Title: LIFE SCIENCE TEXT: Genetics
Course: Biology (A)

Lesson 6.1: Gregor Mendel and the Foundations of Genetics

Lesson Objectives

- Explain Mendel's law of segregation.
- Draw a Punnett square to make predictions about the traits of the offspring of a simple genetic cross.

Check Your Understanding

- What is the genetic material of our cells?
- How does meiosis affect the chromosome number in gametes?

Introduction

For centuries people have been fascinated with the inheritance of human traits. People might say, “You have your father’s eyes.” or, “You have red hair like your granddad; it must have skipped a generation.” These comments show an appreciation of the laws of human inheritance. We inherit traits from our ancestors, and sometimes traits can stay hidden and show up in later generations. Genetics, the study of inheritance, explains how traits are passed on from one generation to the next. Due to recent developments in the field of genetics, we can now seek to understand the inheritance of disease. People today may ask “What are the chances my child will have cystic fibrosis?” and “What is the likelihood that I may have breast cancer if my grandmother had it?” Genetic counselors are trained to address families’ questions about the probabilities of passing on a genetic disorder. When genetic counselors sit down with families to discuss these types of questions, it’s amazing that their answers are derived from the fundamentals of genetics discovered by a monk in the 1800s.

Gregor Mendel

Mendel’s Experiments

The laws of heredity were first developed by an Austrian monk, Gregor Mendel (Figure above), in the 1800s. To study genetics, Mendel chose to work with pea plants because they had easily observable traits and a short generation time (Figure below). For example, pea plants are either tall or short, which are easily identifiable traits. Furthermore, peas can either self pollinate or be cross-pollinated by hand, by transferring the pollen from one flower to the stigma of another. In this way, Mendel could carefully observe the results of crosses between two different types of plants. He studied the inheritance patterns for many different traits in peas, including round seeds versus wrinkled seeds, white flowers versus purple flowers, and tall plants versus short plants. Because of his work, Mendel can be considered the father of genetics.

Characteristics of pea plants.

During Mendel’s time, most people believed that traits were contributed from both parents and blended together as they were passed down from generation to generation. For example, if you crossed a short plant and a tall plant, they would expect the offspring to be medium-sized plants. What Mendel observed, however, was that the offspring of this cross (called the F1 generation, derived from the Latin term filius, meaning sons and daughters) were all tall plants. Based on the blending hypothesis, the result of all tall plants was unexpected.

Next, Mendel let the F1 generation self-pollinate. He then noted that 75% of the resulting offspring, the F2 generation, were tall, while 25% were short. Therefore, shortness appeared to have skipped a generation. Mendel found this same mathematical result over and over again with all the traits he studied. In all, Mendel studied seven characteristics, with almost 20,000 F2 plants analyzed. For example, purple flowers and white flowers were crossed to produce plants with only purple flowers in the F1 generation. Then after self-pollination, the F2 generation had 75% purple flowers and 25% white flowers. These results did not reflect what you would expect if the blending model of inheritance was correct.

Dominance

Mendel had to come up with a new theory of inheritance to explain his results. His explanation, the law of segregation, is still one of the fundamental laws of modern genetics. He proposed that each pea plant had two hereditary factors for each trait. There were two possibilities for each hereditary factor, such as short or tall. One factor is dominant to the other, meaning it masks the effects of the recessive factor. However, each parent could only pass on one of these factors to the offspring. Therefore, during the formation of gametes, sperm or egg, the heredity factors must separate so there is only one factor per gamete. When fertilization occurs, the offspring then have two hereditary factors.

This law explained what Mendel had seen in the F1 generation, because the two heredity factors were the short and tall factors and each individual in the F1 would have one of each factor, and as the tall factor is dominant to the short factor, all the plants appeared tall. In the F2 generation, produced by self-pollination of the F1, 25% of the offspring could have two short heredity factors, so they would appear short. 75% would have at least one tall heredity factor and will be tall.

In genetics problems, the dominant factor is labeled with a capital letter (T) while the recessive factor is labeled with a lowercase letter (t). If we designate the letter T or t to represent the heritable factor, as each individual has two factors for each trait, the possible combinations are Tt, TT, and tt. Plants with TT would be tall while plants with tt would be short. Since T is dominant to t, plants that are Tt would be tall, as with the F1 generation we described that inherited one factor from the TT tall parent and one factor from the tt short parent.

Probability and Punnett Squares

To visualize the results of a genetic cross, a Punnett square is helpful. An example of a Punnett square (Figure below) that shows the results of a cross between two purple flowers that each have one dominant factor and one recessive factor (Bb). Notice how the possible factors in the sperm (B or b) are lined up the side of the square while the possible factors in the egg (B or b) are lined up across the top. The possible offspring are represented by the letters in the boxes, with one factor coming from each parent.

Notice how the Punnett square can help you predict the outcome of the crosses. Only one of the plants out of the four, or 25% of the plants, has white flowers (bb). The other 75% have purple flowers (BB, Bb) because the color purple is a dominant trait in pea plants.

Now imagine you cross one of the white flowers (bb) with a purple flower that has both a dominant and recessive factor (Bb). The only possible gamete in the white flower is the recessive (b), while the purple flower can have gametes with either dominant (B) or recessive (b). If you write out the Punnett cross, you will see that 50% of the offspring will be purple and 50% of the offspring will be white.

