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Human and Environmental Genetics, Mutations, Birth Defects, Cancer
Human Genetics
We previously mentioned the ABO blood types. Hopefully, you recall that the possible alleles for this gene are IA, IB, and i. From this, the following genotypes and corresponding phenotypes are possible:
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On the surface of all of our cells are antigens which are substances that our immune systems use to distinguish “me” from a foreign invader. For the ABO blood group gene, the A and B alleles code for production of special short-chain polysaccharides which are the antigens. Type O is the lack of A and/or B antigens which are found on the surface of RBCs (red blood cells). In actuality, the O allele codes for a more simple polysaccharide that doesn’t trigger generation of antibodies, but for our purposes, it’s kind of like there’s no O antigen. Our immune systems are supposed to make antibodies against foreign invaders (measles, mumps, kidney transplants, blood transplants = transfusions, etc.) but not against “me”. Normally, someone’s immune system will not make antibodies against any of the antigens on that person’s own cells. That’s why, when someone needs a transplant, an attempt is made to find tissue that matches the person’s own tissue as closely as possible. so his/her immune system doesn’t make antibodies against the transplant and “reject” it.
A person with type A blood can/does make anti-B antibodies so can receive blood from type A, and in an emergency, type O (type O is not used unless it is really necessary because that blood would have some anti-A and anti-B antibodies in it and could cause a problem when it mixed with the person’s blood). Type B blood can make anti-A antibodies so can receive type B (and in an emergency, type O). Type AB blood won’t make either anti-A or anti-B antibodies because it has both A and B antigens on its cells, so a person who is type AB can, in theory, receive any any other blood type (but the best idea is still to use only AB). Because of this, type AB is called the universal recipient. Type O, which has neither antigen, can make both anti-A and anti-B antibodies, thus can only receive type O. However, because, in theory, it contains no antigens to sensitize someone with types A, B, or AB blood, it can, in theory, be given to anyone and so is called the universal donor.
Rh factor is another, totally different, unrelated gene, that just happens to code for another type of cell-surface antigen that also just happens to occur on RBCs. This blood trait was named after Rhesus monkeys where it was first discovered. Actually the Rh gene has multiple alleles, but most people are + or - for the one most common “D” allele, so it’s treated as though it just has two alleles. Thus, Rh+ is the presence of this antigen (a dominant allele symbolized by R), and Rh- is, for our purposes, the absence of any antigen (a recessive allele symbolized by “r”).
A person has alleles for antigens for BOTH the ABO and the Rh blood groups, so if you’re doing a genetic cross where you’re looking at both traits, you have to treat it as a dihybrid cross. For example, consider the cross IAiRr × IBiRr. The Punnett square for this cross would look like:
| IAR | IAr | iR | ir | |||||||||||||||||
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| IBR |
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| IBr | ||||||||||||||||||||
| iR | ||||||||||||||||||||
| ir | ||||||||||||||||||||
Notice the “strange” phenotype ratio of 3:1:3:1:3:1:3:1.
A special case dealing with Rh factor is that of an Rh- woman married to an Rh+ man. Recall from our discussion on testcrosses that this means, if he’s RR, all of their children will be Rh+ and if he’s Rr, half of the children will be Rh+. Since Rh- blood doesn’t have the Rh cell surface antigen, the mother can make anti-Rh+ antibodies, but needs exposure to the Rh+ antigens first to do so. When she’s pregnant with her first baby, hopefully all will be well because she probably has had no previous exposure to Rh+ blood. Blood cells don’t cross the placenta, so her blood shouldn’t be exposed to the baby’s blood and everything should be OK. As the baby is being born, due to the bleeding, etc., some of the baby’s blood will probably come into contact with hers. From this exposure, she can develop anti-Rh+ antibodies. While blood cells don’t cross the placenta, antibodies do, and normally this is a good thing: that’s how a newborn baby gets its immunity for the first few weeks.
