CoChat
Sign Up
Cited by 115DNA and Nucleic Acid ChemistryChromosomal and Genetic VariationsEvolution and Genetic Dynamics

Non-B DNA: a major contributor to small- and large-scale variation in nucleotide substitution frequencies across the genome

Open access
Guiblet, Wilfried M, Cremona, Marzia A, Harris, Robert S, Chen, Di, Eckert, Kristin A, Chiaromonte, Francesca, Huang, Yi-Fei, Makova, Kateryna D·2021·Nucleic Acids Research
DOI 10.1093/nar/gkaa1269PMC PMC7897504
Open this paper in CoChat — free accountOpen PDF

Abstract

Approximately 13% of the human genome can fold into non-canonical (non-B) DNA structures (e.g. G-quadruplexes, Z-DNA, etc.), which have been implicated in vital cellular processes. Non-B DNA also hinders replication, increasing errors and facilitating mutagenesis, yet its contribution to genome-wide variation in mutation rates remains unexplored. Here, we conducted a comprehensive analysis of nucleotide substitution frequencies at non-B DNA loci within noncoding, non-repetitive genome regions, their ±2 kb flanking regions, and 1-Megabase windows, using human-orangutan divergence and human single-nucleotide polymorphisms. Functional data analysis at single-base resolution demonstrated that substitution frequencies are usually elevated at non-B DNA, with patterns specific to each non-B DNA type. Mirror, direct and inverted repeats have higher substitution frequencies in spacers than in repeat arms, whereas G-quadruplexes, particularly stable ones, have higher substitution frequencies in loops than in stems. Several non-B DNA types also affect substitution frequencies in their flanking regions. Finally, non-B DNA explains more variation than any other predictor in multiple regression models for diversity or divergence at 1-Megabase scale. Thus, non-B DNA substantially contributes to variation in substitution frequencies at small and large scales. Our results highlight the role of non-B DNA in germline mutagenesis with implications to evolution and genetic diseases.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1093/nar/gkaa1269

Cites

12 of 12 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • G4s have emerged as drivers of genomic plasticity, both through small- and large-scale genomic variations.

    “Recently, G4s have emerged as drivers of genomic plasticity, both through small- and large-scale genomic variations (4,77).”

    From G-quadruplex-mediated genomic instability drives SNVs in cancer (2024) · cites this paper as [4]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 137

  1. [1]Hodgkinson A., Eyre-Walker A. Variation in the mutation rate across mammalian genomes. Nat. Rev. Genet. 2011; 12: 756– 766. 21969038
  2. [2]Makova K.D., Hardison R.C. The effects of chromatin organization on variation in mutation rates in the genome. Nat. Rev. Genet. 2015; 16: 213– 223. 25732611 PMC4500049
  3. [3]Xie K.T., Wang G., Thompson A.C., Wucherpfennig J.I., Reimchen T.E., MacColl A.D.C., Schluter D., Bell M.A., Vasquez K.M., Kingsley D.M. DNA fragility in the parallel evolution of pelvic reduction in stickleback fish. Science. 2019; 363: 81– 84. 30606845 PMC6677656
  4. [4]Gojobori T., Li W.H., Graur D. Patterns of nucleotide substitution in pseudogenes and functional genes. J. Mol. Evol. 1982; 18: 360– 369. 7120431
  5. [5]Bulmer M. Neighboring base effects on substitution rates in pseudogenes. Mol. Biol. Evol. 1986; 3: 322– 329. 3444408
  6. [6]Coulondre C., Miller J.H., Farabaugh P.J., Gilbert W. Molecular basis of base substitution hotspots in Escherichia coli. Nature. 1978; 274: 775– 780. 355893
  7. [8]Lercher M.J., Hurst L.D. Human SNP variability and mutation rate are higher in regions of high recombination. Trends Genet. 2002; 18: 337– 340. 12127766
  8. [9]Stamatoyannopoulos J.A., Adzhubei I., Thurman R.E., Kryukov G.V., Mirkin S.M., Sunyaev S.R. Human mutation rate associated with DNA replication timing. Nat. Genet. 2009; 41: 393– 395. 19287383 PMC2914101
