Abstract
The aim of the present work was to explore the intriguing association of maternal folate regulator gene polymorphisms and mutations with the incidence of chromosome 21 nondisjunction and Down syndrome birth. We tested polymorphisms/mutations of DNMT3B and RFC1 genes for their association with meiotic errors in oocyte among the 1215 Down syndrome child-bearing women and 900 controls. We observed that 23 out of 31 variants of DNMT3B and RFC1 exhibited an association with meiosis II nondisjunction in maternal age-independent manner. Additionally, we have reported 17 novel mutations and 1 novel polymorphic variant that are unique to the Indian Bengali speaking cohort and increased odds in favour of meiosis II nondisjunction. We hypothesize that the risk variants and mutations of DNMT3B and RFC1 genes may cause reduction in two or more recombination events and also cause peri-centromeric single exchange that increases the risk of nondisjunction at any age of women. In silico analyses predicted the probable damages of the transcripts or proteins from the respective genes owing to the said polymorphisms. These findings from the largest population sample tested ever revealed that mutations/polymorphisms of the genes DNMT3B and RFC1 impair recombination that leads to chromosome 21 nondisjunction in the oocyte at meiosis II stage and bring us a significant step closer towards understanding the aetiology of chromosome 21 nondisjunction and birth of a child with Down syndrome to women at any age.
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References
Acquaviva L, Székvölgyi L, Dichtl B (2012) The COMPASS Subunit Spp1 links histone methylation to initiation of meiotic recombination. Science 339:215–218. https://doi.org/10.1126/science.1225739
Adzhubei I, Jordan DM, Sunyaev SR (2013) Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet Chapter 7: Unit7.20. https://doi.org/10.1002/0471142905
Bosco P, Guéant-Rodriguez R-M, Anello G et al (2003) Methionine synthase (MTR) 2756 (A –> G) polymorphism, double heterozygosity methionine synthase 2756 AG/methionine synthase reductase (MTRR) 66 AG, and elevated homocysteinemia are three risk factors for having a child with Down syndrome. Am J Med Genet A 121A:219–224. https://doi.org/10.1002/ajmg.a.20234
Božović IB, Stanković A, Živković M et al (2015) Altered LINE-1 methylation in mothers of children with Down syndrome. PLoS ONE 10:e0127423. https://doi.org/10.1371/journal.pone.0127423
Bernard P, Maure JF, Partridge JF et al (2001) Requirement of heterochromatin for cohesion at centromeres. Science 294:2539–2542. https://doi.org/10.1126/science.1064027
Buard J, Barthès P, Grey C (2009) Distinct histone modifications define initiation and repair of meiotic recombination in the mouse. EMBO J 28:2616–2624. https://doi.org/10.1038/emboj.2009.207
Capriotti E, Fariselli P, Casadio R (2005) I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure. Nucleic Acids Research 33:W306–W310. https://doi.org/10.1093/nar/gki375
Capriotti E, Altman RB, & Bromberg Y (2013) Collective judgment predicts disease-associated single nucleotide variants. BMC Genomics 14 Suppl3:S2. https://doi.org/10.1186/1471-2164-14-S3-S2
Chango A, Emery-Fillon N, de Courcy GP et al (2000) A polymorphism (80G->A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia. Mol Genet Metab 70:310–315. https://doi.org/10.1006/mgme.2000.3034
Cheng J-M, Liu Y-X (2017) Age-related loss of cohesion: causes and effects. Int J Mol Sci. https://doi.org/10.3390/ijms18071578
