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Genomic Features: Content Sensors, Nucleotide Skew Plot, Strand Asymmetry, and DNA Methylation

  • Xuhua Xia
Chapter

Abstract

This chapter introduces tools to characterize genomic features and illustrates how a phylogenetic perspective can fundamentally alter one’s conclusion on genomic evolution. The chapter starts by explaining content sensors (e.g., nucleotide, dinucleotide, triplet frequencies, etc.) in contrast to signal sensors (e.g., 5’ and 3’ splice sites, branchpoint sites, SD sequences, anti-SD sequences, Kozak consensus in mammalian mRNAs, sense and stop codons, etc.). Frequently used indices for characterizing genomic content sensors include various word skews, with the simplest being GC skew often used to identify the origin of DNA replication in prokayrotes. Single-origin replication in most bacterial genomes results in strong mutation bias between leading and lagging strands which can be graphically revealed by various skew plots. Confounding these strand biases is the genomic modification by DNA methylation which can have profound effect on genome evolution. Association between CpG deficiency and CpG-specific DNA methylation was challenged previously with two mycoplasma genomes but is restored by a phylogeny-based reanalysis and re-interpretation of the genomic data.

References

  1. Abdel-Hameed EA, Ji H, Shata MT (2016) HIV-induced epigenetic alterations in host cells. Adv Exp Med Biol 879:27–38CrossRefPubMedGoogle Scholar
  2. Arbibe L, Sansonetti PJ (2007) Epigenetic regulation of host response to LPS: causing tolerance while avoiding toll errancy. Cell Host Microbe 1(4):244–246CrossRefPubMedGoogle Scholar
  3. Bao J, Bedford MT (2016) Epigenetic regulation of the histone-to-protamine transition during spermiogenesis. Reproduction 151(5):R55–R70CrossRefPubMedPubMedCentralGoogle Scholar
  4. Bestor TH, Coxon A (1993) The pros and cons of DNA methylation. Curr Biol 6:384–386CrossRefGoogle Scholar
  5. Bibikova M, Barnes B, Tsan C, Ho V, Klotzle B, Le JM, Delano D, Zhang L, Schroth GP, Gunderson KL et al (2011) High density DNA methylation array with single CpG site resolution. Genomics 98(4):288–295CrossRefPubMedGoogle Scholar
  6. Bierne H, Hamon M, Cossart P (2012) Epigenetics and bacterial infections. Cold Spring Harb Perspect Med 2(12):a010272CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bigaud E, Corrales FJ (2016) Methylthioadenosine (MTA) regulates liver cells proteome and methylproteome: implications in liver biology and disease. Mol Cell Proteomics 15(5):1498–1510CrossRefPubMedPubMedCentralGoogle Scholar
  8. Birney E, Stamatoyannopoulos JA, Dutta A, Guigo R, Gingeras TR, Margulies EH, Weng Z, Snyder M, Dermitzakis ET, Thurman RE et al (2007) Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447(7146):799–816CrossRefGoogle Scholar
  9. Bogenhagen DF, Clayton DA (2003) The mitochondrial DNA replication bubble has not burst. Trends Biochem Sci 28(7):357–360CrossRefPubMedGoogle Scholar
  10. Bolden JE, Peart MJ, Johnstone RW (2006) Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5(9):769–784CrossRefGoogle Scholar
