Supplemental Lecture (97/06/10 update) by Stephen T. Abedon (abedon.1@osu.edu)

  1. Chapter title: Pedigree Analysis
    1. A list of vocabulary words is found toward the end of this document
    2. Humans are unique among organisms in many ways, but one way which is near and dear to a geneticist's heart is that humans are not susceptible to genetic experimentation. In practice, we humans actually share this characteristic with many long lived organisms who delay first births. In short, it is not terribly convenient to perform experimental crosses if one has to wait 15 years between generations. However, for humans, one also has to add that our system of morality uniquely does not allow such experimentation on humans. This is an unfortunate state of affairs since there is no other organism for which practical knowledge of their genetics would be more useful, especially in the case of the genetics of heritable diseases.
    3. In a perfect example of necessity being the mother of invention, however, it has been found that human genetics may readily be inferred so long as good records have been kept within large families. This formal mechanism of inference is termed pedigree analysis. In this lecture we will discuss many aspects of human genetics, in particular considering strategies of pedigree analysis whereby we will attempt to infer the genetics of human conditions based on knowledge of marriage (mating) and affliction in large extended families.
  2. Autosome
    1. An autosome is a eucaryote chromosomes other than a sex chromosomes.
  3. Sex chromosome [X chromosome, Y chromosome]
    1. Eucaryote chromosomes of many species (of, particularly, animals) may be distinguished into two general categories: Those that are involved in the determination of gender (sex chromosomes) and those that are not (autosomes).
    2. In humans, the female gender is determined by the absence of a Y chromosome and the presence of an X chromosome while the male is determined by the presence of a Y chromosome. Since females have only X chromosomes, the only combination of chromosomes that normally occurs is XX (i.e., female) and XY (i.e., male).
    3. Note that a human lacking an X chromosome is also inviable since the X chromosome carries a number of valuable genes (i.e., just YY and just Y are not viable). The same cannot be said for the Y chromosome which is of value only in the determination of gender.
    4. Note that not all species employ chrosomal (i.e., genetic) differences to determine gender. In fact, there are a whole range of strategies by which gender is determined in the natural world, and it is not unheard of for organisms to switch gender during normal, adult maturation.
  4. Chromosome number
    1. Humans possess 23 chromosomes per haploid. Of these 23, 22 are autosomes while the 23rd is either one of two sex chromosomes, X or Y.
    2. The chromosome number found in other species usually differs from that in humans. Chromosome number, however, tends to be invariant within species (typically by definition).
  5. Karyotype
    1. Metaphase mitosis chromosomes may be arranged so that they are visible through a light microscope.
    2. In such an arrangement, called a karyotype, chromosomes display a variety of differentiating characteristics including length from centromere (arm length), overall length, and patterns of banding (the latter upon staining with particular chromosome staining dyes).
    3. From this karyotype chromosomes are named numerically, for the most part with increasing number with decreasing size (i.e., length). Thus, autosome number 1 is the largest of human chromosomes while autosome number 21 is the smallest (note that autosome number 22 is not actually the smallest of human chromosomes---a violation of convention that apparently represents an early cytogenetical error that was caught only after everyone was used to this erroneous designation, therefore doomed to be forever an exception to the rule).
  6. Homologous [nonhomologous] chromosome [homologue]
    1. A chromosome of the same type found in an individual. That is, the homologue of one chromosome 21 in a human individual's cell is the other chromosome 21. A nonhomologous chromosome (to chromosome 21) would be chromosome numbers 1-20, 22, X, or Y.
  7. Nondisjunction
    1. A failure of chromosomes to separate during meiosis or mitosis
    2. In meiosis this leads to gametes which contain a surplus or deficit of one or more chromosome.
  8. Trisomies and monosomies
    1. A consequence of a meiotic nondisjunction.
    2. A trisomy is the presence of three or more homologous chromosomes upon fertilization (and thus in the resulting individual).
    3. A monosomy has only a single example of a particularly type of chromosome rather than the expected two (i.e., in a diploid individual).
    4. Note that the vast majority of human autosomal trisomies and monosomies are inviable, most prior to birth.
  9. Trisomy 21 [Down syndrome]
    1. The only long term viable human trisomy. Down syndrome exhibiting individuals have, in the simplest of cases, three autosome number 21s rather than the normal two.
  10. Translocation
    1. The breakage and joining of a section of one chromosome to a second, nonhomologous chromosome.
    2. Translocations are a means by which partial trisomies may be attained (i.e., an individual may hold three copies of a particular section of a given chromosome with the third copy attached to a nonhomologous chromosome).
