I have divided the second major topic (Genetics) into nine subtopics. Each subtopic is handled separately. This review is organized in the following format: subtopic outline, discussion of the subtopic, and finally references for that subtopic.
Subtopics Discussed
- DNA and Chromosomes: Life's Blueprint
- The Cell Cycle: Duplicating Life
- Meiosis and Gametogenesis
- Fertilization and Early Fetal Development
- RNA, Protein Synthesis, and Gene Expression
- Patterns of Genetic Inheritance
- Genetic Disease and Disorders
- Cancer: The Cell Cycle Gone Awry
- Genetic Testing, Genomics, and Genetic Technology
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Subtopic 1: DNA and Chromosomes: Life's Blueprint
Outline
I. DNA
A. Structure of DNA
B. Replication of DNA
II. Chromosomes
III. The Relationship of DNA, Chromosomes, and Genes
(Image left from microsoft clipart)
Discussion 1.1 DNA
Structure of DNA
The instructions for life are found in the nucleus of the cell. DNA (deoxyribonucleic acid) is the material that the instructions for life are written with. DNA is shaped into a spiral referred to as a double helix. If it were uncoiled, DNA would look like a ladder. The "sides" are constructed of repeating phosphate and sugar molecules and the "rungs" going down the middle are made of pairs of nitrogen containing bases. Another way to describe the structure of DNA is to say that it is composed of repeating units of nucleotides. Each nucleotide consists of a single nitrogen-containing base, a sugar (deoxyribose), and phosphoric acid (phosphate).
The bases of the nucleotides in DNA "pair up" in a specific way. Guanine always pairs with cytosine, thymine will always pair with adenine. Guanine and Adenine are know as purines and are composed of two rings. Thymine and Cytosine are composed of one ring and are called pyrimidines. The shapes of these complimentary base pairs fit together. They are held together by hydrogen bonds. The images below illustrate the structure of DNA and the nucleotides.
DNA Replication
DNA replication is the way that the cell passes on its genetic information when the cell divides. The complimentary base pairing mentioned above is what allows DNA to be replicated in a way that protects against sequencing errors.
Generally, the genetic material is not visible even with a microscope. But just prior to the start of DNA replication, the chromatin (or strands of genetic material composed of DNA) begins to condense. Now an enzyme called DNA polymerase splits open the double-helix exposing its bases and brings in complimentary bases which are free in the nucleus. This process forms a new strand of DNA.
The old strand serves as a template for the new strand. Each double helix now contains one "old" strand of DNA and one "new" strand of DNA. If there are any breaks in the sugar-phosphate structure of the sides of the DNA, another enzyme seals these to complete the process and produce two identical DNA strands. Rarely, an error in replication occurs where the base sequence is altered somehow. If this happens, another enzyme is responsible for repairing the error. If an error persists and is not repaired it is called a mutation. Mutations will be discussed in more detail later in this review. The process of DNA replication is illustrated below.
![[image[47].png]](http://lh6.ggpht.com/cmcbride2008/SL-DgHmyCmI/AAAAAAAAAgs/8P8QqEza7ck/s1600/image%5B47%5D.png)
Image taken from my unit I lab
Discussion 1.2 Chromosomes
Chromosomes
When the strands of chromatin condense prior to replication, chromosomes are formed. The shape of the chromosomes are formed by proteins (histones) that wrap around the condensed DNA strands. Each cell contains twenty-three pair of chromosomes. The pair of chromosomes that control gender are referred to as the sex chromosomes. The remaining twenty-two pair of chromosomes that do not impact gender are called autosomes.
When the genetic material condenses at the beginning of cell division it is possible to see the chromosomes with a microscope. Scientist do this by obtaining a cell sample from blood and then chemically stimulate the cell cycle. When the chromosomes most compact and are visible, cell division is stopped. Because replication has already occurred, each chromosome is now composed of two sister chromatids which are exact copies of one another. The chromosomes are stained and arranged into homologous pairs. This is called a karyotyping. The image below shows the karyotype of a normal male.
Discussion 1.3 DNA, Chromosomes, and Genes
The chromosomes contain regions called genes. Each gene corresponds to a particular trait (though some traits are controlled by several genes). Because one member of each pair of chromosomes is received from each parent, one gene (or allele) for each trait is received from each parent. Genes and inheritance will be discussed in more detail later in this review. The image to the left shows the relationship between DNA, chromosomes, and genes.
(photo left) www.oncolink.org/library/images/id818-1.gif
References
Images obtained from Aris site for Human Biology by Sylvia Mader (http://highered.mcgraw-hill.com/classware/selfstudy.do?isbn=0072986867 chapter resources - power point presentation), unless otherwise cited under image. All additional information for this subtopic obtained from Human Biology; Mader, Sylvia S., and instructor power point presentation.
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Subtopic 2: The Cell Cycle: Duplicating Life
Outline
I. The Cell Cycle
A. Interphase
B. Cell Divison
II. Control of the Cell Cycle
(photo right) http://www.nikonsmallworld.com/gallery.php?grouping=year&year=2004&imagepos=18
Discussion 2.1 The Cell Cycle
Interphase
The process of cell division allows the body to repair injury, replenish cells that wear out, and to grow. The cell cycle is a constant process for many of the cells of the body. Some cells complete the cycle very quickly while other cells never complete the cell cycle at all.
In addition to DNA replication, the cell undergoes other changes in preparation for cell division. This period of preparation is called interphase and takes up most of the overall time of the cell cycle. Interphase is divide into three stages: G1, S, and G2. During G1 the cell doubles its organelles and synthesizes the proteins it needs for DNA replication and to condense the genetic material from loose chromatin into chromosomes. The S stage is when the DNA is replicated (as discussed above). The G2 stage is another time of growth and when the cell performs protein synthesis of the proteins it will need to complete the process of cell division.
Cell division is the next stage of the cell cycle and is further divided into mitosis and cytokinesis. During mitosis the nuclear material of the cell is divided and the cell prepares to become two cells. Cytokinesis is the actual separation of the cytoplasm of the cell to form two new cells.
Mitosis
Prophase - Prophase is the first stage of mitosis. During prophase the the nucleolus disappears and the nuclear membrane starts to break up allowing the chromosomes to move free in the cytoplasm. The centrosomes begin to produce spindle fibers and also move away from one another toward opposite sides of the cell. Since DNA re
plication already occurred during interphase each chromosome is now composed of two identical sister chromatids. The sister chromatids are joined together by a region called the centromere (see image right). As the spindle fibers form, they branch out and attach to the chromosomes at the centromeres.
Metaphase - Metaphase is the next phase of mitosis. Now the spindle occupies a good portion of the cell and the chromosomes begin to line up in the middle of the cell. The spindle fibers begin to pull the sister chromatids apart. Other spindle fibers overlap with fibers from the opposite centrosome and work to push the chromosomes apart. The spindle fibers are able to get longer or shorter by adding or removing it's protein subunits called tubulin.
Anaphase - The third stage of mitosis is anaphase. During anaphase the spindle fibers succeed in pulling the sister chromatids apart and begin to move them toward opposite sides of the cell. This allows each of the two daughter cells to receive the same genetic material.
Telophase - Finally, the cell is ready to divide. In telophase, the cleavage furrow is visible (cleft that forms between daughter cells), the spindle disappears, the nucleus and nucleolus reappear, and the chromosomes become chromatin again and are no longer condensed.
Cytokinesis - During cytokinesis the cell begins to pinch in half. This happens because of actin filaments located in a ring along the edge of the cell. The filaments contract and thus pinch the cell into two daughter cells. This process allows each new cell to maintain an intact cell wall during the entire process of cell division.
The result of mitosis is two cells that have the exact same genetic material and a complete set of organelles needed for cellular functions. The images to the left illustrate mitosis. The image below shows the stages of the cell cycle as well (this image is actually of a cancer cell). The link below is a fun little game I found. It just presents the basics of the cell cycle in an entertaining way. http://nobelprize.org/educational_games/medicine/2001/
As mentioned earlier, one of the reasons for cell division is to replace cells that have worn out. What happens to these old cells? Apoptosis is the way the body rids itself of old, damaged, or worn out cells. This is a kind of "programmed suicide" of cells. When the cell cycle and the process of apoptosis do not function properly cancer results. 
(image right)http://www.cbp.pitt.edu/faculty/yong_wan/index.html
Discussion 2.2
Control of the Cell Cycle
The cell cycle is controlled by cooperation between several molecules, proteins, protein receptors, and genes. The control of the cell cycle can be described in four phases. During reception an external stimulus causes a signal to be delivered to the cell. This stimulus may be from growth factors or hormones. A receptor protein in the cell membrane receives this signal and relays it to other proteins that form a pathway through the cell's cytoplasm. This system of proteins is called the signal transduction pathway. When the signal reaches the nucleus it is relayed to the appropriate genes. The genes that are responsible for stimulating the cell cycle are called proto-oncogenes and the genes that stop the cell cycle are called tumor-suppressor genes. Next, the genes stimulate the processes of transcription and translation to produce proteins. Finally, the proteins act to cause the cell cycle to either be stimulated or inhibited.