  9. [10]Boulikas T. Evolutionary consequences of nonrandom damage and repair of chromatin domains. J. Mol. Evol. 1992; 35: 156– 180. 1501255
  10. [11]Ying H., Epps J., Williams R., Huttley G. Evidence that localized variation in primate sequence divergence arises from an influence of nucleosome placement on DNA repair. Mol. Biol. Evol. 2010; 27: 637– 649. 19843619 PMC2822288
  11. [14]Ananda G., Chiaromonte F., Makova K.D. A genome-wide view of mutation rate co-variation using multivariate analyses. Genome Biol. 2011; 12: R27. 21426544 PMC3129677
  12. [15]Gaffney D.J., Keightley P.D. The scale of mutational variation in the murid genome. Genome Res. 2005; 15: 1086– 1094. 16024822 PMC1182221
  13. [16]Hodgkinson A., Chen Y., Eyre-Walker A. The large-scale distribution of somatic mutations in cancer genomes. Hum. Mutat. 2012; 33: 136– 143. 21953857
  14. [17]Agarwal I., Przeworski M. Signatures of replication timing, recombination, and sex in the spectrum of rare variants on the human X chromosome and autosomes. Proc. Natl. Acad. Sci. U.S.A. 2019; 116: 17916– 17924. 31427530 PMC6731651
  15. [18]Terekhanova N.V., Seplyarskiy V.B., Soldatov R.A., Bazykin G.A. Evolution of local mutation rate and its determinants. Mol. Biol. Evol. 2017; 34: 1100– 1109. 28138076 PMC5850301
  16. [19]Watson J.D., Crick F.H.C. Genetical implications of the structure of deoxyribonucleic acid. Nature. 1953; 171: 964– 967. 13063483
  17. [20]Wilkins M.H.F., Stokes A.R., Wilson H.R. Molecular structure of nucleic acids: molecular structure of deoxypentose nucleic acids. Nature. 1953; 171: 738– 740. 13054693
  18. [21]Franklin R.E., Gosling R.G. Molecular configuration in sodium thymonucleate. Nature. 1953; 171: 740– 741. 13054694
  19. [22]Huppert J.L., Balasubramanian S. Prevalence of quadruplexes in the human genome. Nucleic Acids Res. 2005; 33: 2908– 2916. 15914667 PMC1140081
  20. [23]Georgakopoulos-Soares I., Morganella S., Jain N., Hemberg M., Nik-Zainal S. Noncanonical secondary structures arising from non-B DNA motifs are determinants of mutagenesis. Genome Res. 2018; 28: 1264– 1271. 30104284 PMC6120622
  21. [24]Du X., Gertz E.M., Wojtowicz D., Zhabinskaya D., Levens D., Benham C.J., Schäffer A.A., Przytycka T.M. Potential non-B DNA regions in the human genome are associated with higher rates of nucleotide mutation and expression variation. Nucleic Acids Res. 2014; 42: 12367– 12379. 25336616 PMC4227770
  22. [25]Mirkin S.M. Others Discovery of alternative DNA structures: a heroic decade (1979–1989). Front. Biosci. 2008; 13: 1064– 1071. 17981612
  23. [26]Cer R.Z., Bruce K.H., Mudunuri U.S., Yi M., Volfovsky N., Luke B.T., Bacolla A., Collins J.R., Stephens R.M. Non-B DB: a database of predicted non-B DNA-forming motifs in mammalian genomes. Nucleic Acids Res. 2011; 39: D383– D391. 21097885 PMC3013731
  24. [27]Sen D., Gilbert W. Formation of parallel four-stranded complexes by guanine-rich motifs in DNA and its implications for meiosis. Nature. 1988; 334: 364– 366. 3393228
  25. [28]Rich A., Nordheim A., Wang A.H. The chemistry and biology of left-handed Z-DNA. Annu. Rev. Biochem. 1984; 53: 791– 846. 6383204
  26. [29]Mirkin S.M., Lyamichev V.I., Drushlyak K.N., Dobrynin V.N., Filippov S.A., Frank-Kamenetskii M.D. DNA H form requires a homopurine-homopyrimidine mirror repeat. Nature. 1987; 330: 495– 497. 2825028
  27. [30]Panayotatos N., Wells R.D. Cruciform structures in supercoiled DNA. Nature. 1981; 289: 466– 470. 7464915
  28. [31]Lilley D.M. The inverted repeat as a recognizable structural feature in supercoiled DNA molecules. Proc. Natl. Acad. Sci. U.S.A. 1980; 77: 6468– 6472. 6256738 PMC350306
  29. [32]Sinden R.R., Pytlos-Sinden M.J., Potaman V.N. Slipped strand DNA structures. Front. Biosci. 2007; 12: 4788– 4799. 17569609
  30. [33]Barbič A., Zimmer D.P., Crothers D.M. Structural origins of adenine-tract bending. Proc. Natl. Acad. Sci. U.S.A. 2003; 100: 2369– 2373. 12586860 PMC151347
  31. [34]Neidle S. Oxford Handbook of Nucleic acid Structure. 1999; Oxford University Press.
