The etiology of Down syndrome: Maternal MCM9 polymorphisms increase risk of reduced recombination and nondisjunction of chromosome 21 during meiosis I within oocyte
Autoři:
Upamanyu Pal aff001; Pinku Halder aff001; Anirban Ray aff002; Sumantra Sarkar aff003; Supratim Datta aff003; Papiya Ghosh aff005; Sujay Ghosh aff001
Působiště autorů:
Cytogenetics and Genomics Research Unit, Department of Zoology, University of Calcutta, Taraknath Palit Siksha Prangan (Ballygunge Science College Campus), Kolkata, West Bengal, India
aff001; Department of Zoology, Bangabasi Morning College (affiliated to University of Calcutta), Kolkata, West Bengal, India
aff002; Department of Paediatric Medicine, Institute of Post Graduate Medical Education and Research (IPGMER), Bhowanipore, Kolkata, West Bengal, India
aff003; Department of Paediatric Medicine, Diamond Harbour Government Medical College & Hospital, Diamond Harbour, West Bengal, India
aff004; Department of Zoology, Bijoykrishna Girls’ College (Affiliated to University of Calcutta), Howrah, West Bengal, India
aff005
Vyšlo v časopise:
The etiology of Down syndrome: Maternal MCM9 polymorphisms increase risk of reduced recombination and nondisjunction of chromosome 21 during meiosis I within oocyte. PLoS Genet 17(3): e1009462. doi:10.1371/journal.pgen.1009462
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1009462
Souhrn
Altered patterns of recombination on 21q have long been associated with the nondisjunction chromosome 21 within oocytes and the increased risk of having a child with Down syndrome. Unfortunately the genetic etiology of these altered patterns of recombination have yet to be elucidated. We for the first time genotyped the gene MCM9, a candidate gene for recombination regulation and DNA repair in mothers with or without children with Down syndrome. In our approach, we identified the location of recombination on the maternal chromosome 21 using short tandem repeat markers, then stratified our population by the origin of meiotic error and age at conception. We observed that twenty-five out of forty-one single nucleotide polymorphic sites within MCM9 exhibited an association with meiosis I error (N = 700), but not with meiosis II error (N = 125). This association was maternal age-independent. Several variants exhibited aprotective association with MI error, some were neutral. Maternal age stratified characterization of cases revealed that MCM9 risk variants were associated with an increased chance of reduced recombination on 21q within oocytes. The spatial distribution of single observed recombination events revealed no significant change in the location of recombination among women harbouring MCM9 risk, protective, or neutral variant. Additionally, we identified a total of six novel polymorphic variants and two novel alleles that were either risk imparting or protective against meiosis I nondisjunction. In silico analyses using five different programs suggest the risk variants either cause a change in protein function or may alter the splicing pattern of transcripts and disrupt the proportion of different isoforms of MCM9 products within oocytes. These observations bring us a significant step closer to understanding the molecular basis of recombination errors in chromosome 21 nondisjunction within oocytes that leads to birth of child with Down syndrome.
