#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

APOBEC3A is a prominent cytidine deaminase in breast cancer


Autoři: Luis M. Cortez aff001;  Amber L. Brown aff001;  Madeline A. Dennis aff001;  Christopher D. Collins aff001;  Alexander J. Brown aff001;  Debra Mitchell aff001;  Tony M. Mertz aff001;  Steven A. Roberts aff001
Působiště autorů: School of Molecular Biosciences and Center for Reproductive Biology, Washington State University, Pullman, WA, United States of America aff001;  Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, United States of America aff002;  School of Molecular Biosciences, Washington State University-Vancouver, Vancouver, WA, United States of America aff003
Vyšlo v časopise: APOBEC3A is a prominent cytidine deaminase in breast cancer. PLoS Genet 15(12): e32767. doi:10.1371/journal.pgen.1008545
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008545

Souhrn

APOBEC cytidine deaminases are the second-most prominent source of mutagenesis in sequenced tumors. Previous studies have proposed that APOBEC3B (A3B) is the major source of mutagenesis in breast cancer (BRCA). We show that APOBEC3A (A3A) is the only APOBEC whose expression correlates with APOBEC-induced mutation load and that A3A expression is responsible for cytidine deamination in multiple BRCA cell lines. Comparative analysis of A3A and A3B expression by qRT-PCR, RSEM-normalized RNA-seq, and unambiguous RNA-seq validated the use of RNA-seq to measure APOBEC expression, which indicates that A3A is the primary correlate with APOBEC-mutation load in primary BRCA tumors. We also demonstrate that A3A has >100-fold more cytidine deamination activity than A3B in the presence of cellular RNA, likely explaining why higher levels of A3B expression contributes less to mutagenesis in BRCA. Our findings identify A3A as a major source of cytidine deaminase activity in breast cancer cells and possibly a prominent contributor to the APOBEC mutation signature.

Klíčová slova:

BT474 cells – Gene expression – Genetic causes of cancer – Haplotypes – Mutagenesis – RNA extraction – RNA sequencing – Sequence motif analysis


Zdroje

1. Roberts SA, Lawrence MS, Klimczak LJ, Grimm SA, Fargo D, Stojanov P, et al. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nat Genet. 2013;45(9):970–6. Epub 2013/07/16. doi: 10.1038/ng.2702 23852170; PubMed Central PMCID: PMC3789062.

2. Burns MB, Temiz NA, Harris RS. Evidence for APOBEC3B mutagenesis in multiple human cancers. Nat Genet. 2013;45(9):977–83. Epub 2013/07/16. doi: 10.1038/ng.2701 23852168; PubMed Central PMCID: PMC3902892.

3. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–21. Epub 2013/08/16. doi: 10.1038/nature12477 23945592; PubMed Central PMCID: PMC3776390.

4. Refsland EW, Harris RS. The APOBEC3 family of retroelement restriction factors. Curr Top Microbiol Immunol. 2013;371:1–27. Epub 2013/05/21. doi: 10.1007/978-3-642-37765-5_1 23686230; PubMed Central PMCID: PMC3934647.

5. Henderson S, Chakravarthy A, Su X, Boshoff C, Fenton TR. APOBEC-Mediated Cytosine Deamination Links PIK3CA Helical Domain Mutations to Human Papillomavirus-Driven Tumor Development. Cell Rep. 2014. Epub 2014/06/10. doi: 10.1016/j.celrep.2014.05.012 24910434.

6. Roper N, Gao S, Maity TK, Banday AR, Zhang X, Venugopalan A, et al. APOBEC Mutagenesis and Copy-Number Alterations Are Drivers of Proteogenomic Tumor Evolution and Heterogeneity in Metastatic Thoracic Tumors. Cell Rep. 2019;26(10):2651–66 e6. doi: 10.1016/j.celrep.2019.02.028 30840888.

7. Law EK, Sieuwerts AM, LaPara K, Leonard B, Starrett GJ, Molan AM, et al. The DNA cytosine deaminase APOBEC3B promotes tamoxifen resistance in ER-positive breast cancer. Sci Adv. 2016;2(10):e1601737. doi: 10.1126/sciadv.1601737 27730215; PubMed Central PMCID: PMC5055383.