  32. [35]Zhao J., Bacolla A., Wang G., Vasquez K.M. Non-B DNA structure-induced genetic instability and evolution. Cell. Mol. Life Sci. 2010; 67: 43– 62. 19727556 PMC3017512
  33. [36]Hänsel-Hertsch R., Beraldi D., Lensing S.V., Marsico G., Zyner K., Parry A., Di Antonio M., Pike J., Kimura H., Narita M. et al. G-quadruplex structures mark human regulatory chromatin. Nat. Genet. 2016; 48: 1267– 1272. 27618450
  34. [37]Baral A., Kumar P., Halder R., Mani P., Yadav V.K., Singh A., Das S.K., Chowdhury S. Quadruplex-single nucleotide polymorphisms (Quad-SNP) influence gene expression difference among individuals. Nucleic Acids Res. 2012; 40: 3800– 3811. 22238381 PMC3351168
  35. [38]Hizver J., Rozenberg H., Frolow F., Rabinovich D., Shakked Z. DNA bending by an adenine–thymine tract and its role in gene regulation. Proc. Natl. Acad. Sci. U.S.A. 2001; 98: 8490– 8495. 11438706 PMC37463
  36. [39]Belotserkovskii B.P., Liu R., Tornaletti S., Krasilnikova M.M., Mirkin S.M., Hanawalt P.C. Mechanisms and implications of transcription blockage by guanine-rich DNA sequences. Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 12816– 12821. 20616059 PMC2919923
  37. [40]Wittig B., Dorbic T., Rich A. Transcription is associated with Z-DNA formation in metabolically active permeabilized mammalian cell nuclei. Proc. Natl. Acad. Sci. U.S.A. 1991; 88: 2259– 2263. 2006166 PMC51210
  38. [41]Parkinson G.N., Lee M.P.H., Neidle S. Crystal structure of parallel quadruplexes from human telomeric DNA. Nature. 2002; 417: 876– 880. 12050675
  39. [42]Moye A.L., Porter K.C., Cohen S.B., Phan T., Zyner K.G., Sasaki N., Lovrecz G.O., Beck J.L., Bryan T.M. Telomeric G-quadruplexes are a substrate and site of localization for human telomerase. Nat. Commun. 2015; 6: 7643. 26158869 PMC4510649
  40. [43]Sahakyan A.B., Murat P., Mayer C., Balasubramanian S. G-quadruplex structures within the 3′ UTR of LINE-1 elements stimulate retrotransposition. Nat. Struct. Mol. Biol. 2017; 24: 243. 28134931
  41. [44]Brázda V., Laister R.C., Jagelská E.B., Arrowsmith C. Cruciform structures are a common DNA feature important for regulating biological processes. BMC Mol. Biol. 2011; 12: 33. 21816114 PMC3176155
  42. [45]Mani P., Yadav V.K., Das S.K., Chowdhury S. Genome-wide analyses of recombination prone regions predict role of DNA structural motif in recombination. PLoS One. 2009; 4: e4399. 19198658 PMC2635932
  43. [46]van Wietmarschen N., Merzouk S., Halsema N., Spierings D.C.J., Guryev V., Lansdorp P.M. BLM helicase suppresses recombination at G-quadruplex motifs in transcribed genes. Nat. Commun. 2018; 9: 271. 29348659 PMC5773480
  44. [47]Maizels N., Gray L.T. The G4 genome. PLoS Genet. 2013; 9: e1003468. 23637633 PMC3630100
  45. [48]Aranda A., Pérez-Ortín J.E., Benham C.J., del Olmo M.L.Í. Analysis of the structure of a natural alternating d (TA) n sequence in yeast chromatin. Yeast. 1997; 13: 313– 326. 9133735
  46. [49]Mao S.-Q., Ghanbarian A.T., Spiegel J., Cuesta S.M., Beraldi D., Di Antonio M., Marsico G., Hänsel-Hertsch R., Tannahill D., Balasubramanian S. DNA G-quadruplex structures mold the DNA methylome. Nat. Struct. Mol. Biol. 2018; 25: 951– 957. 30275516 PMC6173298
  47. [50]Halder R., Halder K., Sharma P., Garg G., Sengupta S., Chowdhury S. Guanine quadruplex DNA structure restricts methylation of CpG dinucleotides genome-wide. Mol. Biosyst. 2010; 6: 2439– 2447. 20877913
  48. [51]Jara-Espejo M., Peres Line S.R. DNA G-quadruplex stability, position and chromatin accessibility are associated with CpG island methylation. FEBS J. 2020; 287: 483– 495. 31532882
  49. [52]Yuan L., Tian T., Chen Y., Yan S., Xing X., Zhang Z., Zhai Q., Xu L., Wang S., Weng X. et al. Existence of G-quadruplex structures in promoter region of oncogenes confirmed by G-quadruplex DNA cross-linking strategy. Sci. Rep. 2013; 3: 1811. 23657205 PMC3648798
  50. [53]Siddiqui-Jain A., Grand C.L., Bearss D.J., Hurley L.H. Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription. Proc. Natl. Acad. Sci. U.S.A. 2002; 99: 11593– 11598. 12195017 PMC129314
  51. [54]Simonsson T., Pecinka P., Kubista M. DNA tetraplex formation in the control region of c-myc. Nucleic Acids Res. 1998; 26: 1167– 1172. 9469822 PMC147388
  52. [55]Miller D.M., Thomas S.D., Islam A., Muench D., Sedoris K. c-Myc and cancer metabolism. Clin. Cancer Res. 2012; 18: 5546– 5553. 23071356 PMC3505847
  53. [56]Bochman M.L., Paeschke K., Zakian V.A. DNA secondary structures: stability and function of G-quadruplex structures. Nat. Rev. Genet. 2012; 13: 770– 780. 23032257 PMC3725559
