Evolutionary Signatures of Strand Specific Mutagenic Processes

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• Paz Polak (MPI for Molecular Genetics, Berlin)
• Monday 20 September 2010, 16:00-17:00
• Cancer Research UK Cambridge Research Institute, Lecture Theatre.

If you have a question about this talk, please contact Florian Markowetz.

Despite their central role in evolution, there is not yet a good knowledge about the rate of neutrally occurring mutations along mammalian genomes. Fundamental questions about neutral mutation rates such as the relative contribution of replication and transcription and their associated processes to mutation rates are still unanswered.

We establish a comparative analysis of three ore more genomes that correctly handles effects due to the non-stationarity and irreversibility of the nucleotide substitution process. This way we are able to quantify the 12 different rates for exchanges of one nucleotide by another as well as the rate of the neighbor dependent CpG deamination process.

A regional analysis of nucleotide substitution rates along human genes and their flanking regions allows us to quantify the effect of mutational mechanisms associated with transcription in germline cells. There are three transcription-associated substitution patterns that have been observed in mammals, of which two are related to CpG islands. The first is the deamination rate of methylated CpG dinucleotides, which is observed in the vicinity of the 5’ end of genes due to abundance of CpG islands in these regions that are subject to lower methylation levels compared to CpG dinucleotides elsewhere in the genome. The second is a strand asymmetry in complementary substitution rates, which extends from the 5’ end to 1 kbp downstream from the 3’ end, associated with transcription-coupled repair. The third is a localized strand asymmetry, an excess of C >T over G>A substitutions in the nontemplate strand confined to the first 2 kbp downstream of the 5’ end of genes at CpG islands. This pattern might be induced by a higher exposure of the nontemplate strand near the 5’ end of genes that in turn leads to a higher cytosine deamination rate. This type of substitution asymmetry is similar to the one that is observed as a consequence of the somatic hypermutation pathway. It might be that various proteins that are active during somatic hypermutation, such as a DNA mutator, Activation Induced cytidine Deaminase (AID), which solely targets single-stranded DNA , are also active in mammalian germline cells. The necessary ssDNA conformation can be induced by R-loops or G4 structures, which preferentially occur at the 5’ ends of genes.

Hosted by Nitzan Rosenfeld.

This talk is part of the Seminars on Quantitative Biology @ CRUK Cambridge Institute series.

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