Coppedè F, Bosco P, Lorenzoni V et al (2013a) The MTR 2756A>G polymorphism and maternal risk of birth of a child with Down syndrome: a case-control study and a meta-analysis. Mol Biol Rep 40:6913–6925. https://doi.org/10.1007/s11033-013-2810-1
Coppedè F, Bosco P, Tannorella P et al (2013b) DNMT3B promoter polymorphisms and maternal risk of birth of a child with Down syndrome. Hum Reprod 28:545–550. https://doi.org/10.1093/humrep/des376
Coppedè F, Marini G, Bargagna S et al (2006) Folate gene polymorphisms and the risk of Down syndrome pregnancies in young Italian women. Am J Med Genet A 140:1083–1091. https://doi.org/10.1002/ajmg.a.31217
de Moura CM, Bastos PR, Ribeiro JSV et al (2018) DNA (cytosine-5)-methyltransferase 3B (DNMT 3B) polymorphism and risk of Down syndrome offspring. Saudi J Biol Sci 25:101–104. https://doi.org/10.1016/j.sjbs.2017.09.008
Feinberg A. P. (2007). Phenotypic plasticity and the epigenetics of human disease. Nature, 447(7143), 433–440. https://doi.org/10.1038/nature05919
Ginani CTA, Luz JRDD, Silva SVE et al (2022) Association between MTHFR C677T and A1298C gene polymorphisms and maternal risk for Down syndrome: a protocol for systematic review and/or meta-analysis. Medicine 101:e28293. https://doi.org/10.1097/MD.0000000000028293
Ghosh S, Bhaumik P, Ghosh P, Dey SK (2010) Chromosome 21 non-disjunction and Down syndrome birth in an Indian cohort: analysis of incidence and aetiology from family linkage data. Genet Res (camb) 92:189–197. https://doi.org/10.1017/S0016672310000224
Ghosh S, Feingold E, Dey SK (2009) Etiology of Down syndrome: evidence for consistent association among altered meiotic recombination, nondisjunction, and maternal age across populations. Am J Med Genet A 149A:1415–1420. https://doi.org/10.1002/ajmg.a.32932
Ghosh S, Hong C-S, Feingold E et al (2011) Epidemiology of Down syndrome: new insight into the multidimensional interactions among genetic and environmental risk factors in the oocyte. Am J Epidemiol 174:1009–1016. https://doi.org/10.1093/aje/kwr240
Gopalakrishnan S, Sullivan BA, Trazzi S et al (2009) DNMT3B interacts with constitutive centromere protein CENP-C to modulate DNA methylation and the histone code at centromeric regions. Hum Mol Genet 18:3178–3193. https://doi.org/10.1093/hmg/ddp256
Giulietti M, Piva F, D’Antonio M et al (2013) SpliceAid-F: a database of human splicing factors and their RNA-binding sites. Nucleic Acids Research 41(Database issue):D125– D131. https://doi.org/10.1093/nar/gks997
Graves, R. J., Graff, J. C., Esbensen, A. J., Hathaway, D. K., Wan, J. Y., & Wicks, M. N. (2016). Measuring Health-Related Quality of Life of Adults With Down Syndrome. American journal on intellectual and developmental disabilities, 121(4), 312–326. https://doi.org/10.1352/1944-7558-121.4.312
Gu Y (2017) Association between polymorphisms in folate metabolism genes and maternal risk for Down syndrome: a meta-analysis. Mol Clin Oncol 7:367–377. https://doi.org/10.3892/mco.2017.1338
Halder P, Pal U, Ray A et al (2019) Polymorphisms of folate metabolism regulators increase risk of meiosis II nondisjunction of chromosome 21 in oocyte. Meta gene 22:100606. https://doi.org/10.1016/j.mgene.2019.100606
Hollis, N. D., Allen, E. G., Oliver, T. R., Tinker, S. W., Druschel, C., Hobbs, C. A., O'Leary, L. A., Romitti, P. A., Royle, M. H., Torfs, C. P., Freeman, S. B., Sherman, S. L., & Bean, L. J. (2013). Preconception folic acid supplementation and risk for chromosome 21 nondisjunction: a report from the National Down Syndrome Project. American journal of medical genetics. Part A, 161A(3), 438–444. https://doi.org/10.1002/ajmg.a.35796