  54. [57]Haeusler A.R., Donnelly C.J., Periz G., Simko E.A.J., Shaw P.G., Kim M.-S., Maragakis N.J., Troncoso J.C., Pandey A., Sattler R. et al. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature. 2014; 507: 195– 200. 24598541 PMC4046618
  55. [58]Maizels N. G4-associated human diseases. EMBO Rep. 2015; 16: 910– 922. 26150098 PMC4552485
  56. [59]Wolfe A.L., Singh K., Zhong Y., Drewe P., Rajasekhar V.K., Sanghvi V.R., Mavrakis K.J., Jiang M., Roderick J.E., Van der Meulen J. et al. RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer. Nature. 2014; 513: 65– 70. 25079319 PMC4492470
  57. [60]Bacolla A., Wells R.D. Non-B DNA conformations, genomic rearrangements, and human disease. J. Biol. Chem. 2004; 279: 47411– 47414. 15326170
  58. [61]Mirkin S.M. Expandable DNA repeats and human disease. Nature. 2007; 447: 932– 940. 17581576
  59. [62]Orr H.T., Zoghbi H.Y. Trinucleotide repeat disorders. Annu. Rev. Neurosci. 2007; 30: 575– 621. 17417937
  60. [63]Pearson C.E., Sinden R.R. Alternative structures in duplex DNA formed within the trinucleotide repeats of the myotonic dystrophy and fragile X loci. Biochemistry. 1996; 35: 5041– 5053. 8664297
  61. [64]Bacolla A., Tainer J.A., Vasquez K.M., Cooper D.N. Translocation and deletion breakpoints in cancer genomes are associated with potential non-B DNA-forming sequences. Nucleic Acids Res. 2016; 44: 5673– 5688. 27084947 PMC4937311
  62. [65]Bournique E., Dall’Osto M., Hoffmann J.-S., Bergoglio V. Role of specialized DNA polymerases in the limitation of replicative stress and DNA damage transmission. Mutat. Res. 2018; 808: 62– 73. 28843435
  63. [66]Tsao W.-C., Eckert K.A. Detours to Replication: Functions of specialized DNA polymerases during oncogene-induced replication stress. Int. J. Mol. Sci. 2018; 19: 3255. PMC6214091 30347795
  64. [67]Barnes R.P., Hile S.E., Lee M.Y., Eckert K.A. DNA polymerases eta and kappa exchange with the polymerase delta holoenzyme to complete common fragile site synthesis. DNA Repair (Amst.). 2017; 57: 1– 11. 28605669 PMC9642814
  65. [68]Wang G., Vasquez K.M. Impact of alternative DNA structures on DNA damage, DNA repair, and genetic instability. DNA Repair (Amst.). 2014; 19: 143– 151. 24767258 PMC4216180
  66. [71]Wang G., Vasquez K.M. Naturally occurring H-DNA-forming sequences are mutagenic in mammalian cells. Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 13448– 13453. 15342911 PMC518777
  67. [73]De S., Michor F. DNA secondary structures and epigenetic determinants of cancer genome evolution. Nat. Struct. Mol. Biol. 2011; 18: 950– 955. 21725294 PMC3963273
  68. [74]Rodgers K., McVey M. Error-prone repair of DNA double-strand breaks. J. Cell. Physiol. 2016; 231: 15– 24. 26033759 PMC4586358
  69. [75]Zhang Y., Rohde L.H., Wu H. Involvement of nucleotide excision and mismatch repair mechanisms in double strand break repair. Curr. Genomics. 2009; 10: 250– 258. 19949546 PMC2709936
  70. [76]Zhao J., Wang G., Del Mundo I.M., McKinney J.A., Lu X., Bacolla A., Boulware S.B., Zhang C., Zhang H., Ren P. et al. Distinct mechanisms of nuclease-directed DNA-structure-induced genetic instability in cancer genomes. Cell Rep. 2018; 22: 1200– 1210. 29386108 PMC6011834
  71. [78]Krasilnikova M.M., Mirkin S.M. Replication stalling at Friedreich's Ataxia (GAA)n repeats in vivo. Mol. Cell. Biol. 2004; 24: 2286– 2295. 14993268 PMC355872
  72. [80]Cheung I., Schertzer M., Rose A., Lansdorp P.M. Disruption of dog-1 in Caenorhabditis elegans triggers deletions upstream of guanine-rich DNA. Nat. Genet. 2002; 31: 405– 409. 12101400
  73. [81]Wang G., Christensen L.A., Vasquez K.M. Z-DNA-forming sequences generate large-scale deletions in mammalian cells. Proc. Natl. Acad. Sci. U.S.A. 2006; 103: 2677– 2682. 16473937 PMC1413824
  74. [82]Collins N.S., Bhattacharyya S., Lahue R.S. Rev1 enhances CAG·CTG repeat stability in Saccharomyces cerevisiae. DNA Repair (Amst.). 2007; 6: 38– 44. 16979389
  75. [83]Marcadier J.L., Pearson C.E. Fidelity of primate cell repair of a double-strand break within a (CTG)·(CAG) tract. J. Biol. Chem. 2003; 278: 33848– 33856. 12807901
  76. [84]Vasquez K.M., Wang G. The yin and yang of repair mechanisms in DNA structure-induced genetic instability. Mutat. Res. 2013; 743-744: 118– 131. 23219604 PMC3661696
  77. [85]Guiblet W.M., Cremona M.A., Cechova M., Harris R.S., Kejnovská I., Kejnovsky E., Eckert K., Chiaromonte F., Makova K.D. Long-read sequencing technology indicates genome-wide effects of non-B DNA on polymerization speed and error rate. Genome Res. 2018; 28: 1767– 1778. 30401733 PMC6280752
  78. [86]Ramsay J., Silverman B.W. Henry Overton Wills Professor of Mathematics B W Silverman Functional Data Analysis. 2005; Springer Science & Business Media.