Leland Hartwell, Tim Hunt and Paul Nurse received the Nobel Prize in Medicine in 2001 for the discovery of the molecules "CDK" and "Cyclin" which are key proteins that together help to coordinate the cell cycle. (1)
(image left)http://nobelprize.org/nobel_prizes/medicine/laureates/2001/illpres/
Sometimes the cell cycle doesn't proceed as it should. For example, occasionally when a wound heals the cell cycle continues on after the wound has healed completely. This causes a keloid scar. Other times, this continuation of the cell cycle produces benign and cancerous tumors. (Cancer will be discussed in more detail later in this review.) Other problems that can arise related to the cell cycle are caused when the growth factors or other stimulating factors do not function properly.
References
(1) Nobelprize.org. Images obtained from Aris site for Human Biology by Sylvia Mader (http://highered.mcgraw-hill.com/classware/selfstudy.do?isbn=0072986867 chapter resources - power point presentation), unless otherwise cited under image. All additional information for this subtopic obtained from Human Biology; Mader, Sylvia S., and instructor power point presentation.
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Subtopic 3: Meiosis and Gametogenesis
Outline
I. Meiosis
A. Meiosis I
B. Meiosis II
II. Gametogenesis
A. Spermatogenesis
B. Oogenesis
(picture left)http://www.dreamstime.com/human-sperm-and-egg-fertilization-glow-image4187190
Discussion 3.1 Meiosis
The process of mitosis begins with one cell and makes an exact copy of it. The "parent" cell and the "copy" both have twenty three pair of chromosomes. In contrast, the process of meiosis begins with one cell that has the diploid number of chromosomes (23 pair) and ends with four haploid cells (half the usual chromosome number). This is because meiosis is a specialized form of cell division that is used to produce the gametes (eggs in females and sperm in males). It is necessary for the gametes to be haploid because when the sperm and egg are brought together during fertilization the chromosome number will be diploid again. In addition, the four cells present at the end of meiosis are not copies of the cell that began the process, nor are they copies of each other. They are all genetically unique and thus all the gametes are unique.
Meiosis I
Meiosis begins much the same as mitosis. Prior to prophase I of meiosis the DNA is replicated, the cell increa
ses in size, and the organelles double.
Prophase I - At this point meiosis begins to differ from mitosis. During prophase I of meiosis the homologous chromosomes (chromosomes that have genes for the same traits) pair up in what is called synapsis and exchange genetic material. This exchange of genetic information is called crossing-over. (See image right). Notice that crossing-over occurs between non-sister chromatids. This is one of the processes of meiosis that ensures that the daughter cells will be genetically different from the parent cell and from each other.
Metaphase I - After crossing-over has occurred the homologous chromosomes line up in the middle of the cell. Their arrangement is random (independent alignment) so that either pair (maternal or paternal indicated by different colors in image to the right) can be facing either side of the cell. This is another mechanism that creates genetic variability.
(image right)http://www.sciencecases.org/mitosis_meiosis/mitosis_meiosis2.asp
Anaphase I and Telophase I - The remaining steps of Meiosis I proceed the same as in mitosis except that in anaphase I of meiosis instead of sister chromatids being pulled apart, the homologous chromosomes are pulled apart by the spindle. Also, the result of telophase I in meiosis is two haploid cells that carry different genetic information.
Again, the key differences in mitosis and meiosis I are related the genetic identity of the cells. The goal of mitosis is to end with two identical cells, while the goal of meiosis I is to produce two cells that are genetically different from one another and that are also genetically different from the original cell. This is accomplished by 1) crossing over, 2)independent alignment of chromosomes and 3)homologous pairs are split rather than sister chromatids.
Meiosis II
Meiosis II proceeds exactly as mitosis; however, there is no duplication of genetic material prior to it's start. Also, both daughter cells produced by meiosis I are dividing in meiosis II. The result is four daughter cells that are all genetically different from one another and from the original cell that started the process. This is possible even though the sister chromatids are being separated because of crossing-over that occurred during meiosis I. (The image below is a comparison of mitosis and meiosis.)
Discussion 3.2 Gametogenesis
As mentioned above, meiosis is the process that creates the gametes or sex cells and therefore meiosis is specialized depending on if it is taking place in the testes of the male (spermatogenesis) or the ovaries of the female (oogenesis). While both spermatogenesis and oogenesis still follow the sequence of events outline above in the discussion on meiosis there are some differences that are of importance.
Spermatogenesis
The process of spermatogenesis is continuously occurring in males beginning with puberty when the sex organs mature. Around 400 million sperm are produced per day. The original diploid cell that enters into meiosis I is referred to as the primary spermatocyte in spermatogenesis. During meiosis I the primary spermatocyte divides into two secondary spermatocytes that are haploid. The two secondary spermatocytes complete meiosis II and divide into four cells which are also haploid and are called spermatid. Now, the four spermatids undergo metamorphasis and maturation to become sperm.
Quite a few structural changes occur to produce mature sperm cells. The maturing spermatid are housed in the cytoplasm of serotoli cells (right) which are specialized epithelial cells of tubules in the testes. The serotoli cells are believed to nourish the spermatid as they develop into sperm. (2)
http://www.answers.com/topic/spermatogenesis
The process of meiosis and the production of eggs in the female (oogenesis) differs from spermatogenesis in a number of ways. At birth or shortly after birth the follicles in ovaries of females contain approximately seven million primary oocytes that are stalled in prophase I of meiosis I. After a women reaches puberty and begins to ovulate, with each cycle a single oocyte (sometimes two) continues with meiosis I to produce the secondary oocyte and the first polar body. The secondary oocyte receives the majority of the cytoplasm and the first polar body will not be allowed to mature. The polar bodies serve as a way to discard the extra chromosomes created by duplication while still maintaining genetic variability. (1)
The secondary oocyte now leaves the ovary and moves into the oviduct. At this point meiosis again stalls. The secondary oocytes reaches metaphase II and stops unless fertilization is initiated by sperm entering the cell. If the secondary oocyte (or egg) is fertilized then meiosis II will continue producing more polar bodies. After meiosis II is complete the polar bodies will disentigrate. The resulting egg is haploid until it fuses with the sperm to form the diploid zygote.
References
(1) Wikipedia online encyclopedia. (2) Answers.com. http://www.answers.com/topic/spermatogenesis. Images obtained from Aris site for Human Biology by Sylvia Mader (http://highered.mcgraw-hill.com/classware/selfstudy.do?isbn=0072986867 chapter resources - power point presentation), unless otherwise cited under image. All additional information for this subtopic obtained from Human Biology; Mader, Sylvia S., and instructor power point presentation. ______________________________________________________________________
Subtopic 4: Early Fetal Development
Outline
I. Fertilization
II. Preembryotic Development
(picture right)http://en.wikipedia.org/wiki/Embryo#The_human_embryo
Discussion 4.1 Fertilization
When the products of meiosis mature the sperm (in males) and the egg (in females) is produced. As discussed in the section on meiosis the sperm and egg are both haploid. During fertilization the nucleus of the sperm and the nucleus of the egg merge. This creates a haploid single cell known as a zygote. The zygote it the first cell of a new human being that carries half of the chromosomes of the mother and half of the chromosomes of the father.
The egg has a plasma membrane that is covered in microvilli, as well as two other layers outside the plasma membrane. The outermost layer is the corona radiata, which is made up of layers of cells from the follicle of the ovary. These cells were responsible for nourishing the egg before it was released from the follicle. Between the corona radiata and the plasma membrane of the egg is a region of extracellular matrix called the zona pellucida.
Fertilization begins with a number of sperm actively trying to penetrate the outer membranes of the egg. Typically, several sperm are able to make their way through the corona radiata but only one actually gets all the way through to the cytoplasm of the cell. This is accomplished because of the unique structure of the sperm. The sperm is basically a heal and tail. The tail is used to propel the sperm so that it can reach the egg that is making its way through the oviduct. The head of the sperm contains the nucleus and little else. Between the head and tail is a cylindrical middle region composed of the energy producing mitochandria.
Once the sperm reach the egg it (or several sperm actually) pushes through the corona radiata. When the zona pellucida is reached the sperm binds itself to the matrix. The head of the sperm (called the acrosome) releases digestive enzymes that eat through the zona pellucida. Fianlly, a sperm makes its way into the cell membraneof the egg and fuses with it. Once this happens the plasma membrane depolarizes which prevents any other sperm from fusing with it. Also, cortical granules which are vesicles in the cell release enzyme that prevent the zona pellucida from being penetrated. Now, the head of the sperm (containing the nucleus and genetic material of the father) breaks away from the body of the sperm and fuses with the nucleus of the egg.
