The Hardy–Weinberg principle states that both allele and genotype frequencies in a population remain constant or are in equilibrium from generation to generation unless specific disturbing influences are introduced. Those disturbing influences include non-random mating, mutations, selection, limited population size, random genetic drift and gene flow. Genetic equilibrium is a basic principle of population genetics.
The Hardy-Weinberg principle is like a Punnett square for populations, instead of individuals. A Punnett square can predict the probability of offspring's genotype based on parents' genotype or the offsprings' genotype can be used to reveal the parents' genotype. Likewise, the Hardy-Weinberg principle can be used to calculate the frequency of particular alleles based on frequency of, say, an autosomal recessive disease.
In the simplest case of a single locus with two alleles: the dominant allele is denoted A and the recessive a and their frequencies are denoted by p and q; freq(A)=p; freq(a)=q; p + q = 1. If the population is in equilibrium, then we will have freq(AA)=p2 for the AA homozygotes in the population, freq(aa)=q2 for the aa homozygotes, and freq(Aa)=2pq for the heterozygotes.
Based on these equations, we can determine useful but difficult-to-measure facts about a population. For example, a patient's child is a carrier of a recessive mutation that causes cystic fibrosis in homozygous recessive children. The parent wants to know the probability of her grandchildren inheriting the disease. In order to answer this question, the genetic counselor must know the chance that the child will reproduce with a carrier of the recessive mutation. This fact may not be known, but disease frequency is known. We know that the disease is caused by the homozygous recessive genotype; we can use the Hardy-Weinberg principle to work backward from disease occurrence to the frequency of heterozygous recessive individuals.
|A (p)||a (q)|
|Males||A (p)||AA (p²)||Aa (pq)|
|a (q)||Aa (pq)||aa (q²)|
The final three possible genotypic frequencies in the offspring become:
These frequencies are called Hardy-Weinberg frequencies (or Hardy-Weinberg proportions). This is achieved in one generation, and only requires the assumption of random mating with an infinite population size.
Sometimes, a population is created by bringing together males and females with different allele frequencies. In this case, the assumption of a single population is violated until after the first generation, so the first generation will not have Hardy-Weinberg equilibrium. Successive generations will have Hardy-Weinberg equilibrium.
The remaining assumptions affect the allele frequencies, but do not, in themselves, affect random mating. If a population violates one of these, the population will continue to have Hardy-Weinberg proportions each generation, but the allele frequencies will change with that force.
How these violations affect formal statistical tests for HWE is discussed later.
Unfortunately, violations of assumptions in the Hardy-Weinberg principle does not mean the population will violate HWE. For example, balancing selection leads to an equilibrium population with Hardy-Weinberg proportions. This property with selection vs. mutation is the basis for many estimates of mutation rate (call mutation-selection balance).
Where the A gene is sex-linked, the heterogametic sex (e.g., mammalian males; avian females) have only one copy of the gene (and are termed hemizygous), while the homogametic sex (e.g., human females) have two copies. The genotype frequencies at equilibrium are and for the heterogametic sex but , and for the homogametic sex.
For example, in humans red-green colorblindness is an X-linked recessive trait. In western European males, the trait affects about 1 in 12, () whereas it affects about 1 in 200 females (, compared to ), very close to Hardy-Weinberg proportions.
If a population is brought together with males and females with different allele frequencies, the allele frequency of the male population follows that of the female population because each receives its X chromosome from its mother. The population converges on equilibrium very quickly.
The simple derivation above can be generalized for more than two alleles and polyploidy.
Consider an extra allele frequency, . The two-allele case is the binomial expansion of , and thus the three-allele case is the trinomial expansion of .
More generally, consider the alleles A1, ... Ai given by the allele frequencies to ;
giving for all homozygotes:
and for all heterozygotes:
The Hardy–Weinberg principle may also be generalized to polyploid systems, that is, for organisms that have more than two copies of each chromosome. Consider again only two alleles. The diploid case is the binomial expansion of:
and therefore the polyploid case is the polynomial expansion of:
where c is the ploidy, for example with tetraploid (c = 4):
Depending on whether the organism is a 'true' tetraploid or an amphidiploid will determine how long it will take for the population to reach Hardy-Weinberg equilibrium.
