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Article / Publication Details
Chromosomal aneuploidy is a fundamental characteristic of the human species. In this review we summarize the knowledge about the origin and mechanisms of nondisjunction in human trisomy 21 that has accumulated during the last decade by using DNA polymorphism analysis. The first molecular correlate of nondisjunction in humans is altered recombination, meiosis I errors being associated with reduced recombination and maternal meiosis II errors with increased recombination between the nondisjoined chromosomes. Thus, virtually all maternal meiotic errors of chromosome 21 seem to be initiated in meiosis I. Advanced maternal age remains the only well documented risk factor for maternal meiotic nondisjunction, but there is, however, still a surprising lack of understanding of the basic mechanisms behind the maternal age effect.
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- Angell R: First-meiotic-division nondisjunction in human oocytes. Am J Hum Genet 61:23–32 (1997).
- Antonarakis SE, Avramopoulos D, Blouin J-L, Talbot CC Jr, Schinzel AA: Mitotic errors in somatic cells cause trisomy 21 in about 4.5% of cases and are not associated with advanced maternal age. Nature Genet 3:146–150 (1993).
- Antonarakis SE, Lewis JG, Adelsberger PA, Petersen MB, Schinzel AA, Binkert F, Schmid W, Pangalos C, Raoul O, Chakravarti A, Hafez M, Cohen MM, Roulston D, Schwartz S, Mikkelsen M, Tranebjaerg L, Greenberg F, Hoar DI, Rudd NL, Warren AC, Metaxotou C, Bartsocas C: Parental origin of the extra chromosome in trisomy 21 as indicated by analysis of DNA polymorphisms. New Engl J Med 324:872–876 (1991).
- Antonarakis SE, Petersen MB, McInnis MG, Adelsberger PA, Schinzel AA, Binkert F, Pangalos C, Raoul O, Slaugenhaupt SA, Hafez M, Cohen MM, Roulson D, Schwartz S, Mikkelsen M, Tranebjærg L, Greenberg F, Hoar DI, Rudd NL, Warren AC, Metaxotou C, Bartsocas C, Chakravarti A: The meiotic stage of nondisjunction in trisomy 21: determination by using DNA polymorphisms. Am J hum Genet 50:544–550 (1992).
- Avramopoulos D, Mikkelsen M, Vassilopoulos D, Grigoriadou M, Petersen MB: Apolipoprotein E allele distribution in parents of Down’s syndrome children. Lancet 347:862–865 (1996).
- Aymé S, Lippman-Hand A: Maternal-age effect in aneuploidy: does altered embryonic selection play a role? Am J hum Genet 34:558–565 (1982).
- Broman KW, Murray JC, Sheffield VC, White RL, Weber JL: Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am J hum Genet 63:861–869 (1998).
- Chakravarti A, Slaugenhaupt SA: Methods for studying recombination on chromosomes that undergo nondisjunction. Genomics 1:35–42 (1987).
- Clarke R, Daly L, Robinson K, Nanghten E, Cahalane S, Fowler B, Graham I: Hyperhomocysteinemia: an independent risk factor for vascular disease. New Engl J Med 324:1149–1155 (1991).
- Davies KE, Harper K, Bonthron D, Krumlauf R, Polkey A, Pembrey ME, Williamson R: Use of a chromosome 21 cloned DNA probe for the analysis of non-disjunction in Down syndrome. Hum Genet 66:54–56 (1984).
- Down JLH: Observations on an ethnic classification of idiots. London Hospital Clinical Lectures and Reports 3:259–262 (1866).
- Economou EP, Bergen AW, Warren AC, Antonarakis SE: The polydeoxyadenylate tract of Alu repetitive elements is polymorphic in the human genome. Proc natl Acad Sci, USA 87:2951–2954 (1990).
- Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJH, den Heijer M, Kluijtmans LAJ, van den Heuvel LP, Rozen R: A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genet 10:111–113 (1995).
- Gaulden ME: Maternal age effect: the enigma of Down syndrome and other trisomic conditions. Mutat Res 296:69–88 (1992).