Hou Z, Matherly LH (2014) Biology of the major facilitative folate transporters SLC19A1 and SLC46A1. Curr Top Membr 73:175–204. https://doi.org/10.1016/B978-0-12-800223-0.00004-9
Ittisoponpisan S, Islam SA, Khanna T et al (2019) Can predicted protein 3D structures provide reliable insights into whether missense variants are disease associated? Journal of Molecular Biology 431: 2197–2212. https://doi.org/10.1016/j.jmb.2019.04.009
Jaiswal SK, Sukla KK, Kumari N et al (2015) Maternal risk for down syndrome and polymorphisms in the promoter region of the DNMT3B gene: a case–control study. Birth Defects Res Part A Clin Mol Teratol 103:299–305. https://doi.org/10.1002/bdra.23348
James SJ, Pogribna M, Pogribny IP et al (1999) 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. https://doi.org/10.1093/ajcn/70.4.495
Jackson RA, Nguyen ML, Barrett AN et al (2016) Synthetic combinations of missense polymorphic genetic changes underlying Down syndrome susceptibility. Cell Mol Life Sci 73:4001–4017. https://doi.org/10.1007/s00018-016-2276-0
Lamb NE, Feingold E, Savage A et al (1997) Characterization of susceptible chiasma configurations that increase the risk for maternal nondisjunction of chromosome 21. Hum Mol Genet 6:1391–1399. https://doi.org/10.1093/hmg/6.9.1391
Lee SJ, Jeon H-S, Jang J-S et al (2005) DNMT3B polymorphisms and risk of primary lung cancer. Carcinogenesis 26:403–409. https://doi.org/10.1093/carcin/bgh307
Lefter M, Vis JK, Vermaat M et al (2021) Next generation HGVS nomenclature checker. Bioinformatics. https://doi.org/10.1093/bioinformatics/btab051
Lejeune J, Gautier M, Turpin R (1959) Study of somatic chromosomes from 9 mongoloid children. C R Hebd Seances Acad Sci 248:1721–1722
Liao YP, Zhang D, Zhou W et al (2014) Combined folate gene MTHFD and TC polymorphisms as maternal risk factors for Down syndrome in China. Genet Mol Res GMR 13:1764–1773. https://doi.org/10.4238/2014.March.17.4
Mendes, C. C., Zampieri, B. L., Arantes, L. M. R. B., Melendez, M. E., Biselli, J. M., Carvalho, A. L., Eberlin, M. N., Riccio, M. F., Vannucchi, H., Carvalho, V. M., Goloni-Bertollo, E. M., & Pavarino, É. C. (2021). One-carbon metabolism and global DNA methylation in mothers of individuals with Down syndrome. Human cell, 34(6), 1671–1681. https://doi.org/10.1007/s13577-021-00586-0
Mirouze M, Lieberman-Lazarovich M, Aversano R et al (2012) Loss of DNA methylation affects the recombination landscape in Arabidopsis. Proc Natl Acad Sci U S A 109:5880–5885. https://doi.org/10.1073/pnas.112084110
Migliore L, Migheli F, Coppedè F (2009) Susceptibility to aneuploidy in young mothers of Down syndrome children. Sci World J 9:1052–1060. https://doi.org/10.1100/tsw.2009.122
Migliore L, Boni G, Bernardini R et al (2006) Susceptibility to chromosome malsegregation in lymphocytes of women who had a Down syndrome child in young age. Neurobiol Aging 27:710–716. https://doi.org/10.1016/j.neurobiolaging.2005.03.025
Oliver TR, Feingold E, Yu K et al (2008) New insights into human nondisjunction of chromosome 21 in oocytes. PLoS Genet 4:e1000033. https://doi.org/10.1371/journal.pgen.1000033
Penrose LS (1933) The relative effects of paternal and maternal age in mongolism. J Genet 27:219–224. https://doi.org/10.1007/BF02984413
Penrose LS (1934) The relative aetiological importance of birth order and maternal age in mongolism. Proc R Soc B Biol Sci 115:431–450. https://doi.org/10.1098/rspb.1934.0051
Ray A, Oliver TR, Halder P et al (2018) Risk of Down syndrome birth: consanguineous marriage is associated with maternal meiosis-II nondisjunction at younger age and without any detectable recombination error. Am J Med Genet A 176:2342–2349. https://doi.org/10.1002/ajmg.a.40511
Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6:597–610. https://doi.org/10.1038/nrg1655
Scala I, Granese B, Sellitto M et al (2006) Analysis of seven maternal polymorphisms of genes involved in homocysteine/folate metabolism and risk of Down syndrome offspring. Genet Med 8:409–416. https://doi.org/10.1097/01.gim.0000228206.21793.82
Schwarz JM, Rödelsperger C, Schuelke M et al (2010) MutationTaster evaluates disease-causing potential of sequence alterations. Nature Methods 7:575–576. https://doi.org/10.1038/nmeth0810-575
Serrano-Quílez J, Roig-Soucase S, Rodríguez-Navarro S (2020a) Sharing marks: H3K4 methylation and H2B ubiquitination as features of meiotic recombination and transcription. Int J Mol Sci 21:4510. https://doi.org/10.3390/ijms21124510
Shaw GM, Zhu H, Lammer EJ et al (2003) Genetic variation of infant reduced folate carrier (A80G) and risk of orofacial and conotruncal heart defects. Am J Epidemiol 158:747–752. https://doi.org/10.1093/aje/kwg189
Shen H, Wang L, Spitz MR et al (2002) A novel polymorphism in human cytosine DNA-methyltransferase-3B promoter is associated with an increased risk of lung cancer. Cancer Res 62:4992–4995
Sherman SL, Allen EG, Bean LH, Freeman SB (2007) Epidemiology of Down syndrome. Ment Retard Dev Disabil Res Rev 13:221–227. https://doi.org/10.1002/mrdd.20157
Stanisławska-Sachadyn A, Mitchell LE, Woodside JV et al (2009) The reduced folate carrier (SLC19A1) c.80G>A polymorphism is associated with red cell folate concentrations among women. Ann Hum Genet 73:484–491. https://doi.org/10.1111/j.1469-1809.2009.00529.x
Steuerwald N, Cohen J, Herrera RJ et al (2001) Association between spindle assembly checkpoint expression and maternal age in human oocytes. Mol Hum Reprod 7:49–55. https://doi.org/10.1093/molehr/7.1.49
Stuppia L, Gatta V, Gaspari AR et al (2002) C677T mutation in the 5,10-MTHFR gene and risk of Down syndrome in Italy. Eur J Hum Genet 10:388–390. https://doi.org/10.1038/sj.ejhg.5200819
Serrentino ME, Borde V (2012) The spatial regulation of meiotic recombination hotspots: are all DSB hotspots crossover hotspots? Exp Cell Res 318:1347–1352. https://doi.org/10.1016/j.yexcr.2012.03.025
Sigurdsson MI, Smith AV, Bjornsson HT et al (2009) HapMap methylation-associated SNPs, markers of germline DNA methylation, positively correlate with regional levels of human meiotic recombination. Genome Res 19:581–589. https://doi.org/10.1101/gr.086181.108
Sommermeyer V, Béneut C, Chaplais E et al (2013) Spp1, a member of the Set1 Complex, promotes meiotic DSB formation in promoters by tethering histone H3K4 methylation sites to chromosome axes. Mol Cell 49:43–54. https://doi.org/10.1016/j.molcel.2012.11.008
Suresh RV, Narayannapa S et al (2017) Association of RFC1 A80G gene polymorphism with advanced maternal age in risk of Down syndrome. Curr Med Res Pract 7:6–10. https://doi.org/10.1016/j.cmrp.2016.11.001
Sukla KK, Jaiswal SK, Rai AK et al (2015) Role of folate-homocysteine pathway gene polymorphisms and nutritional cofactors in Down syndrome: a triad study. Hum Reprod 30:1982–1993. https://doi.org/10.1093/humrep/dev126
Venselaar H, Te Beek T A H, Kuipers R K P et al (2010) Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinformatics 11:548. https://doi.org/10.1186/1471-2105-11-548
Vraneković J, Babić Božović I, Bilić Čače I et al (2020) Methylenetetrahydrofolate reductase dimer configuration as a risk factor for maternal Meiosis I-derived Trisomy 21. Hum Hered 85:61–65. https://doi.org/10.1159/000515121
