Mutation and genetic variation Mutations are raw material of evolution. Mutations are raw material of evolution. No variation means no evolution and mutations.

Mutation and genetic Mutation and genetic variationvariation Mutations are raw material of Mutations are raw material of

evolution.evolution.

No variation means no evolution No variation means no evolution and mutations are the ultimate and mutations are the ultimate source of variation.source of variation.

Where do new alleles Where do new alleles come from?come from? DNA made up of sequence of DNA made up of sequence of

nucleotides. Each nucleotide nucleotides. Each nucleotide includes a sugar, phosphate and includes a sugar, phosphate and one of four possible nitrogenous one of four possible nitrogenous bases (adenine and guanine [both bases (adenine and guanine [both purines], and thymine and purines], and thymine and cytosine [both pyrimidines]).cytosine [both pyrimidines]).

4.1a

4.

4.1b + 4.1d

Where do new alleles Where do new alleles come from?come from? The opposite strands of the DNA The opposite strands of the DNA

molecule are complementary because molecule are complementary because the strands are held together by bonds the strands are held together by bonds between the opposing bases and between the opposing bases and adenine bonds only with thymine and adenine bonds only with thymine and cytosine only with guanine.cytosine only with guanine.

Thus, knowing the sequence on one Thus, knowing the sequence on one strand enables one to construct the strand enables one to construct the sequence on the other strand.sequence on the other strand.

4.2

Where do new alleles Where do new alleles come from?come from? Sequence of bases in DNA codes for Sequence of bases in DNA codes for

protein structure as each three protein structure as each three base sequence codes for one amino base sequence codes for one amino acid in the protein chain.acid in the protein chain.

[To refresh yourself on basic DNA [To refresh yourself on basic DNA structure and protein synthesis see structure and protein synthesis see any Introductory Biology textbook]any Introductory Biology textbook]

4.3a

Where do new alleles Where do new alleles come from?come from? When DNA is synthesized an When DNA is synthesized an

enzyme called DNA polymerase enzyme called DNA polymerase reads one strand of DNA molecule reads one strand of DNA molecule and constructs a complementary and constructs a complementary strand.strand.

If DNA polymerase makes a If DNA polymerase makes a mistake and it is not repaired, a mistake and it is not repaired, a mutation has occurred.mutation has occurred.

4.2

Types of mutationsTypes of mutations

A mistake that changes one base on a A mistake that changes one base on a DNA molecule is called a DNA molecule is called a pointpoint mutation.mutation.

Two forms:Two forms:– Transition: one pyrimidine (T or C) Transition: one pyrimidine (T or C)

substituted for the other pyrimidine or one substituted for the other pyrimidine or one purine substituted for the other purine (A purine substituted for the other purine (A or G). or G).

– Transversion: purine substituted for Transversion: purine substituted for pyrimidine or vice versa pyrimidine or vice versa

Fig 4.4


Transitions more common than Transitions more common than transversions. Perhaps because transversions. Perhaps because transitions cause less disruption transitions cause less disruption to the DNA molecule and so are to the DNA molecule and so are less likely to be noticed by DNA less likely to be noticed by DNA repair molecules.repair molecules.


Not all mutations cause a change Not all mutations cause a change in amino acid coded for. These in amino acid coded for. These are called are called silent mutationssilent mutations. .

Mutations that do cause a change Mutations that do cause a change in amino acid are called in amino acid are called replacementreplacement mutationsmutations..


Another type of mutation occurs Another type of mutation occurs when bases are inserted or when bases are inserted or deleted from the DNA molecule. deleted from the DNA molecule.

This causes a change in how the This causes a change in how the whole DNA strand is read (a whole DNA strand is read (a frame shift mutation) and frame shift mutation) and produces a non-functional produces a non-functional protein.protein.

Mutation ratesMutation rates

Most data on mutations comes from Most data on mutations comes from analysis of loss-of-function mutations.analysis of loss-of-function mutations.

Loss-of-function mutations cause Loss-of-function mutations cause gene to produce a non-working gene to produce a non-working protein.protein.

Examples of loss-of-function Examples of loss-of-function mutations include: insertions and mutations include: insertions and deletions, mutation to a stop codon deletions, mutation to a stop codon and insertion of jumping genes. and insertion of jumping genes.


Some mutations cause readily Some mutations cause readily identified phenotypic changes.identified phenotypic changes.

