Biology
Chapter 8: Cell Division: Meiosis
Lecture
Cell Division: Mitosis
Web Lecture
Chromosomal defects
Chromosomal defects affect an entire chromosome. Entire gene sequences may be missing or duplicated, causing extensive and often fatal genetic change in the developing organism.
Polyploidy is a condition where a pair of chromosomes is duplicated, so that the resulting offspring has a different number of chromosomal pairs from the parent. This condition occurs frequently in plants, but rarely in animals, and among humans is unknown--apparently polyploidy is invariably fatal. The opposite condition, in which an entire chromosome pair is missing, is also unobserved.
However, humans can sometimes develop and reach birth with three copies of a chromosome (a pair and a half). This condition, called trisomy, is only observed in four chromosomes (13, 18, 21, and 22) and in two of these (13, 18), the child always dies within the first year. Trisomy of chromosomes #21 or #22 is not necessarily fatal, however, and results in a condition called Down's syndrome, which occurs about 15 times for every 10000 births. The victims have characteristic facial features, are often susceptible to certain kinds of heart diseases, and are often retarded.
Consider what trisomy means: the carrier has an extra copy of every gene on the #21 chromosome. This includes genes which produce functional proteins and genes which produce regulatory molecules that can control the production of other proteins. It also includes sets of genes which might normally be suppressed or activated at different stages of development. Excessive amounts of a functional gene means that the system gets too much of a good thing. Excessive amounts of a suppressor molecule might mean that less of a functional protein can be made. Excessive amounts of a development-controlling gene may mean that the protein produced doesn't get turned off (or turned on) at the correct stage of cell differentiation. As a result, the victim of trisomy will have a range of problems, which may even vary in severity.
Monosomy in autosomal chromosomes (#1 - #22) is apparently always fatal in humans, since it is never observed in live births.
Sex chromosome defects
When trisomy (three copies) or monosomy (only one copy) affects chromosome #23, the sex chromosome, the effects can be serious but not necessary fatal. In normal males, the chromosomal makeup is XY, one of each sex type. In normal females, the chromosomal makeup is XX, and one of the Xs is mostly inactivated to form a dense chromatin complex called a Barr body. There are four cases of deviation from this pattern which will result in viable humans, however.
| XXY | Male with some male activities suppressed by possession of an inactivated X chromosome. |
| XO | Sterile female: apparently the extra X is required for proper development of the ova. |
| XYY | Tall males, with severe acne. |
| XXX | Normal females with no noticeable problems. |
Single-Gene Defects
Autosomal defects involve mutations in the DNA sequences of specific genes, which may occur through the mutation mechanisms we have discussed earlier (missense, nonsense, and base shift mutations), because transposons have "jumped" into the gene sequence and disrupted it, or because part of the chromosome is missing.
Most autosomal defects are recessive. This means that if the normal allele is R and the defective recessive allele is r, those inheriting an RR or Rr allele set for the gene will be normal, and only those with recessive genes on both chromosomes (rr) will suffer the genetic complications. Autosomal recessive diseases include PKU or phenylketonuria, sickle-cell anemia, cystic fibrosis, and Tay-Sachs disease.
PKU is a serious enzyme deficiency; its victims break down certain enzymes into poisons which can disrupt the development of the neurological system. It can, however, be easily controlled by diet during infancy and early childhood, so most states now require testing at birth.
Sickle-cell anemia is a defect which blocks hemoglobin from dissolving in the cell. Instead, hemoglobin forms crystals which result in crescent or sickle-shaped red blood cells which cannot carry as much oxygen as normal cells and which block the capillaries so that normal blood cells can't flow through easily. Its victims—most of whom are of African descent—usually die in childhood. However, those individuals who are heterozygous for the gene (Rr) have a greater resistance to malaria than those who are homozygous for the healthy allele (RR), so the recessive allele actually is useful.