Keep in mind that the birth of each offspring is an independent event and has the same probability, so the traits of a previous offspring do not influence the next offspring. In the cross discussed above with two Bb flowers, each offspring has a 75% chance of being purple and a 25% chance of being white. For example, even if the first three offspring in the cross have purple flowers, it does not mean that the next plant must have white flowers. All probability tells you is that overtime the averages of many, many offspring will work out to a predicted ratio.

The Punnett Square of a white flower (bb) crossed with a purple flower (Bb)
 | b | b
B | Bb | bb
b | Bb | bb

The Punnett Square of a cross between two purple flowers (Bb)

Lesson Summary

- Gregor Mendel is considered the father of genetics, the science of studying inheritance.
- According to Mendel’s law of segregation, an organism has two factors for each trait, but each gamete only contains one of these factors.
- A Punnett square is useful for predicting the outcomes of crosses.

Review Questions

1. What is the term for the offspring of a cross, or the first generation?
2. What is the F2 generation?
3. Who is considered the father of genetics?
4. Why did Mendel select peas as a model for studying genetics?
5. In peas, yellow seeds (Y) are dominant over green seeds (y). If a yy plant is crossed with a YY plant, what ratio of plants in the offspring would you predict?
6. In peas, purple flowers (P) are dominant over white flowers (p). If a pp plant is crossed with a Pp plant, what ratio of plants in the offspring would you predict?
7. In guinea pigs, black fur (B) is dominant over white fur (b). If a BB guinea pig is crossed with a Bb guinea pig, what ratio of guinea pigs in the offspring would you predict?
8. In guinea pigs, smooth coat (S) is dominant over rough coat (s). If a SS guinea pig is crossed with a ss guinea pig, what ratio of guinea pigs in the offspring would you predict?
9. In humans, unattached ear lobes are dominant over attached ear lobes. If two parents have attached earlobes, what is the predicted ratio in the offspring?
10. Why would it be much easier to study genetics in pea plants than in people?

Further Reading / Supplemental Links

- http://www.mendelweb.org/MWtoc.html
- http://www.estrellamountain.edu/faculty/farabee/BIOBK/BioBookgenintro.html
- http://sonic.net/~nbs/projects/anthro201/
- http://anthro.palomar.edu/mendel/mendel_1.htm

Vocabulary

dominant
Masks the expression of the recessive trait.

F1 generation
The first filial generation; offspring of the P or parental generation.

F2 generation
The second filial generation; offspring from the self-pollination of the F1 generation.

gametes
Haploid cells involved in sexual reproduction, such egg and sperm.

genetics
The study of inheritance.

Punnett square
Visual representation of a genetic cross that helps predict the expected ratios in the offspring, first described by Reginald C. Punnett in the early 20^th century.

recessive
Expression is masked by the dominant factor (allele); only expressed if both factors are recessive.

Points to Consider

- Do you think all traits follow this simple pattern where one factor controls the trait?
- Can you think of other examples where Mendel’s law does not seem to fit?

Lesson 6.2: Modern Genetics

Lesson Objectives

- Explain Mendel’s laws with our modern understanding of chromosomes.
- Explain how codominant traits are inherited.
- Distinguish between phenotype and genotype.
- Explain how polygenic traits are inherited.

Check Your Understanding

- What is a visual representation of a genetic cross?
- What is stated in Mendel’s law of segregation?

Introduction

Although Mendel laid the foundation for modern genetics, there were still a lot of questions left unanswered. How is inheritance determined for traits that do not seem to follow a simple dominant-recessive pattern? What exactly are the hereditary factors that determine traits in organisms? And how do these factors work? One of the great achievements of this past century was the discovery of DNA as the genetic material. And it is the DNA that makes up the hereditary factors that Mendel identified. By applying our modern knowledge of DNA and chromosomes, we can explain Mendel’s findings and build on them.

Traits, Genes, and Alleles

Interpreting Mendel’s discoveries through the eye of modern genetics, we now know that Mendel’s hereditary factors are made up of DNA. Recall that our DNA is wound into chromosomes. Each of our chromosomes contains a long chain of DNA that encodes hundreds, if not thousands, of genes. Each of these genes can have slightly different versions from individual to individual. These variants of genes are called alleles. For example, remember that for the height gene in pea plants there are two possible alleles, the dominant allele for tallness (T) and the recessive allele for shortness (t).

Genotype and Phenotype

Genotype refers to the combination of alleles that an individual has for a certain gene. For each gene, an organism has two alleles, one on each chromosome of a homologous pair of chromosomes. The genotype is often referred to with the letter combinations that were introduced in the previous lesson, such as TT, Tt, and tt. When an organism has two of the same alleles for a specific gene, it is homozygous for that gene. An organism can be either homozygous dominant (TT) or homozygous recessive (tt). If an organism has two different alleles (Tt) for a certain gene, it is known as heterozygous. Genes have a specific place on a specific chromosome, so in the heterozygous individual these alleles are in the same location on each homologous chromosome.

Phenotype refers to the visible traits or appearance of the organism, as determined by the genotype. For example, the phenotypes of Mendel’s pea plants were either tall or short, or were purple-flowered or white-flowered. Keep in mind that plants with different genotypes can have the same phenotype. For example, both a pea plant that is homozygous dominant for the tall trait (TT) and heterozygous plant (Tt) would have the phenotype of being tall plants. The recessive phenotype only occurs if the dominant allele is absent, which is when an individual is homozygous recessive (tt).

