Mendelian Inheritance

For thousands of years farmers and herders have been selectively breeding their plants and animals in order to produce more productive hybrids. It was somewhat of a hit or miss process since the actual mechanisms governing inheritance were unknown. Knowledge of these genetic mechanisms finally came as a result of careful laboratory breeding experiments carried out over the last century and a half.
The invention of better microscopes inthe 1890's allowed biologists to discover the basic facts of cell division and sexual reproduction. Genetic research then shifted to understanding what really happens in the transmission of hereditary traits from parents to children. A number of ideas were suggested to explain heredity, but Gregor Mendel, a Central European monk, who effectively explained the basics. His ideas had been published in 1866 but largely went unrecognized until 1900, long after his death. His early adult life was spent in relative obscurity doing basic genetics research and teaching high school mathematics, physics, and Greek in Brno (now in the Czech Republic). In his later years when he became the abbot of his monastery and put aside his scientific work.
Mendel's research was with plants, but the basic underlying principles of heredity that he discovered also apply to animals because the mechanisms of heredity are essentially the same for all complex life forms. Through the selective growing of common pea plants (Pisum sativum) over many generations, Mendel discovered that certain traits show up in offspring plants without any blending of parent characteristics. For instance, the pea flowers are either purple or white--intermediate colors do not appear in the offspring of cross-pollinated pea plants. Mendel observed seven traits that are easily recognized and apparently only occur in one of two forms:
1. Flower color I- purple or white
2. Flower position - axil or terminal
3. Stem length - long or short
4. Seed shape - round or wrinkled
5. Seed color - yellow or green
6. Pod shape - inflated or constricted
7. Pod color - yellow or green
This observation that there are traits that do not show up in offspring plants with intermediate forms was very important because the leading theory in biology at the time was that inherited traits blend from generation to generation. Most of the leading scientists in the 19th century accepted this "blending theory." Charles Darwin proposed another equally wrong theory known as "pangenesis”. This held that hereditary "particles" in our bodies are affected by the things we do during our lifetime. These modified particles were thought to migrate via blood to the reproductive cells and subsequently could be inherited by the next generation. This was essentially a variation of Lamarck's incorrect idea of the "inheritance of acquired characteristics."
Mendel picked common garden pea plants for the focus of his research because they can be grown easily in large numbers and their reproduction can be manipulated. Also pea plants have both male and female reproductive organs. As a result, they can either self-pollinate themselves or cross-pollinate with another plant. Thus Mendel was able to selectively cross-pollinate purebred plants with particular traits and observe the outcome over many generations.
In cross-pollinating plants that either produce yellow or green peas exclusively, Mendel found that the first offspring generation (f1) always has yellow peas. However, the following generation (f2) consistently has a 3:1 ratio of yellow to green. This 3:1 ratio occurs in later generations as well. Mendel realized that this is the key to understanding the basic mechanisms of inheritance.
He came to three important conclusions from these experimental results:
1. Inheritance of each trait is determined by "units" or "factors" (now called genes) that are passed on to descendents unchanged
2. An individual inherits one such unit from each parent for each trait
3. A trait may not show up in an individual but can still be passed on to the next generation.
It is important to realize that in this experiment the starting parent plants were homozygous for pea color. That is to say, they each had two identical forms (or alleles ) of the gene for this trait--2 yellows or 2 greens. The plants in the f1 generation were all heterozygous. In other words, they each had inherited two different alleles--one from each parent plant.
Note that each of the f1 generation plants inherited a Y allele from one parent and a G allele from the other. When the f1 plants breed, each has an equal chance of passing on either Y or G alleles to each offspring.
With all of the seven pea plant traits that Mendel examined, one form appeared dominant over the other. Which is to say, it masked the presence of the other allele. For example, when the genotype for pea color is YG (heterozygous), the phenotype is yellow. However, the dominant yellow allele does not alter the recessive green one in any way. Both alleles can be passed on to the next generation unchanged. Mendel's observations from these experiments can be summarized in two principles:
1. The principle of segregation
2. The principle of independent assortment
According to the principle of segregation, for any particular trait, the pair of alleles of each parent separate and only one allele passes from each parent on to an offspring. Which allele in a parent's pair of alleles is inherited is a matter of chance. We now know that this segregation of alleles occurs during the process of sex cell formation (i.e., meiosis).
According to the principle of independent assortment, different pairs of alleles are passed to offspring independently of each other. The result is that new combinations of genes present in neither parent are possible. For example, a pea plant's inheritance of the ability to produce purple flowers instead of white ones does not make it more likely that it would also inherit the ability to produce yellow peas in contrast to green ones. Likewise, the principle of independent assortment explains why the human inheritance of a particular eye color does not increase or decrease the likelihood of having 6 fingers on each hand. Today, we know this is due to the fact that the genes for independently assorted traits are located on different chromosomes.
These two principles of inheritance, along with the understanding of unit inheritance and dominance, were the beginnings of our modern science of genetics. However, Mendel did not realize that there are exceptions to these rules.
One of the reasons that Mendel carried out his breeding experiments with pea plants is that he could observe inheritance patterns in up to two generations a year. Geneticists today usually carry out their breeding experiments with species that reproduce much more rapidly so that the amount of time and money required is significantly reduced. Fruit flies and bacteria are commonly used for this purpose now. Fruit flies reproduce in about 2 weeks from birth, while bacteria, such as E. coli, reproduce in only 3-5 hours.