- Griffin DK, Abruzzo MA, Millie EA, Feingold E, Hassold TJ: Sex ratio in normal and disomic sperm: evidence that the extra chromosome 21 preferentially segregates with the Y chromosome. Am J hum Genet 59:1108–1113 (1996).
- Grouchy J de: 21p– maternel en double exemplaire chez un trisomique 21. Ann Génét 13:52–55 (1970).
- Hassold TJ, Jacobs PA: Trisomy in man. A Rev Genet 18:69–97 (1984).
- Hassold T, Chen N, Funkhouser J, Jooss T, Manuel B, Matsuura J, Matsuyama A, Wilson C, Yamane JA, Jacobs PA: A cytogenetic study of 1000 spontaneous abortions. Ann hum Genet 44:151–178 (1980).
- Hassold T, Chiu D, Yamane JA: Parental origin of autosomal trisomies. Ann hum Genet 48:129–144 (1984).
- Hassold T, Quillen SD, Yamane JA: Sex ratio in spontaneous abortions. Ann hum Genet 47:39–47 (1983).
- Hawley RS, Frazier JA, Rasooly R: Separation anxiety: the etiology of nondisjunction in flies and people. Hum molec Genet 3:1521–1528 (1994).
- Hook EB: Down syndrome: frequency in human populations and factors pertinent to variation in rates, in de la Cruz FF, Gerald PS (eds): Trisomy 21 (Down syndrome): Research Perspectives, pp 3–67 (University Park Press, Baltimore 1981).
- Hook EB, Cross PK: Paternal age and Down’s syndrome genotypes diagnosed prenatally: no association in New York State data. Hum Genet 62:167–174 (1982).
- Hook EB, Cross PK, Regal RR: Factual, statistical and logical issues in the search for a paternal age effect for Down syndrome. Hum Genet 85:387–388 (1990).
- Huether CA, Martin RLM, Stoppelman SM, D’Souza S, Bishop JK, Torfs CP, Lorey F, May KM, Hanna JS, Baird PA, Kelly JC: Sex ratios in fetuses and liveborn infants with autosomal aneuploidy. Am J med Genet 63:492–500 (1996).
- Hug E: Das Geschlechtsverhältnis beim Mongolismus. Ann Pædiatr 177:31–54 (1951).
- Jabs EW, Warren AC, Taylor EW, Colyer CR, Meyers DA, Antonarakis SE: Alphoid DNA polymorphisms for chromosome 21 can be distinguished from those of chromosome 13 using probes homologous to both. Genomics 9:141–146 (1991).
- James RS, Ellis K, Pettay D, Jacobs PA: Cytogenetic and molecular study of four couples with multiple trisomy 21 pregnancies. Eur J hum Genet 6:207–212 (1998).
- James SJ, Pogribna M, Pogribny IP, Melnyk S, Hihe RJ, Gibson JB, Yi P, Tafoya DL, Swenson DH, Wilson VL, Gaylor DW: Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome. Am J Clin Nutr 70:495–501 (1999).
- Juberg RC, Jones B: The Christchurch chromosome (Gp–): mongolism, erythroleukemia and an inherited Gp– chromosome (Christchurch). New Engl J Med 282:292–297 (1970).
- Juberg RC, Mowrey PN: Origin of nondisjunction in trisomy 21 syndrome: all studies compiled, parental age analysis, and international comparisons. Am J med Genet 16:111–116 (1983).
- Lamb NE, Feingold E, Savage A, Avramopoulos D, Freeman S, Gu Y, Hallberg A, Hersey J, Karadima G, Pettay D, Saker D, Shen J, Taft L, Mikkelsen M, Petersen MB, Hassold T, Sherman SL: Characterization of susceptible chiasma configurations that increase the risk for maternal nondisjunction of chromosome 21. Hum molec Genet 6:1391–1399 (1997).
- Lamb NE, Freeman SB, Savage-Austin A, Pettay D, Taft L, Hersey J, Gu Y, Shen J, Saker D, May KM, Avramopoulos D, Petersen MB, Hallberg A, Mikkelsen M, Hassold TJ, Sherman SL: Susceptible chiasmate configurations of chromosome 21 predispose to non-disjunction in both maternal meiosis I and meiosis II errors. Nature Genet 14:400–405 (1996).