Incomplete Dominance and Codominance

In all of Mendel’s experiments, he worked with traits where a single gene controlled the trait and where one allele was always dominant to the other. Although the rules that Mendel derived from his experiments explain many inheritance patterns, the rules do not explain them all. There are in fact exceptions to Mendel’s rules, and these exceptions usually have something to do with the dominant allele.

One exception to Mendel’s rules is that one allele is always completely dominant over a recessive allele. Sometimes an individual has an intermediate phenotype between the two parents, as there is no dominant allele. This pattern of inheritance is called incomplete dominance.

An example of incomplete dominance is the color of snapdragon flowers. One of the genes for flower color in snapdragons has two alleles, one for red flowers and one for white flowers. A plant that is homozygous for the red allele will have red flowers, while a plant that is homozygous for the white allele will have white flowers. On the other hand, the heterozygote will have pink flowers (Figure below). Neither the red nor the white allele is dominant, so the phenotype of the offspring is a blend of the two parents.

Pink snapdragons are an example of incomplete dominance.

Another example of incomplete dominance is sickle cell anemia, a disease in which the hemoglobin protein is produced incorrectly and the red blood cells have a sickle shape. A person that is homozygous recessive for the sickle cell trait will have red blood cells that all have the incorrect hemoglobin. A person who is homozygous dominant will have normal red blood cells. And because this trait has an incomplete dominance pattern of expression, a person who is heterozygous for the sickle cell trait will have some misshapen cells and some normal cells (Figures below and below). These heterozygous individuals have a fitness advantage; they are resistant to severe malaria. Both the dominant and recessive alleles are expressed, so the result is a phenotype that is a combination of the recessive and dominant traits.

Sickle cell anemia causes red blood cells to become misshapen and curved (upper figure) unlike normal, rounded red blood cells (lower figure).

Sickle cell anemia causes red blood cells to become misshapen and curved (upper figure) unlike normal, rounded red blood cells (lower figure).

An example of a codominant trait is ABO blood types (Figure below), named for the carbohydrate attachment on the outside of the blood cell. In this case, two alleles are dominant and completely expressed (designated I^A and I^B), while one allele is recessive (i). The I^A allele encodes for red blood cells with the A antigen, while the I^B allele encodes for red blood cells with the B antigen. The recessive allele (i) doesn’t encode for any antigens. An antigen is a substance that provokes an immune response, your body’s defenses against disease, which will be discussed further in the Diseases and the Body's Defenses chapter. Therefore a person with two recessive alleles (ii) has type O blood. As no dominant (I^A and I^B) allele is present, the person cannot have type A or type B blood.

There are two possible genotypes for type A blood, homozygous (I^AI^A) and heterozygous (I^Ai), and two possible genotypes for type B blood (I^Bi and I^BI^B). If a person is heterozygous for both the I^A and I^B alleles, they will express both and have type AB blood with both antigens on each red blood cell. This pattern of inheritance is significantly different than Mendel’s rules for inheritance because both alleles are expressed completely and one does not mask the other.

An example of codominant inheritance is ABO blood types.

Polygenic Traits and Environmental Influences

Another exception to Mendel’s rules is polygenic inheritance, which is when a trait is controlled by more than one gene. Often these traits are in fact controlled by many genes on many chromosomes. Each dominant allele has an additive effect, so the resulting offspring can have a variety of genotypes, from no dominant alleles to several dominant alleles. In humans, some examples of polygenic traits are height and skin color. People are neither short nor tall, as was seen with the pea plants studied by Mendel, which has only one gene that encodes for height. Instead, people have a range of heights determined by many genes. Similarly, people have a wide range of skin colors. Polygenic inheritance often results in a bell shaped curve when you analyze the population (Figure below). That means that most people are intermediate in the phenotype, such as average height, while very few people are at the extremes, such as very tall or very short.

Polygenic traits tend to result in a distribution that resembles a bell-shaped curve, with few at the extremes and most in the middle. There may be 4 or 6 or more alleles involved in the phenotype. At the left extreme, individuals are completely dominant for all alleles, and at the other extreme, individuals are completely recessive for all alleles. Individuals in the middle have various combinations of recessive and dominant alleles. Other polygenic traits in dairy cattle are of extreme economic importance in agriculture .

Most polygenetic traits are partially influenced by the environment. For example, height is partially influenced by nutrition in childhood. If a child is genetically programmed to be average height but does not get a proper diet, he or she may be below average in size.

Other examples of environmentally influenced traits are mental illnesses like schizophrenia and depression. A person may be genetically predisposed to have depression, so when that person's environment contributes major stresses like losing a job or losing a close relative, the person is more likely to become depressed.

Linkage

Linkage refers to particular genetic position or loci, of alleles inherited together, suggesting that they are physically on the same chromosome, and located close together on that chromosome. A crossing-over event during prophase I of meiosis is rare between linked loci. Alleles for genes on different chromosomes are not linked; they sort independently (independent assortment) of each other during meiosis.

A gene is also said to be linked to a chromosome if it is physically located on that chromosome. For example, a gene (or loci) is said to be linked to the X-chromosome if it is physically located on the X-chromosome.

Linkage Maps

The frequency of recombination refers to the rate of crossing-over (recombination) events between two loci. This frequency can be used to estimate genetic distances between the two loci, and create a linkage map. In other words, the frequency can be used to estimate how close or how far apart the two loci are on the chromosome.

In the early 20^th century, Thomas Hunt Morgan demonstrated that the amount of crossing over between linked genes differs. This led to the idea that the frequency of crossover events would indicate the distance separating genes on a chromosome. Morgan's student, Alfred Sturtevant, developed the first genetic map, also called a linkage map.

