Mutations are errors in the genotype that create new alleles and can result in a variety of genetic disorders. In order for a mutation to be inherited from one generation to another, it must occur in sex cells, such as eggs and sperm, rather than in somatic cells. The best way to detect whether a genetic disorder exists is to use a karyotype, a photograph of the chromosomes from an individual cell, usually lined up in homologous pairs, according to size.
Autosomal Mutations
Some human genetic illnesses are inherited in a Mendelian fashion. The disease phenotype will have either a clearly dominant or clearly recessive pattern of inheritance, similar to the traits in Mendel’s peas. Such a pattern will usually only occur if the disease is caused by an abnormality in a single gene. The mutations that cause these diseases occur in genes on the autosomal chromosomes, as opposed to sex-linked diseases, which we cover later in this chapter. (Be careful not to confuse autosomal chromosomes with somatic cells; autosomal chromosomes are the chromosomes that determine bodily characteristics and exist in all cells, both sex and somatic.)
Recessive Disorders
A Mendelian genetic illness initially arises as a new mutation that changes a single gene so that it no longer produces a protein that functions normally. Some mutations, however, result in an allele that produces a nonfunctional protein. A disease resulting from this sort of mutation will be inherited in a recessive fashion: the disease phenotype will only appear when both copies of the gene carry the mutation, resulting in a total absence of the necessary protein. If only one copy of the mutated allele is present, the individual is a heterozygous carrier, showing no signs of the disease but able to transmit the disease gene to the next generation. Albinism is an example of a recessive illness, resulting from a mutation in a gene that normally encodes a protein needed for pigment production in the skin and eyes. The pedigree shown below diagrams three generations of a hypothetical family affected by albinism.
The pedigree demonstrates the characteristic features of autosomal recessive inheritance. The parents of an affected individual usually show no signs of disease, but both must at least be heterozygous carriers of the disease gene. Among the offspring of two carriers, 25 percent will have the disease, 50 percent will be carriers, and 25 percent will be noncarriers. No offspring produced by a carrier and a noncarrier will have the disease, but 50 percent will be carriers. Although not shown in this pedigree, offspring produced by two individuals who have the disease in their phenotype, which means both parents are recessive homozygous, will all develop the disease.
Many recessive illnesses occur with much greater frequency in particular racial or ethnic groups that have a history of intermarrying within their own community. For example, Tay-Sachs disease is especially common among people of Eastern European Jewish descent. Other well-known autosomal recessive disorders include sickle-cell anemia and cystic fibrosis.
Dominant Disorders
Usually, a dominant phenotype results from the presence of at least one normal allele producing a protein that functions normally. In the case of a dominant genetic -illness, there is a mutation that results in the production of a protein with an abnormal and harmful action. Only one copy of such an allele is needed to produce disease, because the presence of the normal allele and protein cannot prevent the harmful action of the mutant protein. If a recessive mutation is like a car with an engine that cannot start, a dominant mutation is like a car with an engine that explodes. A spare car will solve the problem in the first case, but will do nothing to protect the garage in the second case.
Huntington’s disease, which killed folksinger Woody Guthrie, is a dominant genetic illness. A single mutant allele produces an abnormal version of the Huntington protein; this abnormal protein accumulates in particular regions of the brain and gradually kills the brain cells. By middle age, this progressive brain damage produces severely disturbed physical movements, loss of intellectual functions, and personality changes. The pedigree shown below diagrams three generations of a hypothetical family with Huntington’s disease.
This pedigree demonstrates the characteristic features of autosomal dominant inheritance. Notice that all affected individuals have at least one parent with the disease. Unlike recessive inheritance, there is no such thing as a carrier: the disease will affect all heterozygous individuals. Among the offspring of an affected heterozygote and an unaffected person, 50 percent will be affected and 50 percent will be unaffected. None of the children born to two unaffected individuals will have the disease. (Although not shown in this pedigree, homozygous dominant mutations often produce very severe cases of the disease, because the amount of the abnormal protein is doubled and the normal protein is entirely absent.)