Wang SS, Qiao FY, Feng L et al (2008) Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome in China. J Zhejiang Univ Sci B 9:93–99. https://doi.org/10.1631/jzus.B071059
Wang S, Wang C, Qiao F et al (2013) Polymorphisms in genes RFC-1/CBS as maternal risk factors for Down syndrome in China. Arch Gynecol Obstet 288:273–277. https://doi.org/10.1007/s00404-013-2760-9
Warren AC, Chakravarti A, Wong C et al (1987) Evidence for reduced recombination on the nondisjoined chromosomes 21 in Down syndrome. Science 237:652–654. https://doi.org/10.1126/science.2955519
Wilson IM, Davies JJ, Weber M et al (2006) Epigenomics: mapping the methylome. Cell Cycle 5:155–158. https://doi.org/10.4161/cc.5.2.2367
Xie S, Wang Z, Okano M et al (1999) Cloning, expression and chromosome locations of the human DNMT3 gene family. Gene 236:87–95. https://doi.org/10.1016/s0378-1119(99)00252-8
Yang M, Gong T, Lin X et al (2013) Maternal gene polymorphisms involved in folate metabolism and the risk of having a Down syndrome offspring: a meta-analysis. Mutagenesis 28:661–671. https://doi.org/10.1093/mutage/get045
Zampieri BL, Biselli JM, Goloni-Bertollo EM et al (2012) Maternal risk for Down syndrome is modulated by genes involved in folate metabolism. Dis Markers 32:73–81. https://doi.org/10.3233/DMA-2011-0869
Zelkowski M, Olson MA, Wang M et al (2019) Diversity and determinants of meiotic recombination landscapes. Trends Genet 35:359–370. https://doi.org/10.1016/j.tig.2019.02.002
Zhu S, Zhang H, Tang Y et al (2012) DNMT3B polymorphisms and cancer risk: a meta analysis of 24 case-control studies. Mol Biol Rep 39:4429–4437. https://doi.org/10.1007/s11033-011-1231-2
Acknowledgements
We are indebted to the participating families and physician friends who helped in procuring tissue samples. The departmental instrumental facilities were supported by University Grants Commission-University with Potential for Excellence II (UGC-UPE II), Department of Science and Technology-Fund for Improvement of S&T Infrastructure (DST-FIST), Department of Science and Technology-Promotion of University Research and Scientific Excellence (DST-PURSE) programme at the University of Calcutta.
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This work was supported by the grant from the Department of Science and Technology, Government of West Bengal (WB-DST), India (Grant number SG/WBDST/S&T 1000114/2016) and University of Potential excellence (UGC-UPE II) (Grant No. UPE-4004214/20UGC-UPE II). The author PH has received fellowship award (Ref. No: 21/06/2015(i)EU-V) from University Grants Commission (UGC), New Delhi, India.
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PH: data curation, formal analysis, investigation, methodology, software, writing—original draft, writing—review and editing, visualization, validation; UP: data curation, methodology, writing—review and editing; AG: data curation; PG: investigation, writing—review and editing, project administration; AR: formal analysis, methodology, writing—review and editing; SS: resources, writing—review and editing; SG: conceptualization, funding acquisition, investigation, resources, writing—original draft, writing—review and editing, visualization, supervision, project administration.
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Halder, P., Pal, U., Ganguly, A. et al. Genetic aetiology of Down syndrome birth: novel variants of maternal DNMT3B and RFC1 genes increase risk of meiosis II nondisjunction in the oocyte. Mol Genet Genomics 298, 293–313 (2023). https://doi.org/10.1007/s00438-022-01981-4
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DOI: https://doi.org/10.1007/s00438-022-01981-4