30 March 2005
Lecture 31
Reading, Chapter 6 and 7
VI. Genes
F. Patterns of inheritance
Gregor Mendel was an Austrian monk who initiated the field of genetics in the latter part of the 19th century by observing the inheritance of traits in peas. He was a great scientist for two reasons. First, he chose to ignore the complex inheritance of traits determined by multiple genes and instead concentrated on the inheritance of traits determined by single genes, for which he could detect understandable patterns. Second, he allowed for some variability in his results, e.g. not expecting perfect ratios of traits resulting from his crosses. The ability to see through complexity and identify underlying principles is a consistent attribute of great scientists.
1. Flower color in peas
Flower color was one of the traits Mendel experimented with in his studies. In Mendel's peas, flower color was either white or purple. If a white-flowered pea plant that had never shown any purple flowers for many generations was crossed with a purple-flowered pea plant that had never shown any white flowers for generations, all the offspring had purple flowers. For this reason, the purple trait was said to be dominant over the white trait, which was said to be recessive. If the purple-flowered offspring were crossed with each other, however, three-quarters of the offspring were purple while one quarter were unexpectedly white.
Now that we understand meiosis, Mendel's results are easy to explain. Pea plants (and most organisms) are diploid, meaning that their nuclei contain two sets of chromosomes. Thus, there are two versions of every gene, including the one for flower color. These two versions are called alleles, for example a pea plant would have one allele for flower color from its male parent and a second allele for flower color from its female parent. The allele that confers purple flower color may be designated A. It codes for a protein that participates in synthesis of the purple pigment anthocyanin. The allele that confers white flower color may be designated a. It codes for a protein that would participate in synthesis of anthocyanin but it is defective, perhaps because of a mutation. The first cross described above was between a purple-flowered plant with two A alleles (AA) and a white-flowered plant with two a alleles (aa). Gametes produced by these parent plants are haploid and therefore possess only one of the two possible allele types. In this case, all gametes from the purple parent possessed the A allele while all gametes from the white parent possessed the a allele.
The offspring of this cross, which result from fusion of gametes, all possess one A allele and one a allele (Aa). The a allele does not contribute to anthocyanin synthesis but the A allele does. For this reason, all offspring from this cross are purple and the purple trait is said to be dominant over the white trait.
The Aa generation will produce gametes possessing either A or a, half of each. The possible allele combinations in their offspring are AA, Aa, aA, and aa. The aa combination has no gene for anthocyanin synthesis, will have white flowers, and will represent about 1/4 of the offspring. The others will be purple, since all have at least one gene for anthocyanin synthesis.
2. Sickle cell disease
Before going further with simple genetics, let's define some terms:
allele - one of two versions of a particular gene that is present in a diploid organism. Only one of these two was present in each of the gametes that gave rise to the organism.
dominant allele - an allele that always produces a trait.
recessive allele - an allele that only produces a trait if the dominant allele for the trait is absent.
heterozygous - an individual that has two different alleles for a trait, for example Aa.
homozygous - an individual that has two alleles for a trait that are the same, for example aa or AA.
A number of human diseases, generally referred to as genetic diseases, are the result of unusual or non-functional alleles for important genes. These provide some of the best illustrations of human genetics because controlled breeding experiments are difficult to apply to human subjects. Sickle cell disease results from a base substitution in a gene that codes for the hemoglobin protein of red blood cells. The mutant protein sticks together in rod-like structures when it is not binding oxygen. The rod-like structures deform the red blood cells into an abnormal sickle shape that can clog small blood vessels and is attacked by macrophages. The health effects of this make sickle cell disease fatal before age 30, in most cases.
Let's designate the gene for normal hemoglobin as HbA and the gene for sickling hemoglobin Hba. If a person having two normal hemoglobin alleles (HbA HbA, homozygous) has children with a person having two sickling alleles (Hba Hba, also homozygous), all their children will be heterozygous for this trait (HbA Hba). These children will not have sickle cell disease because the HbA allele makes enough normal hemoglobin that sickling does not normally occur, even though the Hba allele and some sickling hemoglobin are present.
If two people that are heterozygous for sickle cell disease (HbA Hba) have children, the possible combinations of their alleles are HbA HbA , HbA Hba , Hba HbA , and Hba Hba. The last homozygous combination will confer sickle cell disease but the others will not. Thus, children of two heterozygotes have a 1 in 4 chance of inheriting sickle cell disease.
