Etiology of Down Syndrome: Evidence for Consistent Association Among Altered Meiotic Recombination, Nondisjunction, and Maternal Age Across Populations

Overview

Journal Am J Med Genet A

Specialty Genetics

Date 2009 Jun 18

PMID 19533770

Citations 32

Authors

Sujoy Ghosh

Eleanor Feingold

Subrata Kumar Dey

Affiliations

Soon will be listed here.

Abstract

Down syndrome caused by meiotic nondisjunction of chromosome 21 in humans, is well known to be associated with advanced maternal age, but success in identifying and understanding other risk factors has been limited. Recently published work in a U.S. population suggested intriguing interactions between the maternal age effect and altered recombination patterns during meiosis, but some of the results were counter-intuitive. We have tested these hypotheses in a population sample from India, and found that essentially all of the results of the U.S. study are replicated even in our ethnically very different population. We examined meiotic recombination patterns in a total of 138 families from the eastern part of India, each with a single free trisomy 21 child. We genotyped each family with a set of STR markers using PCR and characterized the stage of origin of nondisjunction and the recombination pattern of maternal chromosome 21 during oogenesis. Our sample contains 107 maternal meiosis I errors and 31 maternal meiosis II errors and we subsequently stratified them with respect to maternal age and the number of detectable crossover events. We observed an association between meiosis I nondisjunction and recombination in the telomeric 5.1 Mb of chromosome 21. By contrast, in meiosis II cases we observed preferential pericentromeric exchanges covering the proximal 5.7 Mb region, with interaction between maternal age and the location of the crossover. Overall reduction of recombination irrespective of maternal age is also evident in meiosis I cases. Our findings are very consistent with previously reported data in a U.S. population and our results are the first independent confirmation of those previous reports. This not only provides much needed confirmation of previous results, but it suggests that the genetic etiology underlying the occurrence of trisomy 21 may be similar across human populations.

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References

Koehler K, Hawley R, Sherman S, Hassold T . Recombination and nondisjunction in humans and flies. Hum Mol Genet. 1996; 5 Spec No:1495-504. DOI: 10.1093/hmg/5.supplement_1.1495. View

Lamb N, Freeman S, Pettay D, Taft L, Hersey J, Gu Y . Susceptible chiasmate configurations of chromosome 21 predispose to non-disjunction in both maternal meiosis I and meiosis II. Nat Genet. 1996; 14(4):400-5. DOI: 10.1038/ng1296-400. View

Marston A, Tham W, Shah H, Amon A . A genome-wide screen identifies genes required for centromeric cohesion. Science. 2004; 303(5662):1367-70. DOI: 10.1126/science.1094220. View

Oliver T, Feingold E, Yu K, Cheung V, Tinker S, Yadav-Shah M . New insights into human nondisjunction of chromosome 21 in oocytes. PLoS Genet. 2008; 4(3):e1000033. PMC: 2265487. DOI: 10.1371/journal.pgen.1000033. View

Cheslock P, Kemp B, Boumil R, Dawson D . The roles of MAD1, MAD2 and MAD3 in meiotic progression and the segregation of nonexchange chromosomes. Nat Genet. 2005; 37(7):756-60. DOI: 10.1038/ng1588. View

Warren A, Chakravarti A, Wong C, Slaugenhaupt S, Halloran S, Watkins P . Evidence for reduced recombination on the nondisjoined chromosomes 21 in Down syndrome. Science. 1987; 237(4815):652-4. DOI: 10.1126/science.2955519. View

Steuerwald N, Cohen J, Herrera R, Sandalinas M, Brenner C . Association between spindle assembly checkpoint expression and maternal age in human oocytes. Mol Hum Reprod. 2001; 7(1):49-55. DOI: 10.1093/molehr/7.1.49. View

Hawley R, Frazier J, Rasooly R . Separation anxiety: the etiology of nondisjunction in flies and people. Hum Mol Genet. 1994; 3(9):1521-8. DOI: 10.1093/hmg/3.9.1521. View

ROSS L, Maxfield R, Dawson D . Exchanges are not equally able to enhance meiotic chromosome segregation in yeast. Proc Natl Acad Sci U S A. 1996; 93(10):4979-83. PMC: 39391. DOI: 10.1073/pnas.93.10.4979. View

10.

Hassold T, Chiu D . Maternal age-specific rates of numerical chromosome abnormalities with special reference to trisomy. Hum Genet. 1985; 70(1):11-7. DOI: 10.1007/BF00389450. View

11.

Wolstenholme J, Angell R . Maternal age and trisomy--a unifying mechanism of formation. Chromosoma. 2001; 109(7):435-8. DOI: 10.1007/s004120000088. View

12.

Antonarakis S . Parental origin of the extra chromosome in trisomy 21 as indicated by analysis of DNA polymorphisms. Down Syndrome Collaborative Group. N Engl J Med. 1991; 324(13):872-6. DOI: 10.1056/NEJM199103283241302. View

13.

Yoon P, Freeman S, Sherman S, Taft L, Gu Y, Pettay D . Advanced maternal age and the risk of Down syndrome characterized by the meiotic stage of chromosomal error: a population-based study. Am J Hum Genet. 1996; 58(3):628-33. PMC: 1914585. View

14.

Lamb N, Feingold E, Savage A, Avramopoulos D, Freeman S, Gu Y . Characterization of susceptible chiasma configurations that increase the risk for maternal nondisjunction of chromosome 21. Hum Mol Genet. 1997; 6(9):1391-9. DOI: 10.1093/hmg/6.9.1391. View

15.

Sherman S, Takaesu N, Freeman S, Grantham M, Phillips C, Blackston R . Trisomy 21: association between reduced recombination and nondisjunction. Am J Hum Genet. 1991; 49(3):608-20. PMC: 1683138. View

16.

Orr-Weaver T . Meiotic nondisjunction does the two-step. Nat Genet. 1996; 14(4):374-6. DOI: 10.1038/ng1296-374. View

17.

Sherman S, Allen E, Bean L, Freeman S . Epidemiology of Down syndrome. Ment Retard Dev Disabil Res Rev. 2007; 13(3):221-7. DOI: 10.1002/mrdd.20157. View

18.

Angell R, Xian J, Keith J, Ledger W, Baird D . First meiotic division abnormalities in human oocytes: mechanism of trisomy formation. Cytogenet Cell Genet. 1994; 65(3):194-202. DOI: 10.1159/000133631. View

19.

Lamb N, Yu K, Shaffer J, Feingold E, Sherman S . Association between maternal age and meiotic recombination for trisomy 21. Am J Hum Genet. 2004; 76(1):91-9. PMC: 1196437. DOI: 10.1086/427266. View

20.

Antonarakis S, Petersen M, McInnis M, Adelsberger P, Schinzel A, Binkert F . The meiotic stage of nondisjunction in trisomy 21: determination by using DNA polymorphisms. Am J Hum Genet. 1992; 50(3):544-50. PMC: 1684265. View