You should have a working knowledge of the following terms:
Introduction and Goals
Genetics is not an abstract science. You probably can see inheritance patterns in your own family. Usually these patterns relate to ear shape, eye color and hair color, etc. This tutorial will show you how a pedigree analysis can provide insight into the genotype of relatives. You will also look at some of the more common human genetic diseases. By the time you finish this tutorial you should have a basic working knowledge of:
- Pedigree analysis
- Cystic fibrosis
- Huntington's disease
- Sickle-cell disease
- The inheritance of dominant and recessive traits
Mendelian Inheritance in Humans
Mendelian inheritance in humans is difficult to study because humans produce relatively few offspring (as compared to most other species) and they have a generation time of about 20 years. These two factors, not to mention ethical issues, make it impossible to design breeding experiments using humans. Nonetheless, there are few traits that are passed on by Mendelian inheritance (e.g., dimples, freckles, and hairlines).
Our understanding of Mendelian inheritance in humans is based on the analysis of matings that have already occurred (the opposite of planned experiments), a family pedigree. Human pedigrees describe the interrelationships between parents and children, over generations, regarding a specific trait. Mendel's laws of inheritance can be used to analyze the pedigree and genotypes of the individuals in the pedigree.
In order to read family pedigrees, it is important to understand the conventions of pedigrees; as shown on the Pedigree Analysis Web page. After reading and understanding the analysis of pedigrees, close the Mendelian Genetics window and return to this page
Inheritance of Recessive Traits
This figure shows the pattern of inheritance that can be observed for a recessive trait. The half-filled symbols denote carriers (heterozygotes). Note that an individual expressing a recessive trait (homozygous recessive) may not appear every generation, but carriers are still present.
This figure shows the pattern of inheritance for albinism, which typically shows a recessive mode of inheritance in humans. In this pedigree (as with most pedigree charts) heterozygotes are not marked, but you can infer their presence by the pattern of expression. Take a close look at this pedigree and locate the two cousins who marry and have children. Can you see why most societies have taboos regarding the marriage of first cousins?
Figure. The pattern of inheritance for a recessive trait. (Click image to enlarge)
Figure. Pedigree for the recessive albinism trait (Click image to enlarge)
Next we will examine three diseases caused by deleterious recessive alleles: cystic fibrosis, phenylketonuria, and sickle-cell disease. Phenotypically normal parents must both be carriers (heterozygous) in order for the disease to be observed in their offspring. Remember, these are recessively inherited traits; an individual must inherit one allele from each carrier parent to exhibit the phenotype. Each time two carriers conceive a child, there is a 25% chance that the child will exhibit the phenotype, a 50% chance that the child will be a carrier, and a 25% chance that the child will be a non-carrier.
Cystic fibrosis (CF) is one of the most common genetic diseases that affects people of Caucasian ancestry. In a room of 20-30 such persons, approximately one is a carrier. The deleterious allele that causes this disease encodes for a protein that is involved in chloride ion transport; as a result, individuals with homozygous alleles for this gene have extreme problems with salt balance in cells (particularly those cells that line the lungs and intestines). This salt imbalance causes the mucous coating of certain cells to become unusually thick, causing affected individuals to have an extreme buildup of mucous.
How does a salt imbalance lead to thick mucous? The answer lies in understanding osmosis. Affected individuals accumulate salt in their epithelial cells (the cells that line body cavities). As a result, the cells become hypertonic (relative to outside the cell) and water is drawn into the cell. The mucous that lies outside the cell (which normally is relatively thin and watery) becomes thickened. This viscous mucous does not clear as efficiently as does normal mucous. This disease is pleiotropic, and a number of symptoms can result (e.g., lung infections, sterility in males).
Why is this deleterious allele so prevalent if it is so bad? Molecular evolutionary analyses of this allele indicate that it first appeared about 52,000 years ago (about the time when nearby eastern human populations were invading Europe to displace the Neanderthals). The prevalence of this gene in modern populations, along with its age, compels researchers to conclude that there must have been some selective advantage for the heterozygous state. What was this advantage? No one knows for sure. Click here and read a short article entitled "A Silver Lining for Cystic Fibrosis?" that presents one possibility. When you return, consider what could be one reason Cystic Fibrosis may have persisted because of Heterozygotic Advantage (keep this in mind when you take the quiz associated with this tutorial)?
Phenylketonuria (PKU) is not as prevalent as cystic fibrosis. About 1 in 50 persons of Caucasian ancestry carry the defective allele. (1 in 64 persons of Asian ancestry have this allele; write this number down because you may need it to answer a question in the quiz associated with this tutorial. The disease is only observed in individuals that are homozygous for the recessive allele, and the main symptom of PKU is mental retardation. The defective allele encodes for a nonfunctional phenylalanine hydrolase enzyme that normally converts the amino acid phenylalanine to the amino acid tyrosine. Those affected with PKU accumulate high levels of phenylalanine (and/or its metabolites), therefore, they have low levels of tyrosine. The high levels of phenylalanine metabolites affect neuronal development, which leads to mental retardation.