Sickle cell disease is relatively common for a single-gene genetic disease with serious health consequences. About 1 in 500 African Americans suffer from this disease. In parts of Africa, up to a third of black Africans are heterozygous for sickle cell disease. A hypothesis that attempts to explain the relatively high frequency of the sickle cell allele in these African populations is that heterozygous individuals show tolerance of the malaria parasite, which is common in the same parts of Africa. The malaria parasite hides from the human immune system by living inside red blood cells. When inside the red blood cells of a sickle cell heterozygote (HbA Hba), the parasite causes the cells to sickle, perhaps by consuming oxygen and driving it down to abnormally low levels in the cell. The sickled cells with parasites inside are attacked and consumed by phagocytes, negating the attempt of the parasite to hide from the immune system. Individuals who are homozygous for normal hemoglobin (HbA HbA) do not have this resistance to malaria and are thus less adapted to life in malaria-prone regions. The advantage conferred by the sickle cell allele (Hba) in heterozygotes offsets the disadvantage that a fourth of their offspring will die from sickle cell disease, if they have children with another sickle cell heterozygote.
3. Huntington's disease
Huntington's disease is a condition in which nerve death accelerates after age 40 and is fatal in about 15 years. It is caused by a mutation in a single gene and it is a dominant trait, perhaps because the mutation causes the gene to inappropriately produce a protein that promotes cell death in nerves.
Let's designate the Huntington's allele as H and the normal allele as h. If a heterozygous person with Huntington's disease (Hh) has children with a person who does not have Huntington's disease, half their children will be Hh and suffer from the disease.
Ordinarily, a dominant allele that kills half the offspring of an individual would be selected against in a population and disappear over time. In the case of Huntington's disease, however, it is not fatal until after human reproductive age so it does not experience selection in the usual way. Huntington's disease also illustrates the usefulness of genetic testing. If an individual has an incidence of the disease in their family, they can have their gene sequences examined for the mutation so that they can make appropriate plans for having or not having children. Such genetic tests would also allow early application of therapies that might delay onset of the disease.
4. Blood types
We have so far discussed unusual cases in which a single gene governs a trait. Study of such traits allowed Mendel and others to begin to understand what genes were. Most traits are governed by multiple genes and their inheritance is much more complex. To illustrate this, we will examine the slightly more complicated case of blood types.
Blood types are governed by a handful of genes. For example, whether you are type O, A, B, or AB is governed by a gene we will call I. I has three alleles: IA, IB, and i. The IA allele codes for an A type recognition protein found on the surfaces of red blood cells. The IB allele codes for a B type recognition protein found on the surfaces of red blood cells. The i allele is defective for some reason and does not produce a recognition protein of this type at all. As you would predict, i is recessive. IA and IB are dominant and exhibit "co-dominance", meaning that if an individual has the IA and IB alleles for I, their blood cells will have both A and B type recognitions proteins. The following table shows how these alleles combine to produce the O, A, B, and AB blood types.
Phenotype
Genotype
Antibodies
Type O blood
Type A blood
or
IA, i
Type B blood
IB, i
Type AB blood
If an individual lacks A or B proteins on their red blood cells, they will have an immune response to any blood cells that have them. Thus, type A blood will have an immune response to types B and AB blood. Type B blood will have an immune response to type A and AB blood. Type O blood will have an immune response to types A, B, and AB blood. Finally, type AB blood will not have an immune response to any of these blood types. Immune responses to transfused blood can be fatal so compatible blood must be used for transfusions. Persons with type O blood have been called "universal donors" because they can give blood to anyone but can receive only type O blood. Persons with AB blood have been called "universal recipients" because they can receive blood of all these types but can give only to another AB individual.
Other genes govern other blood proteins that can also be important to transfusions and other medical procedures. One of these is a group of genes for the "Rh factor", another recognition protein of red blood cells. About 85% of the US population is Rh positive, meaning that their blood cells carry one of several forms of the Rh recognition protein. Others are Rh negative, meaning that their cells lack the Rh recognition protein (their Rh allele is recessive, not producing a protein). If an Rh negative woman becomes pregnant by an Rh positive man, there is a 50% chance that the fetus will be Rh positive if the father is a heterozygote and a 100% chance the fetus will be Rh positive if the father is a homozygote. During this pregnancy, Rh cells from the fetus can leak into the mother's circulatory system and trigger an immune response. The response is too slow to damage the fetus but subsequent Rh positive fetuses can be attacked by antibodies in the mother's blood that pass through the placenta to the fetus (antibodies to A and B proteins can't pass the placenta so A and B blood incompatibilities are not a problem). When a man and woman have an Rh incompatibility, later pregnancies can be protected if the mother receives medication to modify her immune response to the Rh factor around the time of delivery.
A final note. In addition to A, B, and Rh, other blood proteins can make blood from two individuals incompatible. If time allows, an individual to recieve a transfusion should always be tested for compatibility with the blood to be used.