BIMM110      LECTURE 12

Textbook: Strachan and Read, Chapter 2

SLIDES             

 A. Meiotic nondisjunction

1. Nondisjunction in meiosis I or II: what happens? What are the consequences?

- incidence, causes (?)
- trisomy and monosomy; heteroploidy
- paternal or maternal origin ?
              marker chromosomes and polymorphisms

2. Example:
       Suppose all four chromosomes 21 in the parents can be distinguished by molecular-genetic markers

(female) A/B x C/D (male)

parent	meiotic division	disomic gametes	trisomy 21 in zygote
mother	I	AB	ABC, ABD
mother	II	AA, BB	AAC, AAD, BBC, BBD
father	I	CD	ACD, BCD
father	II	CC, DD	ACC, ADD, BCC, BDD

- expected children:      A/C, A/D, B/C, B/D, if no nondisjunction occurs.

FROM OMIM on Down's Syndrome ( OMIM#190685) :

The availability of highly informative DNA markers has allowed the parental origin of the extra chromosome 21 and the meiotic/mitotic origin to be determined. More than 400 families have been studied (Antonarakis et al., 1991, 1992; Antonarakis, 1993; Sherman et al., 1991, 1992) and the results are as follows :
1) Errors in meiosis that lead to trisomy 21 are overwhelmingly of maternal origin; only about 5% occur during spermatogenesis.
2) Most errors in maternal meiosis occur in meiosis I and the mean maternal age associated with these is 32 years (the mean maternal age of the general population is approximately 27 years). Thus, meiosis I errors account for 76 to 80% of maternal meiotic errors and 67 to 73% of all instances of free trisomy 21.
3) Maternal meiosis II errors constitute 20 to 24% of maternal errors and 18 to 20% of all cases of free trisomy 21.
4) In rare families in which there is paternal nondisjunction, most of the errors occur in meiosis II.
5) In 5% of trisomic individuals the supernumerary chromosome 21 appears to result from an error in mitosis. In these cases there is no advanced maternal age and there is no preference for which chromosome 21 is duplicated in the mitotic error.

- relationship to maternal (and paternal?) age: the risk of having a liveborn with Down syndrome at maternal age 30 is 1 in 1,000 and at maternal age 40 is 9 in 1,000 (Hook, 1982; Hook et al., 1983).

- environmental influences ? exposure to risks inthe workplace?
               chromosome counting in human sperm by making "humsters"

B. Clinical aspects

- spontaneous abortions - very high in humans
- autosomal trisomies extremely rare among live births
    exception: Down's syndrome (trisomy 21); the most common cause for mental retardation in humans;
    one in every 600 - 800 births :
            - multiple defects in apparently unrelated functions
            - severity of expression may vary
Web sites: too many to mention, but the following contains a nice summary of the main features and many links to other sites dealing with clinical aspects and basic science issues related to Down's syndrome:

1. for much detailed information OMIM#190685

2. Chromosome 21 databases with the latest mapping information:          Berlin       

3. other rare live births with trisomies: - Patau syndrome (trisomy 13), Edwards syndrome (trisomy 18)

4. trisomy and monosomy involving sex chromosomes are more common (lecture 7)

5. amniocentesis and chorionic villi sampling are methods for prenatal diagnosis; there are many web sites, but the following will get you started:
                                                    Chorionic Villi Sampling
 

 C. Mitotic nondisjunction

1. failure of proper segregation of chromosomes during zygotic divisions or somatic cell divisions

- mosaic formation, if occurrence in early embryo
- relationship to tumorigenesis, if occurrence in somatic cells later in life
- major aneuploidy observed in many tumors

D. Structurally abnormal chromosomes and meiosis

1. Pairing and segregation involving reciprocal translocations

formation of quadrivalent
adjacent I, adjacent II and alternate disjunctions
some normal gametes result, but others have partial duplications or deficiencies
the presence of deficient gametes will be recognized by a reduced fertility of the couple

2. Pairing and segregation involving Robertsonian translocations

one mechanism for generating trisomy 21 comes from the presence of a Robertsonian translocation between chromosomes 21 and 14 (or another telocentric small human chromosome)

3. Pairing and segregation involving pericentric and paracentric inversions

no problems in pairing by the formation of loops
problems arise when there is recombination within the loops
from paracentric inversions and recombination one obtains dicentric and acentric chromosomes as well as one normal and one inverted chromosome
from pericentric inversions one obtains one normal, one inverted and two chromosomes with duplications and deletions

see the following link for a more detailed description

A. Historical

 - Angell, R.R. (1989). Chromosome abnormalities in human preimplantation embryos. Prog. Clin. Biol. Res. 294, 181-187.
- Cohen, M.M. and Levy, H.P. (1989). Chromosome instability syndromes. Adv. Hum. Genet. 18, 43-150.
- Erickson, J.D. (1978). Down syndrome, paternal age, maternal age and birth order. Ann. Hum. Genet. London 41, 289-298.
- Hassold , T.J., and Jacobs, P.A. (1983). Trisomy in man. Ann. Rev. Genet. 18, 69-97.
- Kupke, K.G. and Müller, U. (1989). Parental origin of the extra chromosome in trisomy 18. Am. J. Hum. Genet. 45, 599-605.
- Thompson, R. (1981). Estimating the origins of human trisomics and triploids. Ann. Hum. Genet. 45, 65-78.
- Uchida, I.A., and Freeman, V.C.P. (1985). Trisomy 21 Down syndrome. Hum. Genet. 70, 246-248.
-Gaulden, M.E. (1992). Maternal age effect: The enigma of Down syndrome and other trisomic conditions. Mutat. Res. Rev. Genet. Toxicol. 296, 69-88.
-Martin, R.H., Ko, E., and Rademaker, A. (1991). Distribution of aneuploidy in human gametes: Comparison between human sperm and oocytes. Am. J. Med. Genet. 39, 321-331.

 B. Recent

- Baty, B.J., Blackburn, B.L., and Carey, J.C. (1994). Natural history of trisomy 18 and trisomy 13: I. Growth, physical assessment, medical histories, survival, and recurrence risk. Am. J. Med. Genet. 49, 175-188.
- Guttenbach, M., Schakowski, R., and Schmid, M. (1994). Incidence of chromosome 3, 7, 10, 11, 17 and X disomy in mature human sperm nuclei as determined by nonradioactive in situ hybridization. Hum. Genet. 93, 7-12.
- Patil, N., Peterson, A., Rothman, A., De Jong, P.J., Myers, R.M., and Cox, D.R. (1994). A high resolution physical map of 2.5 Mbp of the Down syndrome region on chromosome 21. Hum. Mol. Genet. 3, 1811-1817.
- Peterson, A., Patil, N., Robbins, C., Wang, L., Cox, D.R., and Myers, R.M. (1994). A transcript map of the Down syndrome critical region on chromosome 21. Hum. Mol. Genet. 3, 1735-1742.
- Sherman, S.L., Petersen, M.B., Freeman, S.B., Hersey, J., Pettay, D., Taft, L., Frantzen, M., Mikkelsen, M., and Hassold, T.J. (1994). Non-disjunction of chromosome 21 in maternal meiosis I: Evidence for a maternal age-dependent mechanism involving reduced recombination. Hum. Mol. Genet. 3, 1529-1535.