Sturtevant proposed that the farther apart linked genes were on a chromosome, the greater the chance that non-sister chromatids would cross over in the region between the genes during meiosis. By determining the number of recombinants - offspring in which a cross-over event has occurred - it is possible to determine the approximate distance between the genes. This distance is called a genetic map unit (m.u.), or a centimorgan, and is defined as the distance between genes for which one product of meiosis in 100 products is a recombinant. So, a recombinant frequency of 1% (1 out of 100) is equivalent to 1 m.u. Loci with a recombinant frequency of 10% would be separated by 10 m.u. The recombination frequency will be 50% when two genes are widely separated on the same chromosome or are located on different chromosomes. This is the natural result of independent assortment. Linked genes have recombination frequencies less than 50%.

Determining recombination frequencies between genes located on the same chromosome allows a linkage map to be developed. Linkage mapping is critical for identifying the location of genes that cause genetic diseases.

Sequencing the genome of agriculturally important animals, such as cattle, can be important in the improvement of production. For more information on this aspect of modern genetics, please see http://www.physorg.com/news188148947.html

Lesson Summary

- Variants of genes are called alleles.
- Genotype is the combination of alleles that an individual has for a certain gene, while phenotype is the appearance caused by the expression of the genotype.
- Incomplete dominance and codominance do not fit Mendel’s rules because one allele does not entirely mask the other.
- In polygenic inheritance, many genes control a trait with each dominant allele having an additive effect.

Review Questions

1. What is a variant of a gene that occurs at the same place on homologous chromosomes?
2. What is the type of allele that only affects the phenotype in the homozygous condition?
3. What type of allele masks the expression of the recessive allele and is therefore expressed in the heterozygote?
4. What is the term for the specific alleles of an individual for a particular trait?
5. What is the term for the appearance of the organism, as determined by the genotype?
6. If a organism has a certain phenotype, such as a tall pea plant, does that mean it must have the same genotype?
7. What is the term for the pattern of inheritance where an individual has an intermediate phenotype between the two parents?
8. IQ in humans varies in humans with most people having an IQ of around 100, and with a few people at the extremes, such as 50 or 150. What type of inheritance do you think this might describe?
9. A dark purple flower is crossed with a white flower of the same species and the offspring have light purple flowers. What type of inheritance does this describe?
10. What is the inheritance pattern where both alleles are expressed?

Further Reading / Supplemental Links

- http://en.wikipedia.org/wiki/Dominant_gene
- http://en.wikipedia.org/wiki/Polygenic_inheritance
- http://staff.jccc.net/pdecell/evolution/polygen.html
- http://www.curiosityrats.com/genetics.html
- http://www.estrellamountain.edu/faculty/farabee/BIOBK/BioBookgenintro.html

Vocabulary

allele
An alternative form of a gene.

co-dominance
A pattern of inheritance where both alleles are equally expressed.

genotype
The genetic makeup of a cell or organism, defined by certain alleles for a particular trait.

homozygous
Having identical alleles for a particular trait.

heterozygous
Having two different alleles for a particular trait.

incomplete dominance
A pattern of inheritance where the offspring has a phenotype that is halfway between the two parents’ phenotypes.

phenotype
The physical appearance that is a result of the genotype.

polygenic inheritance
A pattern of inheritance where the trait is controlled by many genes and each dominant allele has an additive effect.

Points to Consider

- Hypothesize about the genetic differences between males and females.
- Can you name any human genetic disorders?
- If a baby inherits an extra chromosome, what might the result be?

Lesson 6.3: Human Genetics

Lesson Objectives

- List the two types of chromosomes in the human genome.
- Predict patterns of inheritance for traits located on the sex chromosomes.
- Describe how some common human genetic disorders are inherited.
- Explain how changes in chromosomes can cause disorders in humans.

Check Your Understanding

- How many alleles does an individual have for each gene/trait?
- How do we predict the probability of traits being passed on to the next generation?
- What do we call complexes of DNA wound around proteins that pass on genetic information to the next generation of cells?

Introduction

You might know someone who was born with a genetic disorder, such as cystic fibrosis or Down Syndrome. And you might have wondered how someone inherits these types of disorders. It all goes back to Mendel! Mendel’s rules laid the foundation for understanding the genetics of all organisms, including humans. We can apply Mendel’s rules to describe how many human traits and genetic disorders are inherited. Some disorders are caused by a recessive allele, while other disorders are caused by a single dominant allele. Therefore, we can draw a Punnett square to predict the number of offspring that may be affected with these diseases, just like we predicted for other traits in the previous lessons. Since Mendel’s time, we have also expanded our knowledge of inheritance and understand that genes are located on chromosomes. Now we can now explain special inheritance patterns that don’t fit Mendel’s rules.

Sex-linked Inheritance

What determines if a baby is a boy or a girl? Recall that you have 23 pairs of chromosomes, one pair of which are the sex chromosomes. Everyone has two sex chromosomes, X or Y, that determine our sex. Females have two X chromosomes, while males have one Y chromosome and one X chromosome. So if a baby inherits an X from the father and an X from the mother, it will be a girl. If the father’s sperm carries the Y chromosome, it will be a boy. Notice that a mother can only pass on an X chromosome, so the sex of the baby is determined by the father. The father has a 50 percent chance of passing on the Y or X chromosome, hence it is a 50 percent chance whether a child will be a boy or a girl.

