Evolutionary Genetics: Pleiotropy

Pleiotropy (from Greek πλείων pleion, “more”, and τρόπος tropos, “way”) occurs when one gene influences two or more seemingly unrelated phenotypic traits. Therefore, a mutation in a pleiotropic gene may have an effect on several traits simultaneously due to the gene coding for a product used by a myriad of cells or different targets that have the same signaling function.

• He originally defined pleiotropy as when “several characteristics are dependent upon it [inheritance]; these characteristics will then always appear together and may thus appear correlated.”

 

An example of pleiotropy is phenylketonuria, which is an inherited disorder that affects the level of phenylalanine in the body.

 

Pleiotropic gene action can limit the rate of multivariate evolution when natural selection, sexual selection or artificial selection on one trait favors one specific version of the gene (allele), while selection on other traits favors a different allele, which shows how evolution is negatively related with pleiotropy in models. Although some of the evolution in genes can be beneficial, some gene evolution is harmful to an organism. Genetic correlations and responses to selection most often exemplify pleiotropy.

 

Retrieved from:

https://en.wikipedia.org/wiki/Pleiotropy#Phenylketonuria_.28PKU.29

 

What Is Pleiotropy?

Occasionally we see genetic mutations in human beings. A mutation is any sort of genetic alteration that causes a change in the phenotype or expression of that gene. Sometimes we see genetic changes and phenotype changes not from a mutation, but from a gene controlling multiple traits. This is called pleiotropy. As stated, pleiotropy is where one gene winds up controlling multiple phenotypic traits in the organism.

Pleiotropy can be found in many different forms, but mainly it is viewed as causing inherited diseases and disorders. What can also occur is that if that gene has a mutation, it ultimately affects all of the phenotype traits that the gene was controlling. This creates a trickle down effect. As the gene gets mutated, so do the traits it would exhibit.

There is a specific type of pleiotropy called antagonistic pleiotropy, where some of the traits that are expressed end up being beneficial to the organism but the others end up being detrimental. The organism will benefit from one of the expressions, but another might harm the organism

Retrieved from:

http://study.com/academy/lesson/pleiotropy-definition-examples.html

Pleiotropy occurs when one gene influences two or more unrelated phenotypic traits. A mutation in a pleiotropic gene may influence several traits due to the gene coding for a product used by many cells or different targets that have the same signaling function. An example of pleiotropy is PKU. The action of a pleiotropic gene is said to limit the rate of multivariate evolution. Knowing that the evolution in genes can be beneficial or harmful to an individual, evolution is said to be negatively related with pleiotropy.

Since the PAH gene affects multiple traits, it is considered pleiotropic. For example, the PAH gene is not only responsible for processing phenylalanine, it is also responsible for the conversion of phenylalanine to tyrosine (an enzyme used to make hormones, chemicals, and melanin). So, as the gene gets mutated, so do the traits it would exhibit.

Overdominant selection (‘‘heterozygote advantage/Heterosis’’)

Founder effects and genetic drift may increase the frequency of recessive mutations, particularly in small or rapidly growing (e.g., prehistoric) populations. However, such chance effects are unlikely to have occurred in the comparatively large populations that have resided in Europe over the last 3,000–5,000 years. Without a mechanism counteracting the constant loss of recessive disease alleles from these peoples, the frequency of PKU would have fallen to a fraction of its current value. To demonstrate this formally, let us assume all disease-causing PAH gene

Founder effects and genetic drift ruled out to explain the frequency of PKU. Drift is typically most significant in small populations. Since large populations resided in Europe over the last 3,000-5,000 years, these chance event are unlikely.

Rule out drift

Despite suggestions to the contrary [Scriver and Kaufman, 2001], at least three different aspects of genetic drift argue against a strong stochastic component in the extant PKU-associated mutational spectrum of the PAH gene.

 

• First, genetic drift would have affected only singular mutant alleles, not a large

number of mutations.

• Second, drift would have been operating in certain populations, but not in all

populations at the same time.

• Finally, drift would have been equally likely to affect PAH gene mutations

causing PKU and mutations in other genes causing other recessive disorders.

The available molecular and epidemiological data corroborate none of these corollaries so that chance events alone cannot convincingly explain the high incidence of PKU in Europe.

