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Mutation and Genetic Variation
Chapter 4
1
Mutation is the ultimate source of
genetic variation
• Point mutations
– base substitutions, insertions, deletions
• Gene duplications
• Changes in chromosome structure
– inversions, translocations
• Changes in chromosome number
– polyploidy
2
Estimated number of mutations per genome
per generation (see Table 4.1 of Freeman & Herron)
Number of mutant
genes per genome
per generation
Species
Taxonomic group
E. coli
Bacteria
0.0025
S. cerevisiae
Fungi
0.0027
C. elegans
Nematode
0.0360
D. melanogaster Insect
0.1400
mouse
Mammal
0.9000
human
Mammal
1.6000
3
More on mutation rates
• Number of mutations per genome per generation is a
function of:
– The number of genes
– The average number of generations of cell division that precede
gamete production
• The mutation rates on the previous slide are underestimates
of the total mutation rate because they are based only on
mutations of “large” effect
• Spontaneous mutation rates may be subject to natural
selection
– Variation in DNA polymerase affects accuracy of replication:
bacteriophage T4, E. coli
– Efficiency of DNA mismatch repair also under genetic control
• Higher mutation rates may confer a selective advantage in
a novel or changing environment
4
Fitness effects of mutations – 1
• Fig. 4.6a Effect of mutations on viability in 74 “mutation
accumulation” lines of Caenorhabditis elegans
5
Fitness effects of mutations – 2
•
Fig. 4.6b Effect of large random insertions on fitness in E. coli and yeast. The
selection coefficient is the reduction in growth rate (fitness) of mutant cells
relative to non-mutated controls
6
Fitness effects of mutations – summary
• Most mutations are slightly deleterious or
neutral
• Few mutations are beneficial
• New mutations will be heterozygous in
diploids – therefore, recessive mutations
(even good ones) will have no immediate
phenotypic effect and will not be subjected
to natural selection (while heterozygous)
7
Population size, mutation and natural
selection
• Larger populations will have more new mutant alleles of
each gene in each generation
• If humans, on average, have 1.6 new mutations per
genome per generation and have 25,000 genes, then there
will be 1 new mutant allele per gene per (25,000/1.6) ≈
15,600 people in each generation (=100 new mutant alleles
per gene per generation in a population of 1.56 million)
• This calculation suggests that natural selection will be
most effective at producing adaptive evolution in large
populations because larger populations harbor more
genetic variation, which is the “raw material” that
underlies the phenotypic variation upon which natural
selection acts.
8
Where “new” genes come from – gene
duplication
• Duplicate genes can be created by unequal
crossing over
• Duplicated genes can form “gene families” and
“superfamilies”
• Duplicate genes can:
– Remain the same: 45s rRNA genes (increase “dosage”)
– Differentiate, but continue to perform similar functions:
globins (oxygen transport)
– Perform unrelated functions: crystallins and their
ancestors
– Become “junk”: pseudogenes
9
Fig. 4.7 Unequal Cross-over and the origin of
gene duplications
10
The globin superfamily in humans
• The a-globin family
– Chromosome 16
– contains (in order): z, yz, ya2, ya1, a2, a1, q
• The b-globin family
– chromosome 11
– contains (in order): e, Gg, Ag, yb1, d, b
• Myoglobin
– chromosome 22
– found in muscles
• Globin – myoglobin duplication >800 Myr
• Split between a- and b-globin families 450 – 500 Myr (aand b-globin about 46% amino acid sequence similarity)
11
Fig. 4.8 Developmental expression members
of globin gene family
12
Fig. 4.9
Transcription
units in
the
globin
gene
family
13
Some Gene Families
•
•
•
•
•
•
•
Actins
Myosin (heavy chain)
Histones
45s rRNA (human)
Keratins
Globins (a-like)
Globins (b-like)
5-30
5-10
100-1,000
> 300 (5 chromosomes)
> 20
1-5
≥ 50
14
Fig. 4.10 Chromosome inversion
15
Characteristics of Inversions
• Do not generally create new alleles (or genes)
• “Suppress” crossing over when an inversion is
heterozygous with a normal chromosome
– i.e., recombination is prevented or reduced among the
group of genes included within an inversion, so those
genes act as a block or “supergene”, which may be
adaptive
• Occur in many, if not all, organisms, but are
particularly well-known in Drosophila (D.
