravenes the assumption
that “mutation-rate” genes cannot
consistently hitchhike with
beneficial mutations.
● Rates orders of magnitude
greater than point mutations.
Repeat-number Mutations
____________________
● Small, quantitative effects
with fair likelihood of adaptive
advantage.
This contravenes the assumption
that most mutations which affect
fitness will be deleterious.
● Inextricably linked to
mutable sites.
This contravenes the assumption
that “mutation-rate” genes cannot
consistently hitchhike with
beneficial mutations.
● Rates orders of magnitude
greater than point mutations.
This is inexplicable if the
conventional argument is valid.
Repeat-number Mutations
____________________
● Small, quantitative effects
with fair likelihood of adaptive
advantage.
This contravenes the assumption
that most mutations which affect
fitness will be deleterious.
● Inextricably linked to
mutable sites.
This contravenes the assumption
that “mutation-rate” genes cannot
consistently hitchhike with
beneficial mutations.
● Rates orders of magnitude
greater than point mutations.
This is inexplicable if the
conventional argument is valid.
The “mutations are accidents” argument is not valid
for repeat-number mutations.
Individual SSR loci encode two traits at once.
1. Phenotypic effect is encoded by number of repeats.
2. Site-specific mutability is encoded by type of motif and
by repeat purity.
These two traits can vary independently, at the same site.
_______________________________
SSR stability will be favored only when an ancestral number of
repeats consistently yields higher fitness than do variants with
altered repeat numbers.
SSR mutability will be favored when changing circumstances
repeatedly favor mutant alleles.
Selection can favor site-specific mutability whenever the
mutable site is closely and causally linked with mutant
phenotypes, as in SSRs.
Individual SSR loci encode two traits at once.
1. Phenotypic effect is encoded by number of repeats.
2. Site-specific mutability is encoded by type of motif and
by repeat purity.
These two traits can vary independently, at the same site.
_______________________________
SSR stability will be favored only when an ancestral number of
repeats consistently yields higher fitness than do variants with
altered repeat numbers.
SSR mutability will be favored when changing circumstances
repeatedly favor mutant alleles.
Selection can favor site-specific mutability whenever the
mutable site is closely and causally linked with mutant
phenotypes, as in SSRs.
Individual SSR loci encode two traits at once.
1. Phenotypic effect is encoded by number of repeats.
2. Site-specific mutability is encoded by type of motif and
by repeat purity.
These two traits can vary independently, at the same site.
_______________________________
SSR stability will be favored only when an ancestral number of
repeats consistently yields higher fitness than do variants with
altered repeat numbers.
SSR mutability will be favored when changing circumstances
repeatedly favor mutant alleles.
Selection can favor site-specific mutability whenever the
mutable site is closely and causally linked with mutant
phenotypes, as in SSRs.
Individual SSR loci encode two traits at once.
1. Phenotypic effect is encoded by number of repeats.
2. Site-specific mutability is encoded by type of motif and
by repeat purity.
These two traits can vary independently, at the same site.
_______________________________
SSR stability will be favored only when an ancestral number of
repeats consistently yields higher fitness than do variants with
altered repeat numbers.
SSR mutability will be favored when changing circumstances
repeatedly favor mutant alleles.
Selection can favor site-specific mutability whenever the
mutable site is closely and causally linked with mutant
phenotypes, as in SSRs.
Individual SSR loci encode two traits at once.
1. Phenotypic effect is encoded by number of repeats.
2. Site-specific mutability is encoded by type of motif and
by repeat purity.
These two traits can vary independently, at the same site.
_______________________________
SSR stability will be favored only when an ancestral number of
repeats consistently yields higher fitness than do variants with
altered repeat numbers.
SSR mutability will be favored when changing circumstances
repeatedly favor mutant alleles.
Selection can favor site-specific mutability whenever the
mutable site is closely and causally linked with mutant
phenotypes, as in SSRs.
Individual SSR loci encode two traits at once.
1. Phenotypic effect is encoded by number of repeats.
2. Site-specific mutability is encoded by type of motif and
by repeat purity.
These two traits can vary independently, at the same site.
_______________________________
SSR stability will be favored only when an ancestral number of
repeats consistently yields higher fitness than do variants with
altered repeat numbers.
SSR mutability will be favored when changing circumstances
repeatedly favor mutant alleles.
Selection can favor site-specific mutability whenever the
mutable site is closely and causally linked with mutant
phenotypes, as in SSRs.
Individual SSR loci encode two traits at once.
1. Phenotypic effect is encoded by number of repeats.
2. Site-specific mutability is encoded by type of motif and
by repeat purity.
These two traits can vary independently, at the same site.
_______________________________
SSR stability will be favored only when an ancestral number of
repeats consistently yields higher fitness than do variants with
altered repeat numbers.
SSR mutability will be favored when changing circumstances
repeatedly favor mutant alleles.
Selection can favor site-specific mutability whenever the
mutable site is closely and causally linked with mutant
phenotypes, as in SSRs.
A selective advantage based on SSR mutability has been
experimentally demonstrated for “contingency genes” of
pathogenic bacteria.
A selective advantage based on SSR mutability has been
experimentally demonstrated for “contingency genes” of
pathogenic bacteria.
Several eukaryotic examples of adaptive SSR variation
have been reported.
SSR variation affects
vole social behavior
(Hammock et al., 2005)
(Image courtesy L. Young)
SSR variation affects
morphology of dog
breeds.
(after Fondon et al., 2004)
(Image courtesy J. Fondon)
In Australian Drosophila,
average number of
minisatellite repeats in a
heat shock protein gene
changes with latitude.
(after Collinge et al., 2007)
In Hawaiian mints, average
length of a minisatellite in a
gene for flowering time
shifts with island age.
(after Lindquist et al., 2007)
These examples suggest that SSR mutability
can be positively selected.
Site-specific modes of mutation
can be indirectly selected for
immediate advantage in
ecological settings where
environments are variable.
Such selection can plausibly
shape SSR mutability so that
these intrinsically mutable
sequences provide a reliable
supply of low-cost genetic
variation.
Some authors believe it to be as much the
function of the reproductive system to
produce individual differences, or very
slight deviations of structure, as to make
the child like its parents.
Charles Darwin, 1859
On the Origin of Species
Some authors believe it to be as much the
function of the reproductive system to
produce individual differences, or very
slight deviations of structure, as to make
the child like its parents.
Advantageous variation is not
based not on accidental mutation
but on mechanisms such as meiotic
recombination and repeat-based
mutability that produce variants
close to parental forms.
Charles Darwin, 1859
On the Origin of Species
What the devil determines each
particular variation? What makes a tuft
of feathers come on a cock’s head . . . ?
Charles Darwin, 1859
Letter to T.H. Huxley
What the devil determines each
particular variation? What makes a tuft
of feathers come on a cock’s head . . . ?
Charles Darwin, 1859
Letter to T.H. Huxley
Indirect selection for
site-specific mutability can
create evolutionary plasticity
whose consequences benefit
populations and species.
A hundred fifty years ago, Darwin hoped that . . .
A grand and almost untrodden field of
inquiry will be opened, on the causes and
laws of variation.
Charles Darwin, 1859
On the Origin of Species
Despite a century of investigation and much theoretical
progress, our understanding of mutational variation
at the empirical level . . . remains primitive, especially
for multicellular eukaryotes.
C.F. Baer, et al. 2007
Nature Reviews Genetics