 

Overdominant selection (‘‘heterozygote advantage/Heterosis’’)

Overdominant selection thus appears to have played an important role during the history of PKU in European populations, although the exact nature of this effect is still unknown. In any case, its magnitude is likely to have been small because, under balancing selection, the equilibrium disease allele frequency qe is approximately equal to the heterozygous effect h [Gillespie, 1998]. The most likely heterozygote advantage of PKU, therefore, amounts to 1–1.5% and is thus difficult to measure empirically. At the biochemical level, overdominant selection in PKU is probably a consequence of higher phenylalanine levels in heterozygotes than in nonheterozygotes [Woolf et al., 1967]. This elevated amino acid concentration nevertheless must have been advantageous under different climatic conditions and against the back- ground of different diets and social circumstances. A number of possible albeit controversial selective mechanisms have been discussed [Vogel, 1984]. Thus, female carriers of PKU could be shown both to have lower [Woolf et al., 1975; Woolf, 1976, 1978] and higher [Saugstad, 1973; Blyumina, 1974] rates of spontaneous miscarriages than controls. In addition, birth weight in the nonaffected children of PKU carriers has been reported to be increased [Saugstad, 1977], although not consistently so [Smith et al., 1978], when compared to control children. Ochratox- in A, a mycotoxin found in moldy grains and lentils that can induce spontaneous abortions [Dirheimer and Creppy, 1991], has been proposed as a selective agent for PKU [Woolf, 1986]. Furthermore, increased phenylalanine levels caused by protein catabolism at times of starvation [Blyumina, 1981] could have exerted a protective effect in PKU carriers. Although there is currently no evidence supporting this hypothesis, it is certainly possible that overdominant selection in PKU occurred predominantly during periods of epidemics or famine, of which there are many examples in European history.

Heterosis appears to play an important role in European populations. According to the article its magnitudes is likely to have been small and difficult to measure empirically. They suggest that heterosis in PKU is a consequence of higher phenylalanine levels in heterozygotes than in non. This would suggest an elevated AA concentration must have been advantageous under different climatic conditions and against different diets and social circumstances. As stated in the earlier post, female carriers of PKU could be shown to have lower rates of spontaneous miscarriages. Also, this article reported an increase in birth weight of nonaffected children of PKU carriers which would help an infant survive. Finally, increased phenylalanine levels seen with individuals that have PKU could have exerted an protective effect in PKU carriers during periods of epidemics or famine throughout European history.

Retrieved from:

Krawczak, M., & Zschocke, J. (2003). A role for overdominant selection in phenylketonuria? Evidence from molecular data. Human Mutation, 21(4), 394-397.

Differences in various populations (founder effect)

Founder effect definition: event that initiates an allele frequency change in part of the population, which is not typical of the original population.

 

The PKU allele has been suggested to have spread throughout the Orient by a founder effect.

A missense mutation has been identified in the human phenylalanine hydroxylase [PAH; phenylalanine 4-monooxygenase; L-phenylalanine, tetrahydrobiopterin:oxygen oxidoreductase (4-hydroxylating), EC 1.14.16.1] gene in a Chinese patient with classic phenylketonuria (PKU). A G-to-C transition at the second base of codon 413 in exon 12 of the gene results in the substitution of Pro413 for Arg413 in the mutant protein. This mutation (R413P) results in negligible enzymatic activity when expressed in heterologous mammalian cells and is compatible with a classic PKU phenotype in the patient. Population genetic studies reveal that this mutation is tightly linked to restriction fragment length polymorphism haplotype 4, which is the predominant haplotype of the PAH locus in the Oriental population. It accounts for 13.8% of northern Chinese and 27% of Japanese PKU alleles, but it is rare in southern Chinese (2.2%) and is absent in the Caucasian population. The data demonstrate unambiguously that the mutation occurred after racial divergence of Orientals and Caucasians and suggest that the allele has spread throughout the Orient by a founder effect. Previous protein polymorphism studies in eastern Asia have led to the hypothesis that “northern Mongoloids” represented a founding population in Asia. Our results are compatible with this hypothesis in that the PKU mutation might have occurred in northern Mongoloids and subsequently spread to the Chinese and Japanese populations.