  79. [87]Cremona M.A., Xu H., Makova K.D., Reimherr M., Chiaromonte F., Madrigal P. Functional data analysis for computational biology. Bioinformatics. 2019; 35: 3211– 3213. 30668667 PMC6736445
  80. [88]Chiaromonte F., Makova K.D. Paganoni A.M., Secchi P. Using Statistics to Shed Light on the Dynamics of the Human Genome: A Review. Advances in Complex Data Modeling and Computational Methods in Statistics. 2015; Cham Springer International Publishing 69– 85.
  81. [89]Tyekucheva S., Makova K.D., Karro J.E., Hardison R.C., Miller W., Chiaromonte F. Human-macaque comparisons illuminate variation in neutral substitution rates. Genome Biol. 2008; 9: R76. 18447906 PMC2643947
  82. [91]Haeussler M., Zweig A.S., Tyner C., Speir M.L., Rosenbloom K.R., Raney B.J., Lee C.M., Lee B.T., Hinrichs A.S., Gonzalez J.N. et al. The UCSC Genome Browser database: 2019 update. Nucleic Acids Res. 2019; 47: D853– D858. 30407534 PMC6323953
  83. [92]Pruitt K.D., Brown G.R., Hiatt S.M., Thibaud-Nissen F., Astashyn A., Ermolaeva O., Farrell C.M., Hart J., Landrum M.J., McGarvey K.M. et al. RefSeq: an update on mammalian reference sequences. Nucleic Acids Res. 2014; 42: D756– D763. 24259432 PMC3965018
  84. [93]Pollard K.S., Hubisz M.J., Rosenbloom K.R., Siepel A. Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res. 2010; 20: 110– 121. 19858363 PMC2798823
  85. [94]Fishilevich S., Nudel R., Rappaport N., Hadar R., Plaschkes I., Iny Stein T., Rosen N., Kohn A., Twik M., Safran M. et al. GeneHancer: genome-wide integration of enhancers and target genes in GeneCards. Database. 2017; 2017: bax028. PMC5467550 28605766
  86. [95]Stelzer G., Rosen N., Plaschkes I., Zimmerman S., Twik M., Fishilevich S., Stein T.I., Nudel R., Lieder I., Mazor Y. et al. The GeneCards Suite: From gene data mining to disease genome sequence analyses. Curr. Protoc. Bioinformatics. 2016; 54: 1.30.1– 1.30.33. 27322403
  87. [96]Miller W., Rosenbloom K., Hardison R.C., Hou M., Taylor J., Raney B., Burhans R., King D.C., Baertsch R., Blankenberg D. et al. 28-way vertebrate alignment and conservation track in the UCSC Genome Browser. Genome Res. 2007; 17: 1797– 1808. 17984227 PMC2099589
  88. [98]Sahakyan A.B., Chambers V.S., Marsico G., Santner T., Di Antonio M., Balasubramanian S. Machine learning model for sequence-driven DNA G-quadruplex formation. Sci. Rep. 2017; 7: 14535. 29109402 PMC5673958
  89. [99]Cer R.Z., Donohue D.E., Mudunuri U.S., Temiz N.A., Loss M.A., Starner N.J., Halusa G.N., Volfovsky N., Yi M., Luke B.T. et al. Non-B DB v2.0: a database of predicted non-B DNA-forming motifs and its associated tools. Nucleic Acids Res. 2013; 41: D94– D100. 23125372 PMC3531222
  90. [100]Quinlan A.R. BEDTools: the Swiss-Army Tool for genome feature analysis. Curr. Protoc. Bioinformatics. 2014; 47: 11.12.1– 11.12.34. PMC4213956 25199790
  91. [102]Lister R., Pelizzola M., Dowen R.H., Hawkins R.D., Hon G., Tonti-Filippini J., Nery J.R., Lee L., Ye Z., Ngo Q.-M. et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009; 462: 315– 322. 19829295 PMC2857523
  92. [103]Goecks J., Nekrutenko A., Taylor J., Team G. Galaxy: a comprehensive approach for supporting accessible, reproducible, and transparent computational research in the life sciences. Genome Biol. 2010; 11: R86. 20738864 PMC2945788
  93. [104]Afgan E., Baker D., Batut B., van den Beek M., Bouvier D., Cech M., Chilton J., Clements D., Coraor N., Grüning B.A. et al. The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2018 update. Nucleic Acids Res. 2018; 46: W537– W544. 29790989 PMC6030816
  94. [105]ENCODE Project Consortium The ENCODE (ENCyclopedia Of DNA Elements) Project. Science. 2004; 306: 636– 640. 15499007
  95. [106]Derrien T., Estellé J., Marco Sola S., Knowles D.G., Raineri E., Guigó R., Ribeca P. Fast computation and applications of genome mappability. PLoS One. 2012; 7: e30377. 22276185 PMC3261895