8. Nikkila J, Kumar R, Campbell J, Brandsma I, Pemberton HN, Wallberg F, et al. Elevated APOBEC3B expression drives a kataegic-like mutation signature and replication stress-related therapeutic vulnerabilities in p53-defective cells. Br J Cancer. 2017;117(1):113–23. doi: 10.1038/bjc.2017.133 28535155; PubMed Central PMCID: PMC5520199.

9. Green AM, Budagyan K, Hayer KE, Reed MA, Savani MR, Wertheim GB, et al. Cytosine Deaminase APOBEC3A Sensitizes Leukemia Cells to Inhibition of the DNA Replication Checkpoint. Cancer Res. 2017;77(17):4579–88. doi: 10.1158/0008-5472.CAN-16-3394 28655787; PubMed Central PMCID: PMC5581702.

10. Buisson R, Lawrence MS, Benes CH, Zou L. APOBEC3A and APOBEC3B Activities Render Cancer Cells Susceptible to ATR Inhibition. Cancer Res. 2017;77(17):4567–78. doi: 10.1158/0008-5472.CAN-16-3389 28698210; PubMed Central PMCID: PMC5609510.

11. Roberts SA, Sterling J, Thompson C, Harris S, Mav D, Shah R, et al. Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions. Mol Cell. 2012;46(4):424–35. Epub 2012/05/23. doi: 10.1016/j.molcel.2012.03.030 22607975; PubMed Central PMCID: PMC3361558.

12. Nik-Zainal S, Alexandrov LB, Wedge DC, Van Loo P, Greenman CD, Raine K, et al. Mutational processes molding the genomes of 21 breast cancers. Cell. 2012;149(5):979–93. doi: 10.1016/j.cell.2012.04.024 22608084; PubMed Central PMCID: PMC3414841.

13. Haradhvala NJ, Polak P, Stojanov P, Covington KR, Shinbrot E, Hess JM, et al. Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair. Cell. 2016;164(3):538–49. doi: 10.1016/j.cell.2015.12.050 26806129; PubMed Central PMCID: PMC4753048.

14. Morganella S, Alexandrov LB, Glodzik D, Zou X, Davies H, Staaf J, et al. The topography of mutational processes in breast cancer genomes. Nat Commun. 2016;7:11383. doi: 10.1038/ncomms11383 27136393; PubMed Central PMCID: PMC5001788.

15. Seplyarskiy VB, Soldatov RA, Popadin KY, Antonarakis SE, Bazykin GA, Nikolaev SI. APOBEC-induced mutations in human cancers are strongly enriched on the lagging DNA strand during replication. Genome Res. 2016;26(2):174–82. doi: 10.1101/gr.197046.115 26755635; PubMed Central PMCID: PMC4728370.

16. Nik-Zainal S, Davies H, Staaf J, Ramakrishna M, Glodzik D, Zou X, et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature. 2016;534(7605):47–54. doi: 10.1038/nature17676 27135926; PubMed Central PMCID: PMC4910866.

17. Bhagwat AS, Hao W, Townes JP, Lee H, Tang H, Foster PL. Strand-biased cytosine deamination at the replication fork causes cytosine to thymine mutations in Escherichia coli. Proc Natl Acad Sci U S A. 2016;113(8):2176–81. doi: 10.1073/pnas.1522325113 26839411; PubMed Central PMCID: PMC4776466.

18. Hoopes JI, Cortez LM, Mertz TM, Malc EP, Mieczkowski PA, Roberts SA. APOBEC3A and APOBEC3B Preferentially Deaminate the Lagging Strand Template during DNA Replication. Cell Rep. 2016;14(6):1273–82. doi: 10.1016/j.celrep.2016.01.021 26832400; PubMed Central PMCID: PMC4758883.

19. Saini N, Roberts SA, Sterling JF, Malc EP, Mieczkowski PA, Gordenin DA. APOBEC3B cytidine deaminase targets the non-transcribed strand of tRNA genes in yeast. DNA Repair (Amst). 2017;53:4–14. doi: 10.1016/j.dnarep.2017.03.003 28351647; PubMed Central PMCID: PMC5450012.

20. Green AM, Landry S, Budagyan K, Avgousti DC, Shalhout S, Bhagwat AS, et al. APOBEC3A damages the cellular genome during DNA replication. Cell Cycle. 2016;15(7):998–1008. doi: 10.1080/15384101.2016.1152426 26918916; PubMed Central PMCID: PMC4889253.