Retrieved from:

https://www.ncbi.nlm.nih.gov/pubmed/2006152

Why is PKU still here?

This disease along with others might persist in the human population because it decreases the incidence of abortion which could increase population size over time. Women who are PKU carriers have a much lower than average incidence of miscarriage. Since individuals with PKU have an excess of phenylalanine, it can inactivate a poison called ochratoxin. This toxin is produced by fungi and is known to cause spontaneous abortion. Since PKU is prevalent in Ireland and western Scotland, and affects individuals that trace their roots to this part of the world, these individuals may have protective effects if they are PKU carriers because they are able increase population size over time by having a decreased risk of abortion.

 

Retrieved from:

http://www.pbs.org/wgbh/evolution/educators/course/session7/explain_b_pop1.html

 

 Why PKU has survived the centuries?

•      Heterozygotes acquire an unusual edge in survival

•      Heterozygotes get higher levels of phenylalanine, but not enough to trigger mental deterioration

Epigenetic involement

What is epigenetics and why is it important to PKU?

What is epigenetics?

The primary vehicles for epigenetic changes are DNA methylation and histone modification. DNA methylation involves the addition of a methyl group (containing one carbon atom bonded to three hydrogen atoms) to select positions on the cytosine or adenine nucleotides.  Histones are proteins found in cell nuclei. They are the chief protein components of chromatin, which serves as the spool around which DNA winds. Histone modification — which is also the result of methylation — causes the DNA to either stretch out or contract, which causes changes in protein production during transcription, which, as you will remember from the earlier video, is how specific proteins are spun out from DNA instructions.

Epigenetics changes the way genes express themselves with no changes in the underlying DNA sequence. These changes can pass through cell division after cell division for the remainder of the cell’s life and may also be passed down through multiple generations if the changes take place in a sperm or egg cell. More importantly, unlike genetic changes, which can take thousands of years to be noticed, changes in gene expression can result from a single “stress” event and even be noticed in a matter of days — with profound consequences.

Over time, epigenetic changes can profoundly alter our phenotypes. Experiments with identical twins have shown that everything from what we eat, drink, and smoke to the environmental factors we are exposed to — even to stress itself — can alter the way our genes express themselves up and down the line with a totality that is beyond imagining. And even the supplements you take can quickly change how your genes express themselves and, thus, your susceptibility to many diseases such as cancer.1

 

Make sure your diet contains all nutrients

You want to eat foods that provide the building blocks for methylation in the body — and in the proper balance so that you don’t over folate for example. And speaking of folic acid, beans of all kinds are great natural folate sources. Lentils, pintos, garbanzos, navy beans, and kidney beans top the list with asparagus and the leafy greens such as spinach and turnip greens close behind. Other methylation building blocks include:

• Choline
• Methionine
• B12
• B6
• TMG
• SAMe

Retrieved from:

https://jonbarron.org/article/everything-you-need-know-about-epigenetics

 

Why is this information important to PKU?

In order to fine tune gene expression, it is recommended that individuals eat foods that provide the building blocks for methylation in the body. As mentioned from the website, beans and other protein sources are key to providing the building blocks for methylation in the body. Individuals living with PKU may have a disadvantage to fine tuning gene expression because they must restrict the amount of protein intake in their diet.  

Cellular basis for PKU

Mutations in the human phenylalanine hydroxylase gene producing phenylketonuria or hyperphenylalaninemia have now been identified in many patients from various ethnic groups. These mutations all exhibit a high degree of association with specific restriction fragment-length polymorphism haplotypes at the PAH locus.

• About 50 of these mutations are single-base substitutions, including six nonsense mutations and eight splicing mutations, with the remainder being missense mutations.
• One splicing mutation results in a 3 amino acid in-frame insertion.
• Two or 3 large deletions, 2 single codon deletions, and 2 single base deletions have been found.
• Twelve of the missense mutations apparently result from the methylation and subsequent deamination of highly mutagenic CpG dinucleotides.
• Recurrent mutation has been observed at several of these sites, producing associations with different haplotypes in different populations.
• About half of all missense mutations have been examined by in vitro expression analysis, and a significant correlation has been observed between residual PAH activity and disease phenotype.
  • Since continuing advances in molecular methodologies have dramatically accelerated the rate in which new mutations are being identified and characterized, this register of mutations will be updated periodically.