  96. [107]Gardiner-Garden M., Frommer M. CpG islands in vertebrate genomes. J. Mol. Biol. 1987; 196: 261– 282. 3656447
  97. [108]Guelen L., Pagie L., Brasset E., Meuleman W., Faza M.B., Talhout W., Eussen B.H., de Klein A., Wessels L., de Laat W. et al. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature. 2008; 453: 948– 951. 18463634
  98. [109]Zou H., Hastie T. Regularization and variable selection via the elastic net. J. R. Stat. Soc. Series B Stat. Methodol. 2005; 67: 301– 320.
  99. [110]Hon J., Martínek T., Zendulka J., Lexa M. pqsfinder: an exhaustive and imperfection-tolerant search tool for potential quadruplex-forming sequences in R. Bioinformatics. 2017; 33: 3373– 3379. 29077807
  100. [111]Chambers V.S., Marsico G., Boutell J.M., Di Antonio M., Smith G.P., Balasubramanian S. High-throughput sequencing of DNA G-quadruplex structures in the human genome. Nat. Biotechnol. 2015; 33: 877– 881. 26192317
  101. [112]Don P.K., Ananda G., Chiaromonte F., Makova K.D. Segmenting the human genome based on states of neutral genetic divergence. Proc. Natl. Acad. Sci. USA. 2013; 110: 14699– 14704. 23959903 PMC3767554
  102. [113]1000 Genomes Project Consortium Auton A., Brooks L.D., Durbin R.M., Garrison E.P., Kang H.M., Korbel J.O., Marchini J.L., McCarthy S., McVean G.A. et al. A global reference for human genetic variation. Nature. 2015; 526: 68– 74. 26432245 PMC4750478
  103. [115]Cremona M.A., Pini A., Cumbo F., Makova K.D., Chiaromonte F., Vantini S. IWTomics: testing high-resolution sequence-based ‘Omics’ data at multiple locations and scales. Bioinformatics. 2018; 34: 2289– 2291. 29474526 PMC6022652
  104. [116]Cvijović I., Good B.H., Jerison E.R., Desai M.M. Fate of a mutation in a fluctuating environment. Proc. Natl. Acad. Sci. U.S.A. 2015; 112: E5021– E5028. 26305937 PMC4568713
  105. [117]Hwang D.G., Green P. Bayesian Markov chain Monte Carlo sequence analysis reveals varying neutral substitution patterns in mammalian evolution. Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 13994– 14001. 15292512 PMC521089
  106. [118]Fungtammasan A., Walsh E., Chiaromonte F., Eckert K.A., Makova K.D. A genome-wide analysis of common fragile sites: what features determine chromosomal instability in the human genome. Genome Res. 2012; 22: 993– 1005. 22456607 PMC3371707
  107. [119]Campos-Sánchez R., Kapusta A., Feschotte C., Chiaromonte F., Makova K.D. Genomic landscape of human, bat, and ex vivo DNA transposon integrations. Mol. Biol. Evol. 2014; 31: 1816– 1832. 24809961 PMC4069622
  108. [120]Cooper D.N., Bacolla A., Férec C., Vasquez K.M., Kehrer-Sawatzki H., Chen J.-M. On the sequence-directed nature of human gene mutation: the role of genomic architecture and the local DNA sequence environment in mediating gene mutations underlying human inherited disease. Hum. Mutat. 2011; 32: 1075– 1099. 21853507 PMC3177966
  109. [121]Fleming A.M., Burrows C.J. Interplay of Guanine Oxidation and G-Quadruplex Folding in Gene Promoters. J. Am. Chem. Soc. 2020; 142: 1115– 1136. 31880930 PMC6988379
  110. [123]Schiavone D., Jozwiakowski S.K., Romanello M., Guilbaud G., Guilliam T.A., Bailey L.J., Sale J.E., Doherty A.J. PrimPol is required for replicative tolerance of G Quadruplexes in vertebrate cells. Mol. Cell. 2016; 61: 161– 169. 26626482 PMC4712188
  111. [124]Koole W., van Schendel R., Karambelas A.E., van Heteren J.T., Okihara K.L., Tijsterman M. A polymerase theta-dependent repair pathway suppresses extensive genomic instability at endogenous G4 DNA sites. Nat. Commun. 2014; 5: 3216. 24496117
