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05 疾病的单基因遗传 Monogenic Inheritance. single-gene disorder or monogenic disorder
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single-gene disorderor monogenic disorder Some disorders result when a mutation causes the product of a single gene to be altered or missing. These disorders are inherited in simple patterns similar to or identical with those described by Mendel for certain discrete characteristics in garden peas. Therefore, it’s also called Mendelian diseases.
Basic Pattern of Single Gene Inheritance Autosomal Dominant Autosomal Recessive X-linked Dominant X-linked Recessive Y-linked
1. Pedigree and Proband Humans are unique among organisms in many ways, but one way which is near and dear to a geneticist's heart is that humans are not susceptible to genetic experimentation.
The study of inherited Mendelian traits in humans must rely on observations made while working with individual families.
Classical cross fertilization breeding experiments as performed by Mendel are not allowed in humans! Human geneticists are not allowed to selectively breed for the traits they wish to study!
One of most powerful tools in human genetic studies is pedigree analysis.
pedigree They are graphic representations of a family tree which show the biological relationship of the index case, or proband or propositusto the rest of the individuals. A family tree diagram that shows how a particular genetic trait or disease has been inherited.
When human geneticists first began to publish family studies, they used a variety of symbols and conventions. Now there are agreed upon standards for the construction of pedigrees.
2. autosomal dominant inheritance The pattern of autosomal dominant inheritance is perhaps the easiest type of Mendelian inheritance to recognize in a pedigree. One dose of the mutant gene, one mutant allele, is all that is required for the expression of the phenotype.
There are three reasons why an individual with an autosomal dominant disease should always be considered as being a heterozygote until proven otherwise.
A. The disease is usually rare, with only about 1/10,000 individuals affected as an order of magnitude. Affected individuals are most likely to come from affected by normal matings. The normal parent is homozygous recessive, thus assuring that each product of the mating has at least one normal gene.
B. In the extremely rare instances where two affected individuals have mated, the homozygous affected individuals usually are so severely affected they are not compatible with life. The exceptions are the autosomal dominant diseases caused by the somatic expansion of trinucleotide repeat sequences (e.g., Huntington's disease) that we will study later.
C. The mating of very closely related individuals, the most likely way for two affected individuals to know each other, is forbidden in our society.
With the understanding that almost all affected individuals are heterozygotes, and that in most matings involving a person with an autosomal dominant trait the other partner will be homozygous normal, there are four hallmarks of autosomal dominant inheritance.
There are four hallmarks of autosomal dominant inheritance: (1) Except for new mutations, which are rare in nature and extremely rare on examination pedigrees, and the complexities of incomplete penetrance to be discussed later, every affected individual has an affected biological parent. There is no skipping of generations. (2) Males and females have an equally likely chance of inheriting the mutant allele and being affected. The recurrence risk of each child of an affected parent is 1/2.
(3) Normal siblings of affected individuals do not transmit the trait to their offspring. (4)The defective product of the gene is usually a structural protein, not an enzyme. Structural proteins are usually defective when one of the allelic products is nonfunctional; enzymes usually require both allelic products to be nonfunctional to produce a mutant phenotype.
THE PUNNET SQUARE In 1910, Punnett developed a simple method of depicting the possible genotypes one could get from various matings. We call it the Punnett Square.
Suppose a father is heterozygous for an autosomal dominant gene, with allele D, the mutant dominant allele, and allele d, the recessive normal allele. He can produce two types of gametes, D and d. Suppose also his wife is homozygous normal, having both d alleles. The Punnett Square is constructed as follows:
One gamete comes from each parent to produce the genotype of the offspring. Two out of the four possible combinations are affected; two out of four are normal.
3. AUTOSOMAL RECESSIVE INHERITANCE The first, and most important, thing to remember about autosomal recessive inheritance is that most, if not all, affected individuals have parents with normal phenotypes.
Suppose the disease affects one in ten thousand live births, a good order of magnitude estimate for most autosomal recessive diseases. That would make the heterozygote frequency in the population one in fifty (see population genetics for calculations).
The likelihood of two affected persons mating would be 1/10,000 x 1/10,000 or 1/100,000,000. By chance alone there might be two such matings in the Unites States, but no more than 2. The likelihood of an affected and a heterozygote mating would be 1/10,000 x 1/50 x 2(since either parent could be the affected) or 1/250,000. The likelihood of two heterozygotes (heterozygotes are usually called "carriers") mating is 1/50 x 1/50 or 1/2500, more than 99% of all possible matings.
The Punnett Square for autosomal recessive diseases with an affected child in the family almost always looks like the following:
Where the father and mother are both Dd (dd is the recessive affected individual, Dd the heterozygous carrier individual, and DD the homozygous normal individual). The Punnet Square shows the origin of the famous Mendelian ration of 3/4 normal to 1/4 affected.
For most autosomal recessive diseases, but not all, the heterozygote cannot be distinguished from the normal homozygote. In the normal phenotype categories of offspring in the above Punnett Square (Dd and DD produce the same normal phenotype), please note that two of the three are heterozygotes (carriers); one of the three is homozygous normal.
Within the normal siblings of an affected individual the probability of being a carrier is 2/3.
There are five hallmarks of autosomal recessive inheritance: (1) Males and females are equally likely to be affected. (2) On average, the recurrence risk to the unborn sibling of an affected individual is 1/4. (3) The trait is characteristically found in siblings, not parents of affected or the offspring of affected. (4) Parents of affected children may be related. The rarer the trait in the general population, the more likely a consanguineous mating is involved. (5) The trait may appear as an isolated (sporadic) event in small sibships.
When consanguinity is involved, i.e., matings between related individuals, in the production of an affected child the assignment of probabilities changes, especially in the rarer autosomal recessive diseases.
4. X-LINKED DOMINANT INHERITANCE When an X-linked gene is said to express dominant inheritance, it means that a single dose of the mutant allele will affect the phenotype of the female. A recessive X-linked gene requires two doses of the mutant allele to affect the female phenotype.
Affected father x normal mother. Affected mother x normal father.
The following are the hallmarks of X-linked dominant inheritance: (1)The trait is never passed from father to son. (2)All daughters of an affected male and a normal female are affected. All sons of an affected male and a normal female are normal. (3)Matings of affected females and normal males produce 1/2 the sons affected and 1/2 the daughters affected. (4)Males are usually more severely affected than females. The trait may be lethal in males. (5)In the general population, females are more likely to be affected than males, even if the disease is not lethal in males.
5. X-LINKED RECESSIVE INHERITANCE Everyone has heard of some X-linked recessive disease even though they are, in general, rare. Hemophilia, Duchenne muscular dystrophy, Becker muscular dystrophy, and Lesch-Nyhan syndrome are relatively rare in most populations, but because of advances in molecular genetics they receive attention in the media.
More common traits, such as glucose-6-phosphate dehydrogenase deficience or color blindness, may occur frequently enough in some populations to produce a few affected females. However, their effect on individuals is rarely life threatening and medical intervention is not needed. Pedigree 7 shows one typical inheritance pattern for a rare X-linked recessive disease.
the hallmarks of X-linked recessive inheritance (1) As with any X-linked trait, the disease is never passed from father to son. (2) Males are much more likely to be affected than females. If affected males cannot reproduce, only males will be affected. (3) All affected males in a family are related through their mothers. (4) Trait or disease is typically passed from an affected grandfather, through his carrier daughters, to half of his grandsons.
