TNBGGA: The No Bullshit Guide to Genetic Analysis

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chapter_19

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chapter_19 [2024/09/10 07:59] – [Example of the effect of selection on sex-linked mutations] mikechapter_19 [2024/09/18 17:52] (current) – [Cystic fibrosis] mike
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 |  $A/A$  |  $p^2$  |  $p^2$  |  0  | |  $A/A$  |  $p^2$  |  $p^2$  |  0  |
 |  $A/a$  |  $2pq$  |  $2pq$  |  0  | |  $A/a$  |  $2pq$  |  $2pq$  |  0  |
-|  $a/a$  |  $q^2$  |  $q^2(1-s)$  |  $q^2(1-S)-q^2 = -Sq^2$  |+|  $a/a$  |  $q^2$  |  $q^2(1-S)$  |  $q^2(1-S)-q^2 = -Sq^2$  |
 </columns> </columns>
 <caption> <caption>
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 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. {{ref>Fig2}} the estimated value of μ is about 10<sup>-4</sup>. The actual mutation frequency is probably not this high – and the relatively high $q$ for PKU is probably due to a founder effect in the European population or due to a balanced polymorphism (see below). 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. {{ref>Fig2}} the estimated value of μ is about 10<sup>-4</sup>. The actual mutation frequency is probably not this high – and the relatively high $q$ for PKU is probably due to a founder 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 $S < 1$. 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 1% per generation. It will take a long time for this change in environment to have a significant effect on disease frequency. +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. 
  
-===== Example of the effect of selection on dominant mutations:Huntington's disease =====+===== Example of the effect of selection on dominant mutations: Huntington's disease =====
  
 Now let’s determine the steady state allele frequency for a dominant disease with allele frequency $q = f(A)$. In contrast to the situation for recessive alleles, selection will operate against heterozygotes for dominant alleles. For rare dominant traits, almost all affected individuals area heterozygotes; 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 $q$: Now let’s determine the steady state allele frequency for a dominant disease with allele frequency $q = f(A)$. In contrast to the situation for recessive alleles, selection will operate against heterozygotes for dominant alleles. For rare dominant traits, almost all affected individuals area heterozygotes; 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 $q$:
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 ==== Cystic fibrosis ==== ==== Cystic fibrosis ====
  
-A second example of balanced polymorphism is cystic fibrosis, a disease caused by autosomal recessive mutations in the $CFTR$ gene (__c__ystic __f__ibrosis __t__ransmembrane conductance __r__egulator). Mutants disrupt Cl<sup>–</sup> 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 mutation frequency or founder effect (many different $CTFR$ disease alleles have been found although 70% are the ΔF508 allele). Scientists believe that heterozygotes may be more resistant to bacterial infections that cause diarrhea such as typhoid or cholera and that this selection was imposed in densely populated European cities.+A second example of balanced polymorphism is cystic fibrosis, a disease caused by autosomal recessive mutations in the $CFTR$ gene (__c__ystic __f__ibrosis __t__ransmembrane conductance __r__egulator). Mutations in $CTFR$ disrupt Cl<sup>–</sup> 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 mutation frequency or founder effect (many different $CTFR$ disease alleles have been found although 70% are the ΔF508 allele). Scientists believe that heterozygotes may be more resistant to bacterial infections that cause diarrhea such as typhoid or cholera and that this selection was imposed in densely populated European cities.
  
 ==== Lysosomal storage disorders ==== ==== Lysosomal storage disorders ====
chapter_19.1725980396.txt.gz · Last modified: 2024/09/10 07:59 by mike