Klíčová slova:
Age groups – Alleles – Homozygosity – Introns – Medical risk factors – Meiosis – Oocytes – Variant genotypes
Zdroje
1. Antonarakis SE. 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: 872–876. doi: 10.1056/NEJM199103283241302 1825697
2. Oliver TR, Feingold E, Yu K, Cheung V, Tinker S, Yadav-Shah M, et al. New insights into human nondisjunction of chromosome 21 in oocytes. PLoS Genet. 2008;4: e1000033. doi: 10.1371/journal.pgen.1000033 18369452
3. Sherman SL, Allen EG, Bean LH, Freeman SB. Epidemiology of Down syndrome. Ment Retard Dev Disabil Res Rev. 2007;13: 221–227. doi: 10.1002/mrdd.20157 17910090
4. Allen EG, Freeman SB, Druschel C, Hobbs CA, O’Leary LA, Romitti PA, et al. Maternal age and risk for trisomy 21 assessed by the origin of chromosome nondisjunction: a report from the Atlanta and National Down Syndrome Projects. Hum Genet. 2009;125: 41–52. doi: 10.1007/s00439-008-0603-8 19050929
5. Ghosh S, Ghosh P. Genetic Etiology of Chromosome 21 Nondisjunction and Down syndrome Birth: Aberrant Recombination and Beyond. J Down Syndr Chromosom Abnorm. 2015;1. doi: 10.4172/2472-1115.1000102
6. Ghosh S, Feingold E, Dey SK. Etiology of Down syndrome: Evidence for consistent association among altered meiotic recombination, nondisjunction, and maternal age across populations. Am J Med Genet A. 2009;149A: 1415–1420. doi: 10.1002/ajmg.a.32932 19533770
7. Cheslock PS, Kemp BJ, Boumil RM, Dawson DS. The roles of MAD1, MAD2 and MAD3 in meiotic progression and the segregation of nonexchange chromosomes. Nat Genet. 2005;37: 756–760. doi: 10.1038/ng1588 15951820
8. Cheng J-M, Liu Y-X. Age-Related Loss of Cohesion: Causes and Effects. Int J Mol Sci. 2017;18. doi: 10.3390/ijms18071578 28737671
9. Steuerwald N, Cohen J, Herrera RJ, Sandalinas M, Brenner CA. Association between spindle assembly checkpoint expression and maternal age in human oocytes. Mol Hum Reprod. 2001;7: 49–55. doi: 10.1093/molehr/7.1.49 11134360
10. Lamb NE, Feingold E, Savage A, Avramopoulos D, Freeman S, Gu Y, et al. Characterization of susceptible chiasma configurations that increase the risk for maternal nondisjunction of chromosome 21. Hum Mol Genet. 1997;6: 1391–1399. doi: 10.1093/hmg/6.9.1391 9285774
11. Baudat F, Buard J, Grey C, Fledel-Alon A, Ober C, Przeworski M, et al. PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice. Science. 2010;327: 836–840. doi: 10.1126/science.1183439 20044539
12. Berg IL, Neumann R, Lam K-WG, Sarbajna S, Odenthal-Hesse L, May CA, et al. PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability in humans. Nat Genet. 2010;42: 859–863. doi: 10.1038/ng.658 20818382
13. Oliver TR, Middlebrooks C, Harden A, Scott N, Johnson B, Jones J, et al. Variation in the Zinc Finger of PRDM9 is Associated with the Absence of Recombination along Nondisjoined Chromosomes 21 of Maternal Origin. J Down Syndr Chromosom Abnorm. 2016;2. doi: 10.4172/2472-1115.1000115 28702511
14. Griffin WC, Trakselis MA. The MCM8/9 complex: A recent recruit to the roster of helicases involved in genome maintenance. DNA Repair (Amst). 2019;76: 1–10. doi: 10.1016/j.dnarep.2019.02.003 30743181
15. Nishimura K, Ishiai M, Horikawa K, Fukagawa T, Takata M, Takisawa H, et al. Mcm8 and Mcm9 form a complex that functions in homologous recombination repair induced by DNA interstrand crosslinks. Mol Cell. 2012;47: 511–522. doi: 10.1016/j.molcel.2012.05.047 22771115