21. Taylor BJ, Nik-Zainal S, Wu YL, Stebbings LA, Raine K, Campbell PJ, et al. DNA deaminases induce break-associated mutation showers with implication of APOBEC3B and 3A in breast cancer kataegis. Elife. 2013;2:e00534. doi: 10.7554/eLife.00534 23599896; PubMed Central PMCID: PMC3628087.

22. Burns MB, Lackey L, Carpenter MA, Rathore A, Land AM, Leonard B, et al. APOBEC3B is an enzymatic source of mutation in breast cancer. Nature. 2013;494(7437):366–70. Epub 2013/02/08. doi: 10.1038/nature11881 23389445; PubMed Central PMCID: PMC3907282.

23. Starrett GJ, Luengas EM, McCann JL, Ebrahimi D, Temiz NA, Love RP, et al. The DNA cytosine deaminase APOBEC3H haplotype I likely contributes to breast and lung cancer mutagenesis. Nat Commun. 2016;7:12918. doi: 10.1038/ncomms12918 27650891; PubMed Central PMCID: PMC5036005.

24. Li MM, Emerman M. Polymorphism in human APOBEC3H affects a phenotype dominant for subcellular localization and antiviral activity. J Virol. 2011;85(16):8197–207. doi: 10.1128/JVI.00624-11 21653666; PubMed Central PMCID: PMC3147987.

25. Bogerd HP, Wiegand HL, Hulme AE, Garcia-Perez JL, O'Shea KS, Moran JV, et al. Cellular inhibitors of long interspersed element 1 and Alu retrotransposition. Proc Natl Acad Sci U S A. 2006;103(23):8780–5. Epub 2006/05/27. doi: 10.1073/pnas.0603313103 16728505; PubMed Central PMCID: PMC1482655.

26. Chester A, Somasekaram A, Tzimina M, Jarmuz A, Gisbourne J, O'Keefe R, et al. The apolipoprotein B mRNA editing complex performs a multifunctional cycle and suppresses nonsense-mediated decay. EMBO J. 2003;22(15):3971–82. doi: 10.1093/emboj/cdg369 12881431; PubMed Central PMCID: PMC169042.

27. Kidd JM, Newman TL, Tuzun E, Kaul R, Eichler EE. Population stratification of a common APOBEC gene deletion polymorphism. PLoS genetics. 2007;3(4):e63. doi: 10.1371/journal.pgen.0030063 17447845; PubMed Central PMCID: PMC1853121.

28. Nik-Zainal S, Wedge DC, Alexandrov LB, Petljak M, Butler AP, Bolli N, et al. Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer. Nat Genet. 2014;46(5):487–91. doi: 10.1038/ng.2955 24728294; PubMed Central PMCID: PMC4137149.

29. Komatsu A, Nagasaki K, Fujimori M, Amano J, Miki Y. Identification of novel deletion polymorphisms in breast cancer. Int J Oncol. 2008;33(2):261–70. Epub 2008/07/19. 18636146.

30. OhAinle M, Kerns JA, Li MM, Malik HS, Emerman M. Antiretroelement activity of APOBEC3H was lost twice in recent human evolution. Cell Host Microbe. 2008;4(3):249–59. doi: 10.1016/j.chom.2008.07.005 18779051; PubMed Central PMCID: PMC2608726.

31. Suspene R, Mussil B, Laude H, Caval V, Berry N, Bouzidi MS, et al. Self-cytoplasmic DNA upregulates the mutator enzyme APOBEC3A leading to chromosomal DNA damage. Nucleic Acids Res. 2017;45(6):3231–41. doi: 10.1093/nar/gkx001 28100701; PubMed Central PMCID: PMC5389686.

32. Suspene R, Aynaud MM, Guetard D, Henry M, Eckhoff G, Marchio A, et al. Somatic hypermutation of human mitochondrial and nuclear DNA by APOBEC3 cytidine deaminases, a pathway for DNA catabolism. Proc Natl Acad Sci U S A. 2011;108(12):4858–63. doi: 10.1073/pnas.1009687108 21368204; PubMed Central PMCID: PMC3064337.

