Nondisjunction

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Nondisjunction is an occasional mishap of cell division, generally resulting in karyotypes. Ideally, the mitotic spindle distributes chromosomes to daughter cells without error. In nondisjunction, the members of a pair of homologous chromosomes do not move apart properly during meiosis I or sister chromatids fail to separate during meiosis II. In these cases, one gamete receives two of the same type of chromosome and another gamete receives no copy (FIGURE 15.11). The other chromosomes are usually distributed normally. If either of the aberrant gametes unites with a normal one at fertilization, the offspring will have an abnormal chromosome number, known as aneuploidy. If a chromosome is present in triplicate in the fertilized egg (so that the cell has a total of 2n + 1 chromosomes), the aneuploid cell is said to be trisomic for that chromosome. If a chromosome is missing (so that the cell has 2n - 1 chromosomes), the aneuploid cell is monosomic for that chromosome. Mitosis will subsequently transmit the anomaly to all embryonic cells. If the organism survives, it usually has a set of symptoms caused by the abnormal dose of the genes associated with the extra or missing chromosome. Nondisjunction can also occur during mitosis. If such an error takes place early in embryonic development, then the aneuploid condition is passed along by mitosis to a large number of cells and is likely to have a substantial effect on the organism.

Some organisms have more than two complete chromosome sets. The general term for this chromosomal alteration is polyploidy , with the specific terms triploidy (3n ) and tetraploidy (4n ) indicating three or four chromosomal sets, respectively. One way a triploid cell may be produced is by the fertilization of an abnormal diploid egg produced by nondisjunction of all its chromosomes. An example of an accident that would result in tetraploidy is the failure of a 2n zygote to divide after replicating its chromosomes. Subsequent mitosis would then produce a 4n embryo.

Polyploidy is relatively common in the plant kingdom, and we will see in Chapter 24 that the spontaneous origin of polyploid individuals plays an important role in the evolution of plants. In the animal kingdom, polyploid species are much less common, although they are known to occur among the fishes and amphibians. Recently, researchers in Chile have identified the first mammalian candidate for polyploidy, a rodent (Tympanoctomys barrerae ) whose cells seem to be tetraploid (FIGURE 15.12). In general, polyploids are more nearly normal in appearance than aneuploids. One extra (or missing) chromosome apparently disrupts genetic balance more than does an entire extra set of chromosomes.

Alterations of Chromosome Structure

Breakage of a chromosome can lead to four types of changes in chromosome structure. A deletion occurs when a chromosomal fragment lacking a centromere is lost during cell division. The chromosome from which the fragment originated will then be missing certain genes. In some cases, if meiosis is in progress, such a fragment may become attached as an extra segment to a sister chromatid, producing a duplication in the recipient chromosome. (Alternatively, a detached fragment could produce a duplication by attaching to a homologous chromosome, but in that case, the "duplicated" pieces of chromosome might not be identical.) A chromosomal fragment may also reattach to the original chromosome but in the reverse orientation, producing an inversion. A fourth possible result of chromosomal breakage is for the fragment to join a nonhomologous chromosome, a rearrangement called a translocation. FIGURE 15.13 illustrates these different types of structural alterations of chromosomes.

Deletions and duplications are especially likely to occur during meiosis. Homologous (nonsister) chromatids sometimes break and rejoin at "incorrect" places, so that one partner gives up more genes than it receives. The products of such a nonreciprocal crossover are one chromosome with a deletion and one chromosome with a duplication.

A diploid embryo that is homozygous for a large deletion (or has a single X chromosome with a large deletion, in a male) is usually missing a number of essential genes, a condition that is ordinarily lethal. Duplications and translocations also tend to have harmful effects. In reciprocal translocations, in which segments are exchanged between nonhomologous chromosomes, and in inversions, the balance of genes is not abnormal--all genes are present in their normal doses. Nevertheless, inversions and translocations can alter phenotype because a gene’s expression can be influenced by its location among neighboring genes. Human Disorders Due to Chromosomal Alterations

Alterations of chromosome number and structure are associated with a number of serious human disorders. When nondisjunction occurs in meiosis, the result is aneuploidy, an abnormal number of chromosomes in the gamete produced and, later, in the zygote. Although the frequency of aneuploid zygotes may be quite high in humans, most of these chromosomal alterations are so disastrous to development that the embryos are spontaneously (naturally) aborted long before birth. However, some types of aneuploidy appear to upset the genetic balance less than others, with the result that individuals with certain aneuploid conditions can survive to birth and beyond. These individuals have a set of symptoms--a syndrome--characteristic of the type of aneuploidy. Genetic disorders caused by aneuploidy can be diagnosed before birth by fetal testing (p. 265).