  11. Brauch H, Weirich G, Brieger J, Glavac D, Rodl H, Eichinger M, Feurer M, Weidt E, Puranakanitstha C, Neuhaus C et al (2000) VHL alterations in human clear cell renal cell carcinoma: association with advanced tumor stage and a novel hot spot mutation. Cancer Res 60(7):1942–1948PubMedGoogle Scholar
  12. Brown TA, Cecconi C, Tkachuk AN, Bustamante C, Clayton DA (2005) Replication of mitochondrial DNA occurs by strand displacement with alternative light-strand origins, not via a strand-coupled mechanism. Genes Dev 19(20):2466–2476CrossRefPubMedPubMedCentralGoogle Scholar
  13. Cardon LR, Burge C, Clayton DA, Karlin S (1994) Pervasive CpG suppression in animal mitochondrial genomes. Proc Natl Acad Sci USA 91:3799–3803CrossRefPubMedGoogle Scholar
  14. Chambaud I, Heilig R, Ferris S, Barbe V, Samson D, Galisson F, Moszer I, Dybvig K, Wroblewski H, Viari A et al (2001) The complete genome sequence of the murine respiratory pathogen Mycoplasma pulmonis. Nucleic Acids Res 29(10):2145–2153CrossRefPubMedPubMedCentralGoogle Scholar
  15. Chen Q, Yan M, Cao Z, Li X, Zhang Y, Shi J, Feng GH, Peng H, Zhang X, Qian J et al (2016) Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science 351(6271):397–400CrossRefPubMedGoogle Scholar
  16. Chu C, Qu K, Zhong FL, Artandi SE, Chang HY (2011) Genomic maps of long noncoding RNA occupancy reveal principles of RNA-chromatin interactions. Mol Cell 44(4):667–678CrossRefPubMedPubMedCentralGoogle Scholar
  17. Chu C, Quinn J, Chang HY (2012) Chromatin isolation by RNA purification (ChIRP). J Vis Exp 61:e3912Google Scholar
  18. Clark AT (2015) DNA methylation remodeling in vitro and in vivo. Curr Opin Genet Dev 34:82–87CrossRefPubMedPubMedCentralGoogle Scholar
  19. Clayton DA (1982) Replication of animal mitochondrial DNA. Cell 28(4):693–705CrossRefPubMedGoogle Scholar
  20. Clayton DA (2000) Transcription and replication of mitochondrial DNA. Hum Reprod 15(Suppl 2):11–17CrossRefPubMedGoogle Scholar
  21. Deng W, Lee J, Wang H, Miller J, Reik A, Gregory PD, Dean A, Blobel GA (2012) Controlling long-range genomic interactions at a native locus by targeted tethering of a looping factor. Cell 149(6):1233–1244PubMedPubMedCentralCrossRefGoogle Scholar
  22. Deng W, Rupon JW, Krivega I, Breda L, Motta I, Jahn KS, Reik A, Gregory PD, Rivella S, Dean A et al (2014b) Reactivation of developmentally silenced globin genes by forced chromatin looping. Cell 158(4):849–860PubMedPubMedCentralCrossRefGoogle Scholar
  23. Eckhardt F, Lewin J, Cortese R, Rakyan VK, Attwood J, Burger M, Burton J, Cox TV, Davies R, Down TA et al (2006) DNA methylation profiling of human chromosomes 6, 20 and 22. Nat Genet 38(12):1378–1385CrossRefPubMedPubMedCentralGoogle Scholar
  24. Fatemi M, Hermann A, Pradhan S, Jeltsch A (2001) The activity of the murine DNA methyltransferase Dnmt1 is controlled by interaction of the catalytic domain with the N-terminal part of the enzyme leading to an allosteric activation of the enzyme after binding to methylated DNA. J Mol Biol 309(5):1189–1199CrossRefPubMedGoogle Scholar
  25. Fisher RA (1926) The arrangement of field experiments. J Minist Agric 33:503–513Google Scholar
  26. Forrester WC, Epner E, Driscoll MC, Enver T, Brice M, Papayannopoulou T, Groudine M (1990) A deletion of the human beta-globin locus activation region causes a major alteration in chromatin structure and replication across the entire beta-globin locus. Genes Dev 4(10):1637–1649CrossRefPubMedGoogle Scholar