E.g. Achrondoplastic dwarfism is a E.g. Achrondoplastic dwarfism is a dominant disorder. An dominant disorder. An Achrondoplastic individual’s Achrondoplastic individual’s condition must be the result of a condition must be the result of a mutation, if his parents do not mutation, if his parents do not have the condition.have the condition.


Human estimate is 1.6 Human estimate is 1.6 mutations/genome/generation.mutations/genome/generation.

In In DrosophilaDrosophila rate is only 0.14 m/g/g, rate is only 0.14 m/g/g, but when corrected for number of cell but when corrected for number of cell divisions needed to produce sperm divisions needed to produce sperm (400 in humans 25 in (400 in humans 25 in Drosophila) Drosophila) mutation rates per cell division are mutation rates per cell division are very similar.very similar.


These rates are underestimates These rates are underestimates as they are based on loss-of-as they are based on loss-of-function mutations.function mutations.

Direct estimate of number of Direct estimate of number of mutations of all kinds made for mutations of all kinds made for roundworm roundworm CaenorhabditisCaenorhabditis eleganselegans by sequencing by sequencing mitochondrial DNA.mitochondrial DNA.


Roundworms can self-fertilize so Roundworms can self-fertilize so researchers tracked 74 family lines researchers tracked 74 family lines derived from one female and followed derived from one female and followed each for 214 generations.each for 214 generations.

At end sequenced 771,672 base pairs of At end sequenced 771,672 base pairs of mitochondrial DNA. Found 26 mutations mitochondrial DNA. Found 26 mutations giving rate of 1.6X10giving rate of 1.6X10-7-7 mutations per site mutations per site per generation. Ten mutations were per generation. Ten mutations were insertion/deletions and 16 substitutions.insertion/deletions and 16 substitutions.


Applying mutation rates to entire Applying mutation rates to entire genome gives estimate of genome gives estimate of approximately 15 approximately 15 mutations/individual/generation.mutations/individual/generation.

Where do new genes Where do new genes come from?come from? Mutation can produce new alleles, Mutation can produce new alleles,

but new genes are also produced but new genes are also produced and and gene duplicationgene duplication appears to appears to be most important source of new be most important source of new genes.genes.

Gene duplicationGene duplication

Duplication results from unequal Duplication results from unequal crossing over when chromosomes crossing over when chromosomes align incorrectly during meiosis.align incorrectly during meiosis.

Result is a chromosome with an Result is a chromosome with an extra section of DNA that contains extra section of DNA that contains duplicated genesduplicated genes

4.7

Gene duplicationGene duplication

Extra sections of DNA are duplicates Extra sections of DNA are duplicates and can accumulate mutations without and can accumulate mutations without being selected against because the being selected against because the other copies of the gene produce other copies of the gene produce normal proteins.normal proteins.

Gene may completely change over Gene may completely change over time so gene duplication creates new time so gene duplication creates new possibilities for gene function.possibilities for gene function.

Globin genesGlobin genes

Human globin genes are Human globin genes are examples of products of gene examples of products of gene duplication. duplication.

Globin gene family contains two Globin gene family contains two major gene clusters (alpha and major gene clusters (alpha and beta) that code for the protein beta) that code for the protein subunits of hemoglobin.subunits of hemoglobin.


Hemoglobin (the oxygen-carrying Hemoglobin (the oxygen-carrying molecule in red corpuscles) molecule in red corpuscles) consists of an iron-binding heme consists of an iron-binding heme group and four surrounding group and four surrounding protein chains (two coded for by protein chains (two coded for by genes in the Alpha cluster and genes in the Alpha cluster and two in the Beta cluster).two in the Beta cluster).


Ancestral globin gene duplicated Ancestral globin gene duplicated and diverged into alpha and beta and diverged into alpha and beta ancestral genes about 450-500 ancestral genes about 450-500 mya.mya.

Later transposed to different Later transposed to different chromosomes and followed by chromosomes and followed by further subsequent duplications further subsequent duplications and mutations.and mutations.

From Campbell and Reese Biology 7th ed.


Lengths and positions of exons Lengths and positions of exons and introns in the globin genes and introns in the globin genes are very similar. Very unlikely are very similar. Very unlikely such similarities could be due to such similarities could be due to chance.chance.

4.9

Exons (blue), introns (white), number in box is number of nucleotides.


Different genes in alpha and beta families Different genes in alpha and beta families are expressed at different times in are expressed at different times in development.development.

