TNBGGA: The No Bullshit Guide to Genetic Analysis

We first consider the conversion of a wildtypeplugin-autotooltip__default plugin-autotooltip_bigWildtype: a reference strain of an organism that scientists operationally define as “normal” to which mutants are compared. Not to be confused with wild organisms. alleleplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. $A$ to an altered alleleplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. $a$ by mutationplugin-autotooltip__default plugin-autotooltip_bigMutation: a change in the DNA of a gene that results in a change of phenotype compared to a reference wildtype allele. See also: mutant.:

μ is the mutationplugin-autotooltip__default plugin-autotooltip_bigMutation: a change in the DNA of a gene that results in a change of phenotype compared to a reference wildtype allele. See also: mutant. rate. Typical mutationplugin-autotooltip__default plugin-autotooltip_bigMutation: a change in the DNA of a gene that results in a change of phenotype compared to a reference wildtype allele. See also: mutant. rates vary from μ = 10^-4 to 10^-8. Thus, in the absence of any other effects, such as selectionplugin-autotooltip__default plugin-autotooltip_bigSelection: There are two distinct but somewhat related definitions for this term:

In model organism research, a selection is a process through which a researcher is attempting to find rare individuals with certain phenotypes and has some way of enriching for the rare individuals by killing off all other individuals that do not match the search criteria. Contrast to a, for any given geneplugin-autotooltip__default plugin-autotooltip_bigGene: read Chapters 02, 03, 04, 05, and 06 for a definition of gene :-) the frequency of mutantplugin-autotooltip__default plugin-autotooltip_bigMutant: an individual that has a different phenotype than wildtype and likely contains one more mutations that cause this difference. allelesplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. will increase a little each generation because of new mutationsplugin-autotooltip__default plugin-autotooltip_bigMutation: a change in the DNA of a gene that results in a change of phenotype compared to a reference wildtype allele. See also: mutant..

Consider the disease phenylketonuria (PKU), which is an autosomalplugin-autotooltip__default plugin-autotooltip_bigAutosome: any chromosome that is not a sex chromosome. recessiveplugin-autotooltip__default plugin-autotooltip_bigRecessive: used to describe an allele, usually in comparison to wildtype. Recessive alleles do not exhibit their phenotype when combined with a wildtype allele. defect for the geneplugin-autotooltip__default plugin-autotooltip_bigGene: read Chapters 02, 03, 04, 05, and 06 for a definition of gene :-) coding for the enzymeplugin-autotooltip__default plugin-autotooltip_bigEnzyme: a macromolecule, usually a protein (but sometimes an RNA), that functions as a catalyst of some kind of biochemical reaction. phenylalanine hydroxylase. The absence of the enzymeplugin-autotooltip__default plugin-autotooltip_bigEnzyme: a macromolecule, usually a protein (but sometimes an RNA), that functions as a catalyst of some kind of biochemical reaction. prevents phenylalanine from being metabolized causing unusually high levels of phenylalanine in the body leading to severe mental retardation.

Let's say that the alleleplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. frequency for mutantplugin-autotooltip__default plugin-autotooltip_bigMutant: an individual that has a different phenotype than wildtype and likely contains one more mutations that cause this difference. PKU allelesplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. is $q$ and the alleleplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. frequency for wildtypeplugin-autotooltip__default plugin-autotooltip_bigWildtype: a reference strain of an organism that scientists operationally define as “normal” to which mutants are compared. Not to be confused with wild organisms. allelesplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. is $p$. Let's also say that the mutationplugin-autotooltip__default plugin-autotooltip_bigMutation: a change in the DNA of a gene that results in a change of phenotype compared to a reference wildtype allele. See also: mutant. rate for PKU is μ = 10^-4. As $q$ increases, the frequency of individuals with PKU ($q^2$) will also slowly increase with each generation. When $q$ gets high enough, selectionplugin-autotooltip__default plugin-autotooltip_bigSelection: There are two distinct but somewhat related definitions for this term:

In model organism research, a selection is a process through which a researcher is attempting to find rare individuals with certain phenotypes and has some way of enriching for the rare individuals by killing off all other individuals that do not match the search criteria. Contrast to a against homozygotesplugin-autotooltip__default plugin-autotooltip_bigHomozygous: a state for a diploid organism wherein the two alleles for a gene are identical to each other. will counterbalance the formation of new mutationsplugin-autotooltip__default plugin-autotooltip_bigMutation: a change in the DNA of a gene that results in a change of phenotype compared to a reference wildtype allele. See also: mutant. and $q$ will stay constant. In order to treat selectionplugin-autotooltip__default plugin-autotooltip_bigSelection: There are two distinct but somewhat related definitions for this term:

In model organism research, a selection is a process through which a researcher is attempting to find rare individuals with certain phenotypes and has some way of enriching for the rare individuals by killing off all other individuals that do not match the search criteria. Contrast to a quantitatively, we need to introduce two additional concepts called selectiveplugin-autotooltip__default plugin-autotooltip_bigSelection: There are two distinct but somewhat related definitions for this term:

In model organism research, a selection is a process through which a researcher is attempting to find rare individuals with certain phenotypes and has some way of enriching for the rare individuals by killing off all other individuals that do not match the search criteria. Contrast to a disadvantage and fitness.

If a genotypeplugin-autotooltip__default plugin-autotooltip_bigGenotype: the combination of alleles within an organism or strain. When used as a verb, it means to determine the genotype experimentally. has S = 0.75, then fitness = 0.25, meaning that individuals with this genotypeplugin-autotooltip__default plugin-autotooltip_bigGenotype: the combination of alleles within an organism or strain. When used as a verb, it means to determine the genotype experimentally. will reproduce at a rate of only 25% relative to an average individual. Fitness can be thought of as a combination of survival and fertility. Let's put this into the context of the Hardy-Weinberg equilibrium. Recall from Chap. 18 that $f(A/A)=p^2$, $f(A/a)=2pq$, and $f(a/a)=q^2$.

We use the symbol $\Delta q_{sel}$ to mean “the change in $q$ due to selectionplugin-autotooltip__default plugin-autotooltip_bigSelection: There are two distinct but somewhat related definitions for this term:

In model organism research, a selection is a process through which a researcher is attempting to find rare individuals with certain phenotypes and has some way of enriching for the rare individuals by killing off all other individuals that do not match the search criteria. Contrast to a”; from Table 1 we see that $\Delta q_{sel}=-Sq^2$. When the change in alleleplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. frequency caused by mutationplugin-autotooltip__default plugin-autotooltip_bigMutation: a change in the DNA of a gene that results in a change of phenotype compared to a reference wildtype allele. See also: mutant. μ is balanced out by the change in alleleplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. frequency by selectionplugin-autotooltip__default plugin-autotooltip_bigSelection: There are two distinct but somewhat related definitions for this term:

In model organism research, a selection is a process through which a researcher is attempting to find rare individuals with certain phenotypes and has some way of enriching for the rare individuals by killing off all other individuals that do not match the search criteria. Contrast to a ($-Sq^2$), we say the alleleplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. frequency is in a steady state. Mathematically, we say that $\Delta q_{sel}+\mu=-Sq^2+\mu=0$. From this, we can solve for $q$:

For PKU, $q^2 = 10^{-4}$, so $q=10^{-2}$. Also, since PKU is fairly severe, in the pre-modern medicine age of human evolution $S \approx 1$ (that is, just about everyone who had PKU died before they could reproduce). Therefore, based on Fig. 2 the estimated value of μ is about 10^-4. The actual mutationplugin-autotooltip__default plugin-autotooltip_bigMutation: a change in the DNA of a gene that results in a change of phenotype compared to a reference wildtype allele. See also: mutant. frequency is probably not this high – and the relatively high $q$ for PKU is probably due to a founderplugin-autotooltip__default plugin-autotooltip_bigFounder: when making genetically modified organisms, a founder is an individual from the first generation of organisms that are expected to carry the desired genetic modification in the germline, such that the genetic modification has the potential to be passed down to offspring. effect in the European population or due to a balanced polymorphism (see below).

In modern times PKU can be treated by a low-phenylalanine diet; this means that in modern times $S << 1$ (or, you could say that $S \approx 0). In this case, $\Delta q_{sel} = -Sq^2 \approx 0$ as well, and the main thing that will alter allele frequency would be the mutation rate μ. This suggests that the frequency of PKU mutant alleles should start to rise at a rate of $\mu = 10^{-4}$ per generation. Thus, $q$ will only increase by about a factor of 0.01% per generation. It will take a long time for this change in environment to have a significant effect on disease frequency.