- Lejeune J, Gauthier M, Turpin R: Les chromosomes humains en culture de tissus. C R Acad Sci Paris 248:602–603 (1959).
- Li J, Xu M, Zhou H, Ma J, Potter H: Alzheimer presenilins in the nuclear membrane, interphase kinetochores, and centrosomes suggest a role in chromosome segregation. Cell 90:917–927 (1997).
- Litt M, Luty JA: A hypervariable microsatellite revealed by in vitro amplification of a dinucleotide repeat within the cardiac muscle actin gene. Am J hum Genet 44:397–401 (1989).
- Lorber BJ, Grantham M, Peters J, Willard HF, Hassold TJ: Nondisjunction of chromosome 21: comparisons of cytogenetic and molecular studies of the meiotic stage and parent of origin. Am J hum Genet 51:1265–1276 (1992).
- Mikkelsen M, Hallberg A, Poulsen H, Frantzen M, Hansen J, Petersen MB: Epidemiological study of Down’s syndrome in Denmark, including family studies of chromosomes and DNA markers. Dev Brain Dysfunct 8:4–12 (1995).
- Mikkelsen M, Poulsen H, Grinsted J, Lange A: Non-disjunction in trisomy 21: study of chromosomal heteromorphisms in 110 families. Ann hum Genet 44:17–28 (1980).
- Pangalos C, Avramopoulos D, Blouin J-L, Raoul O, deBlois M-C, Prieur M, Schinzel AA, Gika M, Abazis D, Antonarakis SE: Understanding the mechanism(s) of mosaic trisomy 21 by using DNA polymorphism analysis. Am J hum Genet 54:473–481 (1994).
- Pangalos CG, Talbot CC Jr, Lewis JG, Adelsberger PA, Petersen MB, Serre J-L, Rethoré M-O, de Blois M-C, Parent P, Schinzel AA, Binkert F, Boue J, Corbin E, Croquette MF, Gilgenkrantz S, de Grouchy J, Bertheas MF, Prieur M, Raoul O, Serville F, Siffroi JP, Thepot F, Lejeune J, Antonarakis SE: DNA polymorphism analysis in families with recurrence of free trisomy 21. Am J hum Genet 51:1015–1027 (1992).
- Penrose LS: The relative effects of paternal and maternal age in mongolism. J Genet 27:219–224 (1933).
- Petersen MB, Antonarakis SE, Hassold TJ, Freeman SB, Sherman SL, Avramopoulos D, Mikkelsen M: Paternal nondisjunction in trisomy 21: excess of male patients. Hum molec Genet 2:1691–1695 (1993).
- Petersen MB, Frantzen M, Antonarakis SE, Warren AC, Van Broeckhoven C, Chakravarti A, Cox TK, Lund C, Olsen B, Poulsen H, Sand A, Tommerup N, Mikkelsen M: Comparative study of microsatellite and cytogenetic markers for detecting the origin of the nondisjoined chromosome 21 in Down syndrome. Am J hum Genet 51:516–525 (1992).
- Petersen MB, Karadima G, Samaritaki M, Avramopoulos D, Vassilopoulos D, Mikkelsen M: Association between presenilin-1 polymorphism and maternal meiosis II errors in Down syndrome. Am J med Genet (in press).
- Petersen MB, Schinzel AA, Binkert F, Tranebjærg L, Mikkelsen M, Collins FA, Economou EP, Antonarakis SE: Use of short sequence repeat DNA polymorphisms after PCR amplification to detect the parental origin of the additional chromosome 21 in Down syndrome. Am J hum Genet 48:65–71 (1991).
- Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA: Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 239:487–491 (1988).
- Savage AR, Petersen MB, Pettay D, Taft L, Allran K, Freeman SB, Karadima G, Avramopoulos D, Torfs C, Mikkelsen M, Hassold TJ, Sherman SL: Elucidating the mechanisms of paternal non-disjunction of chromosome 21 in humans. Hum molec Genet 7:1221–1227 (1998).