For example, in very young human fetus, For example, in very young human fetus, zeta (from alpha cluster) and epsilon zeta (from alpha cluster) and epsilon (from beta cluster) chains are present (from beta cluster) chains are present initially then replaced. Similarly G-initially then replaced. Similarly G-gamma and A-gamma chains present in gamma and A-gamma chains present in older fetuses are replaced by beta chains older fetuses are replaced by beta chains after birth. after birth.

4.8

Gestation (weeks) Post-birth(weeks)

Fetal hemoglobin has a higher affinity for oxygen than adult hemoglobin.Enhances oxygen transfer from mother to offspring.

Chromosomal Chromosomal alterationsalterations Two major forms important in Two major forms important in

evolution: inversions and evolution: inversions and polyploidy.polyploidy.

InversionsInversions

A chromosome inversion occurs A chromosome inversion occurs when a section of chromosome is when a section of chromosome is broken at both ends, detaches, broken at both ends, detaches, and flips.and flips.

Inversion alters the ordering of Inversion alters the ordering of genes along the chromosome.genes along the chromosome.

4.10


Inversion affects linkage (linkage is the Inversion affects linkage (linkage is the likelihood that genes on a chromosome are likelihood that genes on a chromosome are inherited together i.e., not split up during inherited together i.e., not split up during meiosis).meiosis).

Inverted sections cannot align properly with Inverted sections cannot align properly with another chromosome during meiosis and another chromosome during meiosis and crossing-over within inversion produces non-crossing-over within inversion produces non-functional gametes.functional gametes.

Genes contained within inversion are Genes contained within inversion are inherited as a set of genes also called a inherited as a set of genes also called a “supergene” “supergene”


Inversions are common in Inversions are common in Drosophila Drosophila (fruit flies)(fruit flies)

Frequency of inversions shows clinal Frequency of inversions shows clinal pattern and increases with latitude.pattern and increases with latitude.

Inversions are believed to contain Inversions are believed to contain combinations of genes that work well combinations of genes that work well in particular climatic conditions.in particular climatic conditions.


DrosophilaDrosophila introduced to introduced to Washington and Chile from Old Washington and Chile from Old World. Spread along both coasts World. Spread along both coasts and within a few years had and within a few years had developed similar clines in developed similar clines in number of inversions to those number of inversions to those found in native range.found in native range.

4.11

PolyploidyPolyploidy

Polyploidy is the duplication of Polyploidy is the duplication of entire sets of chromosomes.entire sets of chromosomes.

A polyploid organism has more A polyploid organism has more than two sets of chromosomes.than two sets of chromosomes.

E.g. A diploid (2n chromosomes) E.g. A diploid (2n chromosomes) organism can become tetraploid organism can become tetraploid (4n), [where n refers to one set of (4n), [where n refers to one set of chromosomes].chromosomes].


Polyploidy is common in plants, Polyploidy is common in plants, rare in animals.rare in animals.

Half of all angiosperms (flowering Half of all angiosperms (flowering plants) and almost all ferns are plants) and almost all ferns are polyploid.polyploid.


Polyploid animal taxa include Polyploid animal taxa include earthworms and flatworms, which earthworms and flatworms, which can self-fertilize, and some other can self-fertilize, and some other groups including insects that can groups including insects that can reproduce asexually reproduce asexually (parthenogenesis).(parthenogenesis).


Polyploidy can occur if an individual Polyploidy can occur if an individual produces diploid gametes and self-produces diploid gametes and self-fertilizes generating tetraploid fertilizes generating tetraploid offspring. offspring.

If an offspring later self fertilizes or If an offspring later self fertilizes or crosses with its parent, a population crosses with its parent, a population of tetraploids may develop.of tetraploids may develop.

FIG 4.12


If a sterile plant undergoes If a sterile plant undergoes polyploidy and self-fertilization a polyploidy and self-fertilization a new species can develop new species can develop essentially immediately.essentially immediately.


Cross-fertilization of different species, Cross-fertilization of different species, followed by polyploidy, was followed by polyploidy, was responsible for the development of responsible for the development of many crop plants e.g. wheat. many crop plants e.g. wheat.

Initial cross-fertilization produces Initial cross-fertilization produces sterile offspring, because sterile offspring, because chromosomes cannot pair up during chromosomes cannot pair up during meiosis. meiosis.