Now let’s determine the steady state alleleplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. frequency for a dominantplugin-autotooltip__default plugin-autotooltip_bigDominant: used to describe an allele, usually in comparison to wildtype. Dominant alleles will express their phenotype when combined with a wildtype allele. disease with alleleplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. frequency $q = f(A)$. In contrast to the situation for recessiveplugin-autotooltip__default plugin-autotooltip_bigRecessive: used to describe an allele, usually in comparison to wildtype. Recessive alleles do not exhibit their phenotype when combined with a wildtype allele. allelesplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence., selectionplugin-autotooltip__default plugin-autotooltip_bigSelection: There are two distinct but somewhat related definitions for this term:

In model organism research, a selection is a process through which a researcher is attempting to find rare individuals with certain phenotypes and has some way of enriching for the rare individuals by killing off all other individuals that do not match the search criteria. Contrast to a will operate against heterozygotesplugin-autotooltip__default plugin-autotooltip_bigHeterozygous: a state for a diploid organism wherein the two alleles for a gene are different from each other. for dominantplugin-autotooltip__default plugin-autotooltip_bigDominant: used to describe an allele, usually in comparison to wildtype. Dominant alleles will express their phenotype when combined with a wildtype allele. allelesplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence.. For rare dominantplugin-autotooltip__default plugin-autotooltip_bigDominant: used to describe an allele, usually in comparison to wildtype. Dominant alleles will express their phenotype when combined with a wildtype allele. traits, almost all affected individuals area heterozygotesplugin-autotooltip__default plugin-autotooltip_bigHeterozygous: a state for a diploid organism wherein the two alleles for a gene are different from each other.; that is, $f(A/A)$ is very small. Therefore, while formally $q=f(A/A)+\frac{1}{2}f(A/a)$, we can approximate $q$ by saying that $q \approx \frac{1}{2}f(A/a)$. Let's look at how $S$ and $(1-S)$ affect $q$:

After selectionplugin-autotooltip__default plugin-autotooltip_bigSelection: There are two distinct but somewhat related definitions for this term:

In model organism research, a selection is a process through which a researcher is attempting to find rare individuals with certain phenotypes and has some way of enriching for the rare individuals by killing off all other individuals that do not match the search criteria. Contrast to a, $2Sq$ heterozygotesplugin-autotooltip__default plugin-autotooltip_bigHeterozygous: a state for a diploid organism wherein the two alleles for a gene are different from each other. are lost each generation but only half of their allelesplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. are the dominantplugin-autotooltip__default plugin-autotooltip_bigDominant: used to describe an allele, usually in comparison to wildtype. Dominant alleles will express their phenotype when combined with a wildtype allele. disease allale $A$. Therefore:

Similar to what we discussed above for recessiveplugin-autotooltip__default plugin-autotooltip_bigRecessive: used to describe an allele, usually in comparison to wildtype. Recessive alleles do not exhibit their phenotype when combined with a wildtype allele. mutationsplugin-autotooltip__default plugin-autotooltip_bigMutation: a change in the DNA of a gene that results in a change of phenotype compared to a reference wildtype allele. See also: mutant., in the steady state $\Delta q_{sel}+\mu=0$, except that here $\Delta q_{sel}=-Sq$ for dominantplugin-autotooltip__default plugin-autotooltip_bigDominant: used to describe an allele, usually in comparison to wildtype. Dominant alleles will express their phenotype when combined with a wildtype allele. mutationsplugin-autotooltip__default plugin-autotooltip_bigMutation: a change in the DNA of a gene that results in a change of phenotype compared to a reference wildtype allele. See also: mutant.. As before, we can solve for $q$:

For $S=1$, $q=\mu$. In other words, for dominantplugin-autotooltip__default plugin-autotooltip_bigDominant: used to describe an allele, usually in comparison to wildtype. Dominant alleles will express their phenotype when combined with a wildtype allele. mutationsplugin-autotooltip__default plugin-autotooltip_bigMutation: a change in the DNA of a gene that results in a change of phenotype compared to a reference wildtype allele. See also: mutant. with fitness=0, the only instances of the disease will be due to new mutationsplugin-autotooltip__default plugin-autotooltip_bigMutation: a change in the DNA of a gene that results in a change of phenotype compared to a reference wildtype allele. See also: mutant.. This makes sense, because dominantplugin-autotooltip__default plugin-autotooltip_bigDominant: used to describe an allele, usually in comparison to wildtype. Dominant alleles will express their phenotype when combined with a wildtype allele. mutantplugin-autotooltip__default plugin-autotooltip_bigMutant: an individual that has a different phenotype than wildtype and likely contains one more mutations that cause this difference. allelesplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. with 0 fitness (cannot survive or reproduce) cannot be passed from one generation to the next. In this case, the number of affected individuals will be $2pq \approx 2q = 2\mu$. Any dominantplugin-autotooltip__default plugin-autotooltip_bigDominant: used to describe an allele, usually in comparison to wildtype. Dominant alleles will express their phenotype when combined with a wildtype allele. mutationplugin-autotooltip__default plugin-autotooltip_bigMutation: a change in the DNA of a gene that results in a change of phenotype compared to a reference wildtype allele. See also: mutant. that results in embryonic or early postnatal lethality would be an example of this. Another example would be a dominantplugin-autotooltip__default plugin-autotooltip_bigDominant: used to describe an allele, usually in comparison to wildtype. Dominant alleles will express their phenotype when combined with a wildtype allele. mutationplugin-autotooltip__default plugin-autotooltip_bigMutation: a change in the DNA of a gene that results in a change of phenotype compared to a reference wildtype allele. See also: mutant. that results in sterility.

When $S<1$, the frequency of mutantplugin-autotooltip__default plugin-autotooltip_bigMutant: an individual that has a different phenotype than wildtype and likely contains one more mutations that cause this difference. allelesplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. $q$ can get quite high (this makes sense mathematically; look at Fig. xx). A good example of this is Huntington's disease, which is caused by dominantplugin-autotooltip__default plugin-autotooltip_bigDominant: used to describe an allele, usually in comparison to wildtype. Dominant alleles will express their phenotype when combined with a wildtype allele. mutationsplugin-autotooltip__default plugin-autotooltip_bigMutation: a change in the DNA of a gene that results in a change of phenotype compared to a reference wildtype allele. See also: mutant. in $Htn$, the geneplugin-autotooltip__default plugin-autotooltip_bigGene: read Chapters 02, 03, 04, 05, and 06 for a definition of gene :-) that codes for the Huntingtin proteinplugin-autotooltip__default plugin-autotooltip_bigProtein: a molecule that is formed by the translation of messenger RNAs (mRNAs). Functions that proteins provide are what usually give organisms their phenotypes.. This devastating disease causes late onset neuromuscular degeneration starting at around 36 years of age, eventually leading to death. This obviously is terrible for anyone that is unfortunate enough to be a carrier, but since the disease doesn't manifest until later in life it doesn't decrease reproductive fitness much.

For the final example of a balance between mutationplugin-autotooltip__default plugin-autotooltip_bigMutation: a change in the DNA of a gene that results in a change of phenotype compared to a reference wildtype allele. See also: mutant. and selectionplugin-autotooltip__default plugin-autotooltip_bigSelection: There are two distinct but somewhat related definitions for this term:

In model organism research, a selection is a process through which a researcher is attempting to find rare individuals with certain phenotypes and has some way of enriching for the rare individuals by killing off all other individuals that do not match the search criteria. Contrast to a, consider an X-linkedplugin-autotooltip__default plugin-autotooltip_bigLinkage: two loci are linked to each other if they are less than 50 m.u. apart. Two loci are unlinked if they are either (1) greater than 50 m.u. apart on the same chromosome, or; (2) are on separate chromosomes. recessiveplugin-autotooltip__default plugin-autotooltip_bigRecessive: used to describe an allele, usually in comparison to wildtype. Recessive alleles do not exhibit their phenotype when combined with a wildtype allele. disease alleleplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. with frequency $q = f(a)$. For rare allelesplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. the vast majority of affected individuals who are operated on by selectionplugin-autotooltip__default plugin-autotooltip_bigSelection: There are two distinct but somewhat related definitions for this term:

In model organism research, a selection is a process through which a researcher is attempting to find rare individuals with certain phenotypes and has some way of enriching for the rare individuals by killing off all other individuals that do not match the search criteria. Contrast to a are males, and new mutationsplugin-autotooltip__default plugin-autotooltip_bigMutation: a change in the DNA of a gene that results in a change of phenotype compared to a reference wildtype allele. See also: mutant. will increase the alleleplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. frequency (i.e., $\Delta q_{mut} \approx \mu$).