  27. Frederico LA, Kunkel TA, Shaw BR (1990) A sensitive genetic assay for the detection of cytosine deamination: determination of rate constants and the activation energy. Biochemistry (Mosc) 29(10):2532–2537CrossRefGoogle Scholar
  28. Gapp K, Jawaid A, Sarkies P, Bohacek J, Pelczar P, Prados J, Farinelli L, Miska E, Mansuy IM (2014) Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat Neurosci 17(5):667–669CrossRefPubMedPubMedCentralGoogle Scholar
  29. Goto M, Washio T, Tomita M (2000) Causal analysis of CpG suppression in the Mycoplasma genome. Microb Comp Genomics 5(1):51–58CrossRefPubMedGoogle Scholar
  30. Grigg GW (1996) Sequencing 5-methylcytosine residues by the bisulphite method. DNA Seq 6(4):189–198CrossRefPubMedGoogle Scholar
  31. Grigg G, Clark S (1994) Sequencing 5-methylcytosine residues in genomic DNA. BioEssays 16(6):431–436CrossRefPubMedGoogle Scholar
  32. Hou C, Zhao H, Tanimoto K, Dean A (2008) CTCF-dependent enhancer-blocking by alternative chromatin loop formation. Proc Natl Acad Sci U S A 105(51):20398–20403PubMedPubMedCentralCrossRefGoogle Scholar
  33. Ingrosso D, Perna AF (2009) Epigenetics in hyperhomocysteinemic states. A special focus on uremia. Biochim Biophys Acta 1790(9):892–899CrossRefPubMedGoogle Scholar
  34. Ingrosso D, Cimmino A, Perna AF, Masella L, De Santo NG, De Bonis ML, Vacca M, D’Esposito M, D’Urso M, Galletti P et al (2003) Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia. Lancet 361(9370):1693–1699CrossRefPubMedGoogle Scholar
  35. Insinga A, Minucci S, Pelicci PG (2005a) Mechanisms of selective anticancer action of histone deacetylase inhibitors. Cell Cycle 4(6):741–743CrossRefPubMedGoogle Scholar
  36. Insinga A, Monestiroli S, Ronzoni S, Gelmetti V, Marchesi F, Viale A, Altucci L, Nervi C, Minucci S, Pelicci PG (2005b) Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway. Nat Med 11(1):71–76CrossRefPubMedGoogle Scholar
  37. Ito T, Bulger M, Pazin MJ, Kobayashi R, Kadonaga JT (1997) ACF, an ISWI-containing and ATP-utilizing chromatin assembly and remodeling factor. Cell 90(1):145–155CrossRefPubMedGoogle Scholar
  38. Jin P, Alisch RS, Warren ST (2004a) RNA and microRNAs in fragile X mental retardation. Nat Cell Biol 6(11):1048–1053CrossRefPubMedGoogle Scholar
  39. Josse J, Kaiser AD, Kornberg A (1961) Enzymatic synthesis of deoxyribonucleic acid VII. Frequencies of nearest neighbor base-sequences in deoxyribonucleic acid. J Biol Chem 236:864–875PubMedGoogle Scholar
  40. Kanehisa M (2013) Molecular network analysis of diseases and drugs in KEGG. Methods Mol Biol 939:263–275CrossRefPubMedGoogle Scholar
  41. Kanehisa M, Sato Y, Kawashima M, Furumichi M, Tanabe M (2016) KEGG as a reference resource for gene and protein annotation. Nucleic Acids Res 44(D1):D457–D462CrossRefGoogle Scholar
  42. Karlin S, Burge C (1995) Dinucleotide relative abundance extremes: a genomic signature. TIG 11(7):283–290CrossRefPubMedGoogle Scholar
  43. Karlin S, Mrazek J (1996) What drives codon choices in human genes. J Mol Biol 262:459–472CrossRefPubMedGoogle Scholar
  44. Kioussis D, Vanin E, deLange T, Flavell RA, Grosveld FG (1983) Beta-globin gene inactivation by DNA translocation in gamma beta-thalassaemia. Nature 306(5944):662–666CrossRefGoogle Scholar