The value of studying genetics is in understanding how we can predict the likelihood of inheriting particular traits. This can help plant and animal breeders in developing varieties that have more desirable qualities. It can also help people explain and predict patterns of inheritance in family lines.
One of the easiest ways to calculate the mathematical probability of inheriting a specific trait was invented by an early 20th century English geneticist named Reginald Punnett. His technique employs what we now call a Punnett square. This is a simple graphical way of discovering all of the potential combinations of genotypes that can occur in children, given the genotypes of their parents. It also shows us the odds of each of the offspring genotypes occurring.
Setting up and using a Punnett square is quite simple once you understand. You begin by drawing a grid of perpendicular lines as is commonly illustrated in nearly all biology textbooks.
Next, you put the genotype of one parent across the top and that of the other parent down the left side. For example, if parent pea plant genotypes were YY and GG respectively.
Note that only one letter goes in each box for the parents. It does not matter which parent is on the side or the top of the Punnett square.
Next, all you have to do is fill in the boxes by copying the row and column-head letters across or down into the empty squares. This gives us the predicted frequency of all of the potential genotypes among the offspring each time reproduction occurs.
In another example, if the parent plants both have heterozygous (YG) genotypes, there will be 25% YY, 50% YG, and 25% GG offspring on average. These percentages are determined based on the fact that each of the 4 offspring boxes in a Punnett square is 25% (1 out of 4). As to phenotypes, 75% will be Y and only 25% will be G. These will be the odds every time a new offspring is conceived by parents with YG genotypes.
An offspring’s genotype is the result of the combination of genes in the sex cells or gametes (sperm and ova) that came together in its conception. One sex cell came from each parent. Sex cells normally only have one copy of the gene for each trait (e.g., one copy of the Y or G form of the gene in the example above). Each of the two Punnett square boxes in which the parent genes for a trait are placed (across the top or on the left side) actually represents one of the two possible genotypes for a parent sex cell. Which of the two parental copies of a gene is inherited depends on which sex cell is inherited--it is a matter of chance. By placing each of the two copies in its own box has the effect of giving it a 50% chance of being inherited.
Why is it important to know about Punnett squares? The answer is that they can be used as predictive tools when we are considering having children. Let us assume, for instance, that both you and your mate are carriers for a particularly unpleasant genetically inherited disease such as cystic fibrosis. Of course, you are worried about whether your children will be healthy and normal. For this example, let us define A as being the dominant normal allele and a as the recessive abnormal one that is responsible for cystic fibrosis. As carriers, you and your mate are both heterozygous (Aa). This disease only afflicts those who are homozygous recessive (aa). The Punnett square below makes it clear that at each birth, there will be a 25% chance of you having a normal homozygous (AA) child, a 50% chance of a heterozygous (Aa) carrier child like you and your mate, and a 25% chance of a homozygous recessive (aa) child who probably will eventually die from this condition.
If a carrier (Aa) for such a recessive disease mates with someone who has it (aa), the likelihood of their children also inheriting the condition is far greater (as shown below). On average, half of the children will be heterozygous (Aa) and, therefore, carriers. The remaining half will inherit 2 recessive alleles (aa) and develop the disease.
It is likely that every one of us is a carrier for 3-5 recessive alleles that can cause life-threatening defects if they are inherited from both parents.
Theoretically, the likelihood of inheriting many traits, including useful ones, can be predicted using Punnett squares. It is also possible to construct squares for more than one trait at a time.