In a population with an equal number of males and females, $\frac{1}{3}$ of the X chromosomesplugin-autotooltip__default plugin-autotooltip_bigChromosome: a structure that organizes dsDNA in a cell through interactions with various DNA binding proteins. will be in males. Therefore:

$$\begin{aligned}\Delta q_{sel}&=\frac{1}{3}[\Delta f(X^aY)]\\&=\frac{1}{3}(-Sq)\\&=\frac{-sQ}{3}\end{aligned}$$

As before, in the steady state $\Delta q_{sel}+\mu = \frac{-Sq}{3}+\mu=0$. We can therefore solve for $q$:

When $S=1$ (i.e., when fitness=0), $q=3\mu$. In other words, exactly one-third of the disease allelesplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. in a population will be new mutationsplugin-autotooltip__default plugin-autotooltip_bigMutation: a change in the DNA of a gene that results in a change of phenotype compared to a reference wildtype allele. See also: mutant.. This relationship has been demonstrated for at least two debilitating X-linkedplugin-autotooltip__default plugin-autotooltip_bigLinkage: two loci are linked to each other if they are less than 50 m.u. apart. Two loci are unlinked if they are either (1) greater than 50 m.u. apart on the same chromosome, or; (2) are on separate chromosomes. diseases: hemophilia A and Duchenne muscular dystrophy.

Finally, we will consider a situation in which an alleleplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. is deleterious in the homozygousplugin-autotooltip__default plugin-autotooltip_bigHomozygous: a state for a diploid organism wherein the two alleles for a gene are identical to each other. state but is beneficial in the heterozygousplugin-autotooltip__default plugin-autotooltip_bigHeterozygous: a state for a diploid organism wherein the two alleles for a gene are different from each other. state. The steady state value of $q$ will be set by a balance between selectionplugin-autotooltip__default plugin-autotooltip_bigSelection: There are two distinct but somewhat related definitions for this term:

In model organism research, a selection is a process through which a researcher is attempting to find rare individuals with certain phenotypes and has some way of enriching for the rare individuals by killing off all other individuals that do not match the search criteria. Contrast to a for the heterozygoteplugin-autotooltip__default plugin-autotooltip_bigHeterozygous: a state for a diploid organism wherein the two alleles for a gene are different from each other. and selectionplugin-autotooltip__default plugin-autotooltip_bigSelection: There are two distinct but somewhat related definitions for this term:

In model organism research, a selection is a process through which a researcher is attempting to find rare individuals with certain phenotypes and has some way of enriching for the rare individuals by killing off all other individuals that do not match the search criteria. Contrast to a against the homozygoteplugin-autotooltip__default plugin-autotooltip_bigHomozygous: a state for a diploid organism wherein the two alleles for a gene are identical to each other.. We will need a new parameter, $h$ (the heterozygoteplugin-autotooltip__default plugin-autotooltip_bigHeterozygous: a state for a diploid organism wherein the two alleles for a gene are different from each other. advantage), that represents the increased reproductive fitness of heterozygoteplugin-autotooltip__default plugin-autotooltip_bigHeterozygous: a state for a diploid organism wherein the two alleles for a gene are different from each other. over an average individual.

As before when considering dominantplugin-autotooltip__default plugin-autotooltip_bigDominant: used to describe an allele, usually in comparison to wildtype. Dominant alleles will express their phenotype when combined with a wildtype allele. mutationsplugin-autotooltip__default plugin-autotooltip_bigMutation: a change in the DNA of a gene that results in a change of phenotype compared to a reference wildtype allele. See also: mutant., when we calculate $\Delta q_{sel}$ we have to halve the change in frequency for heterozygotesplugin-autotooltip__default plugin-autotooltip_bigHeterozygous: a state for a diploid organism wherein the two alleles for a gene are different from each other., since only half the allelesplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. of heterozygotesplugin-autotooltip__default plugin-autotooltip_bigHeterozygous: a state for a diploid organism wherein the two alleles for a gene are different from each other. are mutantplugin-autotooltip__default plugin-autotooltip_bigMutant: an individual that has a different phenotype than wildtype and likely contains one more mutations that cause this difference..

$$\begin{aligned}\Delta q_{sel} &=\Delta f(a/a)+\frac{1}{2}\Delta f(A/a)\\ &=-Sq^2+\frac{1}{2}(2hq)\\ &=-Sq^2+hq \end{aligned}$$

When $S=1$, then $\Delta q=0$ when $q^2=hq$, or in other words, when $h=q$.

