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Hardy-Weinberg Equilibrium
RECOMMENDED TEXT
Population Genetics
Deals with Frequencies/distribution of genes (alleles), genotypes, and phenotypes in populations. Factors that maintain equilibrium or change gene, genotype and phenotype frequencies over time.
A Genetic Population
Definition: Large group of inter-breeding individuals which shares a common gene pool. A group of sexually reproducing organisms.
H-W Equilibrium
If a gene has 2 alleles, D and d, with population frequencies of p and q, respectively.
p+q = 1
With 2 different alleles, there are 3 possible genotypes: DD, Dd, & dd. Given allele frequencies of p and q, when a population is in Hardy-Weinberg equilibrium, these genotypes will have frequencies of p2, 2pq, and q2, respectively.
p2 + 2pq + q2 = 1 (A binomial distribution)
H-W Equilibrium
E.g. for a gene with 2 alleles D and d, with population frequencies of p and q respectively. Genotype/phenotype frequencies after 1 generation:
DD (D homozygotes) = p2 Dd (Dd heterozygotes) = 2pq dd (d homozygotes) = q2 Male Gametes
Female Gametes
Punnett Square
H-W Equilibrium
Genotype (and frequency) of male parent Genotype (and frequency) of female parent
H-W Equilibrium
Mating type Mating Frequency
DD x DD DD x Dd Dd x Dd DD x dd Dd x dd dd x dd Total Relative
Allele and genotype frequencies remain the same after each successive generation
H-W Equilibrium
1.0 A1 A1
Genotype Frequency
A2 A2
Male gametes
A1 A1
(p2)
A2 A1
(qp)
A1 A2
0.5
A1 A2
(pq)
A2 A2
(q2)
0.0
1.0
Female gametes
H-W Principle
H-W equilibrium is attained after 1 generation if all assumptions hold true. This equilibrium will be maintained from generation to generation as long as conditions do not change.
Computer simulated graph showing stable gene frequencies in a large randomly mating population in H-W equilibrium.
CALCULATION OF GENE FREQUENCIES Genotype A1A1 Genotype freq. P (Probability) A1A2 H A 2 A2 Q Total 1
Calculate the values of p and q p = (P + H)/Total = (50 + 86/2) = (50 + 43) = 93 = 0.51 181 181 181 q = (Q + H)/Total = (45+ 86/2) = (45+43) = 88 = 0.49 181 181 181
CALCULATIONS OF 2
EXPECTED FREQUENCIES OF THE 3 GENOTYPES Exp. freq. of MM genotype = p2 = 0.512 = 0.2601 Exp. freq. of MN genotype = 2pq = 2 x 0.51 x 0.49 = 0.4998 Exp. freq. of NN genotype = q2 = 0.4902 = 0.2401 EXPECTED NUMBERS OF THE 3 GENOTYPES Exp. number of MM = p2 x 181 = 0.2601 x 181 = 47.1 Exp. number of MN = 2pq x 181 = 0.4998 x 181 = 90.5 Exp. number of NN = q2 x 181 = 0.2401 x 181 = 43.4
CALCULATIONS OF 2
2 = (Obs. No. Exp. No.)2
Exp. No. = (50 47.1)2 + (86 90.5)2 + (45 43.4)2 47.1 90.5 43.4 = 2.92 + -4.52 + 1.62 47.1 90.5 43.4 = 8.41 + 20.25 + 2.56 47.1 90.5 43.4 = 0.179 + 0.224 + 0.059 = 0.462 Compare calculated 2 with theoretical 2
CALCULATIONS OF 2
Check critical 2 value from the table Theoretical 2 = 2[] = 20.05(3-2) = 3.841 Since the calculated 2 (0.462) < theoretical 2 Conclusion: This population did not deviate significantly from expected H-W genotype proportions for the MN locus
GENE FREQUENCIES
(A1 gene) p (A2 gene) q from from 0 0 1 1
p+q = 1
Gene frequencies around 1 or 0 are considered extreme Gene frequencies around 0.5 considered intermediate At intermediate gene frequencies, heterozygotes in a population would be near the max. frequency of 0.5 (50%)
Freq. of carrier (Aa) = 2pq = 2 1/141 140/141 = 1/70 About one in 70 persons is a carrier.