16. Maiorano D, Lutzmann M, Méchali M. MCM proteins and DNA replication. Curr Opin Cell Biol. 2006;18: 130–136. doi: 10.1016/j.ceb.2006.02.006 16495042
17. Lutzmann M, Méchali M. MCM9 binds Cdt1 and is required for the assembly of prereplication complexes. Mol Cell. 2008;31: 190–200. doi: 10.1016/j.molcel.2008.07.001 18657502
18. Park J, Long DT, Lee KY, Abbas T, Shibata E, Negishi M, et al. The MCM8-MCM9 complex promotes RAD51 recruitment at DNA damage sites to facilitate homologous recombination. Mol Cell Biol. 2013;33: 1632–1644. doi: 10.1128/MCB.01503-12 23401855
19. Hustedt N, Saito Y, Zimmermann M, Álvarez-Quilón A, Setiaputra D, Adam S, et al. Control of homologous recombination by the HROB-MCM8-MCM9 pathway. Genes Dev. 2019;33: 1397–1415. doi: 10.1101/gad.329508.119 31467087
20. Wood-Trageser MA, Gurbuz F, Yatsenko SA, Jeffries EP, Kotan LD, Surti U, et al. MCM9 mutations are associated with ovarian failure, short stature, and chromosomal instability. Am J Hum Genet. 2014;95: 754–762. doi: 10.1016/j.ajhg.2014.11.002 25480036
21. Desai S, Wood-Trageser M, Matic J, Chipkin J, Jiang H, Bachelot A, et al. MCM8 and MCM9 nucleotide variants in women with primary ovarian insufficiency. J Clin Endocrinol Metab. 2017;102: 576–582. doi: 10.1210/jc.2016-2565 27802094
22. Lutzmann M, Grey C, Traver S, Ganier O, Maya-Mendoza A, Ranisavljevic N, et al. MCM8- and MCM9-deficient mice reveal gametogenesis defects and genome instability due to impaired homologous recombination. Mol Cell. 2012;47: 523–534. doi: 10.1016/j.molcel.2012.05.048 22771120
23. Guo T, Zheng Y, Li G, Zhao S, Ma J, Qin Y. Novel pathogenic mutations in minichromosome maintenance complex component 9 (MCM9) responsible for premature ovarian insufficiency. Fertil Steril. 2020;113: 845–852. doi: 10.1016/j.fertnstert.2019.11.015 32145932
24. Feingold E, Brown AS, Sherman SL. Multipoint estimation of genetic maps for human trisomies with one parent or other partial data. Am J Hum Genet. 2000;66: 958–968. doi: 10.1086/302799 10712210
25. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7: 248–249. doi: 10.1038/nmeth0410-248 20354512
26. Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet. 2013;Chapter 7: Unit7.20. doi: 10.1002/0471142905.hg0720s76 23315928
27. Ramensky V, Bork P, Sunyaev S. Human non-synonymous SNPs: server and survey. Nucleic Acids Res. 2002;30: 3894–3900. doi: 10.1093/nar/gkf493 12202775
28. Sunyaev SR, Eisenhaber F, Rodchenkov IV, Eisenhaber B, Tumanyan VG, Kuznetsov EN. PSIC: profile extraction from sequence alignments with position-specific counts of independent observations. Protein Eng. 1999;12: 387–394. doi: 10.1093/protein/12.5.387 10360979
29. Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods. 2014;11: 361–362. doi: 10.1038/nmeth.2890 24681721
30. Choi Y, Sims GE, Murphy S, Miller JR, Chan AP. Predicting the functional effect of amino acid substitutions and indels. PLoS One. 2012;7: e46688. doi: 10.1371/journal.pone.0046688 23056405
31. Choi Y. A fast computation of pairwise sequence alignment scores between a protein and a set of single-locus variants of another protein. Proceedings of the ACM Conference on Bioinformatics, Computational Biology and Biomedicine—BCB’ ’ ‘12. New York, New York, USA: ACM Press; 2012. pp. 414–417.