Triticum monococcumTriticum monococcum (AA) X wild (AA) X wild TriticumTriticum (BB) (BB) cross produced sterile hybrid with 14 cross produced sterile hybrid with 14 chromosmomes (AB; 1-7A and 1-7B). chromosmomes (AB; 1-7A and 1-7B). {capitalized letters symbolize species source of {capitalized letters symbolize species source of chromosomes, number denotes individual chromosomes, number denotes individual chromosome e.g. 1A, 3B}chromosome e.g. 1A, 3B}

Polyploidy of first sterile hybrid produced Polyploidy of first sterile hybrid produced Emmer Wheat Emmer Wheat T. turgidum T. turgidum (AABB) which has (AABB) which has 28 chromosomes. Emmer Wheat isn’t sterile. 28 chromosomes. Emmer Wheat isn’t sterile. It has two copies of each chromosome (e.g. two It has two copies of each chromosome (e.g. two 1A chromosomes, two 3B chromosomes, etc.).1A chromosomes, two 3B chromosomes, etc.).


Further cross between Emmer Wheat Further cross between Emmer Wheat and and T.T. tauschiitauschii which has a total of 14 which has a total of 14 chromosomes (DD) produced a sterile chromosomes (DD) produced a sterile hybrid with 21 chromosomes (ABD). hybrid with 21 chromosomes (ABD).

Further polyploid error in meiosis Further polyploid error in meiosis produced produced T.T. aestivumaestivum Bread Wheat Bread Wheat with 42 chromosomes (AABBDD). with 42 chromosomes (AABBDD). Those chromosomes are derived from Those chromosomes are derived from 3 ancestral species.3 ancestral species.

Example of inter-species cross-fertilization and meiotic errors leading toproduction of a fertile hybrid


Genes in polyploid chromosome Genes in polyploid chromosome sets are free to develop new sets are free to develop new functions through natural functions through natural selection and evolution.selection and evolution.

Polyploidy is a key source of Polyploidy is a key source of genetic variation.genetic variation.

What is mutation rate What is mutation rate totopolyploidy in plants?polyploidy in plants? Flowering plants produce diploid gametes Flowering plants produce diploid gametes

at frequency of 0.00465 per generationat frequency of 0.00465 per generation

Thus tetraploid offspring produced at rate Thus tetraploid offspring produced at rate of approx 0.00465 X 0.00465 or 2.16 X 10of approx 0.00465 X 0.00465 or 2.16 X 10--

5 5 per generation (approx. 2 in every per generation (approx. 2 in every 100,000 offspring per generation are 100,000 offspring per generation are tetraploid).tetraploid).

This is comparable to rate of point This is comparable to rate of point mutations in individual genes.mutations in individual genes.

Measuring genetic Measuring genetic variation in variation in populationspopulations Classical view: little genetic variation Classical view: little genetic variation

expected because one allele at a locus expected because one allele at a locus expected to be superior, favored by expected to be superior, favored by natural selection and thus fixed in the natural selection and thus fixed in the population.population.

Now recognized that there is Now recognized that there is substantial genetic variation in natural substantial genetic variation in natural populations.populations.

Identifying genotypesIdentifying genotypes

Gel electrophoresis used to determine Gel electrophoresis used to determine genotypes of individuals.genotypes of individuals.

DNA isolated, amplified and cut using DNA isolated, amplified and cut using restriction enzymes. Different patterns restriction enzymes. Different patterns on gel can be distinguished. on gel can be distinguished.

Also direct sequencing can be used to Also direct sequencing can be used to identify different alleles.identify different alleles.

Calculating allele Calculating allele frequenciesfrequencies Recall Recall ΔΔ32 (delta32) variant of CCR5 32 (delta32) variant of CCR5

gene (CCR5 used as coreceptor by gene (CCR5 used as coreceptor by HIV to enter white blood cells). HIV to enter white blood cells).

ΔΔ32 allele offers protection against 32 allele offers protection against HIV. How can its frequency in a HIV. How can its frequency in a population be estimated?population be estimated?

Calculating allele Calculating allele frequenciesfrequencies Simplest way is to count Simplest way is to count

frequencies, but can also be frequencies, but can also be estimated from the frequencies of estimated from the frequencies of heterozygotes and homozygotes heterozygotes and homozygotes as we will see when we study as we will see when we study Hardy-Weinberg equilibrium Hardy-Weinberg equilibrium shortly.shortly.

How much genetic How much genetic diversity exists in a diversity exists in a typical population?typical population? Electrophoretic studies have Electrophoretic studies have

shown that most populations have shown that most populations have substantial genetic variation.substantial genetic variation.

In general, 33-50% of enzyme loci In general, 33-50% of enzyme loci are polymorphic and average are polymorphic and average individual is heterozygous at 4-individual is heterozygous at 4-15% of loci.15% of loci.