  11. Dosage compensation
    1. By definition, most males contain a deficit of one X chromosome. This represents a sex chromosome monosomy. However, this situation is, obviously, not lethal. Why not?
    2. The answer is that for the X chromosome, it is the presence of two active copies rather than the presence of only one which represents the pathological situation. Thus, males are for the most part not detrimentally affected by their monosomy X. But wait a minute, females have two X chromosomes. Isn't that an obvious contradiction of the above statements.
    3. The answer, of course, is, yes it is. But one would suppose that such a situation would represent strong selective pressure to do something about the problem, and that something is the inactivation of one of the two X chromosomes located in each female cell. Thus, females have effectively one X chromosome per cell.
    4. This strategy is termed dosage compensation (that is, the dose of genes and gene products per X chromosome is the same for both males and females because female are rendered with effectively the same number of X chromosome as males).
  12. Barr body
    1. Inactivated X chromosomes found in the cells of females are called Barr bodies. They were named this before it was understood that Barr bodies are inactivated X chromosomes.
  13. Mosaicism [mosaic]
    1. X chromosomes are inactivated to form Barr bodies both at random and, effectively, irreversibly. Thus, at some point to during the development of the soma, one of the two X chromosomes in each cell then present is inactivated.
    2. Since the information found on each of the two X chromosomes is not necessary identical, Barr body formation leads to individual cells in a females body effectively being genetically of only one of two types, depending on which X chromosome was inactivated.
    3. This situation is known as mosaicism. That is, a female's body consists of a mixture of cells each having had different X chromosomes inactivated.
    4. Note that a mosaic can arise by many other mechanisms involving the change in genetic information (e.g., nondisjunction during mitosis) in the course of soma development.
  14. Sex chromosome trisomies and monosomies
    1. A great range of variation in sex chromosome number exists among viable individuals, a situation which contrasts starkly with the general inviability of autosomal trisomies and monosomies.
    2. Such individuals as XXX females (or higher such as XXXX) tend toward sterility but are otherwise relatively normal.
    3. XO females (only one sex chromosome), on the other hand, are seriously affected.
    4. XXY males (and higher such as XXXY) also tend to develop normally but nevertheless suffer from sterility.
    5. XYY males (and higher such as XYYY), on the other hand, tend to be both relatively normal and fertile.
  15. Pedigree
    1. Pedigrees are a convention for keeping track of human genetic traits used to infer genotype.
    2. Pedigrees are the human equivalent of test crosses.
    3. In a visualization of a pedigree:
      1. males are designated with square symbols.
      2. females with round symbols
      3. lines are drawn to indicated matings, parent-offspring relationships, and relationships between siblings.
    4. See figure 1125.1.
    5. Traits associated with dominant, recessive, sex linked, etc. alleles and loci display characteristic patterns in pedigrees just as they do when following traits in any organism by any means (i.e., in addition to historical). The origin of these patterns are discussed below.
  16. Autosomal dominant allele [e.g., Huntington's Disease, brown eyes]
    1. A phenotype associated with an autosomal dominant allele will, ideally, be present in every individual carrying that allele. In principle, at least, there are no silent carriers of dominant alleles. (Note, I've hedged the above statements because for many alleles their interaction with genes found at different loci and with the environment are sufficient to make the actual expression of an allele variable---genetics can be very complicated.)
    2. For particularly serious early onset diseases caused by dominant alleles, it is likely that neither parent possesses a copy of the offending allele thus implying that allele formed through mutation during or after gamete formation. Such diseases are consequently very rare.
  17. Illustration, example pedigree (1)
  18. Autosomal recessive alleles [silent carriers]
    1. albinism, cystic fibrosis, certain types of hemophilia, Tay-Sachs disease, PKU, blue eyes.
    2. A pedigree following a trait associated with an autosomal recessive allele is often marked by a skipping of generations. That is, children may express a trait which their parents do not.
    3. In such a situation, both parents are heterozygotes, also known as silent carriers.
    4. Thus, as in any typical cross between two heterozygotes, one-fourth of all offspring are expected to be homozygous for one of the alleles (i.e., see Mendelian ratio).
    5. Note that alleles that cause serious, early onset disease are far more likely to be caused by autosomal recessives than autosomal dominants, sex-linked dominants, sex-linked recessives, etc. since the latter each have much higher probabilities of being expressed (and thus selected against) than the former.
    6. For less serious conditions, there is nothing which precludes one or both parents from being homozygotes:
      1. In the case of one parent being a homozygote recessive and the other a homozygote dominant, no offspring will be affected.