Discussion 4.2 Pre-embryonic Development
Once the egg is fertilized by the sperm the new cell is called a zygote. If two eggs are released from the ovaries and both are fertilized the zygotes will develop into fraternal twins. I have some personal experience with fraternal twins (below). (I couldn't resist showing off my babies and doing a little public awareness work for anencephaly).
My daughter Faith was born with a birth defect called anencephaly. Anencephaly is a neural tube defect related to spinabifida. Rather than the spine being affected (as in spinabifida) the neural tube does not close completely. This results in portions of the brain and skull not forming properly or being disintegrated by exposure to the amniotic fluid. Anencephaly is believed to be multifactoral most of the time (just like cancer) where a predisposition to the condition exists genetically, and then environmental factors cause the condition to actually develop. Anencephaly is also believed to be associated with folic acid consumption of the mother PRIOR to becoming pregnant and very early in development (though the mechanisms behind it are not fully understood). This is why many doctors recommend that ALL women of childbearing age take a daily folic acid supplement.
We took part in a research study that is ongoing through Duke University. As part of the study Faith's karyotype was mapped. In Faith's case, it does not appear that any genetic mutations took place to cause her condition because her karyotype was normal. As you can see, my son Connor does not share his sister's condition. Even if Faith's condition were genetic in origin it would not be guaranteed that he would have it. That is because fraternal twins share no more genetic material than normal siblings. Identical twins however, have the exact same genetic material and are always the same gender. Identical twins result from a division of morula (discussed bleow).
The single cell zygote begins to undergo repeated phases of cell divisions. While these divisions are occurring the cell is making it way down the oviduct to the uterus. This journey generally takes about a week to complete. During this time the zygote becomes a ball of cells known as the morula. Usually, the morula is an undefined mass of cells joined together, but sometimes the morula divides into two. If this happens identical twins result. As it continues toward the uterus the morula continues to add cells and becomes a blastocyst.
Once it reaches the blastocyst stage there is a obvious arrangement to the cells. An outer layer is present that will become the chorion which will become a portion of the placenta. Inside this outer layer is a ball of cells that will become the embryo.
At the end of this first week of development the blastocyst implants into the wall of the uterus. The blastocyst is now an embryo. If the embryo implants into the oviduct before it reaches the uterus the result is an ectopic pregnancy. The pregnancy will be miscarried or terminated. Rarely, if an ectopic pregnancy goes undetected for too long the oviduct will rupture which puts the mother at risk. 
References
Images obtained from Aris site for Human Biology by Sylvia Mader (http://highered.mcgraw-hill.com/classware/selfstudy.do?isbn=0072986867 chapter resources - power point presentation), unless otherwise cited under image. All additional information for this subtopic obtained from Human Biology; Mader, Sylvia S., and instructor power point presentation. ____________________________________________________________________________________
Subtopic 5: RNA and Gene Expression
Outline
I. RNA
II. Proteins
III. Transcription
IV. Translation
V. Regulation of Gene Expression
http://www.genome.gov/13514624
Discussion 5.1 RNA
RNA (ribonucleic acid) is a companion to DNA. RNA is typical found as a single strand rather than a double helix but is constructed much the same as DNA with a couple of substitutions. The backbone of RNA is made of the sugar ribose bonded to phosphoric acid rather than deoxyribose. The "rungs" of RNA are constructed from bases; however, RNA uses the base uracil where DNA would use the base thymine.
There are three types of RNA which all serve a different purpose. Ribosomal RNA (rRNA) is constructed in the nucleolus of the nucleus. rRNA joins with proteins to form ribososmes where protein synthesis occurs. Messenger RNA (mRNA) is created in the nucleus of the cell and functions as a replica or facsimile of DNA. After mRNA is formed in the likeness of a portion of DNA it then carries the genetic code to the ribosomes so that they can create proteins. Transfer RNA (tRNA) is also formed in the nucleus. Like mRNA, tRNA uses DNA as a template for its construction; however, tRNA only carries a three letter code (anticodon). Based on this code tRNA picks up corresponding amino acids and carries or transfers them to the ribosomes. These amino acids are the building blocks for proteins. Each of these processes involving R
NA will be explored in more detail in a moment.
Discussion 5.2 Proteins
As mentioned above, amino acids are the subunits of proteins. Protein synthesis is one of the primary functions of DNA and RNA. Proteins are crucial to the functioning of the cell and the human body. Proteins function in many different ways in the body. They compose many of the structural elements of the body, other proteins catalyze reactions, antibodies which fight disease and infection are proteins, and other proteins function in movement of the cells and the body.
In order for proteins to function properly they must maintain their unique shape. This shape is dependent on the number and order of the amino acid subunits. There are only twenty different amino acids in the body which "build" the proteins, but almost unlimited variability is possible in the construction of proteins. This because of the unique shape of proteins. Proteins are not just linear chains of amino acids. They also coil and fold and create bonds to hold these unique shapes. (See image right).
Discussion 5.3 Transcription
Transcription is the process that transfers the genetic code from DNA to mRNA and is the first step in protein synthesis. RNA ploymerase (a type of protein called an enzyme) causes a portion of the DNA to split apart and then joins the RNA nucleotides to form the new mRNA strand. The mRNA is an exact copy of the DNA template with one exception. Wherever DNA has the base thymine, RNA substitutes the base uracil.
The next step toward creating a protein is the processing of the newly formed mRNA strand. This occurs before the mRNA leaves the nucleus of the cell. Processing removes part of the nucleotide sequence that is not needed. After processing, the strand of mRNA travels out of the nucleus and is received by ribosomes in the cytoplasm. This is where the process of translation occurs. (See images below).
Discussion 5.4 Translation
The main structures involved in translation are labeled in the image to the right. As you can see, the ribosome is actually composed of two subunits. A larger unit, which holds two sites to receive tRNA (P site and A site) and a smaller unit which receives the mRNA. Just before translation begins the two subunits come together. This first step of polypeptide synthesis (or protein synthesis) is called initiation.
Then tRNA carrying an amino acid on one end and a set of three bases on the other end joins with the ribosome. The set of bases the tRNA is carrying is called the anticodon and corresponds to the codon (another set of three bases) on the mRNA strand. Each codon corresponds to a different amino acid. This pairing of complimentary codons and anitcodons is how the "blueprint" of protein construction is decoded.
The second phase of translation is called elongation. During this stage the polypeptide chain attached to the P site continues to lengthen one amino acid at a time, as the ribosome moves down the mRNA strand and new tRNA's carrying more amino acids come into the ribosome.
The final stage is termination. This is signaled by the ribosome reaching a stop codon on the mRNA strand. When this happens the process of elongation stops and the structures separate.
Discussion 5.5 Regulation of Gene Expression
Each cell in the body has the same set of chromosomes and thus theoretically all cells should be the same. We know however, that this is not the case. The cells of the body are specialized. A bone cell doesn't look or function anything like a neuron. This is because different genes are expressed in different cells.
Transcription factors are a type of protein that functions to turn on or off certain genes. It is believed that signals (either from inside or outside the cell) tell the DNA of a cell which transcription factors to synthesize. These transcription factors then signal the DNA to "turn on" and "turn off" certain genes. This in turn helps to determine the cells specialization. There are a number of other mechanisms that function to regulate gene expression as well.
One method of controlling gene expression is by controlling which portions of DNA are accessible to be copied into mRNA during transcription. Even if the DNA is transcribed into mRNA other control factors may impact if or how fast the mRNA is processed prior to translation. Still other mRNA strands may be prepared and processed but not translated either because they do not remain active long enough, they do not bind to the ribosomes, or other factors. After tanslation it is possible for a protein to require modification before being usable to the cell. Other proteins may be inhibited by their shape being changed in some way. In other words, there are control mechanisms at work at each stage of protein synthesis to regulate gene expression.
The ability to control genetic expression is an area of great promise and of great controversy. Issues concerning DNA technology will be discussed in section eight of this review.
References
Images obtained from Aris site for Human Biology by Sylvia Mader (http://highered.mcgraw-hill.com/classware/selfstudy.do?isbn=0072986867 chapter resources - power point presentation), unless otherwise cited under image. All additional information for this subtopic obtained from Human Biology; Mader, Sylvia S., and instructor power point presentation.
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Subtopic 6: Genetic Inheritance
http://www.biologie.uni-hamburg.de/b-online/ge10/04.gif
Outline
I. Genotype and Phenotype
II. Simple Inheritance and Punnett Squares
A. Inheritance
B. Punnett Squares
C. Monohybrid Cross
D. Dihybrid Cross
III. Other Inheritance Patterns
A. Polygenic Inheritance
B. Multifactoral Influence
C. Incomplete Dominance
D. Codominance and Multiple Allele Inheritance
E. Sex-Linked Inheritance
Discussion 6.1 Genotype and Phenotype
As discussed in the section on chromosomes, humans have twenty three pair of chromosomes. Genes (or segments of these chromosomes) are what determine our traits. The genotype is the actual genes that are present in an individual. The display of traits an individual inherits is called the phenotype. Phenotype can refer to visible traits (like eye color) or non visible traits (like sickle-cell anemia).
