Download Genetic Variability and allele frequencies Schistosomiasis – human

Genetic Variability and allele
frequencies
Definitions
•Gene: piece of DNA that has some function
• Mutation generates new variants of a gene = alleles
•Locus = gene (gene position)
•Genetic Locus = certain position on a chromosome
• Most natural populations contain genetic variation
• This variation is the raw material for evolution.
•Alleles = different possible DNA variants at a certain locus
•Genotype: set of genes of an individual (often only consider one locus
at a time)
•Phenotype: the physical or biochemical expression of the genotype +
environment
• Evolution = change in genetic composition of a population
… this usually happens through a change in allele frequencies.
Measuring allele frequencies in a population gives us:
Schistosomiasis – human disease caused by
parasite (Schistosoma mansoni)
1. An estimate of the genetic variation of the population
2. insights into the evolutionary history of the population
3. Useful for genetic fingerprinting
•One locus (gene) SM1 (S)
strongly affects susceptibility.
CODOMINANCE:
To measure allele frequency we need to determine the
genotypes of individuals.
Sometimes can infer genotype from phenotype. [F&H sec 4.4]
SS (resistant)
ss (highly susceptible)
Ss (intermediate susceptibility)
Genotype is proportional to phenotype
(high predictability)
1
•A study in Brazil showed that 60% of people are homozygous for the
resistance gene, and 5% homozygous for the susceptiblity gene.
CCR5 gene and the immune response
•However, usually not possible to infer genotype from phenotype – must
look directly at the protein or DNA.
•Normal function is to mediate stimulation of immune system by
chemokines
•For example, use gel electrophoresis
• HIV-1 uses CCR5 as a co-receptor to enter human cells
• In 1996 it was discovered that certain individuals appeared to be resistant
to HIV infection
• These individuals were homozygous for a 32bp deletion in the CCR5
gene (CCR5-Δ32)
• How common is this allele?
Electrophoresis test for the allele
- CCR5-Δ32 is shorter that wild-type (normal, symbol=”+”), and so travels
faster on the gel
- quickly get genotype information for lots of people
Reconstructing history of the
CCR5-Δ32 locus
• CCR5-Δ32 is located on chromosome 3 and
near two short-tandem repeat sites called
GAAT and AFMB.
• GAAT and AFMB are non-coding and have
no effect on fitness. Both GAAT and
AFMB have a number of different alleles.
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•In Ireland, 44 people were tested for the presence of this allele.
[remember: Each person has two copies of the gene]
•40 people had genotype
+/+
4
+/Δ32
0
Δ32/ Δ32
• Out of a total of 88 alleles, only 4 were Δ32.
• Estimate the frequency of the Δ32 allele in Ireland to be 4/88 =
5%
• Generally see that this allele is more frequent in northern Europe
than elsewhere. Outside Europe, the Middle East and western Asia
it is virtually absent.
•How will the AIDS epidemic affect the CCR5-Δ32 allele
frequency, if at all?
A simple model – genes in a bucket.
Imagine a gene with two alleles A and a. In adults of the population …
A is present at 60%
•First, need to understand what would happen to the CCR5-Δ32
without HIV, then figure out if we are seeing something other than
expected.
•Model for the normal behaviour of allele frequencies in a
population – Hardy Weinberg Equilibrium
a
40%
•Imagine mating as a process of throwing all the eggs and sperm into a
(very big) bucket, and when they collide and fuse, they make a new
individual. These individuals grow into adults, and do the genes in a
bucket thing again. Etc. etc.
What will the allele frequency be in the next generation?
Get the genotype frequencies by considering all combinations of egg and
sperm
3
egg
A (0.6)
a (0.4)
A (0.6)
AA (0.6x0.6)
Aa (0.6x0.4)
a (0.4)
Aa (0.6x0.4)
aa (0.4x0.4)
sperm
•Allele A is present in two copies in AA individuals and in one copy in Aa individuals.
• AA = 0.6x0.6 = 0.36
We can make a more generalised version of the mating table.
Freq allele A = p
Freq allele a = q
Total freq of all alleles = p+q=1
•Aa = 2 x 0.6x0.4 = 0.48
• Freq allele A = 0.36 + 1/2 x 0.48 = 0.6
• THE FREQUENCY OF ALLELE A DID NOT CHANGE
egg
•Freq aa = q2
A (p)
a (q)
•Allele frequency in new generation:
sperm
A (p)
•Total of all genotypes = p2 + 2pq + q2 =1
AA (p2)
Aa (pq)
Freq allele A
= p2 + pq
= p(p+q)
a (q)
Aa (pq)
aa (p2 )
=p
•Here we see (formally) again that the frequency of allele A does not
change.
Freq AA = p2
•The allele frequencies are at equilibrium – Hardy Weinberg
Equilibrium
Freq Aa = 2pq
•HWE describes how variation is maintained in a population
Genotype frequencies in next generation
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We made several assumptions when we made our
“genes in a bucket” model:
•1. All individuals survive and produce equal
numbers of offspring (i.e., no selection)
•2.
No new alleles are created (i.e., no mutation)
•3. No individuals moved into or out of the model
(i.e., no migration)
•4. All gametes fuse with another [no luck involved]
(i.e., infinite population size)
•5. Alleles are combined at random (i.e., random
mating)
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