One special pattern of inheritance that doesn’t fit Mendel’s rules is sex-linked inheritance, referring to the inheritance of traits which are due to genes located on the sex chromosomes. The X chromosome and Y chromosome carry many genes and some of them code for traits that have nothing to do with determining sex. Since males and females do not have the same sex chromosomes, there will be differences between the sexes in how these sex-linked traits are expressed.

One example of a sex-linked trait is red-green colorblindness. People with this type of colorblindness cannot distinguish between red and green and often see these colors as shades of brown (Figure below). Boys are much more likely to be colorblind than girls. That’s because colorblindness is a sex-linked recessive trait. Boys only have one X chromosome, so if that chromosome carries the gene for colorblindness, they will be colorblind. As girls have two X chromosomes, a girl can have one X chromosome with the colorblind gene and one X chromosome with a normal gene for color vision. Since colorblindness is recessive, the dominant normal gene will mask the recessive colorblind gene. For a girl to be colorblind, she would have to inherit two genes for colorblindness, which is very unlikely. Many sex-linked traits are inherited in a recessive manner.

A person with red-green colorblindness would not be able to see the number.

A woman can be a carrier of colorblindness, however. A carrier appears normal but is capable of passing on a genetic disorder to her child. Carriers for colorblindness have a heterozygous genotype of one colorblind allele and one normal allele. We can use a Punnett square to predict the probability of a carrier passing on the trait to her children. For example, if a woman who is a carrier for colorblindness has children, her boys would have a 50% chance of being colorblind and her girls have a 50% chance of being carriers.

 | Xc | X
X
(carrier female)

XcX
(normal female)

XX
Y
(colorblind male)

XcY
(normal male)

XY

Human Genetic Disorders

Some human genetic disorders are also X-linked or Y-linked, which means the faulty gene is carried on these sex chromosomes. Other genetic disorders are carried on one of the other 22 pairs of chromosomes; these chromosomes are known as autosomes or autosomal chromosomes.

Some genetic disorders are caused by recessive or dominant alleles of a single gene on an autosome. These disorders would then have the same inheritance pattern as any other dominant or recessive trait. An example of an autosomal recessive genetic disorder is cystic fibrosis. Children with cystic fibrosis have excessively thick mucus in their lungs which makes it difficult for them to breathe. The inheritance of this recessive allele is the same as any other recessive allele, so a Punnett square can be used to predict the probability that two carriers of the disease will have a child with cystic fibrosis.

 | F | f
F
(normal)

FF
(carrier)

Ff
f
(carrier)

Ff
(affected)

ff

Another recessive trait that we mentioned previously was sickle cell anemia. A person with two recessive alleles for the sickle cell trait (aa) will have sickle cell disease. In this disease the hemoglobin protein is formed incorrectly and the person’s red blood cells are misshapen. A person who does not carry the sickle trait has a homozygous dominant genotype (AA). Remember the trait showed incomplete dominance, so a person who is heterozygous for the trait (Aa) would have some sickle-shaped cells and some normal red blood cells.

You can also use a simple Punnett square to predict the inheritance of a dominant autosomal disorder, like Huntington’s disease. If one parent has Huntington’s disease, what is the chance of passing it on to their children? If you draw the Punnett square, you will see that there is a 50 percent chance of the disorder being passed on to the children. Huntington’s disease causes the brain’s cells to break down, leading to muscle spasms and personality changes. Unlike most other genetic disorders, the symptoms usually do not become apparent until middle age.

Genetic diseases can also be carried on the sex-chromosomes. An example of a recessive sex-linked genetic disorder is hemophilia. A hemophiliac’s blood does not clot, or clots very slowly, so he or she can easily bleed to death. As with colorblindness, males are much more likely to be hemophiliacs since the gene is on the X chromosome. Because Queen Victoria of England was a carrier of hemophilia, this disorder was once common in European royal families. Several of her grandsons were afflicted with hemophilia, but none of her granddaughters were affected by the disease, although they were often carriers. Because at the time medical care was very primitive, often hemophiliacs bled to death, and usually at a young age. Queen Victoria’s grandson Frederick died at age 3, and her grandson Waldemar died at age 11 (Figure below).

A pedigree chart shows all the phenotypes for a particular trait in the family. This pedigree chart traces back the occurrence of hemophilia in the British royal family. Those individuals with boxes around them are either female carriers of the trait or males afflicted with the trait.

Many genetic disorders are recessive, meaning that an individual must be homozygous for the recessive allele to be affected. Sometimes these disorders are lethal (deadly), however, heterozygous individuals (unaffected individuals with one dominant allele and one recessive allele) survive. This allows the allele that causes the genetic disorder to be maintained in a population's gene pool. A gene pool is the complete set of unique alleles in a species or population. A mutation is a change in the DNA sequence. New mutations are constantly being generated in a gene pool.

Pedigree Analysis

A pedigree is a chart which shows the inheritance of a trait over several generations. A pedigree is commonly created for families, and it outlines the inheritance patterns of genetic disorders. Figure below shows a pedigree depicting recessive inheritance of a disorder through three generations. Scientists can tell the genetics of inheritance from studying a pedigree, such as whether the trait is sex-linked (on the X or Y chromosome) or autosomal (on a chromosome that does not determine sex), whether the trait is inherited in a dominant or recessive fashion, and possibly whether individuals with the trait are heterozygous or homozygous.

In a pedigree, squares symbolize males, and circles represent females. A horizontal line joining a male and female indicates that the couple had offspring. Vertical lines indicate offspring which are listed left to right, in order of birth. Shading of the circle or square indicates an individual who has the trait being traced. The inheritance of the recessive trait is being traced. A is the dominant allele and a is recessive.

