Transposable elements (TEs) allow rewiring of regulatory networks, and the recent amplification of the ISX-element dispersed 77 functional but suboptimal binding-sites for the dosage-compensation-complex to a newly-formed X-chromosome in Drosophila. Here we identify two linked refining-mutations within ISX that interact epistatically to increase binding affinity to the dosage-compensation-complex. Selection has increased the frequency of this derived haplotype in the population, which is fixed at 30% of ISX-insertions and polymorphic among another 41%. Sharing of this haplotype indicates that high levels of gene-conversion among ISX-elements allow them to 'crowd-source' refining-mutations, and a refining-mutation that occurs at any single ISX-element can spread in two dimensions: horizontally across insertion sites by non-allelic gene-conversion, and vertically through the population by natural selection. These describes a novel route how fully functional regulatory elements can arise rapidly from TEs and implicate non-allelic gene-conversion as having an important role in accelerating the evolutionary fine-tuning of regulatory networks.
- Magnus Nordborg, Gregor Mendel Institute of Molecular Plant Biology, Austrian Academy of Sciences, Austria
© 2015, Ellison & Bachtrog
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Maintaining germline genome integrity is essential and enormously complex. Although many proteins are involved in DNA replication, proofreading, and repair, mutator alleles have largely eluded detection in mammals. DNA replication and repair proteins often recognize sequence motifs or excise lesions at specific nucleotides. Thus, we might expect that the spectrum of de novo mutations – the frequencies of C>T, A>G, etc. – will differ between genomes that harbor either a mutator or wild-type allele. Previously, we used quantitative trait locus mapping to discover candidate mutator alleles in the DNA repair gene Mutyh that increased the C>A germline mutation rate in a family of inbred mice known as the BXDs (Sasani et al., 2022, Ashbrook et al., 2021). In this study we developed a new method to detect alleles associated with mutation spectrum variation and applied it to mutation data from the BXDs. We discovered an additional C>A mutator locus on chromosome 6 that overlaps Ogg1, a DNA glycosylase involved in the same base-excision repair network as Mutyh (David et al., 2007). Its effect depends on the presence of a mutator allele near Mutyh, and BXDs with mutator alleles at both loci have greater numbers of C>A mutations than those with mutator alleles at either locus alone. Our new methods for analyzing mutation spectra reveal evidence of epistasis between germline mutator alleles and may be applicable to mutation data from humans and other model organisms.