In mitosis or cell division, the resulting daughter cells have a full compliment (23 pair) of chromosomes. However, meiosis produces daughter cells (sperm in males and ovum in females) that only contain a single chromosome of each pair. When the sperm and egg are brought together during fertilization the resulting zygote again has paired chromosomes. One of each pair is provided by the egg (or the mother) and one of each pair is provided by the sperm (or the father). In this way, genetic information from both parents is relayed to the child.
Discussion 6.2 Simple Inheritance and Punnett Squares
Genetic Inheritance
The question of which trait will be displayed is a more complicated matter. Each gene is responsible for a trait or characteristic. Some traits (like eye color) actually have several genes that influence them. Again, an allele or gene for each trait is inherited from each parent (genotype). The interaction of these alleles follows certain rules which determine the resulting phenotype.
An individual can inherit either a dominant allele (indicated by a capital letter) or a recessive allele (indicated by a lower case letter) from each parent. If a dominant allele is inherited from both parents, the individual is referred to as having a homozygous dominant genotype for that trait. (Shown in the image to the right as EE in the example for unattached earlobes). Should a recessive allele be inherited from each parent, the individual is referred to as homozygous recessive. (Indicated by ee in the example to the right). Finally, if a dominant allele is inherited from one parent and a recessive allele is inherited from the other parent, the individual is heterozygous. (Ee in the earlobe example.)
Individuals with the homozygous dominant genotype will display the dominant trait, as seen to the right by the individual having unattached earlobes. In this case, there is no other possible option. The gene for unattached earlobes was inherited from both parents. In the same manner, an individual that inherits a recessive allele from both parents will display the recessive trait (attached earlobes). Oftentimes, the recessive trait is expressed as an absence of the trait. In other cases, the trait in question is a recessive trait. This means that an individual with a homozygous recessive genotype will express the trait. What happens when an individual inherits one dominant allele and one recessive allele as in the Ee genotype? A dominant allele "cancels out" a recessive allele. Thus, the dominant trait is expressed. In the example the individual has unattached earlobes even though the recessive allele was received from one parent. The dominant trait was express because they received the dominant allele and the recessive allele is canceled out.
Punnett Squares
It is not always possible to determine the exact genotype of an individual based solely on the genotype of the parents. However, we can determine all the possible genotypes of offspring produced by a particular cross (reproduction of two specimen or individuals). This is accomplished by the use of a Punnett square. There are situations where the rules of inheritance outlined above and Punnett squares can not be used, but in general it is very useful in determining the outcomes of a particular cross. The Punnett square was developed by Reginald Punnett an English geneticist in the early 1900's. (1)
Monohybrid Cross
The image to the right is an example of a Punnett Square for a cross between two individuals that are heterozygous for the trait of freckles. This is known as a monohybrid cross (mono = one trait and hybrid = heterozygous). A crossing of two subjects that are both heterozygous for a trait results in three out of four individuals that display the phenotype of the trait in question and the following ratio of genotypes (1 homozygous dominant: 2 heterozygous dominant: and 1 homozygous recessive). It is important to note that this is a ratio that is achieved after many crosses. It is not possible to predict the genotype or phenotype of a particular offspring in a monohybrid cross.
The results of a dihybrid cross (di = two and hybrid = heterozygous) is shown to the left. As in the monohybrid cross, the results follow the same probability each time. The phenotype ratio is always 9:3:3:1. Again, the outcome of a particular individual can not be predicted. What is shown is all possible outcomes.
In other situations, it is possible to tell the genotype of individuals based on phenotypic evidence alone. For example, if a parent displays a dominant trait and then has a child that shows the recessive trait, we know that the parents genotype is heterozygous. If a parent displays a recessive trait, we know that it is not possible for the children to be homozygous dominant. They will be heterozygous (if they express the trait) or homozygous recessive (if they do not express the trait. If two parents display a recessive trait, then we know that all of their offspring will be homozygous recessive as well. The table below shows the outcome of other common crosses.
| Genotype | Phenotype |
| Monohybrid X Monohybrid | 3:1 (dominant to recessive) |
| Monohybrid X Monohybrid | 1:1 (dominant to recessive) |
| Dihybrid X Dihybrid | 9:3:3:1 (9 both dominant, 3 one dominant, 1 both recessive) |
| Dihybrid X Recessive | 1:1:1:1 (all possible combinations in equal number) |
Discussion 6:3 Other Inheritance Patterns
Polygenetic Inheritance
As mentioned regarding eye color, some traits are influenced by more than one gene. These traits are known as polygenetic traits. Other traits which are polygenetic are skin color and height. In the case of polygenetic traits the observed outcomes follows a bell curve with few having the extremes of the trait. Most people fall in the middle. This is seen in skin color when a person with dark skin and a person with fair skin have children that have a medium skin tone. On the other hand, it is possible for them to have children with either a dark skin color or light skin color.
Multifactoral Traits
Skin color and height are also good examples of multifactoral traits. Multifactoral traits are those influenced by other factors in addition to genetic inheritance. For example, nutrition can influence a person's height and sun exposure can influence skin color.
Some believe that other traits like behavior, intelligence, and mental disease is the result of multifactoral traits. This view attributes these traits partly to genes and partly to environmental factors. Researchers have found some evidence for this belief by studying twins. It has been found that identical twins (having identical genes) that are separated at birth, exhibit more similarities in these traits than fraternal twins (different genes) that were separated at birth. This suggests that these traits are at least partly due to genetic inheritance.
A number of disorders are caused by multifactoral influences on genes. These will be discussed in more detail in the next section of this review.
Incomplete Dominance
Sometimes an individual that has a heterozygous genotype for a trait does not have the dominant pheonotype, they have an intermediary phenotype. In this case, the heterzygote expresses a third phenotype that is in between the dominant and recessive expressions. This is seen when a person with straight hair and a person with curly hair produce a child with wavy hair. The pattern of inheritance of incomplete dominance can be better understood by examining what happens when two people who have wavy hair (are heterozygous) have children. The result is a ratio of 1 (curly-hair): 2 (wavy-hair): 1(straight-hair). This shows that the dominant allele still controls the appearance of the trait (the same as in simple inheritance), but in incomplete dominance more than one dominant allele is necessary for the dominant phenotype to be expressed. Receiving only one dominant allele creates the intermediary phenotype. Of course, receiving only recessive alleles causes the recessive phenotype (straight-hair).
Codominance and Multiple Allele Inheritance
Blood type is an example of multiple allele inheritance. There are three alleles that control blood type but each person only has two of the three alleles. Blood type also is an example of codominance. In codominance, two genes are involved as in polygenic inheritance, but both genes are expressed equally. If a person inherits one allele that carries the antigen for A blood and one that carries the antigen for B blood, then they have the blood type AB. This is because the alleles are codominant and both are expressed. Where does the O blood type come from? A person has the O blood type by two alleles that have neither the A or B antigen. (Indicated in the Punnett square by the letter i).
Sex Linked Inheritance
As mentioned in the section on chromosomes, individuals have one set of chromosomes that are called the sex chromosomes and the remaining twenty-two sets are autosomes. The sex chromosomes differ between gender. Women have two X chromosomes, while men have one X chromosome and one Y chromosomes. Not only do the sex chromosomes control gender but they carry alleles for other traits as well (these are sex-linked traits). If the trait is found on an X chromosome it is referred to as being an X-linked trait. Traits found on the Y chromosome of males are said to be Y-linked. The Y chromosome is much smaller than the X chromosome and carries fewer alleles. Because of this most sex-linked traits are coded by alleles on the X chromosome. In addi
tion, the X and the Y chromosomes do not code for the same traits.
An example of an X linked trait is red-green color blindness. Color blindness is much more common in males because they only need to inherit one allele for color blindness since the Y chromosome does not have an allele for the trait. That means that color blindness in a male is the result of it being passed on the X chromosome from his mother (not from his father as you would suspect). A Punnett Square for a cross between a male with normal vision and a female that is heterozygous for color blindness (a carrier for the trait) is shown to the right.
Most traits that are X-linked are recessive. This means that a female must inherit two recessive allele's to express the trait and a male only needs to inherit one recessive allele to express the trait. A few traits however are X-linked dominant. This means that a females as well as males only need to inherit one dominant allele to inherit the trait. So, all daughters of a man with the trait would also express the trait, but their sons would have to inherit a dominant allele from the mother in order to express the trait.
Other sex-linked traits will be discussed in the next section on genetic disease.
References
(1) Wikipedia online encyclopedia. Images obtained from Aris site for Human Biology by Sylvia Mader (http://highered.mcgraw-hill.com/classware/selfstudy.do?isbn=0072986867 chapter resources - power point presentation), unless otherwise cited under image. All additional information for this subtopic obtained from Human Biology; Mader, Sylvia S., and instructor power point presentation.