 

Retrieved from:

https://www.ncbi.nlm.nih.gov/pubmed/1301187

New treatment for PKU

Pegvaliase:

 

Pegvaliase is an investigational study drug that substitutes the PAH enzyme in PKU by breaking down Phe. It is being developed as a potential treatment for adults with inadequately controlled blood Phe levels.

March 21, 2016

BioMarin Phase 3 Study of Pegvaliase for Phenylketonuria (PKU) Meets Primary Endpoint of Blood Phenylalanine (Phe) Reduction (p<0.0001)

– In 8 week Placebo-Controlled Portion No Benefit in Inattention or Mood Scores Were Observed

-Approximately, 60% of Patients Maintained Phe Levels At or Below Medical Guidelines

over Long-Term Extension Study

 

BioMarin announced today that the pivotal Phase 3 PRISM-2 study (formerly referred to as 165-302) of pegvaliase met the primary endpoint of change in blood Phe compared with placebo (p<0.0001) in preliminary results. During the 8 week PRISM-2 double-blind, placebo-controlled, randomized drug discontinuation trial (RDT), 86 patients were randomized to either remain on pegvaliase or receive matching placebo. The pegvaliase treated group maintained mean blood Phe levels at 527.2 umol/L compared to their RDT baseline of 503.9 umol/L, whereas the placebo treated group mean blood Phe levels increased to 1385.7 umol/L compared to their RDT baseline of 536.0 umol/L . (see Table 1) The treatment effect demonstrated in this study represents an approximately 62% improvement in blood Phe compared to placebo.

“A therapy in development that shows such a substantial reduction in Phe levels could mean that for the first time, PKU patients who cannot comply with dietary protein restriction, can achieve targeted blood Phe levels,” said Barbara Burton,

M.D., Professor of Pediatrics-Genetics, Birth Defects and Metabolism at Northwestern School of Medicine and investigator for the pegvaliase Phase 3 program. “This pegvaliase study represents an important advance for PKU adult patients and a potentially meaningful treatment.”

Retrieved from:

https://npkua.org/Portals/0/PDFs/BMRN_News_2016_3_21_General_Releases.pdf?ver=2016-03-21-114035-647

PKU websites

National PKU Alliance

https://npkua.org/

Mission: Improve the lives of individuals associated with PKU and pursue a cure

• Resources: Dx and recipes
• Education: Learning more about the disease
• Research and Action: UTD information and new treatments

 

Genetics Home Reference- Guide to understanding genetic conditions

https://ghr.nlm.nih.gov/condition/phenylketonuria

Video: Living with PKU

Mutations in the PAH gene on chromosome 12q23.2

Gene Structure:

The PAH gene provides instructions for making an enzyme called phenylalanine hydroxylase. This enzyme is responsible for the first step in processing phenylalanine, which is a building block of proteins (an amino acid) obtained through the diet. Phenylalanine is found in all proteins and in some artificial sweeteners.

Phenylalanine hydroxylase is responsible for the conversion of phenylalanine to another amino acid, tyrosine. The enzyme works with a molecule called tetrahydrobiopterin (BH4) to carry out this chemical reaction. Tyrosine is used to make several types of hormones, certain chemicals that transmit signals in the brain (neurotransmitters), and a pigment called melanin, which gives hair and skin their color. Tyrosine can also be broken down into smaller molecules that are used to produce energy.

Retrieved from:

https://ghr.nlm.nih.gov/gene/PAH

The human PAH gene contains 13 exons which encode a polypeptide of 452 amino acids.

Mutations can either be neutral with respect to phenotype, or pathogenic due to their disruption to enzyme structure and function. More than 500 disease-causing mutations have been identified in patients with PKU or HPA and recorded on the mutation database for PAH.²⁵ The human PAH gene shows great allelic variation and pathogenic mutations have been described in all 13 exons of the PAH gene and its flanking region. The mutations can be of various types:²⁵

• missense mutations: 62% of PAH alleles
• small or large deletions: 13%
• splicing defects: 11%
• silent polymorphisms: 6%
• nonsense mutations: 5%
• insertions: 2%

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2423317/