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SUMMARY:Evolutionary Signatures of Strand Specific Mutagenic Processes - P
 az Polak (MPI for Molecular Genetics\, Berlin)
DTSTART:20100920T150000Z
DTEND:20100920T160000Z
UID:TALK24784@talks.cam.ac.uk
CONTACT:Florian Markowetz
DESCRIPTION:Despite their central role in evolution\, there is not yet a g
 ood \nknowledge about the rate of neutrally occurring mutations along \nma
 mmalian genomes. Fundamental questions about neutral mutation rates \nsuch
  as the relative contribution of replication and transcription and \ntheir
  associated processes to mutation rates are still unanswered.\n\nWe establ
 ish a comparative analysis of three ore more genomes that \ncorrectly hand
 les effects due  to the non-stationarity and \nirreversibility of the nucl
 eotide substitution process. This way we are \nable to quantify the 12 dif
 ferent rates for exchanges of one nucleotide \nby another as well as the r
 ate of the neighbor dependent CpG deamination \nprocess.\n\nA regional ana
 lysis of nucleotide substitution rates along human genes \nand their flank
 ing regions allows us to quantify the effect of \nmutational mechanisms as
 sociated with transcription in germline cells. \nThere are three transcrip
 tion-associated substitution patterns that have \nbeen observed in mammals
 \, of which two are related to CpG islands. The \nfirst is the deamination
  rate of methylated CpG dinucleotides\, which is \nobserved in the vicinit
 y of the 5' end of genes due to abundance of CpG \nislands in these region
 s that are subject to lower methylation levels \ncompared to CpG dinucleot
 ides elsewhere in the genome. The second is a \nstrand asymmetry in comple
 mentary substitution rates\, which extends from \nthe 5' end to 1 kbp down
 stream from the 3' end\, associated with \ntranscription-coupled repair. T
 he third is a localized strand asymmetry\, \nan excess of C ->T over G->A 
 substitutions in the nontemplate strand \nconfined to the first 2 kbp down
 stream of the 5' end of genes at CpG \nislands. This pattern might be indu
 ced by a higher exposure of the \nnontemplate strand near the 5' end of ge
 nes that in turn leads to a \nhigher cytosine deamination rate. This type 
 of substitution asymmetry is \nsimilar to the one that is observed as a co
 nsequence of the somatic \nhypermutation pathway. It might be that various
  proteins that are active \nduring somatic hypermutation\, such as a DNA m
 utator\, Activation Induced \ncytidine Deaminase (AID)\, which solely targ
 ets single-stranded DNA\, are \nalso active in mammalian germline cells. T
 he     necessary ssDNA \nconformation can be induced by R-loops or G4 stru
 ctures\, which \npreferentially occur at the 5' ends of genes.\n \n\nHoste
 d by Nitzan Rosenfeld.
LOCATION:Cancer Research UK Cambridge Research Institute\, Lecture Theatre
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