pseudoobscura, D. subobscura)
16
Frequency of the Est inversion
Fig. 4.11 Inversion frequency clines in D.
subobscura
South America
South latitude
North America
North latitude
17
Polyploidy
• Polyploid means having 3 or more complete haploid
chromosome sets
– e.g. Mendel’s peas were diploid and had 2n = 14 chromosomes
(each haploid set had n = 7 chromosomes). A triploid pea would
have 3n = 21 chromosomes, and a tetraploid pea would have 4n =
28 chromosomes
• Polyploidy is common in higher plants, much rarer in
animals
• More than one-half of angiosperms are polyploid (relative
to ancestors with fewer sets of chromosomes)
18
Fig. 4.12 Origin of tetraploidy in plants
Parent
1st generation
offspring
Cell-division error
causes production
of diploid gametes
Selfs, mates with 4n sibling,
Or backcrosses to parent
2nd generation
offspring
19
Frequency of Polyploidy
• Some studies suggest that flowering plant
species typically produce diploid gametes at
a frequency of 0.00465
• The probability of two diploid gametes
meeting to produce a zygote is, then,
(0.00465)2 = 2.16 x 10-5 (or about 2 out of
every 100,000 offspring are tetraploid)
20
Importance of Polyploidy
• Duplicates all genes, which may evolve new
functions
• A tetraploid, for example, is reproductively
isolated from its diploid “parent” because
the hybrid is triploid and sterile. Thus, the
tetraploid is, in effect, a new species
• Triploids have commercial significance
because they are “seedless”
21
Ploidy in three species of Iris
•
•
•
•
Iris setosa has 2n = 36 chromosomes (n=18)
Iris virginica has 72 chromosomes (4n)
Iris versicolor has 108 chromosomes (6n)
I. Versicolor (common blue flag) may have
been derived by hybridization between the
other two species
• Proportion of polyploid angiosperms is
estimated to be from 30% (Stebbins 1950)
to 50-70% (Stace 1989)
22
How much genetic variation is there? – 1
• Table 4.4 of your text gives the genotypes at the
CCR5 gene in samples from various human
populations (CCR5 protein is the co-receptor that
HIV uses to enter host cells)
• For example, the sample of 102 people from
Iceland is as follows:
Genotype
Number in sample
+/+
75
+/D32
24
D32/D32
3
23
How much genetic variation is there? – 2
• Iceland sample (N = 102):
Genotype
Number in sample
+/+
75
+/D32
24
D32/D32
3
• The frequency of the + allele is:
[(75 x 2) + 24] / (102 x 2) = 0.853
• The frequency of the D32 allele is:
[(3 x 2) + 24] / (102 x 2) = 0.147
• The heterozygosity of this sample is:
24/102 = 0.235
24
How much genetic variation is there? – Variation in
allele frequencies among populations
Frequency of alcohol
dehydrogenase (Adh) alleles
in Australian fruit fly
populations
Geograpic pattern may
result from greater stability
of the AdhS allele at higher
temperatures
25
How much genetic variation is there? – Heterozygosity
• Heterozygosity is a commonly used measure of genetic
variation for conventional genes, such as enzyme-coding
loci
• Heterozygosity increases with the number of alleles at a
locus and is greatest when all alleles have the same
frequency
–
–
–
–
1 allele (a monomorphic locus): HHW = 0
2 alleles with frequencies 0.9 and 0.1: HHW = 2(0.9)(0.1) = 0.18
2 alleles with frequencies 0.5: HHW = 2(0.5)(0.5) = 0.50
4 alleles with frequencies 0.25: HHW = 1 - [4(0.25)2] = 0.75
– Where HHW is the expected heterozygosity when genotypes are in
Hardy-Weinberg proportions
26
Fig. 4.16
Heterozygosity:
enzyme loci
27
How much genetic variation is there? – 3
• Enzyme loci
– 1/3 to 1/2 of genes are polymorphic in a typical
population: that is they have 2 or more alleles with a
frequency > 1% (or 5%)
– a typical individual will be heterozygous at 4 – 15% of
its loci
– variation at enzyme loci is generally assayed by gel
electrophoresis, which will detect only amino acid
sequence differences in the gene products
• We see even more variation when we look directly
at nucleotide sequences of genes – synonymous
substitutions, substitutions in non-translated regions
28
Fig. 4.17 Loss-of-function mutations in a sample of 30,000+
disease-causing alleles of the cystic fibrosis gene
29