- Savage Brown A, Feingold E, Brown KW, Sherman SL: Genome-wide variation in recombination in female meiosis: a risk factor for non-disjunction of chromosome 21. Hum molec Genet 9:515–523 (2000).
- Schupf N, Kapell D, Lee JH, Ottman R, Mayeux R: Increased risk of Alzheimer’s disease in mothers of adults with Down’s syndrome. Lancet 344:353–356 (1994).
- Sherman SL, Petersen MB, Freeman SB, Hersey J, Pettay D, Taft L, Frantzen M, Mikkelsen M, Hassold TJ: Non-disjunction of chromosome 21 in maternal meiosis I: evidence for a maternal age-dependent mechanism involving reduced recombination. Hum molec Genet 3:1529–1535 (1994).
- Sherman SL, Takaesu N, Freeman SB, Grantham M, Phillips C, Blackston RD, Jacobs PA, Cockwell AE, Freeman V, Uchida I, Mikkelsen M, Kurnit DM, Buraczynska M, Keats BJB, Hassold TJ: Trisomy 21: association between reduced recombination and nondisjunction. Am J hum Genet 49:608–620 (1991).
- Stein Z, Stein W, Susser M: Attrition of trisomies as a maternal screening device: an explanation of the association of trisomy 21 with maternal age. Lancet i:944–947 (1986).
- Stene J: Detection of higher recurrence risk for age-dependent chromosome abnormalities with an application to trisomy G1 (Down’s syndrome). Hum Hered 20:112–122 (1970).
- Stene E, Stene J: Controversy concerning paternal age effect in 47,+21 Down’s syndrome. Hum Genet 81:300–301 (1989).
- Stene J, Stene E, Mikkelsen M: Risk for chromosome abnormality at amniocentesis following a child with a non-inherited chromosome aberration. A European collaborative study on prenatal diagnoses 1981. Prenat Diag 4:81–95 (1984).
- Stene E, Stene J, Stengel-Rutkowski S: A reanalysis of the New York State prenatal diagnosis data on Down’s syndrome and paternal age effects. Hum Genet 77:299–302 (1987).
- Thepot F, Mayaux MJ, Czyglick F, Wack T, Selva J, Jalbert P: Incidence of birth defects after artificial insemination with frozen donor spermatozoa: a collaborative study of the French CECOS Federation on 11,535 pregnancies. Hum Reprod 11: 2319–2323 (1996).
- Van Blerkom J, Antczak M, Schrader R: The developmental potential of the human oocyte is related to the dissolved oxygen content of follicular fluid: association with vascular endothelial growth factor levels and perifollicular blood flow characteristics. Hum Reprod 12:1047–1055 (1997).
- Warburton D: Invited editorial. Human female meiosis: new insights into an error-prone process. Am J hum Genet 61:1–4 (1997).
- Warburton D, Kinney A: Chromosomal differences in susceptibility to meiotic aneuploidy. Environ molec Mutagen 28:237–247 (1996).
- Warren AC, Chakravarti A, Wong C, Slaugenhaupt SA, Halloran SL, Watkins PC, Metaxotou C, Antonarakis SE: Evidence for reduced recombination on the nondisjoined chromosomes 21 in Down syndrome. Science 237:652–654 (1987).
- Weber JL, May PE: Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am J hum Genet 44:388–396 (1989).
- Yang Q, Sherman SL, Hassold TJ, Allran K, Taft L, Pettay D, Khoury MJ, Erickson JD, Freeman SB: Risk factors for trisomy 21: maternal cigarette smoking and oral contraceptive use in a population-based case-control study. Genetics in Medicine 1:80–88 (1999).
- Yoon PW, Freeman SB, Sherman SL, Taft LF, Gu Y, Pettay D, Dana Flanders W, Khoury MJ, Hassold TJ: Advanced maternal age and the risk of Down syndrome characterized by the meiotic stage of the chromosomal error: a population-based study. Am J hum Genet 58:628–633 (1996).