Since Mendel's time, our knowledge of the mechanisms of genetic inheritance has grown immensely. For instance, it is now understood that inheriting one allele can, at times, increase the chance of inheriting another or can affect how and when a trait is expressed in an individual's phenotype. Likewise, there are degrees of dominance and recessiveness with some traits. The simple rules of Mendelian inheritance do not apply in these and other exceptions.

Some traits are determined by the combined effect of more than one pair of genes. These are referred to as polygenic, or continuous, traits. An example of this is human stature. The combined size of all of the body parts from head to foot determines the height of an individual. There is an additive effect. The sizes of all of these body parts are, in turn, determined by numerous genes. Human skin, hair, and eye color are also polygenic traits because they are influenced by more than one allele at different loci. The result is the perception of continuous gradation in the expression of these traits.

Apparent blending can occur in the phenotype when there is incomplete dominance resulting in an intermediate expression of a trait in heterozygous individuals. For instance, in primroses, four-o'clocks, and snapdragons, red or white flowers are homozygous while pink ones are heterozygous. The pink flowers result because the single "red" allele is unable to code for the production of enough red pigment to make the petals dark red.
Another example of an intermediate expression may be the pitch of human male voices. The lowest and highest pitches apparently are found in men who are homozygous for this trait (AA and aa), while the intermediate range baritones are heterozygous (Aa). The child killer disease known as Tay-Sachs is also characterized by incomplete dominance. Heterozygous individuals are genetically programmed to produce only 40-60% of the normal amount of an enzyme that prevents the disease.
Fortunately for Mendel, the pea plant traits that he studied were controlled by genes that do not exhibit an intermediate expression in the phenotype. Otherwise, he probably would not have discovered the basic rules of genetic inheritance.

For some traits, two alleles can be codominant. That is to say, both are expressed in heterozygous individuals. An example of this is people who have an AB blood type for the ABO blood system. When they are tested, these individuals actually have the characteristics of both type A and type B blood. Their phenotype is not intermediate between the two.

The ABO blood type system is also an example of a trait that is controlled by more than just a single pair of alleles. In other words, it is due to a multiple-allele series. In this case, there are three alleles (A, B, and O), but each individual only inherits two of them (one from each parent).
Some traits are controlled by far more alleles. For instance, the HLA system, which is responsible for identifying and rejecting foreign tissue in our bodies, can have at least 30,000,000 different genotypes. It is the HLA system which causes the rejection of organ transplants. The more we learn about human genetics the more it becomes clear that multiple-allele series are very common. In fact, it now appears that they are more common than simple two allele ones.