33. Chan K, Roberts SA, Klimczak LJ, Sterling JF, Saini N, Malc EP, et al. An APOBEC3A hypermutation signature is distinguishable from the signature of background mutagenesis by APOBEC3B in human cancers. Nat Genet. 2015;47(9):1067–72. doi: 10.1038/ng.3378 26258849; PubMed Central PMCID: PMC4594173.

34. Petljak M, Alexandrov LB, Brammeld JS, Price S, Wedge DC, Grossmann S, et al. Characterizing Mutational Signatures in Human Cancer Cell Lines Reveals Episodic APOBEC Mutagenesis. Cell. 2019;176(6):1282–94 e20. doi: 10.1016/j.cell.2019.02.012 30849372.

35. Caval V, Suspene R, Shapira M, Vartanian JP, Wain-Hobson S. A prevalent cancer susceptibility APOBEC3A hybrid allele bearing APOBEC3B 3'UTR enhances chromosomal DNA damage. Nat Commun. 2014;5:5129. doi: 10.1038/ncomms6129 25298230.

36. Refsland EW, Stenglein MD, Shindo K, Albin JS, Brown WL, Harris RS. Quantitative profiling of the full APOBEC3 mRNA repertoire in lymphocytes and tissues: implications for HIV-1 restriction. Nucleic Acids Res. 2010;38(13):4274–84. doi: 10.1093/nar/gkq174 20308164; PubMed Central PMCID: PMC2910054.

37. Periyasamy M, Patel H, Lai CF, Nguyen VTM, Nevedomskaya E, Harrod A, et al. APOBEC3B-Mediated Cytidine Deamination Is Required for Estrogen Receptor Action in Breast Cancer. Cell Rep. 2015;13(1):108–21. doi: 10.1016/j.celrep.2015.08.066 26411678; PubMed Central PMCID: PMC4597099.

38. Kouno T, Silvas TV, Hilbert BJ, Shandilya SMD, Bohn MF, Kelch BA, et al. Crystal structure of APOBEC3A bound to single-stranded DNA reveals structural basis for cytidine deamination and specificity. Nat Commun. 2017;8:15024. doi: 10.1038/ncomms15024 28452355; PubMed Central PMCID: PMC5414352.

39. Buisson R, Langenbucher A, Bowen D, Kwan EE, Benes CH, Zou L, et al. Passenger hotspot mutations in cancer driven by APOBEC3A and mesoscale genomic features. Science. 2019;364(6447). doi: 10.1126/science.aaw2872 31249028.

40. Shi K, Carpenter MA, Banerjee S, Shaban NM, Kurahashi K, Salamango DJ, et al. Structural basis for targeted DNA cytosine deamination and mutagenesis by APOBEC3A and APOBEC3B. Nat Struct Mol Biol. 2017;24(2):131–9. doi: 10.1038/nsmb.3344 27991903; PubMed Central PMCID: PMC5296220.

41. Di Noia J, Neuberger MS. Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase. Nature. 2002;419(6902):43–8. doi: 10.1038/nature00981 12214226.

42. Kanu N, Cerone MA, Goh G, Zalmas LP, Bartkova J, Dietzen M, et al. DNA replication stress mediates APOBEC3 family mutagenesis in breast cancer. Genome Biol. 2016;17(1):185. doi: 10.1186/s13059-016-1042-9 27634334; PubMed Central PMCID: PMC5025597.

43. Smith HC. RNA binding to APOBEC deaminases; Not simply a substrate for C to U editing. RNA Biol. 2017;14(9):1153–65. doi: 10.1080/15476286.2016.1259783 27869537; PubMed Central PMCID: PMC5699538.

44. Feng Y, Wong L, Morse M, Rouzina I, Williams MC, Chelico L. RNA-Mediated Dimerization of the Human Deoxycytidine Deaminase APOBEC3H Influences Enzyme Activity and Interaction with Nucleic Acids. J Mol Biol. 2018;430(24):4891–907. doi: 10.1016/j.jmb.2018.11.006 30414963; PubMed Central PMCID: PMC6289724.

45. Shaban NM, Shi K, Lauer KV, Carpenter MA, Richards CM, Salamango D, et al. The Antiviral and Cancer Genomic DNA Deaminase APOBEC3H Is Regulated by an RNA-Mediated Dimerization Mechanism. Mol Cell. 2018;69(1):75–86 e9. doi: 10.1016/j.molcel.2017.12.010 29290613; PubMed Central PMCID: PMC5991973.

