April 22, 2008

Genes and Dominance

Posted in Genetics tagged , , , , , , at 10:45 am by D. Borst

Why are some genes recessive?

So in genetics class, we learn that Mendel began the study of genetics with his study of peas. One of the notions that he developed was that of Dominant and Recessive genes. But in this age of molecular genetics, what does it mean to be dominant or recessive?

Further inquires into the topic have also led to more controversy. Some genes are “incompletely dominant” and some share “codominance.” Mendel’s Law of independent assortment turned out to not be entirely true. Some traits seemed to be inherited only from the mother.

On the other hand, the discovery that we have a diploid genotype provided a very obvious explanation for the presence of two alleles of a gene, and the nature of meiosis explains why alleles separate during the production of gametes. Today I want to focus on what factors, from a molecular biology standpoint, produce genes that act recessive and dominant. The key is the level of expression.

The ABO blood group may be the most common example used to exemplify how molecular biology can underly the dominance and recession patterns that we see in phenotypes. In this system, there are three different versions of the allele: Ia, Ib and i. Ia and Ib are both dominant to i, and Ia and Ib express codominance. Thus a heterozygous mother with type A blood ( Iai) blood who has children with a heterozygous man who has type B glood (Ibi) blood may produce children with bood types A , AB, B or O.

This this is readily explained looking at the genes that underlie the ABO blood system. Underlying the ABO blood system is part of the antigen system that the body uses to distinguish self from not self. A sequence of carbohydrates called H antigen is ligated to cell membranes in the golgi apparatus. How it is processed there determines what type of bood someone will have. Individuals with the gene for Ia, weather they have one or two copies of the gene will express a protein which will append a N-acetyl gucosamine residue to the H antigen. In individuals with the gene for Ib blood, there is a homologous protein that varies in that it ligates a galactose to the H factor. Those with the gene for i blood have a gene that has suffered a frameshift mutation, making the protein expressed nonfunctional.

This is nicely demonstrated below in an image from wikimedia commons.
Thank you InvictaHOG

Image produced by InvictaHOG for Wikimedia.

The different proteins expressed dont interact In any way to regulate one another–if you have the protein to append galactose to H antigen then you will get B type antigens, and if you have the protein to apend N-acetyl glucosamine, you will get A type antigens. However since these proteins that append sugars onto H antigen are generally not operating at capacity, if you have the defective protein (the one created by the i genotype) and one of the others, you wont get any H antigens exposed, you will only get the other type of antigen. One copy of the gene for one of the effective antigens is enough to make all the H antigens into A or B antigens. Furthermore, presence of both Ib and Ia means that both A and B antigens will be expressed.

Thus the ABO system is clearly explained using molecular genetics. However, the prevalence of this example has led to an inappropriate assumption about recessive genes, that at their core, recessive genes are always the result of some gene that creates a defective protein. This is far from true.

To more thoroughly explore the genesis of recessive phenotypes, let us review the cannon of molecular biology. The cannon states that genes are transcribed into mRNA, which is then translated into proteins. Proteins then go and do the work, which may be to regulate transcription of DNA sequences, build structures, or any number of other effects. At any one of these steps, expression levels of the gene can be regulated.

For instance, the degree of expression of a gene can be controlled via the promoters that proceed a gene. These promoters call sigma factors which cause RNA polymerase to bind to the DNA and transcribe the gene sequence. Over expression of one allele compared with another would be one way one allele could be dominant over another, especially if the two products of the allele share a common substrate that is scarce. It is likely that except in cases of massive preferential expression this will only lead to incomplete dominance instead of classic Mendelian dominance, but it is possible.

Using the same mechanism, but through different means, one allele may directly or indirectly cause the repression of the other allele’s expression, either to modification of the promoters expressed, direct binding of the other gene, or modification of the sequence with covalently bonded groups. These methods would be expected to produce more complete dominance than simply differing levels of expression. Processes such as these may create complex dominance and recessivity patterns where dominance is not transitive, i.e. if gene A is dominant of B and gene B over C, C is not necessarily recessive to A.

As such, each gene may express a fully functional protein but in the presence of the other be effectively silenced. However there are other points in the process at which an allele can be made recessive. Once a DNA is transcribed into mRNA it must be translated into proteins to generate its effect (that is assuming that proteins are the ultimate effectors of phenotype, this is not actually true: many enzymatic portions of RNA have been found now, however the same concepts apply). Some mRNA’s are translated many times into proteins, some are translated only a few times before they are degraded. The signals upon the RNA strand that determine this, and the stability of the molecule itself plays into this. While this is a different point of expressional control, its effects are similar to what has already been discussed, so I will not go into it further.

Once translated, proteins undergo further modification. These modifications can alter the activity level of enzymes. This difference in activity levels can also affect dominance: Presence of two genes results in the expression of two proteins, A and L (where L is a protein which dephosphorylates A, causing a massive increase in activity) may result in dominance of al over b.

Remember, dominance and recessivity is a intellectual construct that biologists use to describe relationships between alleles and phenotypes. Any way in which the production of a phenotype can be altered is a point at which one allele may change to become dominant over another. The recessive O allele of the ABO blood group is only one instance of how recessivity can occur.

Review

So remember:

  • Alleles are represented in the genome by the copies of a gene present on chromosomes from the mother and father.

  • In the ABO blood group system, alleles for A and B type blood are codominant, and both are dominant to the O allele. The O allele is recessive because it is a nonfunctional version of the A and B alleles.

  • Recessive Alleles are not always nonfunctional.

  • At many different stages genes can differ to produce dominance and recession.

  • Differential levels of expression, wether caused by the nature of the allele itself or the effect of the alleles on each other can affect dominance, as can differing levels of mRNA translation and degredation of both the mRNA and the protein.

  • Post translational modifications such as glycoslyation and phosphorylization play a large role in affecting the activity levels of different proteins and can affect dominance.

  • While dominance patterns as put forth by Mendel are useful, they are ultimately constructs that do not fully describe the complexity of interactions between copies of the same gene. The details of the entire process from transcription to activity affects phenotypic outcomes.

  • The environment in which the gene is being expressed can change dominance effects, temporarily or permanently.

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2 Comments »

  1. waheeda said,

    it is a very good information for me since i take genetic course this semester.tq very much

  2. 1kGood idea.6v I compleatly agree with last post. eri
    паркет 4y


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