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Transcription induces strand-specific mutations at the 5 end of human genes

Summary: Transcription induces strand-specific mutations
at the 5 end of human genes
Paz Polak1
and Peter F. Arndt
Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
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 germ line cells. Our analysis reveals
three distinct patterns of substitution rates. First, a sharp decline in the deamination rate of methylated CpG
dinucleotides, which is observed in the vicinity of the 5 end of genes. Second, 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. Finally, a localized strand asymmetry, an excess of CT over GA substitution
in the nontemplate strand confined to the first 1­2 kbp downstream of the 5 end of genes. We hypothesize that
higher exposure of the nontemplate strand near the 5 end of genes leads to a higher cytosine deamination rate. Up
to now, only the somatic hypermutation (SHM) pathway has been known to mediate localized and strand-specific
mutagenic processes associated with transcription in mammalia. The mutational patterns in SHM are induced by
cytosine deaminase, which just targets single-stranded DNA. This DNA conformation is induced by R-loops, which
preferentially occur at the 5 ends of genes. We predict that R-loops are extensively formed in the beginning of
transcribed regions in germ line cells.
[Supplemental material is available online at www.genome.org.]
Understanding the processes that lead to spontaneous DNA mu-


Source: Arndt, Peter - Max-Planck-Institut für molekulare Genetik
Spang, Rainer - Computational Molecular Biology Group, Max-Planck-Institut für molekulare Genetik


Collections: Biology and Medicine; Biotechnology; Computer Technologies and Information Sciences; Physics