Chromosomal Disorders
Recessive and dominant characteristics result from the mutation of a single gene. Some genetic disorders result from the gain or loss of an entire chromosome. Normally, paired homologous chromosomes separate from each other during the first division of meiosis. If one pair fails to separate, an event called nondisjunction, then one daughter cell will receive both chromosomes and the other daughter cell will receive none. When one of these gametes joins with a normal gamete from the other parent, the resulting offspring will have either one or three copies of the affected chromosome, rather than the usual two.
A single chromosome contains hundreds to thousands of genes. A zygote with three copies of a chromosome (trisomy), instead of the usual two, generally cannot survive embryonic development. Chromosome 21 is a major exception to this rule; individuals with three copies of this small chromosome (trisomy 21) develop the genetic disorder called Down syndrome. People with Down syndrome show at least mild mental disabilities and have unusual physical features including a flat face, large tongue, and distinctive creases on their palms. They are also at a much greater risk for various health problems such as heart defects and early Alzheimer’s disease.
The absence of one copy of a chromosome (monosomy) causes even more problems than the presence of an extra copy. Only monosomy of the X chromosome (discussed below) is compatible with life.
Polyploidy occurs when a failure occurs during the formation of the gametes during meiosis. The gametes produced in this instance are diploid rather than haploid. If fertilization occurs with these gametes, the offspring receive an entire extra set of chromosomes. In humans, polyploidy is always fatal, though in many plants and fish it is not.
Sex Chromosomes and Sex-Linked Traits
Dominant and recessive illnesses occur with equal frequency in males and females. This is because the genes involved are located on autosomes, which are the same in both genders. Many physical traits, however, obviously do differ between the two genders. In addition, gender dramatically affects the inheritance of certain traits and illnesses that have no obvious connection to sexual characteristics.
These sex-linked traits are controlled by genes located on the sex chromosomes. Humans have 46 chromosomes, including 44 autosomes (nonsex chromosomes) and the two sex chromosomes, which can be either X or Y. The autosomes come in 22 homologous pairs, present in both males and females. Females also possess a homologous pair of X chromosomes, while males have one X chromosome and one Y chromosome (the master gene for “maleness” is located on the Y chromosome). All eggs have an X chromosome, so the sex of a child is determined at the time of fertilization by the type of sperm. If the fertilizing sperm carries an X chromosome, the child will be female; if it carries a Y chromosome, the child will be male. The X chromosome is much larger than the tiny Y chromosome, and most of the genes on the X chromosome do not have a homologous counterpart on the Y.
Genes on autosomes will always be present in two copies: one inherited from the maternal parent, the other from the paternal parent. The traits controlled by such autosomal genes will be generally unaffected by gender and will follow Mendelian patterns of inheritance (with the exceptions noted in previous sections). In contrast, genes on the X chromosome (X-linked genes) are present in two copies in females but only one copy in males. Female offspring will inherit one copy of an X-linked gene from each parent, but male offspring must inherit the Y chromosome from their father and therefore always inherit only the maternal allele of any X-linked gene. For example, color blindness and hemophilia are sex-linked disorders. The mutated gene that causes these disorders is recessive and exists on the X chromosome. In order for a female, who is XX, to have a phenotype that is color blind or hemophiliac, both of her parents have to have the recessive gene. But since males have only one X chromosome inherited from their mother, if their mother expresses the recessive mutation, that trait will automatically be expressed in the male child’s phenotype, since the male has no other gene to assert dominance over the recessive mutation.
The pedigree shown below diagrams three generations of a hypothetical family affected by hemophilia A.
This pedigree demonstrates many of the characteristic features of X-linked recessive inheritance. Heterozygous females are carriers who do not express the disease. In contrast, all males with the mutated allele will express the disease; there are no male carriers. Affected males will transmit the mutated allele to none of their sons but to all of their daughters, who will then all be carriers. Heterozygous females will transmit the disease to one-half of their sons, and one-half of their daughters will be carriers. Affected males generally have an unaffected father and a mother who is a carrier; 50 percent of their maternal uncles will have the disease.
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