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Subtopic 7: Genetic Disease and Disorders
Outline
I. Changes in Chromosomes
A. Changes in Chromosome Number
B. Changes in Chromosome Structure
II. Genetically Inherited Disorders
A. Autosomal Recessive Disorders
B. Incomplete Dominance Disorders
C. Sex Linked Disorders
(picture left)http://www.icsia.net/en/wp-content/uploads/2008/03/genes.jpg
Discussion 7.1 Changes in Chromosomes
Changes in Chromosome Number
Occasionally, the processes and mechanisms discussed previously such as meiosis don't proceed normally. When problems occur in these processes genetic disease is usually the result. One way that problems can occur is if a person receives too many or too few chromosomes. Typically, this happens due to nondisjunction. Nondisjunction occurs during meiosis I when a homologous pair of chromosomes fails to split and both go to the same daughter cell. Nondisjunction can also occur in Meiosis II if sister chromatids fail to separate.
Trisomy and Down Syndrome
If an egg that contains an extra chromosomes is fertilized (by a normal sperm) the result is called a trisomy, because one chromosome will now be represented three times. The development of the individual which has a trisomy depends on which chromosome is affected. One of the most common conditions involving a trisomy is Down syndrome. In Down syndrome chromosome 21 is found in triplicate. Most individuals with Down syndrome survive. The result of Down syndrome is a number of externally recognizable characteristics as well as varying degrees of mental retardation. Risk factors for having a child with Down syndrome include the age of the mother and to some degree the age of the father.
By studying Down syndrome researchers have been able to identify a gene that is believed to be responsible for some instances of mental retardation. It has been name the Gart gene and causes an elevated production of purines.
Monosomy and Turner Syndrome
If an egg that contains one too few chromosomes is fertilized (by a normal sperm) the result is called a monsomy. The result is that one chromosome only has one copy. Individuals which have too few chromosomes do not do as well as those with too many. However, the chance for survival is much greater if the monosomy occurs with the sex chromosomes rather than an autosome. It has been found that in women with normal genetic inheritance one of the X chromosomes actually becomes inactive (known as a Barr body). A condition called Turner syndrome results when a female only has one X chromosome. Typically, those with Turner syndrome are of average intelligence, short with characteristic folds of skin on the neck,do not go through puberty, and do not develop secondary sexual characteristics without hormone supplements.
Poly-X Females, Klinefelter Syndrome, and Jacobs Syndrome
In other cases individuals will have an extra copy of the sex chromosomes. Women who are have three X chromosomes are called poly-X females. Poly-x females have no significant physical indication of the extra X chromosome, though they may have menstrual difficulties. Men can also have an extra X chromosome (XXY) which results in Klinefelter syndrome. Men with Klinefelter syndrome generally have very mild symptoms that something is wrong and only a small percentage are even diagnosed prior to puberty. They may have mild learning difficulties related to speech and language development. They also have low testosterone levels and generally can not reproduce naturally. Another possibility that can be caused by disjunction is a male the receives an extra Y chromosome (XYY) which is known as Jacobs syndrome. Men with Jacobs syndrome were once thought to be more aggressive or more prone to criminal behavior but that theory has lost steam due to recent research findings. Typically, the only difficulties men with Jacobs syndrome experience are in regards to speech and reading difficulty.
Changes in Chromosome Structure
A number of different conditions such as radiation, chemical exposure, or viruses can cause the actual structure of chromosome to change.
Deletion
Sometimes an end of a chromosome will break off or an internal piece of a chromosome will be lost due to two breaks. This causes a deletion. When chromosome 7 loses an end piece the result is Williams syndrome. In Williams syndrome, individuals have a characteristic "pixie" appearance. They also typically experience academic difficulties but excel in verbal skills and musical abilities. Also, people who have Williams syndrome lack the gene that controls elastin production. This causes cardiovascular system problems and causes their skin to age early.
Another condition that results from a deletion is Cri du chat syndrome. In this case, chromosome 5 loses an end piece. People with this syndrome are mentally retarded and have various head and facial deformities. They also have a characteristic cry (hence the name of the condition which means cat's cry) due to problems with the glottis and larynx.
Translocation
Sometimes rather than being lost a portion of a chromosome is moved onto another non-homologous chromosome. It has been found that some cases of Down syndrome are due to a translocation that occurred between chromosome 21 and 14 in a previous generation. Alagille syndrome is caused bya translocation between chromosomes 2 and 20. Alagille syndrome causes certain characteristic facial structure and severe itching. Other conditions caused by translocation of chromosomes are a tendency toward chronic myelogenous leukemia and Burkett lymphoma.
Duplication and Inversion
Other times, a portion of a segment of genetic material will be duplicated or inverted on its chromosome. These situations can causes other changes in chromosome structure to occur such as deletions. (see images below).
Discussion 7.2 Genetically Inherited Disorders
Quite a few diseases and disorders are inherited. Just like any other trait many disorders can be inherited by the patterns of simple inheritance (a single set of alleles codes for the condition). The condition can be dominant (inherited by the passing of just one dominant allele from one parents) or recessive (inherited by receiving a recessive allele from each parent). A condition that is inherited by dominant alleles are known as an autosomal dominant disorder and those inherited by recessive alleles are autosomal recessive disorders.
Genetic counselors use pedigree charges (seen below) to determine if a condition is autosomal dominant or autosomal recessive and to show the pattern of inheritance for the condition.
Autosomal Recessive Disorders
Knowing the probable outcomes of offspring is also of utmost importance to those with certain genetically inherited diseases or who are carriers for an inherited disease. For example, Tay-sachs Disease and Cystic Fibrosis are autosomal recessive genetic diseases. That means that these diseases are caused by mutations on an autosome (one of the 22 pair of chromosomes other than the sex chromosomes) and that the disease only appears if an individual is homozygous recessive.
So, if two individuals are both carriers (heterozygous) for the disease, they have a 25% chance of having a child that has the disease. If one parent has the disease (thus is homozygous recessive), the couple would have a 50% chance of having a child with the disease (assuming the other parent is a carrier or heterozygous). Even if the other parent were not a carrier (and one has the disease), it would be very important to their children to know that they would all be carriers of the disorder.
Tay-sachs disease is characterized by a lack of the lysosomal enzyme hexosaminidase. As a result lipid containing bodies build up in the tissue of the brain and cause slowed development and death typically by one year of age.
A similar disorder phenylketonuria (PKU) is another autosomal recessive disorder. In PKU individuals do not have an enzyme needed to metabolize the amino acid phenylalanine. A special diet that eliminates phenylalanine is n
ecessary to prevent the build up of the amino acid and mental retardation.
Another autosomal recessive disorder is cystic fibrosis . People with CF have unusually thick mucus. This affects the lungs and causes digestive problems by clogging the pancreatic ducts. It is believed this results from an inability of chloride ions to pass through the plasma membrane (right). This alters the sodium and water flow of the cell as well. The lack of water is what causes the thick mucous secretions.
Sickle-Cell disease is also an autosomal recessive disorder. Normally, red blood cells are concave disks, but in persons with sickle-cell the red blood cells are sickle-shaped. Sickle-cell was first described in the U.S.in 1910 by a cardiologist named James Herrick and his intern Ernest Irons when they examined the blood of a dental student from the West Indies. Later, in the early 1950's Anthony Allison, a doctor working in North Africa noticed that the distribution of sickle-cell corresponded with the distribution of the worst form of malaria. He concluded that this was the only explanation for the fact that the sickle-cell mutation persisted in such prevalence.
It was discovered that malaria does indeed play a part in sickle-cell anemia. A portion of the life cycle of the protozoan that causes malaria is spent in the red blood cells of its human host. If an individual has sickle-cell their red blood cells are removed by the spleen because they are malformed and aren't able to carry oxygen. This is little advantage to those who are homozygous recessive for sickle-cell because they are often debilitated by the disease and typically die early. But those who are heterozygous for the sickle-cell trait also have the sickle shaped cells in certain conditions. This gives those who are heterozygous for sickle-cell a distinct advantage in fighting malaria and they are typically do suffer complications of sickle-cell as do those who are homozygous recessive for the trait. This principle is known as balanced polymorphism because the heterozygous genotype is favorable over both the normal genotype and the homozygous recessive genotype.
Incomplete Dominance Disorders
Incomplete dominance disorders are disorders that vary depending on how many alleles for the trait an individual has. Familial hypercholesterolemia (FH) is an example. The condition is caused by mutated alleles that code for the LDL-cholesterol receptor proteins found the the plasma membrane of the cell. If an individual has has no mutated alleles for LDL receptor proteins then they have the normal number of receptors. If they have one mutated allele they have half the usual number of receptors and will generally experience cardiovascular disease early in life and may die by middle age. If an individual has two mutated alleles they have no receptors and will generally die in childhood of cardiovascular disease.(3)
Sex Linked Disorders
Colorblindness (discussed previously) is an example of a recessive X-linked disorder. Again, most sex-linked disorders are X-linked or found on the X chromosome because the Y chromosome is much smaller and carriers fewer alleles. Also, mentioned previously, most X-linked disorders are recessive. Very few X-linked dominant disorders are known. Other X-linked recessive disorders are muscular dystrophy and hemophilia.
