Human Meiosis
Nondisjunction
Developmentally lethal chromosome abnormalities may affect as many as 25% of normal appearing human oocytes, obtained for in vitro fertilization (Plachot et al. 1988; Van Blerkom 1994; Wall et al. 1996). These abnormalities include aneuploidies (more or less than the appropriate chromosome number and type) and multinucleations.
The most common cause of aneuploidies is nondisjunction during meiosis. Nondisjunction means that a chromosome pair failed to separate during the meiotic division. This will create one daughter cell with an extra chromosome and another daughter cell with one too few chromosomes. If the nondisjunction occurs during the first meiotic division (meiosis I), all the gametes derived will be abnormal. Half of them will contain neither members of the chromosome pair, while the other half will contain both homologous chromosomes (Figure 1A). In humans, for example, if nondisjunction of chromosome 13 occurs during first meiotic division, half the gametes will have an extra copy of chromosome 13 and thus contain 24 chromosomes instead of the normal haploid number of 23. The other half of the gametes derived from this primary gametocyte will lack both copies of chromosome 13. Thus, these gametes will only have 22 chromosomes. When these gametes unite with the gamete of the opposite sex, no embryo will be viable. The zygotes would either contain 47 chromosomes (23 + 24) or 45 chromosomes (23 + 22). In the first instance, the fetus would contain three copies of chromosome 13 instead of two. This is called trisomy 13 and the fetus has extra fingers, cleft lip, small head, and triangular nose. Most of these fetuses die in the uterus, but those who survive to be born usually die within the first year. The other fetuses from this nondisjunction would lack any chromosome 13. This is called monosomy 13, and such embryos are unable to live.
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| Figure 1 Results of male meiotic disjunction involving a single pair of chromosomes. Assume that all the other chromosomes are normal. (A) Events and outcomes nondisjunction in the first meiotic division.(B) Events and outcome of nondisjunction in the second meiotic division. (From Mange and Mange, 1999.) |
If nondisjunction occurs in meiosis II, only two of the four gametes will be abnormal. Two gametes will have an extra chromosome, two will have an absence of the chromosome (Figure 1B)
The most important result of human chromosome nondisjunction is Down Syndrome (trisomy 13). Down Syndrome appears in about 1 in every 1000 live births, and it is due to nondisjunction of chromosome 21. Chromosome 21 is actually the smallest human autosome, and it has regulatory genes that control mental functions, stature, and the morphogenesis of hearts, fingers, and facial musculature. Trisomy 13 is the only human trisomy that allows a person to live. Often, however, intense medical intervention is needed since these persons are prone to infections and may need surgery at birth to correct heart and digestive tube problems. Most children with Down syndrome learn to talk, but their IQ scores range widely, from about 20 to 85. Infants with trisomies of chromosomes 13 and 18 are sometimes born, but their developmental anomalies are too great, and the babies usually die shortly after birth (see Mange and Mange, 1999).
The other chromosomes whose trisomic conditions are tolerated involve the sex chromosomes. X chromosome inactivation means that only one X chromosome is active in any cell, no matter how many X chromosomes there may be. The Y chromosome appears to be inactive in most all cells except for those involving the formation of the male gonads and gametes. Therefore, sex chromosome monosomies and trisomies can produce infertility, but they are not lethal. XXY individuals have the Klinefelter Syndrome. They are males (since the Y chromosome functions), but the presence of the extra X appears to interfere with gametogenesis. The phenotype varies, but many XXY individuals are unaware of having anything wrong with them except that they are sterile and have larger than average breasts for men. Others have a mild mental retardation or learning disability. XO (monosomy X) individuals are said to have Turner Syndrome. They are females who are usually short, broad-necked, and sterile. Most other functions, including mental abilities, are normal. XYY (due to a nondisjunction of the Y chromosome) individuals are often taller than their counterparts, and they may have learning disabilities as well. Although there once had been thought to be an association of these XYY individuals with aggressive behavior, these associations have not held up. Most XYY males are probably neither large nor aggressive, and those imprisoned XYY persons are usually not there for violent crimes (Nora and Fraser, 1989).
Nondisjunction in Down Syndrome
Since the 1930s, a maternal age effect was shown in the incidence of Down Syndrome. Until recently, women over 35 years old produced more than half the cases of Down Syndrome, even though they accounted for less than 15% of all births. While older women often have older husbands, statistical analyses were able to sort out these variables. Women below the age of 25 have about a 1/1500 chance of bearing a child with Down Syndrome. Women at 35 years old have a 1/355 chance of Down Syndrome. After that, the chances rise such that a 45 year old woman has one chance in 23 of bearing a child with Down Syndrome. No appreciable paternal effect has been seen. (Hecht and Hook, 1994, 1996; Yoon et al., 1996; Mange and Mange, 1999).
This has been confirmed and extended by looking at DNA polymorphisms on chromosome 21. The slight differences in non-coding regions between different people's chromosomes allow one to determine whether the extra chromosome is from the mother or the father. Moreover, these polymorphisms enable one to see whether the nondisjunction took place during the first or second meiotic division. (By looking at markers near the kinetochore, one can see if parental heterozygosity for the markers is retained in the affected offspring. If parental heterozygosity is retained, then a member of both chromosome sets had to be inherited, and the nondisjunction occurred in the first meiotic division. If the parental heterozygosity is not maintained, then the extra chromosome came from the nondisjunction of only one of the original pair, i.e., in the second meiotic division.) The study of Yoon and colleagues (1996) concluded that 86% of the trisomy 21 cases from 1989-1993 in Atlanta were maternal in origin, 9% were paternal in origin, and 5% occurred during the mitotic divisions of the embryo. They also showed that 75% of the maternally originated Down Syndrome cases arose from nondisjunction during the first meiotic division, and 25% originated in the second meiotic division. In paternally derived Down Syndrome, half occurred during first division, half during second division. There was a pronounced maternal age effect, as well (Figure 2).