Importantly, the symptoms associated with this disease can be prevented with proper nutrition. Phenylalanine is an amino acid found in many proteins; therefore, patients affected with PKU can escape the disease by strictly limiting themselves to low protein diets. Providing that PKU is detected early (most states require that all newborns be tested), proper nutrition will prevent the disease. There are doctors, lawyers, and teachers who are homozygous for PKU, yet they lead relatively normal lives (albeit with a life-long restricted diet).
PKU is a good example of not only a disease caused by a recessive allele, but also an example of a genetic state whereby the phenotype is strongly affected by the environment - with the proper diet, the phenotype is not expressed.
Sickle-cell disease is one of the most common genetic diseases that affects persons of African ancestry. About 10% of such persons carry the allele for this trait. (In some areas of Africa, upwards of 40% carry the allele.) Individuals that carry homozygous alleles for sickle-cell disease suffer from a number of problems including anemia, pain, fever, and fatigue. The sickle-cell trait affects the hemoglobin molecule found in red blood cells, which is involved in oxygen transport. Left untreated, patients with sickle-cell disease typically die by the age of thirty.
As with cystic fibrosis, the prevalence of the allele in the population suggests that there is some benefit to carrying it in a heterozygous state. Indeed, this is the case. It is known that those individuals with heterozygous alleles are less susceptible to malaria than those with homozygous alleles. It is not surprising then that the highest frequency of this allele is found in areas where malaria is prevalent. This allele is probably the best example of natural selection in humans.
Inheritance of Dominant Traits
Example 1. Wooly hair results from a dominant allele; therefore, individuals that are homozygous dominant (WW) or heterozygous (Ww) have this trait. Individuals that are homozygous recessive (ww) for this gene have normal hair.
Example 2. Brachydactyly - a condition associated with shortness of fingers and toes.
The pedigree examples shown here best fit a dominant pattern of inheritance because:
- The trait does not skip a generation.
- Where one parent is affected, about half of the progeny are affected.
- Sexes are about equally affected.
Figure. Pedigree of Wooly Hair. (Click image to enlarge)
Figure. Pedigree of Brachydactyly. (Click image to enlarge)
Huntingtons Disease (HD) is a hereditary disease that causes progressive damage to the nervous system. It generally develops subtly in a person's thirties or forties (though it can begin any time between childhood and old age). It is characterized by difficulties in three areas: uncontrollable movements, dementia, and psychiatric disturbances. Unlike the previous diseases described, which were caused by recessive alleles, HD is caused by a dominant allele. Most HD sufferers have one copy of the deleterious allele and one normal allele, so each child has a 50% chance of inheriting the disease. As you just read in the description of inheritance of dominant traits, HD does not skip generations.
It is important to note the late onset of this disease. This disease becomes noticeable after the normal child-bearing age. Also, consider that the life expectancy of men in America in the year 1900 was forty-six. Therefore, for much of modern human history (about 100,000-150,000 years) this disease probably was not prevalent because people died of other causes before HD symptoms appeared.
Presented here is a pedigree for wooly hair.
The man at the top of the pedigree has normal hair, so his genotype is ww. His wife has wooly hair, but must be heterozygous (Ww) since three of their six children have normal hair.
A pedigree not only allows a geneticist to understand the past, but it helps to predict the occurrence of a trait in future generations.
Figure. Pedigree of Wooly Hair. (Click image to enlarge)
If a wooly hair grandson marries a normal hair woman and they plan on having three children, the probability that all three children will have wooly hair is 1/8. Since the man is heterozygous (Ww) and the wife is homozygous (ww), each child has a 1/2 probability of inheriting the wooly hair allele (1/2 X 1/2 X 1/2 = 1/8).
This animation will help you check your understanding of pedigree analysis.
The pattern of phenotypic expression can be quite useful in determining the mode of transmission for a given characteristic. In fact, geneticists often study the expression of particular traits in family lineages, or pedigrees, in order to gain insight into the mode of expression for a given character trait. Not only can pedigree analyses provide insight into the mode of transmission, but importantly, they can be used to predict the genotype of particular individuals. This tutorial examined some human genetic diseases, including cystic fibrosis, PKU, and sickle-cell disease. These diseases are found in individuals that are homozygous for the gene, but as you learned, the heterozygous state has a well-documented advantage in the case of the sickle-cell disease and a probable advantage in the case of cystic fibrosis. Moreover, you learned that the phenotype can be affected by the environment; in the case of PKU, a person that is homozygous for the gene can escape the disease with a proper diet.
Not all genetic diseases that behave in a Mendelian fashion behave recessively. Huntington's disease is a degenerative disease of the nervous system. Individuals with either homozygous or heterozygous genotypes develop this disease, ensuring that the defective allele is expressed in all generations as a dominant character trait. Individuals carrying this dominant allele do not begin to show symptoms until late in life (after their child-bearing years), and so, natural selection cannot act directly to affect the frequency of this allele in the population. In other words, through their reproductive years, individuals with this detrimental allele are just as fit (likely to reproduce) as normal individuals.