32. Choi Y, Chan AP. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics. 2015;31: 2745–2747. doi: 10.1093/bioinformatics/btv195 25851949
33. Li W, Godzik A. Cd-hit: a fast program for clustering and comparing large sets of protein or nucleotide sequences. Bioinformatics. 2006;22: 1658–1659. doi: 10.1093/bioinformatics/btl158 16731699
34. Desmet F-O, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res. 2009;37: e67. doi: 10.1093/nar/gkp215 19339519
35. Lamb NE, Freeman SB, Savage-Austin A, Pettay D, Taft L, Hersey J, et al. Susceptible chiasmate configurations of chromosome 21 predispose to non-disjunction in both maternal meiosis I and meiosis II. Nat Genet. 1996;14: 400–405. doi: 10.1038/ng1296-400 8944019
36. Chernus JM, Allen EG, Zeng Z, Hoffman ER, Hassold TJ, Feingold E, et al. A candidate gene analysis and GWAS for genes associated with maternal nondisjunction of chromosome 21. PLoS Genet. 2019;15: e1008414. doi: 10.1371/journal.pgen.1008414 31830031
37. Jorde LB, Watkins WS, Carlson M, Groden J, Albertsen H, Thliveris A, et al. Linkage disequilibrium predicts physical distance in the adenomatous polyposis coli region. Am J Hum Genet. 1994;54: 884–898. 8178829
38. Ottolini CS, Newnham L, Capalbo A, Natesan SA, Joshi HA, Cimadomo D, et al. Genome-wide maps of recombination and chromosome segregation in human oocytes and embryos show selection for maternal recombination rates. Nat Genet. 2015;47: 727–735. doi: 10.1038/ng.3306 25985139
39. Hou Y, Fan W, Yan L, Li R, Lian Y, Huang J, et al. Genome analyses of single human oocytes. Cell. 2013;155: 1492–1506. doi: 10.1016/j.cell.2013.11.040 24360273
40. Lee Y, Gamazon ER, Rebman E, Lee Y, Lee S, Dolan ME, et al. Variants affecting exon skipping contribute to complex traits. PLoS Genet. 2012;8: e1002998. doi: 10.1371/journal.pgen.1002998 23133393
41. Anna A, Monika G. Splicing mutations in human genetic disorders: examples, detection, and confirmation. J Appl Genet. 2018;59: 253–268. doi: 10.1007/s13353-018-0444-7 29680930
42. López-Bigas N, Audit B, Ouzounis C, Parra G, Guigó R. Are splicing mutations the most frequent cause of hereditary disease? FEBS Lett. 2005;579: 1900–1903. doi: 10.1016/j.febslet.2005.02.047 15792793
43. Wang G-S, Cooper TA. Splicing in disease: disruption of the splicing code and the decoding machinery. Nat Rev Genet. 2007;8: 749–761. doi: 10.1038/nrg2164 17726481
44. Fairbrother WG, Holste D, Burge CB, Sharp PA. Single nucleotide polymorphism-based validation of exonic splicing enhancers. PLoS Biol. 2004;2: E268. doi: 10.1371/journal.pbio.0020268 15340491
45. Cooper DN. Functional intronic polymorphisms: Buried treasure awaiting discovery within our genes. Hum Genomics. 2010;4: 284–288. doi: 10.1186/1479-7364-4-5-284 20650817
46. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536: 285–291. doi: 10.1038/nature19057 27535533
47. Park E, Pan Z, Zhang Z, Lin L, Xing Y. The expanding landscape of alternative splicing variation in human populations. Am J Hum Genet. 2018;102: 11–26. doi: 10.1016/j.ajhg.2017.11.002 29304370
48. Middlebrooks CD, Mukhopadhyay N, Tinker SW, Allen EG, Bean LJH, Begum F, et al. Evidence for dysregulation of genome-wide recombination in oocytes with nondisjoined chromosomes 21. Hum Mol Genet. 2014;23: 408–417. doi: 10.1093/hmg/ddt433 24014426
Článek vyšel v časopise
PLOS Genetics
2021 Číslo 3
- S diagnostikou Parkinsonovy nemoci může nově pomoci AI nástroj pro hodnocení mrkacího reflexu
- Proč při poslechu některé muziky prostě musíme tančit?
- Chůze do schodů pomáhá prodloužit život a vyhnout se srdečním chorobám
- Metamizol jako analgetikum první volby: kdy, pro koho, jak a proč?
- „Jednohubky“ z klinického výzkumu – 2024/44
Nejčtenější v tomto čísle
- DNA polymerase theta suppresses mitotic crossing over
- IKAROS is required for the measured response of NOTCH target genes upon external NOTCH signaling
- activin-2 is required for regeneration of polarity on the planarian anterior-posterior axis
- The etiology of Down syndrome: Maternal MCM9 polymorphisms increase risk of reduced recombination and nondisjunction of chromosome 21 during meiosis I within oocyte