However, if this mother becomes pregnant again, anti-Rh+ antibodies will probably go into baby #2’s blood, and if baby #2 is Rh+, these antibodies can react with his/her blood, making it agglutinate. This is when the blood cells clump together due to an antigen-antibody interaction, which is a major problem if it happens in a baby’s body (the baby might need to be given a total transfusion at birth). To prevent this from happening, after the birth of baby #1, the mother is given a shot called Rhogam which contains the very antibodies they’re trying to prevent her body from forming! The idea is that if the mother has antibodies (which are “only” proteins) already floating around in her blood, her immune system won’t get “turned on” and learn how to make antibodies. Antibodies are produced by white blood cells (WBCs) only if/after they have been exposed to an antigen and only if a lot of other WBCs aren’t already making that antibody. Presence of a lot of a particular antibody would indicate that other cells are manufacturing it, so by giving her Rhogam, it tricks her WBCs into “thinking” that “somebody else” is making antibodies so “I don’t have to.” Since antibodies are only protein, they don’t last forever and eventually go away. If her WBCs never get turned on to make more, no more will be made, so by the time baby #2 comes along things should be OK. For this reason, it is also important for an Rh- woman to get Rhogam after a miscarriage or an abortion.
| Agglutination |
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When doing blood typing, a drop of each of anti-A, anti-B, and anti-D (= anti-Rh+) antisera (antibodies) is placed into its own circle on a glass slide. Then a drop of the person’s blood is added to each drop of antiserum. If the mixture turns “grainy,” that indicates that agglutination has taken place, therefore the person has/is that blood type. In this photo, the person’s blood reacted with the anti-D antiserum, thereby indicating that the person is Rh+. |
Sickle-cell anemia is a mutation of only one nucleotide in the gene that codes for hemoglobin. This is a recessive trait (not really – see following explanation – but for our purposes, it’s easier to think of it that way), so S = normal hemoglobin and s = sickle-cell hemoglobin. SS is a normal person while
ss has sickle-cell anemia. Many people with ss die from complications associated with the abnormally-shaped RBCs that result from the sickle-cell anemia. Sickle-cell is common among African Blacks from areas where there’s a lot of
malaria.
Malaria is caused by a parasite (Kingdom Protista: Plasmodium vivax) that invades RBCs and lives best in normal RBCs, thus people who are SS are more likely to die
from malaria. When the parasite invades a RBC with sickle-cell hemoglobin, the cell sickles in response and then is destroyed by the body (and the parasite along with it). The parasites have a harder time multiplying and infecting people who are ss,
so ss is fairly resistant to malaria (but dies from sickle-cell). The heterozygote (Ss) exhibits incomplete dominance or codominance: the S allele codes for normal hemoglobin and the s allele codes for sickle-cell hemoglobin, so the person has some of
each. Normally the person is OK, but under stress, some RBCs will sickle (don’t send that person up to Denver to
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| A photo, taken by Dr. Fankhauser, of a prepared slide of blood cells infected with Plasmodium vivax |
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When we’re talking about all of a person’s genes/chromosomes, we refer to that person’s genome, which means all of an organism’s genetic material. To study this in humans, a karyotype is done. This involves obtaining blood cells, growing them in tissue culture for a few days, staining the cells, photographing the chromosomes in the cells, cutting out chromosomes from the picture, and lining them up in pairs by size (#1 to 23). Note that pair #23 consists of unmatched XY, which normally makes the person male, or matched XX, which normally makes the person female. The source of blood for children and adults is a finger prick. For an unborn baby, amniocentesis is done. Karyotyping is used to screen for an abnormal number of chromosomes (for example, three of chromosome #21, which produces Down Syndrome). |
| A photo of human white blood cells that were specially cultured, treated with Colcemid, and stained to show chromosomes. |
Remember when we were discussing meiosis, it was mentioned that meiosis in human females is unusual in that it starts during embryonic development, then stops in about prophase I. Once a female reaches puberty, normally one “egg” per cycle goes farther through the process of meiosis. This means that the “eggs” in a 40-year-old woman have been sitting around “waiting” for twice as long as those in a 20-year-old woman, and sometimes they “forget” how to divide properly. Sometimes, both homologous chromosomes in a pair will be pulled to one pole of the cell, while the other end gets none from that pair. Nondisjunction is the non-separation of homologous chromosomes during meiosis, and after fertilization, results in the condition of trisomy for that particular chromosome: trisomy 21 produces Down Syndrome. A more general term for possessing an abnormal number of chromosomes is aneuploidy, having extra copies or not enough of certain chromosome(s). Statistically, it has been shown that there is a correlation between maternal age and chances of having a baby with Down Syndrome. At age 40, a woman’s chances of having a baby with Down Syndrome are about 1/100, and at 45 about 3/100. That’s why doctors want to do amniocentesis on older women (interestingly, several years ago when a doctor wanted to do some testing on me, for something totally unrelated, her advice to me was basically, “Don’t worry about it, the chances are only about 20/100 that there might be a problem.”). Also, the risk of complications from amniocentesis, including possible premature labor and expulsion of the baby, is about 1/100 and the risk of complications from chorionic villi sampling is about 2/100. It is also true that the father’s age can affect sperm production thus also influences chances of Down Syndrome too (caused by nondisjunction in meiosis during sperm production).