Muscular dystrophy is a condition that causes the muscles to atrophe and typically leads to death by the age of 20. The cause of the disease is the lack of a protein (dystrophin) that is involved in the storage of calcium in the reticulum of muscle fibers. Because the dystrophin is missing, calcium leaches into the muscle cells and actually dissovles the muscle fibers. The problem is exacerbated by the fact that when the body attempts to repair the damage fibrous scar tissue forms which restricts the blood flow and causes more cells to die.
Hemophilia
Hemophilia is an X-linked recessive disorder that causes uncontrolled bleeding. There are two variations but both are due to a lack of clotting factors. Today both clotting factors that hemophiliacs lack are available as products of bioengineering.
Other Genetically Inherited Disorders (2)
| Disorder | Method of Inheritance | Mutation/ Cause | Symptoms | Incidence |
| Fragile X Syndrome | X-linked Recessive | FMR1 gene that codes for FMR1 protein | Causes mental retardation and attention disorders to varying degrees | Affects 1 in 2000 boys, 1 in 260 women are carriers |
| Polycystic Kidney Disease (ADPKD) | Autosomal Dominant | Mutation of PKD1 gene | Kidney cells develop into cysts, kidneys fail, other organs develop cysts, also may cause heart disease | Adult onset, affects 1 in 500 to 1 in 1000 |
| Polycystic Kidney Disease (ARPKD) | Autosomal Recessive | Mutation of PKD2 gene | Kidneys fail to develop normally in utero or are only partially formed | Affects 1 in 10,000 unborn and infants, usually fatal |
| Hemochromatosis | Autosomal Recessive | mutation of hemochromatosis gene | Body absorbs too much iron which builds up in the organs and causes organ damage | Most common genetic disorder in US, affects 1 in every 200-400 |
| Neurofibromatosis (NF1) | Autosomal Dominant | Mutation of NF1 gene on chrom 17 | Growths develop from nerve tissue and affects the peripheral nervous system,may cause learning disabilities | Affects 1 in 4,000 cafe au lait spot are a characteristic |
| Neurofibromatosis (NF2) | Autosomal Dominant | Mutation of NF2 gene on chrom 22 | Growths develop from nerve tissue and affect the central nervous system | Adult onset, affects 1 in 40,000 |
| Beta-thalassemia | Autosomal Recessive | Globin protein is missing | Red blood cells die, leads to severe anemia and early death if untreated | Most common genetic disorder in the world, affects 1 in 10 of Mediterranean decent |
References
(1) Wikipedia online encyclopedia. (2) Dolan DNA learning Center http://www.dnalc.org/ddnalc/websites/ygyh.html. (3)Washington University St. Louis http://www.nslc.wustl.edu/sicklecell/sicklecell.html. Images obtained from Aris site for Human Biology by Sylvia Mader (http://highered.mcgraw-hill.com/classware/selfstudy.do?isbn=0072986867 chapter resources - power point presentation), unless otherwise cited under image. All additional information for this subtopic obtained from Human Biology; Mader, Sylvia S., and instructor power point presentation.
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Subtopic 8: Cancer: The Cell Cycle Gone Awry
Outline
I. Carcinogenesis
II. Genetics of Cancer
A. Gain of Function Mutations
B. Loss of Function Mutations
C. The Cell Immortal
III. Types of Cancers
IV. Causes and Prevention
A. Genetic Predisposition
B. Environmental Causes and Risk Limitation
V. Diagnosis and Treatment
A. Diagnosis
B. Treatment
http://img.timeinc.net/time/quotes/2006/12/1215_breast_cancer.jpg
Discussion 8.1 Carcinogenesis
Carcinogenesis: The Progression of Cancer
Cancer begins as a single cell that mutates in such a way that it no longer follows the rules that govern cell division. It is as if the cell decided "I don't want to be a skin cell!" . . . and it stages a hostile take over of the body. The cell doesn't look or function like the cells around it. It may have more or less chromosomes and its nucleus is larger than normal. This rouge cell begins to divide uncontrollably .
It's daughter cells also share the initial mutation so they divide uncontrollably as well. As the divisions continue other mutations may occur. Normally, if a cell has a mutation it will undergo apoptosis (commit suicide), but cancer cells don't do this. They just keep dividing and passing on their mutated DNA. Normally cells stop dividing when they hit a neighboring cell but cancer cells just keep going, building up on on top of another until a tumor is formed. The tumor even creates a blood supply for itself by forming new blood vessels (angiogenesis).
Then, a cell emerges that has just the right combination of mutations to allow it break away from the tumor. The cytoskeleton of the cancer cells lacks structure so the cancer cell is able to invade neighboring blood vessels or lymph vessels. Now it is free to roam throughout the body and invade other organs forming tumors and preventing those organs from functioning as they should. Once this has occurred (metastasis), the prognosis for cancer's "host" is grim.
This represents the progression or stages of cancer if it goes untreated or if treatment fails. This is known as carcinognesis. The table below shows the stages of carcinogenesis and the characteristics of each stage. Occasionally, a tumor forms that is enclosed in a membranous capsule. This is called a benign tumor, because it is not able to penetrate the capsule to invade surrounding tissues. Other times a tumor will be discovered that is composed of epithelium and has not gone below the basement membrane of tissue. This is known as cancer in situ.
| Stages of Carcinogenesis |
| Initiation - one cell mutates and divides uncontrollably. |
| Promotion - a tumor is formed and more mutations occur. |
| Progression - one cell gains the ability to invade other tissues. |
Discussion 8.2 The Genetics of Cancer
How can a process that sustains life go so wrong that it can end life? It all goes back to that one cell and its genes. Normal cells have genes called proto-oncogenes that promote the cell cycle. Proto-oncogenes tell the ribosomes to synthesize proteins that cause the cells to divide and prevent apoptosis. If these genes mutate they becomes oncogenes. Oncogenes do the work of proto-oncogenes to excess. This type of mutation is a gain-of-function mutation.
Some oncogenes function by either coding for growth factors to be synthesized for by coding for more growth factor receptor proteins to be created. This makes the cell receive more growth factor than it normal
ly would. Thus the cell is able to divide at a much faster rate than normal.
Other mutations to proto-oncogenes cause the protein Ras to be produced in excess. Ras activates cyclin which stimulates DNA replication. Similarly the proto-oncogene known as cyclin-D causes cyclin to be produced directly. If there is a mutation to the cyclin-D gene then cyclin will be available to the cell all the time.
A mutation to another gene produces a protein that blocks p53. p53 is a protein that stimulates enzymes that repair mutationsto DNA or if the cell is too badly damaged p53 causes the cell to undergo apoptosis. If p53 is blocked the cell will not be able to repair any mutations that arise nor will it be able to undergo apoptosis. The image to the right shows the difference between the function of a normal proto-oncogene and a mutated proto-oncogene (oncogene).
In addition to proto-oncogenes that stimulate the cell to divide and prevent apoptosis, there are also tumor-suppressor genes that tell the ribosomes to create proteins to "turn off" the cell cycle. If a mutation occurs in a tumor-suppressor gene it loses its ability to inhibit the cell cycle or cause apoptosis. This type of mutation is a loss of function mutation.
The cyclin D gene is activated by a protein called retinoblastoma (RB). When the p16 gene that codes for the production of RB mutates the cyclin D gene is always active. Now, the cell undergoes DNA replication over and over again without the cell ever dividing.
Another tumor-supressor gene is responsible for coding for the protein Bax which causes the cell to undergo apoptosis. If the Bax gene mutates then the Bax protein is not produced and the cell does not undergo apoptosis.
The Cell Immortal
In addition to the mutations discussed above that either stimulate the cell cycle or prevent the suppression of the cell cycle, there are other ways that cancer cells don't follow the rules. Typically, a cell divides around 70 times and then undergoes apoptosis. This happens because the ends of chromosomes have special arrangements of DNA known as telomeres. Telomeres function like stop signs that keep the enzymes responsible for repairing broken DNA strands from connecting the end of one chromosome to the next. With each division of the cell (and thus each replication of the chromosomes), the telomeres at the ends of the chromosomes get shorter. After enough divisions the telomeres are gone and the repair enzymes bind the free ends of the chromosomes together. This alteration of DNA signals the cell to undergo apoptosis.
In cancer cells however, the gene that codes for the protein telomerase is turned on. Telomerase is a repair enzyme for telomeres. Rather than using up the telomere and signally the time for cell death, cancer cells just keep repairing the telomeres and the cell can divide indefinitely.