Chromosomal Disorders

Some children are born with genetic defects that are not carried by a single gene. Instead, an error in a larger part of the chromosome or even in an entire chromosome causes the disorder. Usually the error happens when the egg or sperm is forming. One common example is Down syndrome (Figure below). Children with Down syndrome are mentally disabled and have collection of recognizable physical deformities. Down syndrome occurs when a baby receives an extra chromosome from one of his or her parents. Usually a child would have one chromosome 21 from its mother and one chromosome 21 from its father. But in an individual with Down syndrome, there are three copies of chromosome 21. Down syndrome is therefore also known as Trisomy 21.

A child with Down syndrome.

Another example of a chromosomal disorder is Klinefelter syndrome, in which a male inherits an extra “X” chromosome. These individuals have underdeveloped sex organs and elongated limbs, and have difficulty learning new things. Outside of chromosome 21 and the sex chromosomes, most embryos with extra chromosomes do not even make it to the fetal stage. Because chromosomes carry many, many genes, a disruption of a chromosome potentially causes severe problems with development of the fetus.

Besides diseases caused by duplicated chromosomes, other chromosomal disorders occur when the structure of a chromosome is disrupted. For example, if a tiny portion of chromosome 5 is missing, the individual will have cri du chat (cat’s cry) syndrome. These individuals have misshapen facial features and the infant’s cry resembles a cat’s cry.

Lesson Summary

- Some human traits are controlled by genes on the sex chromosomes.
- Human genetic disorders can be inherited through recessive or dominant alleles, and they can be located on the sex chromosomes or autosomes.
- Changes in chromosome number can lead to disorders like Down syndrome.

Review Questions

1. How many chromosomes do you have in each cell of your body?
2. How is Down's syndrome inherited?
3. A son cannot inherit colorblindness from his father. Why not?
4. One parent is a carrier of the cystic fibrosis gene, while the other parent does not carry the allele. Can their child have cystic fibrosis?

Further Reading / Supplemental Links

- http://www.articlesbase.com/health-articles/what-is-haemophilia-412305.html
- http://geneticdisorderinfo.wikispaces.com/
- http://www.hhmi.org/biointeractive/vlabs/cardiology/index.html

Vocabulary

autosomes
The chromosome other than the sex chromosomes.

carrier
A person who is heterozygous for a recessive genetic disorder; the person does not have the disease but can pass the disease allele to the next generation.

sex-linked trait
A trait that is due to a gene located on a sex chromosome, usually the X-chromosome.

Points to Consider

- Human cloning is illegal in many countries. Do you agree with these restrictions?
- Why would it be helpful to know all the genes that make up human DNA?
- It may be possible in the future to obtain the sequence of all your genes. Would you want to take advantage of this opportunity? Why or why not?

Lesson 6.4: Genetic Advances

Lesson Objectives

- Explain how clones are made.
- Explain how vectors are made.
- Explain what sequencing a genome tells us.
- Describe how gene therapy works.

Check Your Understanding

- What part of the cell contains the genetic material?
- What are the base pairing rules for DNA?

Introduction

Since Mendel’s time, there have been rapid advances in the understanding of genetics. As scientists understand better how DNA works, they can develop technologies that allow us to reveal the genetic secrets encoded in our DNA and even alter an organism’s DNA. Genetic engineering (or biotechnology or DNA technology) has helped us better understand and predict the inheritance of genetic diseases, produce new medicines, and even produce new food products. DNA technology has also made an impact on fighting crime. Because DNA is unique to an individual, the DNA in just a few hairs at a crime scene can help identify a criminal. This technology, known as DNA fingerprinting, has also helped innocent imprisoned people to appeal their case and clear their names. DNA technology has revolutionized not only criminal justice, but also many other aspects of our lives.

Recombinant DNA

Recombinant DNA is the combination of DNA from two different sources. It is useful in gene cloning and in identifying the function of a gene, as well as producing useful proteins. Human insulin for treating diabetes has been produced through recombinant DNA methods. In this process, a gene of interest (or piece of DNA of interest) is placed into a host cell, such as a bacterium, so the gene can be copied (and cloned) and the protein that results from that gene can be produced.

To place the gene of interest into a host cell, a vector, or carrier molecule, is needed to the carry foreign DNA into the host cell. Bacteria have small accessory rings of DNA in the cytoplasm, called plasmids. When putting foreign DNA into a bacterium (a host cell), the plasmids are often used as a vector. Viruses can also be used as vectors.

The first step of making recombinant DNA involves a restriction enzyme that cuts the vector and the foreign (exogenous) DNA. Restriction enzymes cut DNA at specific sequences, such as GAATTC as shown in Figure below . There are more than 3,000 known restriction enzymes, most cutting the DNA at a unique sequence. This reaction results in the plasmid opening up a gap with “sticky ends,” which can attach with the complimentary base pairs on the sticky ends of the foreign DNA. Then the enzyme DNA ligase seals the foreign DNA in its new place inside the plasmid. These altered plasmids are introduced back into the bacteria, a process called transformation (Figure below). The bacteria will express the foreign gene.

Restriction enzymes cut DNA at specific sequences, in this example the sequence GAATTC." The enzyme cuts between the G and A on each strand, producing overhanging sticky ends.