Because amniocentesis typically can’t be done before about the fourth to fifth month of pregnancy, more doctors now are trying chorionic villi sampling because it can be done earlier. However, this process is more invasive: the mucus plug in the woman’s cervix that seals off her uterus to protect the unborn baby from infection is removed, and instruments are inserted, around the baby, to take a sample of the placenta. The results can be confusing if the technician gets some of the mother’s tissue as well as the baby’s. These procedures are basically used to decide whether to follow up with abortion. Because there have been a number of lawsuits against doctors in recent history, most doctors will strongly urge women over 35 to have one or the other of these tests done. For a couple who feel comfortable with the possibility of abortion, these tests can give them some information about their baby’s genetics that could possibly influence their decision, but a couple who are morally opposed to abortion might not wish to risk having one of these procedures performed to gain information that will be more easily observed in a few months when the baby is born. Recently, various insurance companies have suggested making amniocentesis for women over 35 mandatory because it’s cheaper for them to pay for an abortion than medical care for the child for the rest of his/her life. What’s your opinion: if a couple has serious moral/religious objections to abortion, do you think their health insurance provider should make it mandatory that they must have amniocentesis and possibly an abortion performed?
Nondisjunction also occurs in the sex chromosomes. We see nondisjunction of sex chromosomes and chromosome #21 more often because those affect the person LESS, so the person is more likely to live. Most other aneuploids result in death before birth and miscarriage, or shortly after. Sometimes it’s not a whole chromosome, but a big piece, that’s missing, or perhaps a big piece breaks off and attaches to another chromosome before meiosis occurs. Some forms of Down syndrome involve an extra piece of #21 stuck on another chromosome. This is called translocation.
There are a number of other genetic disorders that “frequently” affect humans. The alleles for these disorders are not equally prevalent in all ethnic groups. Some recessive disorders include cystic fibrosis, which causes an abnormally large amount of mucus in the lungs and is most common among Caucasians (whites); Tay Sachs, which is a neurological disorder and is most common among eastern European Jewish people; and sickle-cell, which was just discussed and is most prevalent in African Blacks. There are also some disorders that are dominant alleles, so if someone is a heterozygote, (s)he will have that trait. Since about the only way someone could be homozygous dominant would be if both parents passed on that allele, most people who have these disorders are heterozygotes. There is, thus, a 50% chance they will pass these alleles to their children, assuming the trait is such that they live long enough to reproduce. One such dominant trait is achondroplasia. In this disorder, if an individual would be AA, that baby would die before birth and the mother would have a miscarriage. An individual with genotype Aa would be a dwarf, and aa is normal height. Huntington’s disease is another dominant disorder that is a progressive deterioration of the person’s nervous system that starts in middle age, after the person may already have had children. Because it’s a dominant allele, if a child gets that allele, (s)he will get the disease, thus some couples might choose to not have children if they knew one of them had the allele. There is a test available to tell if a person has Huntington’s, so if a person chose to have this test, a couple could make that decision. Because Huntington’s destroys the nervous system, the person gradually loses control of body and brain functions until the nerves won’t control his/her heart and breathing, then dies. Thus, if a person chose to have the test done, (s)he would know ahead of time that in a few years (s)he could gradually deteriorate into a helpless state. Each time (s)he dropped something or forgot something, (s)he might be tormented by the idea that this was a sign that the disease was beginning. Woody Guthrie, who wrote “This Land is Your Land” died of Huntington’s in 1967. His son Arlo Guthrie (who wrote “Alice’s Restaurant”), is now a grandfather and has not shown any signs of the disease, but several of Woody’s other children have died from Huntington’s. What’s your opinion: if you were in that situation, do you think you’d want to have the test done?
Here’s an hypothetical situation (borrowed from BSCS): suppose a big-name company is looking for a very knowledgeable person to work on research and development for an important project that promises to make lots of money for the corporation. Because of this, they’re looking for someone who will stay with the company for 10 or 20 years. In return, they’re willing to pay quite a large salary for this position. The top candidate for the position is a person who is 35, and who has a family history of Huntington’s disease. The #2 candidate’s qualifications are considerably less. If the company hires their #1 choice, there’s a 50% chance that in as few as 5 years, they may be in a position where they’re paying for disability insurance for this person who is now institutionalized and can no longer work, plus having to go through the whole process of hiring someone else to take over in the middle of the project, which could be financially very expensive for them. Because of this, they’d like to require the candidate to undergo genetic testing to determine if he has Huntington’s and not hire him if he does, but he doesn’t want to know ahead of time if he had the disease. This test is not a part of what they normally require for all new employees. What’s your opinion: Should the company mandate this test for this particular person against his wishes? Should they deny him employment if he refuses to have the test done?