      2. In the case of one parent being a homozygote recessive and the other a heterozygote, half of the offspring, on average, will be affected.
      3. In the case of one both parents being homozyote recessives, all offspring will be affected.
  19. Illustration, example pedigree (2)
  20. Sex-linked dominant alleles [sex linkage]
    1. Males haploid for X chromosome:
    2. Since males carry only a single X chromosome, they are effectively haploid for that chromosome. Thus, there is no such thing as recessive or dominant allele when it comes to the genes found on a male's X chromosome.
    3. Haploid phenotype reflect the presence of whatever allele is present, period.
    4. However, since females are diploid for the X chromosome, a given allele found on the X chromosome may be considered to be recessive or dominant when found in females.
    5. A sex linked dominant allele has a variation on the pattern displayed by autosomal dominant alleles. That is:
      1. one-half of the offspring of an afflicted heterozygote female will be similarly afflicted (gender independent).
      2. only the female progeny of males will be afflicted (because the male donates an X chromosome to his female progeny).
    6. As with any sex-linked allele, males can pass the allele only on to their daughters, not their sons.
  21. Alleles found on Y chromosome
    1. Though rare, a trait associated with a loci found on the Y chromosome would be passed from father to son, only, and not skip generations. That is, it would always be expressed in the haploid state and never found in females.
  22. Sex-linked recessive alleles
    1. red-green color blindness, certain types of hemophilia.
    2. Sex-linked recessives show interesting patterns that result in part from genetics and in part from allele frequencies. That is, like all recessive traits, the likelihood of finding a homozygous recessive at any given loci (given random mating) is a function of the frequency of that allele in the general population (likelihood equals frequency squared).
    3. For a rare allele, the likelihood of finding the allele in a heterozygous state is much greater (equal simply to the frequency of the allele) than in a homozygous individual.
    4. Thus, for relatively rare recessive alleles found on X chromosomes, the likelihood that a women will carry the allele is much higher than the likelihood that the women will display the phenotype associated with that allele. Half of their sons, however, will receive an X chromosome carrying that recessive allele.
    5. Since the sons are haploid for the X chromosome, they display that associated trait so long as they carry one copy of the allele.
    6. Thus, for sex-linked recessive alleles the likelihood that a male will display the associated trait is equal to the frequency of the allele in the general population while the probability that any given female will carry it is equal to frequency of the allele squared.
    7. As with any sex-linked allele, males can pass the allele only on to their daughters, not their sons.
  23. Codominance
    1. Neither recessive nor dominant:
      1. Certain allelic combinations exert neither dominance nor recessiveness. Instead, both alleles exert an influence on phenotype. Such allelic combinations are said to display codominance.
      2. Codominance both helps and hinders pedigree analysis.
    2. It's a hindrance because it implies that at least three phenotypes are possible for three genotypes (AA, Aa, and aa).
    3. However, this also can make pedigree analysis terribly easy because phenotype maps 1:1 onto genotype.
  24. ABO blood group
    1. A slightly complicated example of a system in which there exists both multiple alleles, recessive alleles, dominant alleles, and codominance.
    2. Particularly, red blood cell surface markers (a.k.a., antigens) come in three varieties (actually more, but this is sufficient for both our discussion here and to describe most individuals), variety A, variety B, and variety O.
    3. Permissible genotypes include AA, AB, AO, BB, BO, and OO.
    4. Both A and B display dominance toward O, and codominance toward each other.
    5. Thus, AA and AO individuals display phenotype A, AB individuals display phenotype AB, BB and BO individuals display phenotype B, and OO individuals display phenotype O.
    6. Antibodies to blood antigens:
      1. Individuals which do not have the B allele see the B antigen as foreign and consequently have antibodies which are reactive with the B antigen. Similarly, individuals who do not have an A allele have antibodies which are reactive to A antigen. The existence of these antibodies makes it inadvisable to receive blood (i.e., via a transfusions) from individuals whose red blood cell display the wrong (A or B) maker.
