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3861

  1. No+mainitsepa+edes+yksi.
  2. Genomin+muokkaamiseen+sisältyy+valtavasti+riskejä.+DNA+on+erittäin+huolellisesti+järjesteltyä+informaatiota,+jossa+solun+käyttämät+jaksot+voivat+limittyä,+olla+sisäkkäin,+ne+voivat+sijaita+eri+kromosomeissa+ja+niitä+voidaan+lukea+molempiin+suuntiin+(5'+ja+3').+Solu+pitää+yllä+DNA:n+kieliopin+eheyttä+epigeneettisillä+mekanismeillaan.+Aiheuttamalla+muutoksen+yhteen+kohtaan+DNA:ta+voi+samalla+aiheuttaa+vaarallisen+ketjureaktion.+Miksi?Ihmisen+genomissa+ei+ole+kuin+n.+19'000+proteiinien+koodaamiseen+käytettävää+DNA-jaksoa,+mutta+erilaisten+proteiinien+määrä+kehossamme+on+jopa+n.+kuusi+miljoonaa.+Miten+tämä+on+mahdollista?+Tekniikka+perustuu+monimutkaiseen+mekanismiin+nimeltään+vaihtoehtoinen+silmukointi+(alternative+splicing),+jossa+yhtä+ja+samaa+DNA-jaksoa+lukemalla+solumme+voivat+valmistaa+tuhansia+erilaisia+proteiineja+eri+käyttötarkoituksiin.+Tätä+pleiotropiksikin+kutsuttua+'geenien'+monitoiminnallisuutta+ohjaavat+epigeneettiset+tekijät+ja+mekanismit.+DNA+on+vain+passiivista+tietovarantoa+solulle+ja+DNA:n+ensisijainen+tehtävä+on+tulla+luetuksi+transkriptioon,+jonka+tuloksena+solu+valmistaa+toiminnallisia+RNA-molekyylejä.+Nämä+ovat+ohjelmallisia+elementtejä+ja+niillä+on+useita+tehtäviä+solussa,+kudoksissa+ja+elimistössä.Sinun+kaikissa+soluissasi+(neuroneja+ja+T-soluja+lukuunottamatta)+on+täsmälleen+samat+DNA-jaksot.+Solujen+erilaistuminen+perustuu+epigeneettiseen+ohjelmointiin.+Eliöissä+tapahtuvan+muutoksen+taustalta+löytyvät+siis+epigeneettiset+mekanismit+ja+tekijät.+Tämän+vuoksi+voimme+havaita+eliöryhmien+sisäistä+muuntelua,+mutta+evoluutiolle+ei+ole+mekanismia.+Tiede+ei+tunne+sellaista+mekanismia,+joka+saisi+aikaan+biologisen+informaation+lisäystä+siten,+että+se+johtaisi+toiminnallisen+tai+rakenteellisen+monimutkaisuuden+kasvuun+eliöissä.
  3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541967/"Many+studies+have+reported+that+CpG-SNPs+are+associated+with+different+diseases,+such+as+type+2+diabetes,+breast+cancer,+coronary+heart+disease,+and+psychosis+which+show+a+clear+interaction+between+genetic+(SNPs)+and+epigenetic+(DNA+methylation)+regulation."https://www.nature.com/articles/modpathol2009130"Loss+of+expression+of+the+O6-methylguanine+DNA+methyltransferase+(MGMT)+protein+is+a+frequent+occurrence+in+many+types+of+cancer,+including+30–46%+of+sporadic+colorectal+cancers.9,+10,+11,+12,+13+This+is+almost+invariably+associated+with+methylation+of+the+MGMT+promoter.9+MGMT+is+a+ubiquitously+expressed+DNA+repair+protein+that+protects+against+mutagenesis+by+repairing+mutagenic+O6-methylguanines+within+DNA.+By+direct+cleavage+of+the+methyl+adducts,+the+enzyme+can+restore+the+affected+guanine+nucleotides+to+normal.14+If+this+fails+to+occur,+O6-methylguanines+can+pair+erroneously+with+thymine+during+DNA+replication,+resulting+in+G:C>A:T+transitions+in+the+DNA,+which+can+be+important+in+neoplastic+transformation.""Recently,+MGMT+methylation+was+found+to+be+closely+associated+with+the+C>T+SNP+(rs16906252)+within+the+first+exon+of+MGMT+in+colorectal+cancer."https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004585"Surprisingly,+hydroxymethylated+sites+are+consistently+associated+with+elevated+C+to+G+transversion+rates+at+the+level+of+segregating+polymorphisms,+fixed+substitutions,+and+somatic+mutations+in+tumors."https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578878/"DNA+hypomethylation+promotes+genomic+instability+4,+in+many+cases+leading+to+an+increased+mutational+load+and+activation+of+proto-oncogenes."https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930698/"DNA+methylation+has+been+linked+to+mismatch+repair+(MMR)+deficiency+and+genomic+instability+in+multiple+contexts,+in+both+cell+lines+and+in+disease.