ince every mutant allele for an autosomal dominant disease is expressed, and by definition a disease is a deleterious phenotype, how do autosomal dominant diseases stay in the population? Shouldn't they be eliminated by natural selection against deleterious phenotypes? There appears to be four phenomena that maintain these deleterious alleles in the population:
- Variable Expressivity
- Late Onset
- High Recurrent Mutation Rate
- Incomplete Penetrance
One example of variable expressivity is Marfan syndrome. Marfan syndrome is an autosomal dominant disease caused by a mutation in collagen formation. It affects about 1/60,000 live births. Symptoms of Marfan syndrome include skeletal, optical, and cardiovascular abnormalities. Skeletal abnormalities include arachnodactyly (long fingers and toes), extreme lengthening of the long bones, scoliosis, rib and sternum abnormalities, among others. Optical abnormalities almost always include ectopia lentis, a dislocation of the lens into the anterior chamber of the eye. Cardiovascular abnormalities may be numerous and include possible dissecting aneurysms, which are largely responsible for the shorter life span of Marfan syndrome patients as a group. Each patient may express all of the symptoms, or only a few. That is variable expressivity. Each patient with the mutant allele for Marfan syndrome expresses at least one of the symptoms, but the physician may have to look closely. Almost all are taller than average, but a lot of non-Marfan individuals are tall. Almost all have long fingers, but so do a lot of non-Marfan persons. Some may be very mildly affected and lead normal lives while others, more severely affected, have a shorter life expectancy. The disease is maintained in the population through recurrent mutations and the matings of less severely affected individuals with normal individuals. The extent of severity of affected does not affect the severity of expression in the next generation, that is, the offspring of mildly affected individuals range from mildly affected to severely affected, with equal probability.
Some autosomal dominant diseases do not express themselves until later in life, well beyond the reproductive years. The individuals who will develop the disease have passed the mutant allele along to their offspring before they themselves know they are affected. In some cases even grandchildren are born before the affected grandparent shows the first signs of the disease. Huntington disease, sometimes called Huntington's Chorea because of the choreic movements expressed as the disease progresses, is a good example of a late onset disease. Age of onset varies from the teens to the late sixties, with a mean age of onset between ages 35 and 45. Nearly 100% of the individuals born with the defective allele will develop the disease by the time they are 70. The disease is progressive with death usually occurring between four and twenty-five years after the first symptoms develop. Emotional changes often are the first symptoms.
At the gene level, it is caused by the expansion of an unstable trinucleotide repeat sequence, CAG, in the coding region of the gene. What is inherited at birth in Huntington disease is a gene with several repeats and the instability that allows somatic recombination and extension. Somatic mutations introduced by the expansion of trinucleotide repeat sequences do not have to occur in coding regions to produce a mutant allele. Other diseases, such as myotonic dystrophy, an autosomal dominant disease where expression is delayed, result from molecular defects at the gene level that are caused by the expansion of unstable trinucleotide sequences. (In the case of myotonic dystrophy the sequence is CTG.) However, this unstable sequence lies in a non-translated region of the gene. In both diseases the size of the inherited expansion correlates to the age of onset or the severity of disease, but is not absolutely predictable on an individual basis. One cannot sequence the gene and precisely predict the age of onset of Huntington disease.
Achondroplasia is one of the major causes of dwarfism. Motor skills may not develop as quickly as their normal siblings, but intelligence is not reduced. It occurs in about 1/10,000 live births.
Like many autosomal dominant diseases, individuals homozygous for the mutant allele do not survive to term. Almost 85% of the cases are the result of new mutations, where both parents have a normal phenotype. The mutation rate for achondroplasia may be as much as 10 times the "normal" mutation rate in humans. This high recurrent mutation is largely responsible for keeping the mutant gene in the population at its present rate. Several other autosomal dominant genetic diseases have high recurrent mutation rates but achondroplasia is probably the best known.
Incomplete penetrance should never be confused with variable expressivity. In diseases with variable expressivity the patient always expresses some of the symptoms of the disease and varies from very mildly affected to very severely affected. In autosomal dominant diseases with incomplete penetrance, the person either expresses the disease phenotype or he/she doesn't. Incomplete penetrance and variable expressivity are phenomena associated only with dominant inheritance, never with recessive inheritance. The following pedigree illustrates incomplete penetrance in a known autosomal dominant disease.
In the above pedigree, there is ample evidence for autosomal dominant inheritance:
Late onset, high recurrent mutation rate, variable expressivity, and incomplete penetrance only occur in autosomal dominant diseases, never in recessive diseases unless there is medical intervention to prevent the development of symptoms in neonatal children.
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