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Evolutionary Signatures of Mutagenic Processes Associated with Transcription

Monday, October 25, 2010 - 10:00
Campus des Cordeliers 15, rue de l'école de médecine 75006 Paris Salle Déjerine - escalier B - 2ème étage
Max Planck Institute for Molecular Genetics. Berlin

Unraveling the evolutionary forces responsible for variations of neutral substitution patterns among taxa or along genomes is a major prerequisite for detecting selection within sequences. In general, one assumes that mutations acted upon the two strands of the DNA molecule symmetrically, i.e. the substitution process does not distinguish between the forward and backward strand. For example, under this symmetry the rate for C->T transitions equals to the rate of G->A transitions. However, several cellular mechanisms (transcription of a gene being one) might break this symmetry of the two strands. We establish a comparative analysis of three or more genomes that allows us 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 reveals two distinct patterns of reverse complement symmetry breaking: (1) a strand asymmetry in complementary substitution rates, which extends from the 5'-end to 1 kbp downstream to the 3'-end, associated with transcription coupled repair (TCR), (2) a localized strand asymmetry, in form of an excess of C->T over G->A substitutions in the non-template strand. Surprisingly the last asymmetry is confined to the first 1-2 kbp downstream of the 5'-end of genes, requiring that, in addition to TCR, other processes are active in these regions. We argue that a higher exposure of the non-template strand near the 5'-end of genes leads to a higher cytosine deamination rate.

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