This image shows a line drawing of a plasmid. The plasmid is drawn as two concentric circles that are very close together, with two large segments and one small segment depicted. The two large segments (1 and 2) indicate antibiotic resistances usually used in a screening procedure, and the small segment (3) indicates an origin of replication. The resulting DNA is a recombinant DNA molecule.

One application of recombinant DNA technology is producing the protein insulin, which is needed to treat diabetes. Previously, insulin had been extracted from the pancreases of animals. Through recombinant DNA technology, bacteria were created that carry the human gene which codes for the production of insulin. These bacteria become tiny factories that produce this protein. A step-by-step depiction of the cloning of the insulin gene is shown below in (Figure below).

A step-by-step depiction of the cloning of the insulin gene. The plasmid is opened up with restriction enzymes and the gene of interest (human cDNA) is inserted into the plasmid with complementary linkers, producing the recombinant plasmid. The plasmid is transfected into bacterial cells, where the human protein is produced.

Cloning

Cloning is the process of creating an exact replica of an organism. The clone’s DNA is exactly the same as the parent’s DNA. Bacteria and plants have long been able to clone themselves through processes of asexual reproduction. In animals, however, cloning does not happen naturally.

Animals can now be cloned in a laboratory, however. In 1997, a sheep named Dolly was the first mammal ever to be successfully cloned. The process of producing an animal like Dolly starts with a single cell from the animal that is going to be cloned. In the case of Dolly, cells from the mammary glands were taken from the adult that was to be cloned. These cells are called somatic, meaning they come from the body and are not gametes like sperm or egg. Remember that somatic cells have a diploid number of chromosomes. Next, the nucleus was removed from this cell. The nucleus was placed in a donor egg that had already had the nucleus removed. The new cell then divided after the stimulation of an electric shock, and development proceeded normally just as if the embryo had formed naturally. The resulting embryo was implanted in a surrogate mother sheep, where it continued its development. This process is shown in Figure below.

To clone an animal, a nucleus from the animals cells are fused with an egg cell (from which the nucleus has been removed) from a donor.

Cloning is not always successful, though. Most of the time, this cloning process does not result in a healthy adult animal. The process has to be repeated many times until it works. In fact, 277 tries were needed to produce Dolly. This high failure rate is one reason that human cloning is banned in the United States. In order to produce a cloned human, many attempts would result in the surrogate mothers experiencing miscarriages, stillbirths, or deformities in the infant. There are also many additional ethical considerations related to human cloning.

Human Genome Project

A person’s genome is all of his or her genetic information; in other words, the human genome is all the information that makes us human. The Human Genome Project (Figure below) was an international effort to sequence all 3 billion bases that make up our DNA and to identify within this code the over 20,000 human genes. Scientists also completed a chromosome map, identifying where the genes are located on each of the chromosomes. The Human Genome Project was completed in 2003. Though the Human Genome Project is finished, analysis of the data will continue for many years.

To complete the Human Genome Project, all 23 pairs of chromosomes in the human body were sequenced. Each chromosome contains thousands of genes. This is a karyotype, a visual representation of an individuals chromosomes lined up by size.

There are many exciting applications of the Human Genome Project. The genetic basis for many diseases can be more easily determined, and now there are tests for over 1,000 genetic disorders. The National Institutes of Health, the United States government’s premiere biomedical research community, is also looking for ways to reduce the costs of sequencing so that people can have a map of their individual genome. Although some disorders are caused by a single gene, many other illnesses are caused by a combination of several genes and a person’s lifestyle. Analysis of your own genome could determine if you are at risk for specific diseases. Knowing you might be genetically prone to a certain disease would allow you to better seek preventive lifestyle changes and medical screenings.

A genetic map shows the location (or loci) of a gene on a chromosome. Genetic maps are important tools to help researchers understand genes and genetic diseases. Knowing where genes are in relation to other genes and knowing the order of genes on a chromosome is an important aspect of human genetics. The frequency of recombination (crossing-over during prophase I of meiosis) allows geneticists to estimate the distance between loci. Because crossing-over occurs relatively rarely at any location along the chromosome, the frequency of recombination between two locations depends on their distance. The farther apart genes are on the same chromosome, the more likely there is to be a cross-over event between them. The likelihood of a cross-over event between two closely located genes (said to be linked) is small.

Gene Therapy

Gene therapy is the insertion of genes into a person’s cells to cure a genetic disorder. There are two main types of gene therapy; one done inside the body and one done outside the body. In ex vivo gene therapy, done outside the body, cells are removed from the patient and the proper gene is inserted using a virus as a vector. Then the modified cells are placed back into the patient. One of the first uses of this type of gene therapy was in the treatment of a young girl with a rare genetic disease, Adenosine deaminase deficiency, or ADA deficiency. People with this disorder are missing the ADA enzyme, which breaks down a toxin called deoxyadenosine. If the toxin is not broken down, it accumulates and destroys immune cells. As a result, individuals with ADA deficiency do not have a healthy immune system to fight off infections. In the gene therapy treatment for this disorder, bone marrow stem cells were taken from the girl’s body and the missing gene was inserted in these cells outside the body. Then the modified cells were put back into her bloodstream. This treatment proved sufficient to restore the function of her immune system, but only with continual repeated treatments.

During in vivo gene therapy, done inside the body, the vector with the gene of interest is introduced directly into the patient and taken up by the patient’s cells. The vector is inserted where the gene product is needed. For example, cystic fibrosis gene therapy is targeted at the respiratory system, so a solution with the vector can be sprayed into the patient’s nose. Recently in vivo gene therapy was also used to partially restore the vision of three young adults with a rare type of retinal disease that is congenital, meaning present at birth.