46. Bransteitter R, Pham P, Scharff MD, Goodman MF. Activation-induced cytidine deaminase deaminates deoxycytidine on single-stranded DNA but requires the action of RNase. Proc Natl Acad Sci U S A. 2003;100(7):4102–7. doi: 10.1073/pnas.0730835100 12651944; PubMed Central PMCID: PMC153055.

47. Chelico L, Pham P, Calabrese P, Goodman MF. APOBEC3G DNA deaminase acts processively 3' —> 5' on single-stranded DNA. Nat Struct Mol Biol. 2006;13(5):392–9. doi: 10.1038/nsmb1086 16622407.

48. Xiao X, Yang H, Arutiunian V, Fang Y, Besse G, Morimoto C, et al. Structural determinants of APOBEC3B non-catalytic domain for molecular assembly and catalytic regulation. Nucleic Acids Res. 2017;45(12):7540. doi: 10.1093/nar/gkx564 28645149; PubMed Central PMCID: PMC5499557.

49. Ito F, Fu Y, Kao SA, Yang H, Chen XS. Family-Wide Comparative Analysis of Cytidine and Methylcytidine Deamination by Eleven Human APOBEC Proteins. J Mol Biol. 2017;429(12):1787–99. doi: 10.1016/j.jmb.2017.04.021 28479091; PubMed Central PMCID: PMC5530319.

50. Tang F, Lao K, Surani MA. Development and applications of single-cell transcriptome analysis. Nat Methods. 2011;8(4 Suppl):S6–11. doi: 10.1038/nmeth.1557 21451510; PubMed Central PMCID: PMC3408593.

51. Liu Z, Lee Y, Jang J, Li Y, Han X, Yokoi K, et al. Microfluidic cytometric analysis of cancer cell transportability and invasiveness. Sci Rep. 2015;5:14272. doi: 10.1038/srep14272 26404901; PubMed Central PMCID: PMC4585905.

52. Zetterberg A. Nuclear and cytoplasmic nucleic acid content and cytoplasmic protein synthesis during interphase in mouse fibroblasts in vitro. Exp Cell Res. 1966;43(3):517–25. doi: 10.1016/0014-4827(66)90022-x 5957742.

53. Land AM, Law EK, Carpenter MA, Lackey L, Brown WL, Harris RS. Endogenous APOBEC3A DNA cytosine deaminase is cytoplasmic and nongenotoxic. J Biol Chem. 2013;288(24):17253–60. doi: 10.1074/jbc.M113.458661 23640892; PubMed Central PMCID: PMC3682529.

54. Mussil B, Suspene R, Aynaud MM, Gauvrit A, Vartanian JP, Wain-Hobson S. Human APOBEC3A isoforms translocate to the nucleus and induce DNA double strand breaks leading to cell stress and death. PLoS One. 2013;8(8):e73641. doi: 10.1371/journal.pone.0073641 23977391; PubMed Central PMCID: PMC3748023.

55. Landry S, Narvaiza I, Linfesty DC, Weitzman MD. APOBEC3A can activate the DNA damage response and cause cell-cycle arrest. EMBO Rep. 2011;12(5):444–50. doi: 10.1038/embor.2011.46 21460793; PubMed Central PMCID: PMC3090015.

56. Chen TW, Lee CC, Liu H, Wu CS, Pickering CR, Huang PJ, et al. APOBEC3A is an oral cancer prognostic biomarker in Taiwanese carriers of an APOBEC deletion polymorphism. Nat Commun. 2017;8(1):465. doi: 10.1038/s41467-017-00493-9 28878238; PubMed Central PMCID: PMC5587710.

57. Middlebrooks CD, Banday AR, Matsuda K, Udquim KI, Onabajo OO, Paquin A, et al. Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors. Nat Genet. 2016;48(11):1330–8. doi: 10.1038/ng.3670 27643540.