There are two classes of genes that can have an effect on how other genes function. They are called modifying genes and regulator genes.
Modifying genes alter how certain other genes are expressed in the phenotype. For instance, there is a dominant cataract gene which will produce varying degrees of vision impairment depending on the presence of a specific allele for a companion modifying gene. However, cataracts also can be promoted by common environmental factors such as excessive ultraviolet radiation.
Regulator genes can either initiate or block the expression of other genes. They control the production of a variety of chemicals in plants and animals. For instance, the time of production of specific proteins that will be new structural parts of our bodies can be controlled by such regulator genes. Shortly after conception, regulator genes work as master switches orchestrating the timely development of our body parts. They are also responsible for changes that occur in our bodies as we grow older. In other words, they control the aging process. Regulator genes are also referred to as homeotic genes.

Some genes are incompletely penetrant. That is to say, their effect does not normally occur unless certain environmental factors are present. For example, you may inherit a gene for diabetes but never get the disease unless you become greatly overweight, persistently stressed psychologically, or do not get enough sleep on a regular basis. Similarly, the gene that causes the chronic disease known as multiple sclerosis may be triggered by a herpes virus.

There are three categories of genes that may have different effects depending on an individual's gender. These are referred to as:
1. Sex-limited genes
2. Sex-controlled genes
3. Genome imprinting
Sex-limited genes are ones that are inherited by both men and women but are normally only expressed in the phenotype of one of them. The heavy male beard is an example. While women have facial hair it is most often very fine and comparatively sparse.
In contrast, sex-controlled genes are expressed in both sexes but differently. An example of this is gout , a disease that causes painfully inflamed joints. If the gene is present, men are nearly eight times more likely than women to have severe symptoms.
Some genes are known to have a different effect depending on the gender of the parent from whom they are inherited. This phenomenon is referred to as genome imprinting. Apparently, diabetes , psoriasis, and some rare genetically inherited diseases, such as a form of mental retardation known as Angelman syndrome ,can follow this inheritance pattern.

A single gene may be responsible for a variety of traits. This is called pleiotropy. The complex of symptoms that are collectively referred to as sickle-cell trait is an example. A single gene results in irregularly shaped red blood cells that painfully block blood vessels, cause poor overall physical development, as well as related heart, lung, kidney, and eye problems. Another pleiotropic trait is albinism . The gene for this trait not only results in a deficiency of skin, hair, and eye pigmentation but also causes defects in vision.

Lastly, it is now known that some genetically inherited diseases have more severe symptoms each succeeding generation due to segments of the defective genes being doubled in their transmission to children (as illustrated below). These are referred to as stuttering alleles or unstable alleles. Examples of this phenomenon are Huntington's disease, fragile-X syndrome, and the myotonic form of muscular dystrophy .
Mendel believed that all units of inheritance are passed on to offspring unchanged. Unstable alleles are an important exception to this rule.

The phenotype of an individual is not only the result of inheriting a particular set of parental genes. The specific environmental characteristics of the uterus in which a fertilized egg is implanted and the health of the mother can have major impacts on the phenotype of the future child. For instance, oxygen deprivation or inappropriate hormone levels can cause lifelong, devastating effects. Likewise, accidents, poor nutrition, and other environmental influences throughout life can alter an individual's phenotype.
Geneticists study identical or monozygotic twins to determine which traits are inherited and which ones were acquired following conception. Since monozygotic twins come from the same zygote, they are genetically identical. If there are any differences in their phenotypes, the environment must be responsible. Such differences show up in basic capabilities such as handedness. In some cases, one monozygotic twin will be clearly right-handed while the other will be left-handed. However, it is known that there is a tendency for left-handedness to be common in some families. This suggests that there may be both genetic and environmental influences in the development of this trait.

Researchers have identified over 13,000 genetically inherited human traits. More than 5,000 of them are diseases or other abnormalities. As we learn more about the inheritance patterns for these traits, it is becoming clear that at least some of the twelve exceptions to the simple Mendelian rules of inheritance described here are, in fact, relatively common. Genes that follow simple rules of dominance increasingly seem to be rare. It would not be surprising if other "exceptions" to Mendelian genetics were discovered in the future, especially as the Human Genome Project nears completion.