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Meiotic Cas9 expression mediates gene conversion in the male and female mouse germline

Highly efficient gene conversion systems have the potential to facilitate the study of complex genetic traits using laboratory mice and, if implemented as a "gene drive," to limit loss of biodiversity and disease transmission caused by wild rodent populations. It has previous been shown that such a system of gene conversion from heterozygous to homozygous after a sequence targeted CRISPR/Cas9 double-strand DNA break (DSB) is feasible in the female mouse germline. In the male germline, however, all DSBs were instead repaired by end joining (EJ) mechanisms to form an "insertion/deletion" (indel) mutation, suggesting that timing Cas9 expression to coincide with meiosis I is critical to favor conditions when homologous chromosomes are aligned and interchromosomal homology-directed repair (HDR) mechanisms predominate. Using a Cas9 knock-in allele at the Spo11 locus, Weitzel et al. show that meiotic expression of Cas9 does indeed mediate gene conversion in the male as well as in the female germline. The image shows male germline stem cells (magenta only) and expression of Cas9 in meiotic spermatocytes marked by the overlap of magenta and green.

Image Credit: Alexander Weitzel

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