  45. Korenke GC, Fuchs S, Krasemann E, Doerr HG, Wilichowski E, Hunneman DH, Hanefeld F (1996) Cerebral adrenoleukodystrophy (ALD) in only one of monozygotic twins with an identical ALD genotype. Ann Neurol 40(2):254–257CrossRefPubMedGoogle Scholar
  46. Krasemann EW, Meier V, Korenke GC, Hunneman DH, Hanefeld F (1996) Identification of mutations in the ALD-gene of 20 families with adrenoleukodystrophy/adrenomyeloneuropathy. Hum Genet 97(2):194–197PubMedPubMedCentralCrossRefGoogle Scholar
  47. Kungulovski G, Jeltsch A (2016) Epigenome editing: state of the art, concepts, and perspectives. Trends Genet 32(2):101–113CrossRefPubMedGoogle Scholar
  48. Lieberman-Aiden E, van Berkum NL, Williams L, Imakaev M, Ragoczy T, Telling A, Amit I, Lajoie BR, Sabo PJ, Dorschner MO et al (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326(5950):289–293PubMedPubMedCentralCrossRefGoogle Scholar
  49. Lindahl T (1993) Instability and decay of the primary structure of DNA. Nature 362:709–715CrossRefPubMedGoogle Scholar
  50. Lobry JR (1996) Asymmetric substitution patterns in the two DNA strands of bacteria. Mol Biol Evol 13(5):660–665CrossRefPubMedGoogle Scholar
  51. Lopez P, Philippe H, Myllykallio H, Forterre P (1999) Identification of putative chromosomal origins of replication in Archaea. Mol Microbiol 32(4):883–886CrossRefPubMedGoogle Scholar
  52. Ma P, Xia X (2011) Factors affecting splicing strength of yeast genes. Comp Funct Genomics:Article ID 212146, 13 pagesGoogle Scholar
  53. Marin A, Xia X (2008) GC skew in protein-coding genes between the leading and lagging strands in bacterial genomes: new substitution models incorporating strand bias. J Theor Biol 253(3):508–513CrossRefPubMedGoogle Scholar
  54. Morita M, Shimozawa N, Kashiwayama Y, Suzuki Y, Imanaka T (2011) ABC subfamily D proteins and very long chain fatty acid metabolism as novel targets in adrenoleukodystrophy. Curr Drug Targets 12(5):694–706CrossRefGoogle Scholar
  55. Muller HJ, Altenburg E (1930) The frequency of translocations produced by X-rays in Drosophila. Genetics 15(4):283–311PubMedPubMedCentralGoogle Scholar
  56. Murphy J, Mahony J, Ainsworth S, Nauta A, van Sinderen D (2013) Bacteriophage orphan DNA methyltransferases: insights from their bacterial origin, function, and occurrence. Appl Environ Microbiol 79(24):7547–7555CrossRefPubMedPubMedCentralGoogle Scholar
  57. Nur I, Szyf M, Razin A, Glaser G, Rottem S, Razin S (1985) Procaryotic and eucaryotic traits of DNA methylation in spiroplasmas (mycoplasmas). J Bacteriol 164(1):19–24PubMedPubMedCentralGoogle Scholar
  58. Nussinov R (1984) Doublet frequencies in evolutionary distinct groups. Nucleic Acids Res 12(3):1749–1763CrossRefPubMedPubMedCentralGoogle Scholar
  59. Ohta T, Gray TA, Rogan PK, Buiting K, Gabriel JM, Saitoh S, Muralidhar B, Bilienska B, Krajewska-Walasek M, Driscoll DJ et al (1999) Imprinting-mutation mechanisms in Prader-Willi syndrome. Am J Hum Genet 64(2):397–413CrossRefPubMedPubMedCentralGoogle Scholar
  60. Pandey RR, Mondal T, Mohammad F, Enroth S, Redrup L, Komorowski J, Nagano T, Mancini-Dinardo D, Kanduri C (2008) Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. Mol Cell 32(2):232–246CrossRefPubMedGoogle Scholar
