150 years ago, Gregor Mendel described the basic rules of genetics. According to these rules, each parent makes an equal genetic contribution to an offspring in sexually reproducing organisms. The bipolar mitotic spindle controls the equal segregation of paternal and maternal chromosomes during the first cell division.
Being able to rewrite the rules of genetic segregation would expand the technological possibilities of biology and biotechnology, which may allow novel synthetic approaches to engineering animals in the future.
Here, we manipulated the mitotic spindle during the first cell division of Caenorhabditis elegans to segregate maternal and paternal chromosomes into different cell lineages, resulting in non-mendelian segregation of entire genomes.
Non-mendelian genetics was achieved by generating a strain that forms two monopolar spindles instead of one bipolar spindle during the first cell division. Monopolar spindles were generated by up regulating GPR-1 activity to increase microtubule-based cortical force generators to pull apart paternal and maternal pronuclei before nuclear envelope breakdown. Thus, one monopolar spindle was formed from only paternal chromosomes and one monopolar spindle was formed from only maternal chromosomes. The maternal monopolar spindle always formed in the anterior, and the paternal monopolar spindle always formed in the posterior of the zygote. As a consequence, only paternal chromosomes were segregated to P1, and thus to the germline. Thus, this monopolar spindle strain selectively passed on only paternal chromosomes, and thus acted like a “host” after mating: mothers produced F1 offspring with a mixed maternal-paternal genotype, but these hermaphrodites segregated F2 offspring with only paternal chromosomes. We are currently using this non-mendelian segregation to investigate parent-of-origin effects.
Taken together, we found that genetic rules can be rewritten by engineering cell division in an animal to generate non-mendelian segregation of entire genomes. This may be the starting point for a novel, synthetic zoology.
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