Introduction and Learning Objectives
Genetics is not an abstract science. You 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 genotypes of relatives based upon the phenotypes observed. 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
- Identify the symbols used in a pedigree analysis
- Illustrate different patterns of inheritance seen in humans using specific genes (cystic fibrosis, PKU, sickle cell anemia, Huntington’s)
Mendelian Inheritance in Humans
Mendelian inheritance in humans is difficult to study because humans produce relatively few offspring (as compared to many 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. There are many characters in humans that show a Mendelian pattern of inheritance. This web page, the OMIM (Online Mendelian Inheritance in Man - http://www.omim.org/ ) is a catalog of these characters. You can search for a particular character (for example, dimples) to read what is know about its inheritance.
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
Figure 1 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. The term carrier is used because while a heterozygous individual carries a particular allele in its genotype, it does not express it in its phenotype. These is seen when two traits have a complete dominance relationship (one is completely dominant of the other).
Figure 1. Recessive trait. The pattern of inheritance for a recessive trait. (Click image to enlarge)
Figure 2 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 the affected individuals. Take a close look at this pedigree and locate the two cousins who marry and have children. Can you see why many societies have taboos regarding the marriage of first cousins? For more on the biological basis of cultural norms, check out this article on incest taboos.
Figure 2. Pedigree showing the occurrence of albinism in a family (carriers are not indicated in this pedigree). (Click image to enlarge)
Patterns of Inheritance for Three Human Genetic Disorders
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 occur 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 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 show 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 which line body cavities. As a result, the cells become hypertonic, with more dissolved solutes inside the cell than outside the cell, so 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 normal mucous. Cystic fibrosis is pleiotropic, and a number of symptoms can result (e.g., lung infections, sterility in males).
To avoid lung infections, many treatments have been developed to either reduce sputum viscosity or help dislodge it from the lungs. These include various aerosolized drugs, as well as various mechanical methods. In the past, physical therapists would manually pound the patient’s chest to help dislodge sputum; now there are special vests which use air pressure to produce the same effect. Click here to view a video from the manufacturer detailing how these vests work: http://www.thevest.com/airway-clearance/.
Why is this harmful 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, suggests that there probably was some selective advantage for the heterozygous state. What was this advantage? No one knows for sure. Go to the following Web site and read a short article that presents one possibility. Be prepared to answer a question on the tutorial quiz dealing with one explanation for the Heterozygote Advantage?
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, as well as 1 in 34 persons of Irish ancestry. 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 phenyalanine (and/or its metabolites), therefore, they have low levels of tyrosine. The high levels of phenyalanine 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, which is done 24 to 72 hours after a baby is born), 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 condition in which 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 mainly persons of African ancestry. About 10% carry the allele for this trait. (In some areas of Africa, upwards of 40% carry the allele.) Individuals that are homozygous for the sickle cell allele have sickle-cell disease and 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 who are heterozygous are less susceptible to malaria than those who are homozygous for the normal hemoglobin allele.. It is not surprising then that the highest frequency of the sickle cell allele is found in areas where malaria is prevalent. This allele is one of the best examples 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. Figure 3 shows a pedigree for a family that includes individuals with wooly hair.
Figure 3. Pedigree of Wooly Hair. (Click image to enlarge)
Example 2. Brachydactyly - a condition associated with shortness of fingers and toes. The actress Megan Fox has brachydactyly of her thumbs (Figure 5).
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 4. Pedigree of Brachydactyly. (Click image to enlarge)
Figure 5. Megan Fox (actress) has brachydactyly (http://www.zimbio.com/Megan+Fox/articles/VI9q3Ofw_sW/Brachydactyly+Megan+Fox)
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. This condition is also known as Huntington’s chorea (after the Greek χορεία, a quick dance),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.
Figure 6 shows 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.
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).
Figure. Pedigree of Wooly Hair. (Click image to enlarge)
This animation will help you check your understanding of pedigree analysis.
Pedigrees and Puppies!
Your neighbor has a female Labrador retriever. This breed has three coat colors, black, chocolate, and yellow. Black labs are dark as night, chocolate labs are a deep, deep brown, and yellow labs appear light brown to white. Their nose, lips and gums can be either brown or black. Your neighbor’s dog is yellow with a black nose. He breeds his dog with a chocolate lab with a brown nose. A photo of the litter is below (the mother is on the left of Figure 8 and all puppies are either black or yellow and have a black nose). Your neighbor has read on a web site that coat color is due to an epistatic interaction between a gene that determines chocolate or black pigment color (designated B) and a gene that is involved in pigment deposition (designated E). Each gene has a recessive allele that does not function. Black labs are B_/E_; chocolate labs are bb/E_; and yellow labs are __/ee. The “E” gene does not appear to be involved in the deposition of pigment to the nose and gums. He comes to you and wants to know the genotype of his dog and he also is a bit confused about the word epistasis because it seems to him that he can explain his litter based on the action of just one gene.
- Given these facts, what is the most likely genotype of your neighbor’s dog?
- How does this example demonstrate epistasis?
Figure 8. Mom is on the left and she is yellow with a black nose. All of her puppies are either yellow or black and have black noses.
The pattern of phenotypic expression can be helpful in determining the mode of transmission for a given trait. 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 recessive allele, 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 allele 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.
After reading this tutorial, you should have a working knowledge of the following terms:
- heterozygote advantage
Questions? Either send your instructor a message through ANGEL or attend an office hour (the times are posted on ANGEL).