4.16

Frequency distribution of enzyme heterozygosity in plants. Heterozygosity is the mean percentage of loci hetoerozygous per individual or the mean percentage of individuals heterozygous per locus.

Why are populations Why are populations genetically diverse?genetically diverse? Two major hypotheses.Two major hypotheses.

SelectionistSelectionist: Diversity maintained by : Diversity maintained by selection. Selection favors rare selection. Selection favors rare individuals, heterozygotes or different individuals, heterozygotes or different alleles at different times and places.alleles at different times and places.

NeutralNeutral: Most alleles at polymorphic loci : Most alleles at polymorphic loci functionally and selectively equivalent. functionally and selectively equivalent.

Neutralist vs Neutralist vs Selectionist Selectionist controversycontroversy Both neutralist and selectionist Both neutralist and selectionist

schools recognize the importance schools recognize the importance of selection. I.e. that many alleles of selection. I.e. that many alleles are fixed as a result of selection.are fixed as a result of selection.

The disagreement is about the The disagreement is about the proportion of molecular variation proportion of molecular variation that is due to the effects of that is due to the effects of selection.selection.

Neutralist vs Neutralist vs Selectionist Selectionist controversycontroversy Neutralist argument is that most of the Neutralist argument is that most of the

diversity seen in DNA at the molecular diversity seen in DNA at the molecular level is functionally neutral (i.e. does level is functionally neutral (i.e. does not have an effect on fitness). not have an effect on fitness).

In most cases, neutralists argue that a In most cases, neutralists argue that a change in a codon leads to an amino change in a codon leads to an amino acid change that has no effect on the acid change that has no effect on the functioning of the protein produced.functioning of the protein produced.

Neutralist vs Neutralist vs Selectionist Selectionist controversycontroversy Through the process of genetic Through the process of genetic

drift (chance) different alleles drift (chance) different alleles may become fixed in different may become fixed in different populations.populations.

Selectionist would argue that Selectionist would argue that most variation is subject to most variation is subject to selection.selection.

Neutralist vs Neutralist vs Selectionist Selectionist controversycontroversy One way to evaluate the situation in nature is One way to evaluate the situation in nature is

to look at synonymous and non-synonymous to look at synonymous and non-synonymous changes in nucleotides. changes in nucleotides.

Synonymous changes are ones where the Synonymous changes are ones where the codon is changed but the amino acid codon is changed but the amino acid produced is not [i.e. a silent mutation] . This produced is not [i.e. a silent mutation] . This will be invisible to selection and so must be .will be invisible to selection and so must be .

In non-synonymous changes, the amino acid In non-synonymous changes, the amino acid is changed and this change may result in a is changed and this change may result in a phenotypic change and thus be selected for phenotypic change and thus be selected for or against.or against.

McDonald-Kreitman McDonald-Kreitman test test You would expect that if selection acts on most You would expect that if selection acts on most

nucleotides that the ratio Dn/Pn of fixed to nucleotides that the ratio Dn/Pn of fixed to polymorphic nucleotides for non-synonymous codons polymorphic nucleotides for non-synonymous codons would be much higher than the same ratio Ds/Ps for would be much higher than the same ratio Ds/Ps for synonymous codons (not subject to selection). synonymous codons (not subject to selection).

This is because fixation implies a particular nucleotide This is because fixation implies a particular nucleotide is better than the alternatives at that site.is better than the alternatives at that site.

Fixed means that only one nucleotide occurs at a site Fixed means that only one nucleotide occurs at a site in a species, but there are differences between in a species, but there are differences between species. Polymorphic means multiple nucleotides species. Polymorphic means multiple nucleotides occur at a site in a species.occur at a site in a species.

Neutralist vs Neutralist vs Selectionist Selectionist controversycontroversy Using an extension of the McDonald-Using an extension of the McDonald-

Kreitman test it is possible to estimate Kreitman test it is possible to estimate the proportion of nucleotide substitutions the proportion of nucleotide substitutions fixed by natural selection.fixed by natural selection.

It is estimated that 45% of the amino It is estimated that 45% of the amino acid differences between two species of acid differences between two species of Drosophila (D. simulans and D. yakuba) Drosophila (D. simulans and D. yakuba) have been fixed by selection and 35% of have been fixed by selection and 35% of AA differences in primates have been AA differences in primates have been fixed by selection (Barton et al. Evolution fixed by selection (Barton et al. Evolution 2007).2007).

Mutation and genetic variation Mutations are raw material of evolution. Mutations are raw material of evolution. No variation means no evolution and mutations.

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