Biotechnology in Medicine and Agriculture

There are many applications of genetic information, including applications in medicine and agriculture. These applications show daily the significance of biotechnology, and the impact biotechnology has on our society.

Medicine

As mentioned above, one application of recombinant DNA technology is producing the protein insulin. Using biotechnological techniques, the specific gene sequence that codes for human insulin was introduced into the bacteria E. coli. The transformed gene altered the genetic makeup of the bacterial cells, such that in a 24 hour period, billions of E. coli containing the human insulin gene resulted, producing human insulin to be administered to patients. Recombinant DNA technology has allowed mass quantities of insulin to be produced, treating the growing population that relies on this protein.

Though the production of human insulin by recombinant DNA procedures is an extremely significant event, many other aspects of DNA technology are beginning to become reality. In medicine, modern biotechnology provides significant applications in such areas as pharmacogenomics, genetic testing (and prenatal diagnosis), and gene therapy. These applications use our knowledge of biology to improve our health and our lives. Many of these medical applications are based on the findings of the Human Genome Project.

Agriculture

Biotechnology has also led scientists to develop useful applications in agriculture and food science. These include the development of transgenic crops - the placement of genes into plants to give the crop a beneficial trait. Benefits include:

- Improved yield from crops.
- Reduced vulnerability of crops to environmental stresses.
- Increased nutritional qualities of food crops.
- Improved taste, texture or appearance of food.
- Reduced dependence on fertilizers, pesticides and other agrochemicals.

Crops are obviously dependent on environmental conditions. Drought can destroy crop yields, as can too much rain or floods. But what if crops could be developed to withstand these harsh conditions? Biotechnology will allow the development of crops containing genes that will enable them to withstand harsh conditions. For example, drought and excessively salty soil are two significant factors affecting crop productivity. But there are crops that can withstand these harsh conditions. Why? Probably because of that plant's genetics. So scientists are studying plants that can cope with these extreme conditions, trying to identify and isolate the genes that control these beneficial traits. The genes could then be transferred into more desirable crops, with the hope of producing the same phenotypes in those crops.

Thale cress (Figure below), a species of Arabidopsis (Arabidopsis thaliana), is a tiny weed that is often used for plant research because it is very easy to grow and its DNA has been extensively characterized. Scientists have identified a gene from this plant, At-DBF2, that gives the plant resistance to some environmental stresses. When this gene is inserted into tomato and tobacco cells, the cells were able to withstand environmental stresses like salt, drought, cold and heat far better than ordinary cells. If these preliminary results prove successful in larger trials, then At-DBF2 genes could help in engineering crops that can better withstand harsh environments. Researchers have also created transgenic rice plants that are resistant to a rice virus. In Africa, this virus destroys much of the rice crops and makes the surviving plants more susceptible to fungal infections.

Thale cress.

Lesson Summary

- Using recombinant DNA technology, a foreign gene can be inserted into an organism’s DNA.
- Cloning of mammals is still being perfected, but several cloned animals have been created by implanting the nucleus of a somatic cell into a cell in which the nucleus has been removed.
- The Human Genome Project produced a genetic map of all the human chromosomes and determined the sequence of every base pair in our DNA.
- Gene therapy involves treating an illness caused by a defective gene through the use of a vector to integrate a normal copy of the gene into the patient.

Review Questions

1. What is the enzyme used to cut DNA at specific points?
2. What is the term for all the genetic information of the human species?
3. What are the rings of accessory DNA in bacteria that are often used as a vector in genetic engineering?
4. What is the term for producing identical copies of an organism?
5. Can gene therapy cure a disease caused by a virus?
6. What is the vehicle used to introduce foreign DNA into an organism?
7. What is one disease that genetic therapy can help treat?
8. What supplies the cytoplasm of the clone’s cells during the cloning of an organism?
9. What is one application of recombinant DNA technology?
10. Is gene therapy for ADA deficiency a permanent fix?

Further Reading / Supplemental Links

- http://www.ornl.gov/sci/techresources/Human_Genome/home.shtml
- http://history.nih.gov/exhibits/genetics/sect4.htm
- http://learn.genetics.utah.edu/units/disorders/whataregd/ada/
- http://www.lifesitenews.com/ldn/2007/nov/07112003.html
- http://www.le.ac.uk/ge/genie/vgec/sc/genomics.html
- http://en.wikipedia.org/wiki/Recombinant_DNA
- http://www.hhmi.org/biointeractive/vlabs/transgenic_fly/index.html
- http://www.na.fs.fed.us/fhp/ded/

Vocabulary

cloning
Creating an identical copy of an individual with the same genes.

DNA ligase
Enzyme that joins DNA fragments together.

gene therapy
Treatment that provides a new gene to replace a defective gene; potentially "cures" a genetic disease.

Human Genome Project
International effort to sequence all the base pairs in human DNA.

plasmid
An accessory circle of DNA in bacteria.

recombinant DNA
DNA formed by the combination of DNA from two different sources, such as placing a human gene into a bacterial plasmid.

somatic cell
A body cell; not a gamete.

transformation
The process by which bacteria pick up foreign DNA and incorporate it in their genome.

vector
A vehicle, such as a plasmid, used to transfer foreign DNA into an organism.

Points to Consider

Next we begin to discuss evolution, the change in species over time.

- Fossils provide evidence of evolution, but what is a fossil?
- If two animals are similar in structure, would you guess they are closely related? Why or why not?