The possibility of a subtle selectionplugin-autotooltip__default plugin-autotooltip_bigSelection: There are two distinct but somewhat related definitions for this term:

In model organism research, a selection is a process through which a researcher is attempting to find rare individuals with certain phenotypes and has some way of enriching for the rare individuals by killing off all other individuals that do not match the search criteria. Contrast to a for (or against) the heterozygoteplugin-autotooltip__default plugin-autotooltip_bigHeterozygous: a state for a diploid organism wherein the two alleles for a gene are different from each other. for an alleleplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. that appears to be recessiveplugin-autotooltip__default plugin-autotooltip_bigRecessive: used to describe an allele, usually in comparison to wildtype. Recessive alleles do not exhibit their phenotype when combined with a wildtype allele. means that in practice the estimates of μ from alleleplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. frequencies are quite unreliable. For example, let's assume that $q= 10^{-2}$. This could mean $\mu = 10^{-4}$ and $h = 0$, or it could mean $\mu < 10^{-4}$ and $h = 10^{-2}$. Since a 1% increase in heterozygoteplugin-autotooltip__default plugin-autotooltip_bigHeterozygous: a state for a diploid organism wherein the two alleles for a gene are different from each other. advantage would be essentially unmeasurable we wouldn't be able to distinguish these possibilities.

The best understood case of balanced polymorphism is sickle-cell anemia. The alleleplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. of hemoglobin known as β_S^H is recessiveplugin-autotooltip__default plugin-autotooltip_bigRecessive: used to describe an allele, usually in comparison to wildtype. Recessive alleles do not exhibit their phenotype when combined with a wildtype allele. for the disease but is dominantplugin-autotooltip__default plugin-autotooltip_bigDominant: used to describe an allele, usually in comparison to wildtype. Dominant alleles will express their phenotype when combined with a wildtype allele. for malarial resistance. β_S^H is most prevalent in a number of different equatorial populations where malaria is common: sub-Saharan Africa, the Mediterranean, and Southeast Asia. In parts of Africa the frequency of the disease can be as high as ~2.6 %, which means that in these populations $q= 0.16$.

During human history sickle cell disease would almost certainly be fatal ($S \approx 1$) and therefore $h$ must have been about 0.16. This indicates that during evolution the reproductive advantage for an β_S^H heterozygoteplugin-autotooltip__default plugin-autotooltip_bigHeterozygous: a state for a diploid organism wherein the two alleles for a gene are different from each other. was 16%. Many of the most prevalent genetic diseases are suspected to be at a relatively high frequency because of balanced polymorphism.