Genetic counselling is available to help couples with family histories of genetic problems decide whether to have a baby. Based on things like construction of a family pedigree for the gene in question and possibly some genetic testing, if available, the couple is given information and advised of the chances any children they might have will have that disorder. Once a woman is pregnant, there are a variety of prenatal tests that can give them information about the genetic condition of their baby before it’s born. However, many of these tests are not without risks. Ammiocentesis and chorionic villi sampling have already been mentioned. While the book says ultrasound is safe, I’ve heard it suggested lately that the number of times this is done be limited because they just aren’t sure if it really is as safe as it seems. Ultrasound is a non-invasive technique in which very high pitched sound is bounced off the baby, mostly to check his/her size.
OMIM
The Web site Online Mendelian Inheritance in Man is an excellent source of information on human genes.
Cancer
Interestingly, some “apparently” genetic disorders may be caused by viruses. Some viruses can insert their genes permanently into our cells. Herpes viruses like chickenpox and cold sores, mononucleosis, AIDS, and some others that cause cancer do this. Cancer cells are genetically different than normal cells. They lack the normal controls on cell division and can spread to other areas of the body. Occasionally, a cell in someone’s body may turn into a cancer cell, but normally, a healthy immune system then no longer recognizes the cancer cell as part of “me” and destroys it. However, if a person’s immune system gets stressed and run-down, that cancer cell might have a chance to reproduce, until it forms a large enough tumor that the immune system just can’t destroy it all. There are a number of things we can do to help strengthen our immune systems and decrease our chances of getting cancer. Things to avoid include tobacco/smoking, a high-fat diet, synthetic estrogen pills, x-rays, ultraviolet light from tanning beds and the sun, pollutants like asbestos, etc., and a variety of drugs and chemicals known to be carcinogenic. Things we can do to help strengthen our immune systems especially include eating a high fiber diet; vitamins A, C, E, and beta carotene (found in dark green, leafy veggies); foods like garlic and broccoli; and antioxidant minerals like selenium and zinc.
Some further notes on genetics: We tend to think of genes that control what an organism looks like, etc., but genes can also control behavior of animals. For example, bird songs and other courtship rituals are under genetic control. The most successful competitors live and mate and pass on their genes. On a different subject, many of our horticultural plant varieties are polyploid plants. Typically, like us, plants are diploid. Horticulturists have figured out ways to manipulate plants and make triploid or tetraploid plants. Typically these plants are larger and/or have bigger or more ruffled flowers and/or larger seeds. While triploid plants are usually sterile (with three sets of chromosomes they have trouble doing meiosis), tetraploid plants are usually fertile and can reproduce. I believe I read somewhere that the wheat we eat is actually a hexaploid, resulting in seeds that are quite a bit larger than its grass-like ancestor.
Mutations
| Suppose there was some gene on the DNA: | TAC | - | CCA | - | GGC | - | GCT | - | GAA | - | TCA | - | TGC | - | CCA | - | AGC | - | ACT | |||
| That would transcribe to the RNA version: | AUG | - | GGU | - | CCG | - | CGA | - | CUU | - | AGU | - | ACG | - | GGU | - | UCG | - | UGA | |||
| and translate to the amino acid sequence: | start | - | gly | - | pro | - | arg | - | leu | - | ser | - | thr | - | gly | - | ser | - | stop | |||
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| Suppose one of the bases was deleted: | TAC | - | CCA | - | GGC | - | GCT | - | GAT | - | CAT | - | GCC | - | CAA | - | GCA | - | CT? | |||
| This would translate to the amino acid sequence: | start | - | gly | - | pro | - | arg | - | leu | - | val | - | arg | - | val | - | arg | - | ??? | |||
| This would cause a frameshift mutation such that the protein that was formed wouldn’t make sense because it wouldn’t have the right amino acids. Also, since the “stop” code wouldn’t be in the right place, nonsense amino acids from the next gene might be added until the next “stop” codon (ATT, ATC, or ACT) was encountered. If this protein was an enzyme that was supposed to do some job in a person’s body, it would not be able to function properly (if at all). | ||||||||||||||||||||||
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| Suppose two of the bases were deleted: | TAC | - | CCA | - | GGC | - | GCT | - | ATC | - | ATG | - | CCC | - | AAG | - | CAC | - | T?? | |||