One aneuploid condition, Down syndrome, affects approximately one out of every 700 children born in the United States. Down syndrome is usually the result of an extra chromosome 21, so that each body cell has a total of 47 chromosomes (FIGURE 15.14). In chromosomal terms, the cells are trisomic for chromosome 21. Although chromosome 21 is the smallest human chromosome, its trisomy severely alters the individual’s phenotype. Down syndrome includes characteristic facial features, short stature, heart defects, susceptibility to respiratory infection, and mental retardation. Furthermore, individuals with Down syndrome are prone to developing leukemia and Alzheimer’s disease. (It is probably not a coincidence that certain genes associated with the latter two diseases are located on chromosome 21.) Although people with Down syndrome, on average, have a life span shorter than normal, some live to middle age or beyond. Most are sexually underdeveloped and sterile. Most cases of Down syndrome result from nondisjunction during gamete production in one of the parents.

The frequency of Down syndrome correlates with the age of the mother. Down syndrome occurs in 0.04% of children born to women under age 30. The risk climbs to 1.25% for mothers in their early 30s and is even higher for older mothers. Because of this relatively high risk, pregnant women over 35 are candidates for fetal testing to check for trisomy 21 in the embryo. The correlation of Down syndrome with maternal age has not yet been explained. Most cases result from nondisjunction during meiosis I, and recent research suggests the involvement of some age-dependent abnormality in the spindle checkpoint, which delays anaphase until all the kinetochores are attached to the spindle (like the M-phase checkpoint of the mitotic cell cycle; see Chapter 12). Trisomies of other chromosomes also increase in incidence with maternal age, although infants with autosomal trisomies rarely survive for long.

Nondisjunction of sex chromosomes produces a variety of aneuploid conditions in humans. Most of these conditions appear to upset genetic balance less than aneuploid conditions involving autosomes. This may be because the Y chromosome carries relatively few genes and because extra copies of the X chromosome become inactivated as Barr bodies in the somatic cells.

An extra X chromosome in a male, producing XXY, occurs approximately once in every 2,000 live births. People with this disorder, called Klinefelter syndrome, have male sex organs, but the testes are abnormally small and the man is sterile. The syndrome often includes breast enlargement and other feminine body characteristics. The affected individual is usually of normal intelligence. Males with an extra Y chromosome (XYY) are not characterized by any well-defined syndrome, although they tend to be somewhat taller than average. Females with trisomy X (XXX), which occurs once in approximately 1,000 live births, are healthy and cannot be distinguished from XX females except by karyotype. Monosomy X, called Turner syndrome, occurs about once in every 5,000 births and is the only known viable monosomy in humans. Although these X0 individuals are phenotypically female, their sex organs do not mature at adolescence, and they are sterile. However, when provided with estrogen replacement therapy, girls with Turner syndrome do develop secondary sex characteristics. Most have normal intelligence.

Even if chromosome number is normal, structural alterations of chromosomes can cause human disorders. Many deletions in human chromosomes (see FIGURE 15.13a), even in a heterozygous state, cause severe physical and mental problems. One such syndrome is known as cri du chat ("cry of the cat"). A child born with this specific deletion in chromosome 5 is mentally retarded, has a small head with unusual facial features, and has a cry that sounds like the mewing of a distressed cat. Such individuals usually die in infancy or early childhood.

Another type of chromosomal structural alteration associated with human disorders is chromosomal translocation, the attachment of a fragment from one chromosome to another, nonhomologous chromosome (see FIGURE 15.13d). Chromosomal translocations have been implicated in certain cancers, including chronic myelogenous leukemia (CML). Leukemia is a cancer affecting the cells that give rise to white blood cells, and in the cancerous cells of CML patients, a reciprocal translocation has occurred. A portion of chromosome 22 has switched places with a small fragment from a tip of chromosome 9. (How such a switch might cause cancer will be discussed in Chapter 19.)

A small fraction of individuals with Down syndrome have a chromosomal translocation of a different sort. All the cells of such people have the normal number of chromosomes, 46. Close inspection of the karyotype, however, shows the presence of part or all of a third chromosome 21 attached to an other chromosome by translocation. eans 1 copy of each chromosome haploid cell) (2n means 2 copies of each chromosome) diploid cell)

           4n            (duplicated chromosomes in diploid cell)
       /         \       (non-disjunction occurs here)
     3n           1n
   /    \       /    \
n+1     n+1    n-1   n-1   (Two gametes have one extra chromosome and the other 2 
                            are missing a chromosome)

          4n             (duplicated chromosomes in diploid cell)
      /        \
     2n        2nthe 
    /  \    /     \      (non-disjunction occurs here)
   n    n  n+1     n-1   (2 Gametes are normal, but on the right side, one gamete 
                          has an extra chromosome, and the other is missing one)