      2. "The blood plasma of many people contains genetically determined antibodies referred to as agglutinins or isoantibodies. These are antibody a (anti-A), which attacks agglutinogen A (i.e., the A protein), and antibody b (anti-B) which attacks B. The antibodies formed by each of the four blood types are shown in Figure 19-4. You do not have antibodies that attack the agglutinogens of your own erythrocytes. A person with blood type A does not have antibody a. But you do have an antibody against any agglutinogen you yourself do not synthesize. Suppose type A blood is accidentally given to a person who does not have A agglutinogens. The person's body recognizes that the A protein is foreign and therefore treats it as an antigen. Antibody a's rush to the foreign erythrocytes, attack them, and cause them to agglutinate (clump)--hence the names agglutinogen and agglutinins. This reaction is another example of an antigen-antibody response. . . In practice, only matching blood types are used for transfusions." (p. 452, Tortora & Anagnostakos, 1981)
    7. Consequently, the universal donor is individuals whose red blood cell display no antigen (OO).
    8. On the other hand, the universal recipient is individuals whose red blood cell display both antigens (AB).
    9. Additional donor-recipient permutations:
      1. AO and AA individuals can receive blood from AA, AO, and OO individuals (but not BB or BO individuals).
      2. BO and BB individuals can receive blood from BB, BO, and OO individuals (but not AA or AO individuals).
      3. Note, however, that "in practice, only matching blood types are used for transfusions." (p. 453, Tortora & Anagnostakos, 1981)
    10. Can you figure out your own ABO genotype? Mine is AO. I know this because my blood is type A and my mother's was type O.
  25. Rh blood group
    1. A simple one locus, two allele, dominant-recessive red blood cell marker. Rh+ gives the marker-present phenotype while Rh- is the marker-absent phenotype.
    2. The rH is an abbreviation of rhesus (as in rhesus macaque), the animal in which rH factors were first described.
    3. "The Rh system is so named because it was first worked out in the blood of the Rhesus monkey. Like the ABO grouping, the Rh system is based on agglutinogens that lie on the surface of erythrocytes. Individuals whose erythrocytes have the Rh agglutinogens are designated Rh+. Those who lack Rh agglutinogens are designated Rh-. . . Under normal circumstances, human plasma does not contain anti-Rh antibodies. However, if an Rh- person receives Rh+ blood, the body starts to make anti-Rh antibodies that will remain in the blood. If a second transfusion of Rh+ blood is given later, the previously formed anti-Rh antibodies will react against the donated blood and a severe reaction may occur. One of the most common problems with Rh incompatibility arises from preganancy. During pregnancy, some of the fetus's blood may leak from the placenta (afterbirth) into the mother's blood stream. If the fetus is Rh+ and the woman is Rh-, she, upon exposure tot he Rh+ fetal cells, will make anti-Rh antibodies. If the woman becomes pregnant again, her anti-Rh antibodies will cross the placenta and make their way into the blood stream of the baby. If the fetus is Rh-, no problem will occur, since Rh- blood does not have the Rh antigen. If the fetus is Rh+, and antigen-antibody response called hemolysis may occur in the fetal blood. Hemolysis means a breakage of erythrocytes resulting in the liberation of hemoglobin. The hemolysis brought on by fetal-maternal incompatibility is called erythroblastosis fetalis or hemolytic disease of newborn. When a baby is born with erythroblastosis, all the blood is slowly removed and replaced with antibody-free blood. It is even possible to transfuse blood into the unborn child if erythroblastosis is suspected. More important, though, is the fact that erythroblastosis can be prevented with an injection of an anti-Rh gamma2-globulin antibody preparation, administered to Rh- mothers right after delivery or abortion. These antibodies tie up the fetal agglutinogens by producing antibodies. Thus the fetus of the next pregnancy is protected. In the case of an Rh+ mother and an Rh- child, there are no complications, since the fetus cannot make antibodies." (p. 453, Tortora & Anagnostakos, 1981)
  26. Sickle cell anemia
    1. On the surface sickle cell anemia appears to be caused by a simple autosomal recessive allele. Thus, those homozygous for the sickle cell allele are stricken with sickle cell anemia while heterozygotes and homozygous, dominant individuals are not.
    2. However, the number of those stricken with sickle cell anemia is actually greater than would be expected given the severity of this disease. Consequently, there exists the possibility that something more is going on than first meets the eye and that that something might be of interest.
    3. As it turns out, what is going on is that the sickle cell heterozygote, though otherwise pretty much normal, is simultaneously more resistant to malaria than homozygous, dominant individuals. In regions in which malaria causes significant disease and mortality, an advantage is accrued by the heterozygote even after factoring in the likelihood that some fraction of that individual's progeny will be afflicted by sickle cell anemia.
    4. Sickle cell anemia consequently is an example of a case of overdominance maintaining a polymorphism in populations living in malaria-prone areas (that is, the greater evolutionary fitness of the heterozygote maintains the frequency of the deleterious allele at artificially high levels).