In addition to rebuilding telomeres to become immortal, cancer cells manage to evade the bodies immune system designed to seek and destroy invading antigens (like viruses) and rouge body cells like cancer and precancerous cells. Specialized cells called "B cells" make antibodies that are designed to destroy cancer cells and "T cells" seek and destroy directly. These cells are always active in the body but cancer cells manage to evade them. (4)
Discussion 8.3 Types of Cancers
Certain tissues are more prone to developing cancerous cells than other tissues. Mutations are much more likely (and thus cancer) in cells that divide very often such as the cells of the digestive and respiratory tracts. In fact, lung cancer is one of the most common causes of cancer death. The risk of lung cancer (as well as other cancers) is exacerbated by smoking. Smoking as it relates to cancer will be discussed in more detail in the section on cancer prevention.
Cancerous tumors are named by where they occur in the body. Carcinomas are cancers that begin in epithelial tissue. Tumors of the glandular epithelial are further classified as adeno-carcinomas. Carcinomas can affect the skin, breast, liver, pancreas, intestine, lungs, prostate, and the thyroid. Sarcomas are found in muscle or connective tissue and can occur in the bones and fibrous connective tissue. Leukemia is a type of cancer that affects the blood. Lymphoma is cancer that arises in the lymphatic tissue. Cancers of the lymphatic system are further specified by whether they are "Hodgkin" or "Non-Hodgkin".
The most common cancer in women is breast cancer and the most common cancer in men is prostate cancer. The chart below shows the latest estimates for new diagnosis and cancer related death from the American Cancer Society.
http://www.cancer.org/docroot/MED/content/MED_1_1_Most_Requested_Graphs_and_Figures_2008.asp
Discussion 8.4 Causes and Prevention of Cancer
Genetic Predisposition
The cause of cancer appears to be multi-factoral, resulting from heredity as well as environmental factors. There are still a lot of unanswered questions regarding how and why cancer develops in some people and not in others but several "cancer" genes have been identified.
One of the first of these identified was the BRCA1 or breast cancer 1 gene. Following it's discovery was the identification of the BRCA 2 gene. Researchers have found that if an individual inherits a mutated copy of one of the BRCA genes from one parent (meaning the mutation is present in all the cells of the body), another mutation to the other allele is necessary before their cancer risk is elevated. In other words, a person who inherits one BRCA 1 mutation and then "acquires" a second BRCA1 mutation is at a higher risk for cancer. Should they have other cancer promoting mutations cancer is likely to develop at the site of the second BRAC1 mutation. Most often mutations of the BRCA genes cause breast or ovarian cancer.
Similarly, if an individual inherits a mutated RB gene (which is a tumor suppressor gene) and then the other RB gene mutates in one of the cells they will be predisposed to cancer. Mutation of the RB gene is associated with retino-blastoma which is a cancerous tumor found in the eye. Secondary mutations are again required for cancer to develop. Reasearchers estimate that between 5 and 7 mutations overall are needed to produce cancer. (4)
Both of the situations above require an individual to acquired a mutation to both genes before their cancer risk increases. If an individual inherits a mutated RET gene (which involves the thyroid); however, they do not need to have a second RET mutation to be at increased risk for thyroid cancer.
Environmental Causes of Cancer and Limiting the Risks
While genetic factors like those discussed above can increase an individuals risk for developing cancer, cancer is not entirely due to genetics. Once an individual has a predisposition to cancer from an inherited mutation, exposure to an environmental carcinogen is necessary to actually cause the process of carcinogenesis to begin.
Environmental factors that take can cause these mutations that lead to cancer are called mutagens. Cancer causing mutagens include radiation, chemicals, pollution, and viruses. Ionizing radiation is a mutagen delivered most often through UV light and X-rays, but exposure also occurs via radon gas and nuclear fuel. Because of this it is recommended that exposure to UV rays from the sun or tanning beds be limited. Also, diagnostic X-rays should be avoided unless absolutely necessary. It is also recommended that all homes be checked for radon gas.
Organic chemicals are also known mutagens. Though pollution and exposure to chemicals (such as pesticides, asbestos, benzidine, and others) are known carcinogens, the vast majority of exposure to chemical mutagens is through tobacco. Approximately 80 % of all cancer in the U.S. is caused by tobacco use. In addition, second hand smoke is believed to cause cancer as well.
Another environmental cause of cancer actually comes from mold. Crops like peanuts, corn, and wheat can be contaminated by mold spores. The mold then produces aflatoxin. The aplatoxin is a known carcinogen that has been linked to liver cancer.
Viruses are another way that cancer causing mutations can be acquired. Several viruses can be linked with various forms of cancer. They are hepatitis B and C, Epstein-Barr virus, and human papillomavirus (HPV). Epstein-Barr is a virus that causes infectious mononucleosis. It is one of the most common viruses with over 95% of people between the ages of 35 and 40 having been infected at some point in their lives. Typically, the virus doesn't cause major complications. There is no direct treatment of the virus itself. The virus remains dormant in the body for the rest of the persons life. Occasionally, the dormant virus reactivates allow a person to become infectious again. Rarely, the virus can lead to Burkitt's lymphoma and nasopharyngeal carcinoma. (1)
HPV is actually a collection of viruses that have been linked to cervical cancer in women. A vaccine is now available that can guard women against infection with HPV viruses and thus greatly reduce the risk of cervical cancer. HPV is also extremely common. Most women who are sexually active are exposed to one form of HPV in their lives.
Both Hepatitis B and C are known to cause liver cancer in some patients. Hepatitis B is often contracted through sexual intercourse or blood to blood through the use of dirty needles or blood transfusion (received prior to donor blood being tested). There is a vaccine for hepatitis B (given in combination with the hepatitis A vaccine). (1)
Hepatitis C is contracted exclusively through blood to blood contact. Prior to 1989 the virus was relatively unknown and there was not a test for donor blood in the U.S. until 1992. That means that anyone who received a blood transfusion or blood products prior to 1992 is at risk for the virus. There is no vaccine for hepatitis C. Treatment with antiviral agents and immune stimulating drugs is available but the success rate of treatment is currently around fifty percent. To complicated matters, the virus often progresses slowly and silently. Symptoms may not appear for decades after the initial infection. An individual may not know they are even infected until irreparable damage has been done to their liver and other organs. Hepatitis C infection is the number one reason for liver transplants in this country. Currently there are around 400,000 people in the U.S. who know they are infected, and around 120,000 new infections diagnosed each year. Add to that the large percentage of individuals who have been infected for a number of years but have yet to show symptoms or be diagnosed. As the postcard below states "1 in 50 Americans have HCV - 2 out of 3 do not know it". Many believe that HCV will be the next major health crisis in this country and will far surpass the severity of the AIDS epidemic in the world. Anyone who had a blood transfusion in the U.S. prior to summer 1992 (later in other countries) or that has ever used IV drugs should be tested for hepatitis C. Because donor blood is now tested most new cases of HCV in this country are the result of IV drug use or vertical transmission from mother to child. (1)(2)(3)
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Another very important element to preventing cancer is diet and exercise. Researchers have found that diets high in fat and obesity correlate to the development of certain cancers. A balanced diet is recommended that includes ample fruits and vegetables, and whole grains. Red meat should be eaten in moderation. It is also recommended that everyone should get 30-45 minutes of exercise at least five days every week.
Discussion 8.4 Diagnosis and Treatment of Cancer
Diagnosis
The first level of defense against cancer is being aware of changes in your own body. The acrostic C-A-U-T-I-O-N is used by the American Cancer Society to help people remember what changes they should pay attention to (listed below).
C - change in bowel or bladder habits
A - sore that does not heal
U - unusual bleeding or discharge
T - thickening or lump in breast or elsewhere
I - Indigestion or difficulty swallowing
O - Obvious change in wart or mole
N - Nagging cough or hoarseness
In addition to watching for these signs that there may be something wrong, individuals should perform routine self checks as well.
Self Breast Exam - monthly for women starting at age 20
Testicles - Men monthly beginning at age 20
Pap Smear - yearly for women beginning by age 21 or three years after becoming sexually active
Mammogram - yearly for women beginning at age 40
Colonoscopy - every five years beginning at age 50
Moles, freckles, and warts should be examined with the following characteristics of melanoma in mind: asymmetrical in shape, irregular borders, variation in color, larger than a pencil eraser (see images to the right).
Treatment of Cancer
The method of treatment chosen after a cancer diagnosis depends heavily on the type of cancer, its location, the progression of the disease, and the individual. When a cancerous tumor is caught before it spreads to other areas of the body (cancer in situ) surgery is often used to remove the tumor. However, there is always a possibility that it has already spread or that some cells may be left behind during surgery, because of this risk surgery is often followed by radiation.
In radiation therapy ionizing radiation is directed at the cancerous tumors which causes the chromosomes to be broken and the cell cycle of the cancerous cells to be stopped.
Chemotherapy uses drugs that are specialized based on the type of cancer and interfere with the cellular processes of the cancer cells. Chemotherapy is administered most often by IV and spreads throughout the body via the blood to catch any cancer cells that may have migrated from the original tumor.