  112. [125]Bacolla A., Wang G., Jain A., Chuzhanova N.A., Cer R.Z., Collins J.R., Cooper D.N., Bohr V.A., Vasquez K.M. Non-B DNA-forming sequences and WRN deficiency independently increase the frequency of base substitution in human cells. J. Biol. Chem. 2011; 286: 10017– 10026. 21285356 PMC3060453
  113. [126]Fleming A.M., Zhou J., Wallace S.S., Burrows C.J. A role for the fifth G-Track in G-quadruplex forming oncogene promoter sequences during oxidative stress: do these ‘Spare Tires’ have an evolved function. ACS Cent Sci. 2015; 1: 226– 233. 26405692 PMC4571166
  114. [127]Capra J.A., Paeschke K., Singh M., Zakian V.A. G-quadruplex DNA sequences are evolutionarily conserved and associated with distinct genomic features in Saccharomyces cerevisiae. PLoS Comput. Biol. 2010; 6: e1000861. 20676380 PMC2908698
  115. [128]Nakken S., Rognes T., Hovig E. The disruptive positions in human G-quadruplex motifs are less polymorphic and more conserved than their neutral counterparts. Nucleic Acids Res. 2009; 37: 5749– 5756. 19617376 PMC2761265
  116. [129]Gros J., Rosu F., Amrane S., De Cian A., Gabelica V., Lacroix L., Mergny J.-L. Guanines are a quartet's best friend: impact of base substitutions on the kinetics and stability of tetramolecular quadruplexes. Nucleic Acids Res. 2007; 35: 3064– 3075. 17452368 PMC1888817
  117. [130]Lee J.Y., Kim D.S. Dramatic effect of single-base mutation on the conformational dynamics of human telomeric G-quadruplex. Nucleic Acids Res. 2009; 37: 3625– 3634. 19359361 PMC2699503
  118. [131]Valton A.-L., Prioleau M.-N. G-quadruplexes in DNA replication: a problem or a necessity. Trends Genet. 2016; 32: 697– 706. 27663528
  119. [132]Piazza A., Adrian M., Samazan F., Heddi B., Hamon F., Serero A., Lopes J., Teulade-Fichou M.-P., Phan A.T., Nicolas A. Short loop length and high thermal stability determine genomic instability induced by G-quadruplex-forming minisatellites. EMBO J. 2015; 34: 1718– 1734. 25956747 PMC4475404
  120. [133]Saini N., Zhang Y., Nishida Y., Sheng Z., Choudhury S., Mieczkowski P., Lobachev K.S. Fragile DNA motifs trigger mutagenesis at distant chromosomal loci in saccharomyces cerevisiae. PLoS Genet. 2013; 9: e1003551. 23785298 PMC3681665
  121. [135]Lai P.J., Lim C.T., Le H.P., Katayama T., Leach D.R.F., Furukohri A., Maki H. Long inverted repeat transiently stalls DNA replication by forming hairpin structures on both leading and lagging strands. Genes Cells. 2016; 21: 136– 145. 26738888
  122. [136]Shastri N., Tsai Y.-C., Hile S., Jordan D., Powell B., Chen J., Maloney D., Dose M., Lo Y., Anastassiadis T. et al. Genome-wide identification of Structure-Forming repeats as principal sites of fork collapse upon ATR inhibition. Mol. Cell. 2018; 72: 222– 238. 30293786 PMC6407864
  123. [137]Chuzhanova N., Chen J.-M., Bacolla A., Patrinos G.P., F̩rec C., Wells R.D., Cooper D.N. Gene conversion causing human inherited disease: Evidence for involvement of non-B-DNA-forming sequences and recombination-promoting motifs in DNA breakage and repair. Hum. Mutat. 2009; 30: 1189Р1198. 19431182 PMC2779867
  124. [138]McKinney J.A., Wang G., Mukherjee A., Christensen L., Subramanian S.H.S., Zhao J., Vasquez K.M. Distinct DNA repair pathways cause genomic instability at alternative DNA structures. Nat. Commun. 2020; 11: 236. 31932649 PMC6957503
  125. [139]Tartier L., Michalik V., Spotheim-Maurizot M., Rahmouni A.R., Sabattier R., Charlier M. Radiolytic signature of Z-DNA. Nucleic Acids Res. 1994; 22: 5565– 5570. 7838708 PMC310117
  126. [140]Ribeiro D.T., Madzak C., Sarasin A., Di Mascio P., Sies H., Menck C.F. Singlet oxygen induced DNA damage and mutagenicity in a single-stranded SV40-based shuttle vector. Photochem. Photobiol. 1992; 55: 39– 45. 1318549
  127. [141]Vowles E.J., Amos W. Evidence for widespread convergent evolution around human microsatellites. PLoS Biol. 2004; 2: E199. 15314644 PMC509290
