As in any human genetic system, the alleles that cause genetic diseases are inherited in a dominant or recessive pattern, and are carried on autosomes or on sex chromosomes (see Chap ter 10). In addition, some human diseases are caused by more extensive chromosomal abnormalities (see Chapter 9). Different inheritance patterns can be seen when genetic diseases are followed over several human generations.
autosomal recessive pattern. PKU, sickle-cell anemia, and cystic fibrosis are all caused by autosomal recessive mutant alleles. Typically, both parents of an affected person are carriers (normal phenotype, heterozygous genotype). Each time they conceive a child, the parents have a 25 percent (one in four) chance of having an affected (homozygous) son or daughter. Because of this low probability and the fact that many families in Western societies now have fewer than four children, it is unusual for more than one child in a family to have an autosomal recessive disease.
In the cells of a person who is homozygous for an autosomal recessive mutant allele, only the nonfunctional, mutant version of the protein it encodes is made. Thus a biochemical pathway or important cell function is disrupted, and disease results. As expected, heterozygotes, with one normal and one mutant allele, often have 50 percent of the normal level of functional protein. For example, people who are heterozygous for the PKU allele have half as many active molecules of phenylalanine hydroxylase in their liver cells as individuals who carry two normal alleles for this enzyme. But by one mechanism or another, this 50 percent suffices for relatively normal cellular function.
AUTOSOMAL DOMINANT PATTERN. Familial hypercholes-terolemia is caused by an abnormal autosomal dominant allele. In this case, the presence of only one mutant allele is enough to produce the clinical phenotype. In people who are heterozygous for familial hypercholesterolemia, having half the normal number of functional receptors for low-density lipoprotein on the surface of liver cells is simply not enough to clear cholesterol from the blood. In autosomal dominance, direct transmission from an affected parent to offspring is the rule.
X-LINKED RECESSIVE PATTERN. Hemophilia is an X-linked recessive condition; that is, the gene locus responsible is on the X chromosome. Thus, a son who inherits a mutant allele on the X chromosome from his mother will have the disease, because his Y chromosome does not contain a normal allele. However, a daughter who inherits one mutant allele will be an unaffected heterozygous carrier, since she has two X chromosomes, and hence two alleles. Because, until recently, few males with these diseases lived to reproduce, the most common pattern of inheritance has been from carrier mother to son, and all rare X-linked diseases are much more common in males than in females.
chromosomal abnormalities. Chromosomal abnormalities also cause human diseases. Such abnormalities include an excess or loss of one or more chromosomes (aneu-ploidy), loss of a piece of a chromosome (deletions), and the transfer of a piece of one chromosome to another chromosome (translocations). About one newborn in 200 is born with a chromosomal abnormality. While some of these abnormalities are inherited, many are the result of meiotic events such as nondisjunction (see Chapter 9).
Many zygotes that have chromosomal abnormalities do not survive development and are spontaneously aborted. Of the 20 percent of pregnancies that are spontaneously aborted during the first 3 months of human development, an estimated half of them have chromosomal abnormalities. For example, few human zygotes with only one X chromosome and no Y survive beyond the fourth month of pregnancy.
One common cause of mental retardation is fragile-X syndrome (Figure 17.5). About one male in 1,500 and one female in 2,000 are affected. These people have a constriction near the tip of the X chromosome that tends to break during preparation for microscopy, giving the name for this syndrome. Although the basic pattern of inheritance is that of an X-linked recessive trait, there are departures from this pattern. Not all people with the fragile-X chromosomal abnormality are mentally retarded, and we will describe the reason for this variation later in the chapter.
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