Cystic fibrosis is widespread in the general Caucasian population--about 1 person in twenty carries the recessive gene, which creates a defective membrane-bound protein gate. In normal humans, the protein passes ions from one side of the cell membrane to the other; but in victims of CF, the gate is effectively closed. The buildup of ions affects the function of the cell; lung and digestive system cells secrete a mucus which provides a haven for bacteria. Without treatment (enzymes to break down the mucus, antibiotics to control infection), the victims die in early infancy. In one of the "success" stories of science in the last decade, however, several pharmaceutical companies and universities combined their research to map and determine the gene involved.
Tay-Sachs causes mental retardation and blindness in its victims, who lack the protein necessary to break down a normal lipid found in the brain. Like sickle-cell anemia, it is generally found in a particular segment of the population--in this case, mostly among those of Eastern European Jewish descent. It is fatal by age five.
While most fatal autosomal defects are recessive (since their victims don't live long enough to reproduce), there are some dominant fatal autosomal defects. The most common is Huntington's disease. Anyone with the defective allele (rr or Rr) will suffer from the disease, which causes loss of muscular coordination, depression, and eventually dementia in its victims, but not until middle age, when they have often married and passed the disease on to their offspring. Genetic research in the United States and Britain has succeeded in identifying the gene responsible for the defect and in finding an easily identified "genetic marker", making it possible to test potential carriers before they have children, or to test the offspring of known carriers.
Sex-linked defects
A number of birth defects or characteristics are linked to genes which reside on the X or Y chromosomes. These include serious problems, like hemophilia, whose victims cannot produce the chemicals necessary to clot their own blood, as well as the inconvenient problem of colorblindness.
The chart below shows the genetic map of Queen Victoria, a female carrying but not displaying hemophilia, and her offspring. Since she married a normal male (non-carrier), her children had a 50-50 chance of receiving one of her dominant hemophilia genes. So some of her sons and daughters were non-carriers; some of her daughters were carriers, but did not display the disease, and one of her sons was afflicted. We will look more closely at inheritance of genetic traits in the next chapter.
Courtesy JM Kimball
Most of the victims of sex-linked defects are males. Only they can inherit a defective Y chromosome, and if they have a defective X chromosome, there is no healthy X chromosome to offset the problem. Females who inherit a defective X chromosome from one parent usually inherit a healthy X chromosome from the other parent, and are less likely to suffer a serious problem as a result.
Genetic testing and Ethical issues
Several methods of genetic testing can be used to identify carriers of defects, giving potential parents the opportunity to decide whether or not to take the chance of engendering children who may suffer from a particular defect. Normally, testing couples is done before a pregnancy begins, so the if the likelihood of passing a genetic defect to offspring is high, the couple may decide to adopt or not to have children.
More controversial is the testing done in early pregnancy. Amniocentesis allows doctors to analyze proteins in the amniotic fluid surrounding the developing child. Chorionic villus sampling (CVS) allows doctors to extract cells from the fetal contribution to the placenta which will be identical to the fetal genetic makeup. Both give doctors enough genetic material to determine the fetal genetic makeup for a number of characteristics; in the case of serious defects, the doctors can then counsel the parents on what to expect. Where it is allowed, the parents may opt to terminate the pregnancy rather than undertake the emotional and financial burden of raising a child with a serious defect.
Many people fear that genetic testing may someday be used to force couples with high risk factors to forego having children, or to force parents to terminate the pregnancy for a child with a known defect. Even if no legal requirements evolve, some people fear that medical insurance companies may require genetic tests before covering a pregnancy and new infant, or refuse payment for the medical costs of treating children with serious genetic defects if the defect was detected and abortion was legally available.
Even defining what a "birth defect" will become a serious problem if genetic testing is widely available for many traits. If insurance companies are required to pay for gene therapy for any deviation from some "normal" gene makeup, even non-fatal, purely cosmetic ones, the cost of providing such therapy may be more than a society can support.
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