  128. [142]Hile S.E., Wang X., Lee M.Y.W.T., Eckert K.A. Beyond translesion synthesis: polymerase κ fidelity as a potential determinant of microsatellite stability. Nucleic Acids Res. 2012; 40: 1636– 1647. 22021378 PMC3287198
  129. [143]Bacolla A., Zhu X., Chen H., Howells K., Cooper D.N., Vasquez K.M. Local DNA dynamics shape mutational patterns of mononucleotide repeats in human genomes. Nucleic Acids Res. 2015; 43: 5065– 5080. 25897114 PMC4446427
  130. [144]Shah K.A., Mirkin S.M. The hidden side of unstable DNA repeats: mutagenesis at a distance. DNA Repair (Amst.). 2015; 32: 106– 112. 25956860 PMC4522329
  131. [145]Hellmann I., Prüfer K., Ji H., Zody M.C., Pääbo S., Ptak S.E. Why do human diversity levels vary at a megabase scale. Genome Res. 2005; 15: 1222– 1231. 16140990 PMC1199536
  132. [146]Duret L., Arndt P.F. The impact of recombination on nucleotide substitutions in the human genome. PLos Genet. 2008; 4: e1000071. 18464896 PMC2346554
  133. [147]Drillon G., Audit B., Argoul F., Arneodo A. Evidence of selection for an accessible nucleosomal array in human. BMC Genomics. 2016; 17: 526. 27472913 PMC4966569
  134. [148]Kouzine F., Wojtowicz D., Baranello L., Yamane A., Nelson S., Resch W., Kieffer-Kwon K.-R., Benham C.J., Casellas R., Przytycka T.M. et al. Permanganate/S1 nuclease footprinting reveals non-B DNA structures with regulatory potential across a mammalian genome. Cell Syst. 2017; 4: 344– 356. 28237796 PMC7432990
  135. [149]Wu T., Lyu R., You Q., He C. Kethoxal-assisted single-stranded DNA sequencing captures global transcription dynamics and enhancer activity in situ. Nat. Methods. 2020; 17: 515– 523. 32251394 PMC7205578
  136. [150]Hänsel-Hertsch R., Spiegel J., Marsico G., Tannahill D., Balasubramanian S. Genome-wide mapping of endogenous G-quadruplex DNA structures by chromatin immunoprecipitation and high-throughput sequencing. Nat. Protoc. 2018; 13: 551– 564. 29470465
  137. [151]Lee D.S.M., Ghanem L.R., Barash Y. Integrative analysis reveals RNA G-quadruplexes in UTRs are selectively constrained and enriched for functional associations. Nat. Commun. 2020; 11: 527. 31988292 PMC6985247

Cited by

Sorted by citations

Authors
Guiblet, W. M., Cremona, M. A., Harris, R. S., Chen, D., Eckert, K. A., Chiaromonte, F., Huang, Y.-F., & Makova, K. D.
Affiliations
Pennsylvania State University (US)
Corresponding author
  • Chiaromonte, Francesca
  • Huang, Yi-Fei
  • Makova, Kateryna D
ORCID
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
2021-01-15
Volume
49
Issue
3
Pages
1497-1516
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
DOI
10.1093/nar/gkaa1269
PMC
PMC7897504
OpenAlex
W3126007358
Cited by
115
References
12
Citations by year
2026: 18 · 2025: 14 · 2024: 22 · 2023: 22 · 2022: 29 · 2021: 9 · 2020: 1
FWCI
6.44
Type
journal article
Language
en
Open access
Licence
Locations
  • Nucleic Acids Research (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • CINECA IRIS Institutional Research Information System (Sant'Anna School of Advanced Studies) (submittedVersion)
Funders
  • National Institutes of Health (R01GM136684, R01CA23715)
  • Clinical and Translational Sciences Institute
  • Institute of Computational and Data Sciences
  • Huck Institutes of the Life Sciences
  • Eberly College of Science of the Pennsylvania State University
  • Pennsylvania Department of Health
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
Keywords
non-B DNA structures, nucleotide substitution rates, G-quadruplex, Z-DNA, direct repeats, inverted repeats, single nucleotide polymorphisms, germline mutagenesis, non-coding genome, DNA secondary structure
MeSH terms
Animals, DNA, Humans, Pongo pygmaeus, Genetic Variation, Genome, Human, Polymorphism, Single Nucleotide, Genetic Loci, Mutation Rate

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review