  27. Inviable
    1. Dead or incapable of surviving due, usually, to a genetic defect. For example, most trisomies create sufficient problems with development that the fetus is rendered inviable, i.e., incapable of surviving outside of the womb and, in many cases, inside the womb as well.
  28. Vocabulary
    1. ABO blood group
    2. Alleles found on Y chromosome
    3. Autosomal dominant allele
    4. Autosomal recessive allele
    5. Autosome
    6. Barr body
    7. Chromosome number
    8. Codominance
    9. Dosage compensation
    10. Down syndrome
    11. Homologous chromosome
    12. Homologue
    13. Karyotype
    14. Monosomy
    15. Mosaic
    16. Nondisjunction
    17. Nonhomologous chromosome
    18. Pedigree
    19. Rh blood group
    20. Sex-linked dominant allele
    21. Sex chromosome
    22. Sex linkage
    23. Sex-linked recessive alleles
    24. Trisomy
    25. Translocation
    26. Trisomy 21
    27. Variation in sex chromosome number
  29. Practice questions
    1. A "disease" which usually is a consequence of nondisjunction is [PEEK]
      1. albinism
      2. Down's syndrome
      3. Huntington's disease
      4. certain types of hemophilia
      5. all of the above
      6. none of the above
    2. A carrier is an individual who "carries" a certain allele. A carrier may express the corresponding trait or may not. The latter is called a "silent carrier." The following pedigree follows a trait that is very rare in most human populations. Assuming no marriage between related individuals, circle all of the persons you are certain are carriers. [PEEK]
    3. Describe three characteristics of a normal human karyotype. [PEEK]
    4. Name at least one way in which a species might do without sex chromosomes? (give one answer) [PEEK]
    5. Give me an example of a phenotypically normal human who does not have 46 chromosomes (ignore fertility issues; use whatever method you consider appropriate to effectively describe/identify such an individual).[PEEK]
    6. A couple is unable to conceive a child. Among other tests, both individuals are karyotyped to rule out sex chromosome number abnormalities. After superficial examination, both individuals are deemed karyotypically normal (i.e., they both have 46 chromosomes, the female with two X chromosomes, the male with one X and one Y). Can we rule out Klinefelter's syndrome? Why or why not? [PEEK]
    7. Turner syndrome individuals are often viable more because they are mosaics rather than because of an inherent robustness associated with the underlying karyotypic abnormality. Propose a mechanism whereby such a mosaic might form (hint: start with a karyotypically normal zygote).[PEEK]
    8. How are the following concepts related: (i) dosage compensation and (ii) the lack of a severe phenotypic consequence associated seen with some trisomies?[PEEK]
    9. Given the ABO blood system, what is the genotype of a universal donor and a universal recipient? [PEEK]
    10. Mixing of donor red blood cells from an individual named Bob with the cell free plasma from either type A or type O, but not type AB individuals results in a clumping of Bob's red blood cells. Plasma is the fraction of blood containing antibody. Bob's wife has blood type AB and, coincidentally, so do both of Bob's parents. Bob's children are all Rh-negative. What is Bob's ABO genotype? [PEEK]
  30. Practice question answers
    1. ii, Down's syndrome
    2. This is an example of a sex-linked recessive. All those who have the trait, the mother's of all the males with the trait, and the daughters of all the males with the trait are certain carriers. The x-ed out individuals are, with reasonable certainty, not carriers.
    3. 23 chromosomes per haploid, 46 chromosomes total, 24 different types of chromosomes, 22 chromsomes typically found in pairs, 2 chromosomes typically found as monosomies, monosomies typically occur in males, 22 autosomes, 2 sex chromosomes, only males have Y chromosome, Y chromosome typically found as monosomy, variation in size, shape, and banding patterns between types, etc.
    4. asexual reproduction, lack of distinct genders, males are haploid/females diploid, gender determined by extra-genetic cues (e.g., temperature).
    5. e.g., XXY, XYYYY, XXXX, etc. But not XO nor any autosomal trisomies nor monosomies.
    6. No, partial trisomy X resulting from translocation.
    7. mitotic nondisjunction involving the X chromosome.
    8. severe consequences associated with a trisomy X are avoided via Barr body formation.
    9. universal donor = OO; universal recipient = AB.
    10. BB or AB.
  31. References
    1. Raven, P.H., Johnson, G.B. (1995). Biology (updated version). Third Edition. Wm. C. Brown publishers, Dubuque, Iowa. pp. 258-278.
    2. Tortora & Anagnostokas, 1981 pp. 452-453 NEED TO UPDATE THIS