+In+the+HCT116+colorectal+cancer+cell+line,+ablation+of+catalytically+active+DNMT1+causes+cell+cycle+arrest+and+apoptosis+due+to+increased+chromosomal+instability.+In+mouse+ES+cells,+loss+of+Dnmt1+also+causes+global+hypomethylation+and+increased+mutation+rates."https://www.ncbi.nlm.nih.gov/pubmed/20846930"If+we+assume+that+CpHpG+methylation+also+occurs+in+the+germline,+and+that+5mC+deamination+can+occur+within+a+CpHpG+context,+then+we+might+surmise+that+methylated+CpHpG+sites+could+also+constitute+mutation+hotspots+causing+human+genetic+disease.+To+test+this+postulate,+54,625+missense+and+nonsense+mutations+from+2,113+genes+causing+inherited+disease+were+retrieved+from+the+Human+Gene+Mutation+Database+(http://www.hgmd.org).+Some+18.2+per+cent+of+these+pathological+lesions+were+found+to+be+C+>+T+and+G+>+A+transitions+located+in+CpG+dinucleotides+(compatible+with+a+model+of+methylation-mediated+deamination+of+5mC),+an+approximately+ten-fold+higher+proportion+than+would+have+been+expected+by+chance+alone."https://www.ncbi.nlm.nih.gov/pmc/articles/PMC33658/"Altered+DNA+methylation+and+genome+instability:+A+new+pathway+to+cancer"http://www.biochemist.org/bio/03905/0012/039050012.pdf"This+increased+genome+instability+is+characterized+by+increased+occurrences+of+mutations,+cells+with+incorrect+chromosome+number,+loss+of+heterochromatin+and+mistakes+in+transcription."https://www.intechopen.com/online-first/a-hypothesis-to-explain-how-the-dna-of-elderly-people-is-prone-to-damage-genome-wide-hypomethylation"A+reduction+in+DNA+methylation+leads+to+genomic+instability,+accumulation+of+endogenous+DNA+damage,+and+sensitivity+to+DNA-damaging+agents."https://jcs.biologists.org/content/112/24/4513"CpG+methylation+reduces+genomic+instability."https://pdfs.semanticscholar.org/d685/909cc287511ce7ab88368a72de1f09e988b8.pdf"As+well,+DNA+methylation+is+thought+to+be+a+major+contributor+of+point+mutations+leading+to+human+genetic+disease,+when+it+precedes+deamination+of+5-methylcytosine+(m5C)+present+within+CpG+dinucleotides.+CpG+dinucleotides+are+hypothesized+to+be+a+hotspot+for+mutations+in+a+variety+of+genes,+where+a+substantial+proportion+of+intragenic+single+base-pair+mutations+(35%)+occur+in+CpG+dinucleotides+and+are+the+result+of+C>T+or+G>A+transitions.+Consequently,+the+rate+of+transitions+at+CpGs+is+suggested+to+be+20-fold+higher+than+transitions+at+non-CpG+sites."https://www.atdbio.com/content/56/Epigenetics#Role-of-base-flipping-in-DNA-methylation"When+cytosine+is+mutated+to+uracil+by+spontaneous+deamination,+the+DNA+glycosylase+enzyme+UDG+(uracil+DNA+glycosylase)+reverses+the+damage,+in+a+base+excision+repair+mechanism.+When+the+equivalent+deamination+reaction+occurs+on+5-methylcytosine,+however,+the+product,+thymine,+is+not+repaired+by+DNA+repair+enzymes."https://jb.asm.org/content/200/24/e00371-18"I+show+that+sites+methylated+by+the+Dcm+enzyme+exhibit+an+8-fold+increase+in+mutation+rate+in+natural+bacterial+populations.+I+also+show+that+modifications+at+other+sites+in+various+bacteria+also+increase+the+mutation