58. Waszak SM, Tiao G, Zhu B, Rausch T, Muyas F, Rodriguez-Martin B, et al. Germline determinants of the somatic mutation landscape in 2,642 cancer genomes. bioRxiv. 2017:208330. doi: 10.1101/208330

59. Maciejowski J, Chatzipli A, Dananberg A, de Lange T, Campbell PJ. APOBEC3B-dependent kataegis and TREX1-driven chromothripsis in telomere crisis. bioRxiv. 2019:725366. doi: 10.1101/725366

60. Basu U, Meng FL, Keim C, Grinstein V, Pefanis E, Eccleston J, et al. The RNA exosome targets the AID cytidine deaminase to both strands of transcribed duplex DNA substrates. Cell. 2011;144(3):353–63. doi: 10.1016/j.cell.2011.01.001 21255825; PubMed Central PMCID: PMC3065114.

61. Pefanis E, Basu U. RNA Exosome Regulates AID DNA Mutator Activity in the B Cell Genome. Adv Immunol. 2015;127:257–308. doi: 10.1016/bs.ai.2015.04.002 26073986; PubMed Central PMCID: PMC4478610.

62. Soros VB, Yonemoto W, Greene WC. Newly synthesized APOBEC3G is incorporated into HIV virions, inhibited by HIV RNA, and subsequently activated by RNase H. PLoS Pathog. 2007;3(2):e15. doi: 10.1371/journal.ppat.0030015 17291161; PubMed Central PMCID: PMC1796622.

63. Wang X, Abudu A, Son S, Dang Y, Venta PJ, Zheng YH. Analysis of human APOBEC3H haplotypes and anti-human immunodeficiency virus type 1 activity. J Virol. 2011;85(7):3142–52. doi: 10.1128/JVI.02049-10 21270145; PubMed Central PMCID: PMC3067873.

64. Ebrahimi D, Richards CM, Carpenter MA, Wang J, Ikeda T, Becker JT, et al. Genetic and mechanistic basis for APOBEC3H alternative splicing, retrovirus restriction, and counteraction by HIV-1 protease. Nat Commun. 2018;9(1):4137. doi: 10.1038/s41467-018-06594-3 30297863; PubMed Central PMCID: PMC6175962.

65. Matsumoto T, Shirakawa K, Yokoyama M, Fukuda H, Sarca AD, Koyabu S, et al. Protein kinase A inhibits tumor mutator APOBEC3B through phosphorylation. Sci Rep. 2019;9(1):8307. doi: 10.1038/s41598-019-44407-9 31165764; PubMed Central PMCID: PMC6549188.

66. Aynaud MM, Suspene R, Vidalain PO, Mussil B, Guetard D, Tangy F, et al. Human Tribbles 3 protects nuclear DNA from cytidine deamination by APOBEC3A. J Biol Chem. 2012;287(46):39182–92. doi: 10.1074/jbc.M112.372722 22977230; PubMed Central PMCID: PMC3493958.

67. Hoopes JI, Hughes AL, Hobson LA, Cortez LM, Brown AJ, Roberts SA. Avoidance of APOBEC3B-induced mutation by error-free lesion bypass. Nucleic Acids Res. 2017;45(9):5243–54. doi: 10.1093/nar/gkx169 28334887; PubMed Central PMCID: PMC5605239.

68. Blokzijl F, Janssen R, van Boxtel R, Cuppen E. MutationalPatterns: comprehensive genome-wide analysis of mutational processes. Genome Med. 2018;10(1):33. doi: 10.1186/s13073-018-0539-0 29695279; PubMed Central PMCID: PMC5922316.

Štítky
Genetika Reprodukční medicína

Článek vyšel v časopise

PLOS Genetics


2019 Číslo 12
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

Důležitost adherence při depresivním onemocnění
nový kurz
Autoři: MUDr. Eliška Bartečková, Ph.D.

Koncepce osteologické péče pro gynekology a praktické lékaře
Autoři: MUDr. František Šenk

Sekvenční léčba schizofrenie
Autoři: MUDr. Jana Hořínková, Ph.D.

Hypertenze a hypercholesterolémie – synergický efekt léčby
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Multidisciplinární zkušenosti u pacientů s diabetem
Autoři: Prof. MUDr. Martin Haluzík, DrSc., prof. MUDr. Vojtěch Melenovský, CSc., prof. MUDr. Vladimír Tesař, DrSc.

Všechny kurzy
Přihlášení
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se

#ADS_BOTTOM_SCRIPTS#