The completely generalized formula is the multinomial expansion of :
The Hardy–Weinberg principle may be applied in two ways, either a population is assumed to be in Hardy–Weinberg proportions, in which the genotype frequencies can be calculated, or if the genotype frequencies of all three genotypes are known, they can be tested for deviations that are statistically significant.
Suppose that the phenotypes of AA and Aa are indistinguishable, i.e., there is complete dominance. Assuming that the Hardy–Weinberg principle applies to the population, then can still be calculated from f(aa):
and can be calculated from . And thus an estimate of f(AA) and f(Aa) derived from and respectively. Note however, such a population cannot be tested for equilibrium using the significance tests below because it is assumed a priori.
Testing deviation from the HWP is generally performed using Pearson's chi-squared test, using the observed genotype frequencies obtained from the data and the expected genotype frequencies obtained using the HWP. For systems where there are large numbers of alleles, this may result in data with many empty possible genotypes and low genotype counts, because there are often not enough individuals present in the sample to adequately represent all genotype classes. If this is the case, then the asymptotic assumption of the chi-square distribution, will no longer hold, and it may be necessary to use a form of Fisher's exact test, which requires a computer to solve. More recently a number of MCMC methods of testing for deviations from HWP have been proposed (Guo & Thompson, 1992; Wigginton et al 2005)
These data are from E.B. Ford (1971) on the Scarlet tiger moth, for which the phenotypes of a sample of the population were recorded. Genotype-phenotype distinction is assumed to be negligibly small. The null hypothesis is that the population is in Hardy–Weinberg proportions, and the alternative hypothesis is that the population is not in Hardy–Weinberg proportions.
|Genotype||White-spotted (AA)||Intermediate (Aa)||Little spotting (aa)||Total|
From which allele frequencies can be calculated:
So the Hardy–Weinberg expectation is:
Pearson's chi-square test states:
There is 1 degree of freedom (degrees of freedom for test for Hardy-Weinberg proportions are # phenotypes - # alleles). The 5% significance level for 1 degree of freedom is 3.84, and since the χ² value is less than this, the null hypothesis that the population is in Hardy–Weinberg frequencies is not rejected.
An Example Using one of the examples from Emigh (1980), we can consider the case where n = 100, and p = 0.34. The possible observed heterozygotes and their exact significance level is given in Table 4.
|Number of Heterozygotes||Significance Level|
Unfortunately, you have to create a table like this for every experiment, since the tables are dependent on both n and p.
where the expected value from Hardy–Weinberg equilibrium is given by
For example, for Ford's data above;
For two alleles, the chi square goodness of fit test for Hardy-Weinberg proportions is equivalent to the test for inbreeding, F = 0.
Mendelian genetics were rediscovered in 1900. However, it remained somewhat controversial for several years as it was not then known how it could cause continuous characteristics. Udny Yule (1902) argued against Mendelism because he thought that dominant alleles would increase in the population. The American William E. Castle (1903) showed that without selection, the genotype frequencies would remain stable. Karl Pearson (1903) found one equilibrium position with values of p = q = 0.5. Reginald Punnett, unable to counter Yule's point, introduced the problem to G. H. Hardy, a British mathematician, with whom he played cricket. Hardy was a pure mathematician and held applied mathematics in some contempt; his view of biologists' use of mathematics comes across in his 1908 paper where he describes this as "very simple".
The principle was thus known as Hardy's law in the English-speaking world until Curt Stern (1943) pointed out that it had first been formulated independently in 1908 by the German physician Wilhelm Weinberg (see Crow 1999). Others have tried to associate Castle's name with the Law because of his work in 1903, but it is only rarely seen as the Hardy-Weinberg-Castle Law.
The curved line in the above diagram is the Hardy-Weinberg parabola and represents the state where alleles are in Hardy-Weinberg equilibrium.
It is possible to represent the effects of Natural Selection and its effect on allele frequency on such graphs (e.g. Ineichen & Batschelet 1975) The De Finetti diagram has been developed and used extensively by A.W.F. Edwards in his book Foundations of Mathematical Genetics.
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