2 years, 1 month ago
What makes a mutation dominant?
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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.
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,
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 but one example comes from the ABO locus. The difference between the A and B loci is determined by 7 nucleotide changes which lead to 4 amino acid changes. Probably only one of these changes is responsible for the change in specificity of the enzyme from alpha-3-Nacetyl-D-galactosaminyltransferase (A) to alpha-3-D-galactosyltransferase . There are also many examples from human evolution where 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.
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 we will consider in lecture 10. A typical example of such mutant gene would be a tumour suppressor gene such as retinoblastoma.
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,
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 but one example comes from the ABO locus. The difference between the A and B loci is determined by 7 nucleotide changes which lead to 4 amino acid changes. Probably only one of these changes is responsible for the change in specificity of the enzyme from alpha-3-Nacetyl-D-galactosaminyltransferase (A) to alpha-3-D-galactosyltransferase . There are also many examples from human evolution where 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.
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 we will consider in lecture 10. A typical example of such mutant gene would be a tumour suppressor gene such as retinoblastoma.
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