Another option is a bone marrow transplants. These are usually done after chemotherapy when chemotherapy drugs are used very aggressively in a short period of time. The chemotherapy drugs are more effective this way because the cancer cells don't have time to develop a resistance to them. Unfortunately the drugs often will also destroy the red bone marrow which is responsible for producing red blood cells. After chemotherapy is completed the patients stem cells (which are screened for cancer cells) or donor stem cells are injected. The new stem cells begin to create new red blood cells.
Newer forms of cancer treatment are now in clinical trials. Among these are various forms of immunotherapy where agents are used to stimulate the body's immune system against the cancer or injecting genetically engineered antibodies. One variation of immunotherapy is to use genetically engineered antibodies that also carry radioactive isotopes or chemotherapy drugs.
Another approach that is being tested currently is a genetically engineered version of an adenovirus that will seek and destroy cells that lack the p53 gene (that is responsible for initiating apoptosis). So, the virus would only attack tumor cells and leave normal cells unharmed.
References(1) Center for Disease Control http://www.cdc.gov/ncidod/diseases/ebv.htm. (2) HCV Advocate http://www.hcvadvocate.org/. (3) National Hepatitis C Advocacy Council www.hepcnetwork.org/frontpostcarden.png. (4) Inside Cancer http://www.insidecancer.org/. Images obtained from Aris site for Human Biology by Sylvia Mader (http://highered.mcgraw-hill.com/classware/selfstudy.do?isbn=0072986867 chapter resources - power point presentation), unless otherwise cited under image. All additional information for this subtopic obtained from Human Biology; Mader, Sylvia S., and instructor power point presentation.
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Subtopic 9: Genetic Testing and Technology
Outline
I. Genetic Testing
A. Prenatal Tests and Embryo Selection
B. Screening and Detection of Cancer
II. Genomics and Proteomics
A. Genomics
B. Proteomics
III. Gene Therapy
A. Ex Vivo Gene Therapy
B. In Vivo Gene Therapy
IV. Cloning and DNA Technology
A. Recombinant DNA
B. Polymerase Chain Reaction
V. Biotechnology Products
A. Bacteria
B. Plants
C. Animals
Discussion 9.1 Genetic Testing
Prenatal Testing and Embryo Selection
Breakthroughs in genetic research and technology have made it possible to not only analyze an individuals genetic make up once they're born, but it is now possible to examine the genetic information of unborn babies and even embryos before they are implanted in the mother's uterus. One of the most common forms of genetic testing is amniocentesis. Amniocentesis is a test done between the 15th and 17th week of gestation. A sample of amniotic fluid is removed (that contains a few fetal cells) by sticking a needle through the mothers stomach into the amniotic sac. The cells are allowed to grow through mitosis in the lab. Once enough cells are present, the chromosomes are removed and karyotyped. Another common genetic test done during pregnancy is called chorionic villi sampling or CVS. In CVS, fetal cells are removed from the villi by a tube inserted vaginally and ran between the lining of the uterus and the chorionic villi. The cells are then karyotyped. CVS allows the genetic testing to be done earlier in the pregnancy (between the 8th and 12th week) and results to be obtained immediately. Despite these benefits, CVS has a higher rate of complications as compared to amniocentesis.
Some take the idea of testing their unborn children for genetic disease one step farther by testing the embryo before it is implanted into the mother's uterus via in vitro fertilization. This has been used for those who have a genetic disorder or are carriers of a genetic disorder. They can test a number of embryos and choose only to have those implanted who do not inherit the disorder in question. Another facet of this is that some embryos have been selected for implantation based on their ability to provide stem cells for an older sibling.
There are a number of ethical concerns that these tests raise. Among those is the argument that these technologies may lead to a society of designer children, where children are selected based not only on their health but on their abilities, looks, or intellect.
Genetic Tests for Cancer
Some tests are used to determine the presence of a particular gene that predisposes an individual to a particular form of cancer. For instance, there are genetic tests that can determine if an individual has inherited the BRCA1 gene involved in breast cancer.
Tumor marker tests are done on a sample of blood to see if the body has formed antigens. For example, there is a test called the prostate-specific antigen test (PSA) that screens for prostate cancer and also a test called CA-125 that screens for ovarian cancer. Another test the AFP or alpha-fetoprotein test screens for liver tumors. Similar blood tests are also used once an individual has already been treated for cancer to check for relapse.
Discussion 9.2 Genomics and Proteomics
Genomics
Genomics is the study of genomes (or the sequence of bases that make up the genes of an organism). The human genome has been mapped and was found to be made up of around three billion paired bases. In addition to identifying the human genome, regions of individual variation called polymorphisms were identified as well. From the sequence of bases of the human genome and the identification of RNA's that pair with the bases, it was discovered that humans have 25,000 genes.
One area that is of particular interest to reseachers are stretches of DNA that doesn't appear to have genes. The function or purpose of these "deserts" aren't understood yet.
Proteomics
Proteomics is the study of cellular proteins. The human proteom (map of the proteins) is obtained from the translation of the genes (which code for the proteins). This is a difficult process because proteins vary from one cell to the next and from one minute to the next. Understanding the three-dimensional shape of proteins is part of proteomics. The shape of proteins determines how the protein functions. New computer technologies are being developed to help with this endeavor.
Discussion 9.3 Gene Therapy
Ex Vivo Gene Therapy
In ex vivo gene therapy, the stem cells of a person with a genetic disorder is removed, and RNA retrovirus carrying a normal gene is added, and then the retrovirus (containing the corrected gene) is returned to the body. This method has been used to treat immunodeficiency disorders and hypercholesterolemia and is being evaluated for use in other conditions.
In Vivo Gene Therapy
In vivo gene therapy is a process similar to ex vivo gene therapy except the corrected gene is injected (or otherwise delivered) to the patient without first harvesting bone marrow. This type of gene therapy has applications for the treatment of cystic fibrosis, cancer, and numerous other conditions.
Discussion 9.4 Cloning and DNA Technology
Gene Cloning and Recombinant DNA
The word cloning in genetics can refer to making an exact copy of DNA, cells, or an entire organism. Genes are cloned by the process of recombinant DNA. This process takes DNA from an individual and a restriction enzyme "cuts" the gene to be cloned away. If the gene contains introns the enzyme reverse transcriptase is used to create a DNA copy of mRNA. This copied DNA (cDNA) lacks introns. The same restriction enzyme is used to cut a plasmid DNA in the same way. Now the gene can be inserted in the plasmid. (The plasmid is a ring of DNA found in bacteria that does not have the chromosomes of the bacteria and replicates independently). Once the gene is inserted into the plasmid the base pairs line up and the enzyme DNA ligase assists in sealing the ring back together. The plasmid or newly formed rDNA is put back into the bacterial cells. As the plasmid replicates multiple copies of the gene is created. Also, it is possible for the bacteria containing the altered plasmid to produce the product of the gene in question. In order for the gene to function in the bacteria, portions of bacteria regulatory genes are included with the gene. An example of a product produced in this fashion is artificial insulin that is not distinguishable from insulin produced by the pancreas. The image to the right illustrates the process of recombinant DNA.
Polymerase Chain Reaction
Polymerase chain reaction (PCR) is used to make copies of specific sequences of DNA. DNA Polymerase is used along with free nucleotides. The DNA is replicated very much the same way it is in the nucleus of the cell except that PCR is a chain reaction, meaning it will occur over and over again. Now the DNA can be evaluated in different ways.
PCR is used in DNA fingerprinting because it will only amplify a particular region of DNA. The number of copies made indicates how many repeats of a particular sequence of bases a piece of DNA has. Once this is done for a known sample it can be compared to an unknown sample. If the pattern of repeats matches in several places there is a very high probability that the two samples are from the same person. This has many applications for forensics. PCR can also be used to test for genetic disorders, viruses, or mutated genes.
Discussion 9.5 Biotechnology Products
Bacteria
By using the process of recombinant DNA discussed above, transgenic organisms can be produced that can created genetic products (like the insulin in the previous example). Other reasons that transgenic bacteria are produces is to protect crops, as in a form of bacteria that was engineered to prevent frost damage. Some bacteria have been engineered to perform their normal functions faster or in a better way such as oil eating bacteria t
hat help clean up oil spills.
Plants
The genetic make up of plants can also be altered to create various desirable traits such as resistance to insects or herbicides. Plants have also been created that can tolerate and actually do better when watered with salt water. Transgenic plants have also been created that produce human hormones, clotting factors and antibodies.
Animals
Transgenic animals have been created using human genes but also genes of other animals. For example, bovine growth hormone has been added to the eggs of other animals. Once the egg is fertilized and grows it produces animals that grow larger than normal. Transgenic pigs are being investigated to supply organs for human transplantation. Just like bacteria and plants have been used to produce genetic products, animals are being developed that can do the same.
References
Images obtained from Aris site for Human Biology by Sylvia Mader (http://highered.mcgraw-hill.com/classware/selfstudy.do?isbn=0072986867 chapter resources - power point presentation), unless otherwise cited under image. All additional information for this subtopic obtained from Human Biology; Mader, Sylvia S., and instructor power point presentation. ___________________________________________________________________________________
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