Exp. genotype frequencies found by expanding (p + q + r)2 Phenotypes : A blood group B blood group AB blood group O blood group
In a Scottish population, the observed numbers of individuals in the A,B, AB and O blood groups are given. What are the gene frequencies in this pop? (evaluate p, q and r)
HUMAN A-B-O BLOOD GROUPS GENOTYPIC AND PHENOTYPIC FREQUENCIES Data of ABO Blood Types in Scottish Population
Phenotype Genotype Exp. genotype Frequencies Observed No. Of Phenotypes IAIA p2 A IAIO 2pr 894 B IBIB IAIO q2 2qr 309 AB IAIB 2pq 70 O IOIO r2 1337 Total 1 1 2610
309/2610 = 0.119
70/2610 = 0.027
1337/2610 = 0.512
Assume that the pop. is in H-W equilibrium. Freq. of Io gene is r Given that r2 = 0.512, therefore r = 0.715
Freq of IA (p) and IB (q) genes can be found indirectly Freq. of A and O phenotypes = p2 + 2pr + r2 = (p + r)2 since p + q + r = 1,
substitute
therefore (p + r) = (1 q)
Freq. of A & O phenotypes = (1 q)2 0.342 + 0.512 = (1 q)2 1 q = 0.854 q = 0.076 (frequency of the IB allele) p=1qr = 1 0.076 0.715 = 0.209 (frequency of IA allele)
http://www.umds.ac.uk/physiology/daveb/brainday/colourblindness/cblind.htm
Color blindness afflicts 8% of males and 0.04 % of human females. Color perception depends on three genes, each producing chemicals sensitive to different parts of the visible light spectrum. Red and green detecting genes are on the X-chromosome, while the blue detection is on an autosome.
A2 q
MALE A1Y A2 Y
Freq. of A1 in whole population p = 2/3 pf + 1/3 pm Freq. of A2 in whole population q = 2/3 qf + 1/3 qm Population at equilibrium: pf = pm and qf = qm
Color blindness in man is due to a recessive sex-linked gene (c) Freq. of colorblind men is 7.8% Freq. of colorblind women is 0.65% What is the freq. of heterozygous women in this pop.?
cc 0.0065 qf2 pm C c 0.078 qm CC pf2 Cc ? 2pfqf
SINGLE GENE LOCUS, SEX-LINKED EXAMPLE FROM HUMANS (COLOR BLINDNESS) p = freq. of normal gene, q = freq. of c.b. gene
Among females : q2f = 0.0065 therefore qf = 0.0065 = 0.081 Among males : qm = 0.078 (given) Overall in pop: Therefore q = 2/3 qf + 1/3 qm = (2/3 0.081) + (1/3 0.076) = 0.08 p = 1 q = 1- 0.08 = 0.92
To calculate if the allele frequency of one population differs from another population: Population II Population I Allele frequency p1 p2 Population size n1 p1 - p2 z score = p1(1-p1) + p2(1-p2) n2x2 n1x2 z score is significantly different if >1.96
p z 0.2 1.28 0.1 1.65 0.05 1.96 0.01 2.58 0.001 3.29
n2
Terminology
Mutation A change in the genetic material, either of a single gene or in the number of structure of the chromosomes. A mutation which occurs in the gametes is inherited but not otherwise (ie, those in somatic cells) Polymorphism The occurrence in a population of two of more genetically determined forms in such frequencies (>1%) that the rarest of them could not be maintained by mutation alone.
Terminology
Genetic drift Changes in gene frequencies when small groups of individuals are separated from or leave a larger populations. Founder effect A type of genetic drift in human populations in which a few members leave to found a new settlement, perpetuating a subset of the alleles in the original population.
NON-RANDOM MATING
I. ASSORTATIVE MATING (selective mating) Leads to increase in frequencies of homozygotes and decrease in heterozygotes. The pop. becomes partially divided into 2 groups, mating takes place more frequently within groups. Most extreme form is inbreeding II. DISSORTATIVE MATING (best case scenario is random mating) Leads to an increase of heterozygotes and a reduction of homozygotes.
