Why are a majority of new mutations recessive?

Answer 1

There are multiple types of effects that result from mutations. The most common effect is a loss of function. Loss of function mutations result in recessive phenotypes (because one good copy of the gene still gives you the phenotype), thus they are recessive alleles. In these cases, usually the recessive gene is the minority.

Some mutations result in gain of function, that is they cause a new protein that causes a new phenotype. Now all you need is a single copy of this mutated gene to get the phenotype, hence it is dominant. In these cases, the dominant allele is the minority (e.g. blood types).

The reason that most mutations are loss of function type (recessive) is because there are many more ways to screw up a gene and/or a protein by mutation then there are to alter or improve its function.

Answer 2

Most mutations are recessive

Why is this? Because most genes code for enzymes. If one gene is inactivated the reduction in the level of activity of the enzyme may not be as much as 50% because the level of transcription of the remaining gene can possibly be up regulated in response to any rise in the concentration of the substrate. Also, the protein itself may be subject to regulation (by phosphorylation for instance) so that its activity can be increased to compensate for any lack of numbers of molecules. In any case, if the enzyme does not control the rate limiting step in the biochemical pathway a reduction in the amount of product may not matter.

In the case of phenylketonuria (PKU) we can see that it is necessary to reduce the enzyme level to below 5% before any effect is apparent in the phenotype. This genetic disease is caused by mutations in the gene coding for the enzyme phenyalanine hydroxylase which converts the amino acid phenylalanine to tryosine. If an individual is homozygous for alleles which completely remove any enzyme activity, phenylalanine cannot be metabolised and it builds up in the circulation to a point where it begins to damage the developing brain. Newborn infants are routinely screened for this condition by the analysis of a tiny drop of blood from a heel prick (Guthrie test). This has revealed that there exist a few people with a condition known as benign hyperphenylalaninemia. These individuals have moderately elevated levels of phenylalanine in their serum. Their phenylalanine hydroxylase enzyme levels are about 5% of normal. Despite this they are apparently perfectly healthy and to not suffer from the brain abnormalities caused by the full blown disease.

What makes a mutation dominant?

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Haploinsufficiency.

In this case, the amount of product from one gene is not enough to do a complete job. Perhaps the enzyme produced is responsible for a rate limiting step in a reaction pathway. Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia leading to telangiectases and arteriovenous malformations of skin, mucosa, and viscera. Death by uncontrollable bleeding occasionally occurs. It is caused by mutation in the gene ENG, which codes for the protein endoglin, a transforming growth factor-beta (TGF-beta) binding protein. Perhaps the TGF-beta is unable to exert sufficient effect on cells when only half the normal amount of receptor is present.
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Dominant negative effect.

The product of the defective gene interferes with the action of the normal allele. This is usually because the protein forms a multimer to be active. One defective component inserted into the multimer can destroy the activity of the whole complex. An example might be Osteogenesis imperfecta, see below
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Gain of function

It is possible to imagine that by mutation a gene might gain a new activity, perhaps an enzyme active site might be altered so that it develops a specificty for a new substrate. That this must be so is self evident, how else could evolution occur? Examples in human genetics of genes with two such different alleles are rare and the only example which I can think of is the A and B alleles of the ABO blood group gene. There are many examples from human evolution however. Many genes have duplicated and subsequently the two duplicates have diverged in their substrate specificities. On chromosome 14 is a little cluster of three related genes, alpha -1-antitrypsin, (AAT), alpha -1-antichymotrypsin, (ACT), and a related gene which has diverged to such an extent that it is probably no longer functional. The structural relationship between AAT and ACT is very obvious and both are protease inhibitors but they now clearly serve slightly different roles because they have different activities against a range of proteases and they are under different regulation.
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Dominance at an organismal level but recessivity at a cellular level.

Some of the best examples of this are to be found in the area of cancer genetics which will be taught later on. Some brief information can be found here. A typical example of such mutant gene would be a tumour suppressor gene such as retinoblastoma.