6.17–6.18: Deviations from the normal chromosome number lead to problems.

Karyotype displaying the chromosome pairs of a normal human male.

Reproduction becomes riskier for women as they become older. Increasingly, their gametes contain incorrect numbers of chromosomes or chromosomes that have been damaged (FIGURE 6-34). These problems can lead to effects on the offspring that range from minor to fatal.

Figure 6.34: Reproduction risks and maternal age. Down syndrome incidence increases as the age of the mother increases.

To find out whether their offspring may have a disorder associated with incorrect numbers of chromosomes, parents can request a quick test for some common genetic problems even before their baby is born. This information is available from an analysis of an individual’s karyotype, a visual display of the complete set of chromosomes. A karyotype can be made for adults or children, but it is most commonly done for a fetus. A karyotype is a useful diagnostic tool because it can be prepared very early in the fetus’s development to assess whether it has an abnormality in the number of chromosomes or in their structure. And because the test shows all of the chromosomes, even the sex chromosomes, it also reveals the sex of the fetus.

Preparing a karyotype takes five steps. (1) Some cells must be obtained from the individual. (2) The cells are then encouraged to divide by culturing them in a test tube with nutrients. (3) After a few days to two weeks of cell division, the cells are treated with a chemical that stops them exactly midway through cell division—a time when the chromosomes are coiled thickly and are more visible than usual. (4) The cells are then placed on a microscope slide, and a stain is added that binds to the chromosomes, making them more easily visible. (5) Finally, the chromosomes are arranged by size and shape and displayed on a monitor (FIGURE 6-35).

Figure 6.35: A human karyotype. A visual display of a complete set of chromosomes.

The first step—obtaining cells to prepare the karyotype—is relatively easy in an adult or child. Usually, cells are collected from a small blood sample (red blood cells do not have a nucleus or chromosomes, but white blood cells do). Collecting cells from a fetus, on the other hand, poses a special problem. Two different methods for collecting cells have been developed.

1. Amniocentesis. This procedure can be done approximately three to four months into a pregnancy (FIGURE 6-36). In one quick motion (and without the use of anesthetic), a 3- to 4-inch needle is pushed through the abdomen, through the amniotic sac, and into the amniotic fluid that surrounds and protects the fetus. Using ultrasound for guidance, the doctor aims for a small pocket of fluid as far as possible from the fetus and withdraws about 2 tablespoons of fluid. This fluid contains many cells from the fetus, which can then be used for karyotype analysis. Any chromosomal abnormalities in the fetus will be present in these cells—and many of them can be seen in the karyotype.

Figure 6.36: Amniocentesis. Fluid surrounding a fetus (and containing some of its cells) is extracted and analyzed to determine the genetic composition of the developing fetus.

2. Chorionic villus sampling (CVS). In this procedure, rather than sampling cells from the amniotic fluid, a small bit of tissue is removed from the placenta, the temporary organ that allows the transfer of gases, nutrients, and waste products between a mother and fetus. A needle is inserted either through the abdomen or through the vagina and cervix, again using ultrasound for guidance. Then a small piece of the finger-like projections from the placenta is removed by the syringe. Because much of the placenta develops from the fertilized egg, much of the placenta consists of cells with the same genetic composition as the embryo. The chief advantage of CVS over amniocentesis is that it can be done several weeks earlier in the pregnancy, usually between the 10th and 12th weeks.

Figure 6.37: Trisomy 21. An extra copy of chromosome 21 causes Down syndrome.

Figure 6.38: An error during meiosis produces gametes with too many or too few chromosomes.

The resulting karyotype, whether from amniocentesis or CVS, will reveal whether the fetus carries an extra copy of any of the chromosomes or lacks a copy of one or more chromosomes. Of all the chromosomal disorders detected by karyotyping, Down syndrome is the most commonly observed. Named after John Langdon Down, the doctor who first described it, in 1866, the syndrome is revealed by the presence of an extra copy of chromosome 21 (FIGURE 6-37). (For this reason, the condition that causes Down syndrome is also called “trisomy 21.”) Striking about 1 in every 1,000 children born, Down syndrome is characterized by a suite of physical and mental characteristics that includes learning disabilities, a flat facial profile, heart defects, and increased susceptibility to respiratory difficulties.

Down syndrome and other disorders caused by a missing chromosome or an extra copy of a chromosome are a consequence of nondisjunction, the unequal distribution of chromosomes during meiosis. Nondisjunction can occur at two different points in meiosis: homologues can fail to separate during meiosis I, or sister chromatids can fail to separate during meiosis II (FIGURE 6-38). In both cases, nondisjunction results in an egg or sperm with zero or two copies of a chromosome rather than a single copy. Any of the chromosomes can fail to separate during cell division, but the ramifications of trisomy (having an extra copy of one chromosome in every cell) are greater for chromosomes with larger numbers of genes.

When trisomy occurs for chromosomes with greater numbers of genes, the likelihood that the developing embryo will survive to birth is reduced. Consequently, we tend to see cases of trisomy that involve only the chromosomes with the fewest genes, such as chromosomes 13, 15, 18, 21, and 22. In fact, observations show that trisomy 1 is never seen (all such fertilized eggs die before implantation in the uterus), trisomy 13 occurs in 1 in 20,000 newborns (and most die soon after birth), while trisomy 21, as we’ve seen, occurs in 1 in 1,000 newborns (many of whom live long lives).

As we mentioned at the beginning of this section, as women become older there are increased problems associated with reproduction. Older women, for example, have more babies with Down syndrome. Why does the risk of having a baby with Down syndrome or some other disorder that results from trisomy increase with increasing age for women, but significantly less so for men? As women age, their gametes tend to have more errors. The reason is that those eggs began meiosis near the time the woman was born, and they may not complete it until she is 40 or more years old. During those decades, the cells may develop problems—including a reduction in the size and stability of the spindle fibers and reduced cohesion between sister chromatids—that interfere with normal cell division. In men, the cells that undergo meiosis are relatively young because new sperm-producing cells are produced every couple of weeks after puberty.

Whereas lacking a non-sex chromosome or having an extra chromosome usually has serious consequences for health, we’ll see in the next section that lacking or having an extra X or Y chromosome has consequences that are much less severe.