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| Figure 2 Estimated birth incidence of maternally derived trisomy 21. The statistics show that the maternal age effect involves nondisjunction in both first and second meiotic divisions. (After Yoon et al., 1996.) |
Oxygen depravation: A possible cause
The cause(s) of these nondisjunctions remain(s) unknown. One of the more interesting speculations involves the correlation of successful development to the oxygenation of the egg while it is in the ovary. Oocytes of equivalent size and equivalent capacity to be fertilized differ in their ability to develop. This is apparent in clinical in vitro fertilization, where a certain percentage of eggs that are successfully fertilized fail to develop. Gaulden (1992) and Van Blerkom and colleagues (1997) showed that follicular fluid surrounding the mature oocytes of a single ovary differ greatly in their content of dissolved oxygen. Most had a range 3.0-5.5% oxygen, while the rest was equally divided between those follicular fluids having less than 1.5% and those in between. Oxygen content had no correlation with oocyte size, maturation, or ability to be fertilized. However, there was a very significant correlation with the ability to reach the 6-8 cell stage by 60h of incubation. Of those with reduced oxygen, only 42% reached the 6-8 cell stage; the moderately oxygenated eggs had a 66% success rate, and the well oxygenated eggs developed to this stage 79% of the time. Moreover, the eggs that reached this stage from the poorly oxygenated follicles were found to have significant defects in chromosome number, spindle arrangement, and cytoplasmic structure. Of all the eggs, 41% had chromosomal anomalies, and 92% of these embryos with chromosome anomalies came from eggs having less than 3% oxygen.
These findings have been linked to the microvasculature around the ovarian follicles. Adjacent follicles can have very different vascular arrangements, some follicles being much better supplied with blood than others. This, in turn, might be due to VEGF production by the follicle cells. VEGF is a potent blood vessel inducer (see p. 480-483), and it is expressed in human follicle cells. VEGF is found in preovulatory follicles at very high levels. There is a correlation between those follicles with high VEGF levels and the amount of dissolved oxygen in the follicular fluid. There is also a correlation between the degree of vascularity surrounding the follicle and the potential of the embryo developing from those follicles to develop well (Chui et al., 1997; Bhal et al., 1999). These studies show that pregnancies from in vitro fertilization occur when the oocytes come from well vascularized follicles, and that few pregnancies arise from embryos whose oocytes came from poorly vascularized follicles.
Therefore, there is a series of correlations between VEGF production by the follicle, vascularity of the follicle, oxygen content in the follicular fluid, and the success of pregnancy and lack of aneuploidy.
Literature Cited
Bhal, P. S., Pugh, N. D., Chui, D. K., Gregory, L., Walker, S. M., and Shaw, R. W. 1999. The use of transvaginal power Doppler ultrasonography to evaluate the relationship between perifollicular vascularity and outcome in in-vitro fertilization treatment cycles. Hum Reprod. 14: 939-945.
Chui, D. K., Pugh, N.D., Walker, S. M., Gregory, L., and Shaw, R. W. 1997. Follicular vascularity--the predictive value of transvaginal power Doppler ultrasonography in an in-vitro fertilization programme: a preliminary study. Hum Reprod. 12: 191-196.
Hecht, C. A. and Hook, E. B. 1994. The imprecision in rates of Down Syndrome by 1-year maternal age intervals: A critical analysis of rates used in biochemical screening. Prenatal Diagn. 14: 729-738.
Hecht, C. A. and Hook, E. B. 1996. Rates of Down syndrome at live birth by one-year maternal age intervals in studies with apparent close to complete ascertainment in populations of European origin: a proposed revised rate schedule for use in genetic and prenatal screening. Amer. J. Med. Genet. 62: 376- 385.
Mange, E. J. and Mange, A. P. 1999. Basic Human Genetics. Second ed. Sinauer Associates, Inc., Sunderland, MA.
Nora, J. J. and Fraser, F. C. 1989. Medical Genetics: Principles and Practice. Third ed., Lea and Febiger, Philadelphia.
Plachot, M. and others, 1988. Are clinical and biological parameters correlated with chromosomal disorders in early life? Human Reprod. 3: 627-635.
Van Blerkom, J. 1994. Developmental failure in human reproduction associated with chromosomal abnormalities and cytoplasmic pathologies in meiotically mature human oocytes. In Van Blerkom, J. (ed.) The Biological Basis of Early Reproductive Failure in the Human: Applications to Medically Assisted Conception. Oxford University Press, Oxford. pp. 283-325.
Van Blerkom, J., Antczak, M., and Schrader, R. 1997. The developmental potential of the human oocyte is related to the dissolved oxygen content of follicular fluid: association with VEGF levels and perifollicular blood flow characteristics. Human Reprod. 12: 1047-1055.
Wall, M. and others, 1993. Cytogenetic and fluorescence in situ hybridization chromosome studies on in vitro fertilized and intracytoplasmically injected "failed-fertilized" human oocytes. Human Reprod. 11: 2230-2238.
Yoon, P. and others, 1996. Advanced maternal age and the risk of Down Syndrome characterized by the meiotic stage of the chromosome error: a population-based study. Amer. J. Hum. Genet. 58: 628-633.