  61. Pazin MJ, Kamakaka RT, Kadonaga JT (1994) ATP-dependent nucleosome reconfiguration and transcriptional activation from preassembled chromatin templates. Science 266(5193):2007–2011CrossRefPubMedGoogle Scholar
  62. Pazin MJ, Sheridan PL, Cannon K, Cao Z, Keck JG, Kadonaga JT, Jones KA (1996) NF-kappa B-mediated chromatin reconfiguration and transcriptional activation of the HIV-1 enhancer in vitro. Genes Dev 10(1):37–49CrossRefPubMedGoogle Scholar
  63. Pazin MJ, Hermann JW, Kadonaga JT (1998) Promoter structure and transcriptional activation with chromatin templates assembled in vitro. A single Gal4-VP16 dimer binds to chromatin or to DNA with comparable affinity. J Biol Chem 273(51):34653–34660CrossRefPubMedGoogle Scholar
  64. Petronis A (2004) The origin of schizophrenia: genetic thesis, epigenetic antithesis, and resolving synthesis. Biol Psychiatry 55(10):965–970CrossRefPubMedGoogle Scholar
  65. Petronis A (2006) Epigenetics and twins: three variations on the theme. Trends Genet 22(7):347–350CrossRefPubMedGoogle Scholar
  66. Petronis A, Gottesman II, Kan P, Kennedy JL, Basile VS, Paterson AD, Popendikyte V (2003) Monozygotic twins exhibit numerous epigenetic differences: clues to twin discordance? Schizophr Bull 29(1):169–178CrossRefPubMedGoogle Scholar
  67. Razin A, Razin S (1980) Methylated bases in mycoplasmal DNA. Nucleic Acids Res 8(6):1383–1390CrossRefPubMedPubMedCentralGoogle Scholar
  68. Rideout WMI, Coetzee GA, Olumi AF, Jones PA (1990) 5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes. Science 249:1288–1290CrossRefPubMedGoogle Scholar
  69. Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, Goodnough LH, Helms JA, Farnham PJ, Segal E et al (2007) Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129(7):1311–1323CrossRefPubMedPubMedCentralGoogle Scholar
  70. Robertson G, Hirst M, Bainbridge M, Bilenky M, Zhao Y, Zeng T, Euskirchen G, Bernier B, Varhol R, Delaney A et al (2007) Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing. Nat Methods 4(8):651–657CrossRefGoogle Scholar
  71. Rodgers AB, Morgan CP, Leu NA, Bale TL (2015) Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress. Proc Natl Acad Sci U S A 112(44):13699–13704CrossRefPubMedPubMedCentralGoogle Scholar
  72. Sancar A, Sancar GB (1988) DNA repair enzymes. Annu Rev Biochem 57:29–67CrossRefPubMedGoogle Scholar
  73. Segurel L, Bon C (2017) On the evolution of lactase persistence in humans. Annu Rev Genomics Hum Genet 18:297–319PubMedPubMedCentralCrossRefGoogle Scholar
  74. Sendler E, Johnson GD, Mao S, Goodrich RJ, Diamond MP, Hauser R, Krawetz SA (2013) Stability, delivery and functions of human sperm RNAs at fertilization. Nucleic Acids Res 41(7):4104–4117CrossRefPubMedPubMedCentralGoogle Scholar
  75. Shadel GS, Clayton DA (1997) Mitochondrial DNA maintenance in vertebrates. Annu Rev Biochem 66:409–435CrossRefPubMedGoogle Scholar
  76. Sharma U, Conine CC, Shea JM, Boskovic A, Derr AG, Bing XY, Belleannee C, Kucukural A, Serra RW, Sun F et al (2016) Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science 351(6271):391–396CrossRefPubMedGoogle Scholar
  77. Sheridan PL, Sheline CT, Cannon K, Voz ML, Pazin MJ, Kadonaga JT, Jones KA (1995) Activation of the HIV-1 enhancer by the LEF-1 HMG protein on nucleosome-assembled DNA in vitro. Genes Dev 9(17):2090–2104CrossRefPubMedGoogle Scholar