| This would translate to the amino acid sequence: | start | - | gly | - | pro | - | arg | - | stop | - | (try) | - | (gly) | - | (phe) | - | (val) | - | ??? | |||
| which would, once again, cause a frameshift mutation. However, once the “stop” codon was reached, translation would stop, resulting in a protein molecule that would be incomplete and unable to function. Note that the “stop” codon did not result specifically because two bases were deleted. That could also occur if just one base was deleted. | ||||||||||||||||||||||
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| Suppose three of the bases that made up one particular codon were deleted: | TAC | - | CCA | - | GGC | - | GCT | - | TCA | - | TGC | - | CCA | - | AGC | - | ACT | |||||
| This would translate to the amino acid sequence: | start | - | gly | - | pro | - | arg | - | ser | - | thr | - | gly | - | ser | - | stop | |||||
| where one amino acid is totally “missing” in the center, but the other codons and amino acids remain unchanged. How serious of an effect this would have would depend on where in the protein molecule the deletion occurred. | ||||||||||||||||||||||
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| Suppose three of the bases that were parts of two adjacent codons were deleted: | TAC | - | CCA | - | GGC | - | GCT | - | GCA | - | TGC | - | CCA | - | AGC | - | ACT | |||||
| This would translate to the amino acid sequence: | start | - | gly | - | pro | - | arg | - | arg | - | thr | - | gly | - | ser | - | stop | |||||
| Now, not only is the protein one amino acid “short,” but the next one in the sequence is also “wrong.” Again, how serious of an effect this would have would depend on where in the protein molecule the deletion occurred. | ||||||||||||||||||||||
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| Suppose there was an “extra” base inserted: | TAC | - | CCA | - | GGC | - | GCT | - | GCA | - | ATC | - | ATG | - | CCC | - | AAG | - | CAC | - | T?? | |
| This would translate to the amino acid sequence: | start | - | gly | - | pro | - | arg | - | arg | - | stop | - | (try) | - | (gly) | - | (phe) | - | (val) | - | ??? | |
| An insertion mutation of 1 or 2 bases would also cause a frameshift mutation, and thus, could cause the same types of missense or nonsense that a deletion mutation would cause. | ||||||||||||||||||||||
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| Suppose there were three “extra” bases inserted between the existing codons: | TAC | - | CCA | - | GGC | - | GCT | - | GAA | - | TTT | - | TCA | - | TGC | - | CCA | - | AGC | - | ACT | |
| This would translate to the amino acid sequence: | start | - | gly | - | pro | - | arg | - | leu | - | lys | - | ser | - | thr | - | gly | - | ser | - | stop | |
| where an “extra” amino acid has been added in the center, but the other codons and amino acids remain unchanged. How serious of an effect this would have would depend on where in the protein molecule the deletion occurred. | ||||||||||||||||||||||
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| Suppose there were three “extra” bases inserted in the middle of a codon: | TAC | - | CCA | - | GGC | - | GCT | - | GAT | - | TTA | - | TCA | - | TGC | - | CCA | - | AGC | - | ACT | |
| This would translate to the amino acid sequence: | start | - | gly | - | pro | - | arg | - | leu | - | asn | - | ser | - | thr | - | gly | - | ser | - | stop | |
| This would result in codons calling for two “wrong” amino acids in place of the one “right” one that used to be there. Note that this is not a frameshift mutation even though the two new amino acids in the center are incorrect. | ||||||||||||||||||||||
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| Insertion or deletion of three bases would not cause a frameshift mutation and would not change the “other” codons and amino acids other than at the insertion/deletion point. Note that it is possible that the result of this could also be the creation of a “stop” code in an incorrect place. If there was one less or more amino acid in a less-critical portion of the protein molecule, that molecule might still be able to function, but if the insertion/deletion occurred in a critical part of the molecule, the protein could be unable to function properly. | ||||||||||||||||||||||
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Birth Defects
Environmental Genetics
Our society is wrestling with a number of ethical issues tied to our modern knowledge of genetics. As citizens and taxpayers, you will be called upon to help set guidelines and legislation to direct what we as a country do with the knowledge of genetics we possess. For further information, please read Dr. Fankhauser’s Genetic Engineering Web page.
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carterjs@uc.edu
Copyright © 1996 by J. Stein Carter. All rights reserved.
This page has been accessed times since 14 Mar 2001.