- Systematic processes
1. MUTATION 2. SELECTION - amount and direction of change are predictable
TYPES OF MUTATION
Changes in genes. Source of new genetic variation Mutation rate is low 10-5 or 10-6 1. NON-RECURRENT MUTATION Rare event Not important A1 A2 2. RECURRENT MUTATION Mutational event at a specific gene locus. It occurs with a characteristic frequency. A1 A2 = mutation rate of gene A1 to A2
RECURRENT MUTATION
2 Types 1. One-way recurrent mutation
A1 (Initial gene freq.) po A2 qo 0) 1)
RECURRENT MUTATION
One-way recurrent mutation
p = mut. rate orig. freq. of A1 p = po p1 : freq. of A1 gene after 1 generation of one-way recurrent mut. p1 = po - po p1 = po (1 ) p2, the freq. of A1 will decrease by the amount p1 p2 = p1 p1 p2 = p1 (1 ) p2 = po (1 ) (1 ) p2 = po (1 )2 Repeating the process for t generations pt = po (1 )t
RECURRENT MUTATION
2. Two-way recurrent mutation
Change of frequencies of the A1 and A2 alleles
A1 po
A2 qo
Forward mut: Freq. of A1 will decrease by - po Backward mut: Freq. of A1 will increase by +vqo Net change in A1 after 1 gen. of 2-way recurrent mut. p = qo - po
RECURRENT MUTATION
Two-way Recurrent Mutation
Gene Frequencies At Equilibrium
AT EQUILIBRIUM - no net change in gene frequencies - pe, qe are equilibrium gene frequencies - qe = pe therefore p = 0 p = qe - pe qe - pe = 0 Let pe = (1-qe) qe - (1 qe) = 0 qe - + qe = 0 qe + qe = u Similarly qe = pe = + +
2. Two-way Recurrent Mutation A state of equilibrium is reached. Equilibrium point dependent on the relative rates of the forward and backward mutation rates qe = pe = + + is about 1/10th as frequent as Genetic variation is maintained
SELECTION
Individuals differ in viability and fertility They therefore contribute different numbers of offspring to the next generation FITNESS (adaptive value or selective value) is the contribution of offspring to the next generation Natural or artificial selection operates on the gene Therefore causing changes in the gene frequency
FITNESS
In a particular environment, the most favored genotype (fittest) has optimum fitness of 1 Contributes the most offspring to the next generation. The fitness (W) of the genotypes selected against is 1- s s is the coefficient of selection This is the proportionate reduction in the gametic contribution of particular genotype s is also referred to as the selection intensity
FITNESS
If s = 0:
Fitness = (1- s) = 1 (no selection against genotype)
If s = 1:
Fitness = 0 (complete selection against genotype)
If s = 0.1: Fitness = 0.9 For every 10 zygotes produced. By the fittest genotype, the genotype with fitness of 0.9 produced only 9. Examine the degrees of dominance in relation to fitness.
TOTAL 1 1-sq2
Initial frequency of a (albino gene) = q Freq. after 1 generation of selection = q1 q1 = q2(1-s) + pq since (1-s) = 0, s=1, and p=1-q 1-sq2 q1 = q (1-q) 1 q2 (substitute 1 q2 = (1-q)(1+q) q1 = q 1+q After 2 generations of selection : q2 q2 = q1 (substitute q1 = q/ 1+q1 ) (1+ q1) q2 = q 1 + 2q
After t generations :
qt =
q100 = 1/141 / 1 + (100 1/141) q100 = 1/241 Therefore freq. of albinos (aa) after 100 gens. q2100 = (1/241)2 = 1/58,080 One person in 58,080 persons is expected to be an albino.
Overdominance
Selection favouring heterozygotes
Genotype Exp. freq Rel. fitness Gametic contribution A1A1 p2 1-s1 p2(1-s1) A 1A 2 2pq 1 2pq A2 A2 q2 1-s2 q2(1-s2) Total 1 1-s1p2-s2q2
Frequency of the A2 allele after 1 generation of selection: q1 = No. of A2 genes New total q1 = q2(1-s2) + pq 1 s1p2 s2q2
Overdominance
Change in gene frequency due to one generation of selection:
q = q1 q q = pq (s1p s2q) 1 s 1 p2 s 2 q2 At equilibrium then s1p = s2q Therefore at equilibrium s1pe = s2qe q=0
Since delta q = q1-q and q1 is given in the previous slide, I tried to solve q1-q by:
q2 (1-s2) + pq -q(1-s1p2-s2q2)
Try and make p common for all terms within the bracket by subst q = 1-p, for the last term, I subst q = 1-p for one of the q in q2
Some of the terms like 1, p and s2q cancel out one another, leaving
= q (s1p2-s2qp)
Take out p = pq (s1p-s2q) Hoola! which is the same as the numerator in the delta q.
Overdominance
Gene frequencies at equilibrium: s1pe = s2qe s1pe = s2 (1- pe) pe = s2 s1 + s2
s 1 pe = s 2 qe s1(1-qe) = s2qe qe = s1 s1 + s2
Equilibrium gene frequencies are dependent on the relative fitness of the two homozygote (s1 and s2)
The 3 genotypes are always present in the pop at fairly high frequencies.