A second example of balanced polymorphism is cystic fibrosis, a disease caused by autosomalplugin-autotooltip__default plugin-autotooltip_bigAutosome: any chromosome that is not a sex chromosome. recessiveplugin-autotooltip__default plugin-autotooltip_bigRecessive: used to describe an allele, usually in comparison to wildtype. Recessive alleles do not exhibit their phenotype when combined with a wildtype allele. mutationsplugin-autotooltip__default plugin-autotooltip_bigMutation: a change in the DNA of a gene that results in a change of phenotype compared to a reference wildtype allele. See also: mutant. in the $CFTR$ geneplugin-autotooltip__default plugin-autotooltip_bigGene: read Chapters 02, 03, 04, 05, and 06 for a definition of gene :-) (cystic fibrosis transmembrane conductance regulator). Mutantsplugin-autotooltip__default plugin-autotooltip_bigMutant: an individual that has a different phenotype than wildtype and likely contains one more mutations that cause this difference. disrupt Cl^– transport, leading to disturbed osmotic balance across in epithelial cell layers of the lungs and intestine. The incidence in European populations is approx. 0.0025; therefore, $q=\sqrt{0.0025}=0.05$. This is a pretty high frequency! This is probably not due to either high mutationplugin-autotooltip__default plugin-autotooltip_bigMutation: a change in the DNA of a gene that results in a change of phenotype compared to a reference wildtype allele. See also: mutant. frequency or founderplugin-autotooltip__default plugin-autotooltip_bigFounder: when making genetically modified organisms, a founder is an individual from the first generation of organisms that are expected to carry the desired genetic modification in the germline, such that the genetic modification has the potential to be passed down to offspring. effect (many different $CTFR$ disease allelesplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. have been found although 70% are the ΔF508 alleleplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence.). Scientists believe that heterozygotesplugin-autotooltip__default plugin-autotooltip_bigHeterozygous: a state for a diploid organism wherein the two alleles for a gene are different from each other. may be more resistant to bacterialplugin-autotooltip__default plugin-autotooltip_bigBacteria: Single-celled organisms that also utilize DNA and the standard genetic code as all organisms on earth, but unlike eukaryotes do not have intracellular membranes and membrane-bound organelles. In this book we use bacteria and prokaryote interchangeably. infections that cause diarrhea such as typhoid or cholera and that this selectionplugin-autotooltip__default plugin-autotooltip_bigSelection: There are two distinct but somewhat related definitions for this term:

In model organism research, a selection is a process through which a researcher is attempting to find rare individuals with certain phenotypes and has some way of enriching for the rare individuals by killing off all other individuals that do not match the search criteria. Contrast to a was imposed in densely populated European cities.

A third example of balanced polymorphism involve lysosomal storage disorders caused by several different autosomalplugin-autotooltip__default plugin-autotooltip_bigAutosome: any chromosome that is not a sex chromosome. recessiveplugin-autotooltip__default plugin-autotooltip_bigRecessive: used to describe an allele, usually in comparison to wildtype. Recessive alleles do not exhibit their phenotype when combined with a wildtype allele. mutationsplugin-autotooltip__default plugin-autotooltip_bigMutation: a change in the DNA of a gene that results in a change of phenotype compared to a reference wildtype allele. See also: mutant.:

All three enzymesplugin-autotooltip__default plugin-autotooltip_bigEnzyme: a macromolecule, usually a protein (but sometimes an RNA), that functions as a catalyst of some kind of biochemical reaction. are involved in the breakdown of glycolipids in the lysosome. When these enzymesplugin-autotooltip__default plugin-autotooltip_bigEnzyme: a macromolecule, usually a protein (but sometimes an RNA), that functions as a catalyst of some kind of biochemical reaction. are defective in individuals homozygousplugin-autotooltip__default plugin-autotooltip_bigHomozygous: a state for a diploid organism wherein the two alleles for a gene are identical to each other. for the disease alleleplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence., excessive quantities of glycolipids build up in cells and can have pathological effects. In particular all three diseases are characterized by mental retardation because of excess glycolipids accumulating in neurons.

All three diseases are ~100x more common in Ashkenazi Jewish populations than in the general population. This group arrived in central Europe in 9th century AD and is currently distributed among the United States, Israel, and the former Soviet Union. One hypothesis that may partially explain why Tay-Sachs alleleplugin-autotooltip__default plugin-autotooltip_bigAllele: a version of a gene. Alleles of a gene are different if they have differences in their DNA sequence. frequency is so high is that heterozygotesplugin-autotooltip__default plugin-autotooltip_bigHeterozygous: a state for a diploid organism wherein the two alleles for a gene are different from each other. may have resistance to tuberculosis, and that Jewish people living in European ghettos around the time of World War 2 may have been under selectionplugin-autotooltip__default plugin-autotooltip_bigSelection: There are two distinct but somewhat related definitions for this term:

In model organism research, a selection is a process through which a researcher is attempting to find rare individuals with certain phenotypes and has some way of enriching for the rare individuals by killing off all other individuals that do not match the search criteria. Contrast to a, although other explanations (such as founderplugin-autotooltip__default plugin-autotooltip_bigFounder: when making genetically modified organisms, a founder is an individual from the first generation of organisms that are expected to carry the desired genetic modification in the germline, such that the genetic modification has the potential to be passed down to offspring. effect) may also be relevant.