  78. Shoemaker R, Deng J, Wang W, Zhang K (2010) Allele-specific methylation is prevalent and is contributed by CpG-SNPs in the human genome. Genome Res 20(7):883–889CrossRefPubMedPubMedCentralGoogle Scholar
  79. Sved J, Bird A (1990) The expected equilibrium of the CpG dinucleotide in vertebrate genomes under a mutation model. Proc Natl Acad Sci U S A 87:4692–4696CrossRefPubMedPubMedCentralGoogle Scholar
  80. Tanabe M, Kanehisa M (2012) Using the KEGG database resource. Curr Protoc Bioinformatics Chapter 1:Unit1 12Google Scholar
  81. Tanaka M, Ozawa T (1994) Strand asymmetry in human mitochondrial DNA mutations. Genomics 22(2):327–335CrossRefPubMedGoogle Scholar
  82. Taramelli R, Kioussis D, Vanin E, Bartram K, Groffen J, Hurst J, Grosveld FG (1986) Gamma delta beta-thalassaemias 1 and 2 are the result of a 100 kbp deletion in the human beta-globin cluster. Nucleic Acids Res 14(17):7017–7029PubMedPubMedCentralCrossRefGoogle Scholar
  83. Tomatsu S, Orii KO, Bi Y, Gutierrez MA, Nishioka T, Yamaguchi S, Kondo N, Orii T, Noguchi A, Sly WS (2004) General implications for CpG hot spot mutations: methylation patterns of the human iduronate-2-sulfatase gene locus. Hum Mutat 23(6):590–598CrossRefPubMedGoogle Scholar
  84. Vlasschaert C, Xia X, Gray DA (2016) Selection preserves Ubiquitin Specific Protease 4 alternative exon skipping in therian mammals. Sci Rep 6:20039CrossRefPubMedPubMedCentralGoogle Scholar
  85. Voelter-Mahlknecht S (2016) Epigenetic associations in relation to cardiovascular prevention and therapeutics. Clin Epigenetics 8:4CrossRefPubMedPubMedCentralGoogle Scholar
  86. Wade PA, Wolffe AP (2001) ReCoGnizing methylated DNA. Nat Struct Biol 8(7):575–577CrossRefPubMedGoogle Scholar
  87. Wei Y, Xia X (2017) The role of +4U as an extended translation termination signal in bacteria. Genetics 205(2):539–549CrossRefPubMedGoogle Scholar
  88. Xia X (1998b) The rate heterogeneity of nonsynonymous substitutions in mammalian mitochondrial genes. Mol Biol Evol 15:336–344CrossRefPubMedGoogle Scholar
  89. Xia X (2003) DNA methylation and mycoplasma genomes. J Mol Evol 57:S21–S28CrossRefPubMedGoogle Scholar
  90. Xia X (2012a) DNA replication and strand asymmetry in prokaryotic and mitochondrial genomes. Curr Genomics 13(1):16–27CrossRefPubMedPubMedCentralGoogle Scholar
  91. Xia X (2013) DAMBE5: a comprehensive software package for data analysis in molecular biology and evolution. Mol Biol Evol 30:1720–1728PubMedPubMedCentralCrossRefGoogle Scholar
  92. Xia X (2017b) Bioinformatics and drug discovery. Curr Top Med Chem 17(15):1709–1726CrossRefPubMedPubMedCentralGoogle Scholar
  93. Xia X (2017d) Self-organizing map for characterizing heterogeneous nucleotide and amino acid sequence motifs. Computation 5(4):43CrossRefGoogle Scholar
  94. Xia X, Li WH (1998) What amino acid properties affect protein evolution? J Mol Evol 47(5):557–564CrossRefPubMedGoogle Scholar
  95. Xia X, Hafner MS, Sudman PD (1996) On transition bias in mitochondrial genes of pocket gophers. J Mol Evol 43:32–40CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  • Xuhua Xia
    • 1
  1. 1.University of Ottawa CAREG and Biology DepartmentOttawaCanada

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