Overdominance
GENETIC POLYMORPHISM More than one genetic form is maintained; A1A1, A1A2, and A2A2 . Genetic variability is maintained. AT EQUILIBRIUM, GENE FREQUENCES ARE MAINTAINED AT INTERMEDIATE LEVELS. Arbitrary range 0.01 to 0.99 The commonest allele is not > 0.99. The rarest allele is not < 0.01 Equilibrium gene frequencies (pe, qe) must be too high to be maintained by balance between mutation and selection.
Overdominance
Example: Sickle-cell anaemia
Sickle-cell anaemia
Such cells occur in people carrying a mutant gene, which causes crystalloid aggregates resulting in functional abnormality along with distorted morphology. The sickle-shaped cells clog small blood vessels, interfere with oxygen transport to various tissues, and cause anemia.
Sickle-cell anaemia: Distribution of Malaria correlates with the distribution of sickle cell gene (Hbs)
Distribution of Malaria
Possible example of overdominance ABO blood group in humans A possible example of heterozygote advantage in AB0 human blood groups. Why are 3 alleles (IA, IB and Io) maintained at intermediate levels in human populations? There may be a correlation with resistance to certain human diseases
Heterozygote Advantage Overdominance for fitness maintains an equilibrium gene frequency at intermediate levels Heterozygote advantage is an attractive explanation for polymorphism But only few examples to support this Haploid organisms have been found to have as much variability as diploid organisms this argues strongly against heterozygote advantages importance
Frequency-dependent selection
Having a phenotype that is rare may itself be an advantage The rare phenotype is favoured. The direction of selection is dependent on the gene frequency - an allele at low frequency is favoured but the same allele at high frequency is selected against. This leads to stable equilibrium gene frequency Birds and fish have been shown to take disproportionately more of the more common type of food when offered a choice This exerts frequency-dependent selection on polymorphic prey, eg snails, giving advantage to individuals with a rare pattern of colouration
Heterogeneous environment
The environment experienced by individuals of a population is not constant: differs from place to place and from time to time If one allele is advantageous in one environment and another in a different environment, stable polymorphism can result without heterozygotes necessarily being on average superior. Selection is complex in such situation: depends on
Dominance relations Individuals choose to breed in the environment to which they are adapted Mating is preferentially between individuals from the same environment or random Etc
Heterogeneous environment
A relatively simple form of selection in a heterogeneous environment results in a cline A cline is a gradient of gene frequency between one locality and another
Frequency of gene X
Location A
Location B
Location C
Location D
Clines are known to be maintained by selection favouring one allele in one locality and another allele in another locality, with limited migration, which allows mating only between individuals from neighbouring parts of the cline
Heterogeneous environment
0.6
North Europeans North Americans South Europeans Asians
0.4
0.3
0.2
0.1
Whites (USA)
Blacks (USA)
Norwegians
Swedes
Jews
South Asians
Danes
Britons
Canadians
S'pore Indians
Japanese
Russians
Italians
Finns
French
Irish
Chinese (China)
Populations
Allele frequencies (weighted averages) of the apolipoproteinB gene in the various populations of the world clustered according to geographical locations.
S'pore Chinese
Taiwanese
Javanese
Transition
Polymorphisms seen at present might possibly be transitional stages in the evolutionary replacement of one allele by another, which has become more advantageous through some environmental change in the past Explain only very few polymorphisms Eg. Study by Kettlewell on industrial melanism in the moth, Biston betularia, a modern example of natural selection The moth is predated on by birds which hunt by day, one mutant carbonaria is very dark, whereas the typical is much lighter. Since the industrial revolution areas in UK and Europe the carbonaria form is the common type. This is because it is well camouflaged against the darkened tree trunks in industrial areas.
Transition
Biston betularia (peppered moth)
Light variety
Melanic and typical forms of the peppered moth a) On a lichen-covered tree b) On a soot covered trunk
Transition
Birmingham-polluted Dorset-unpolluted
Brooker Pg 726
A comparison of the prevalence of the carbonaria mutant and the typical morph of the moth, B. betularia in polluted and unpolluted area
Neutral mutation
Selection force not responsible for polymorphism (unlike previous 4 mechanisms) Polymorphism merely results from balance between mutation and loss by chance, which depends on population size