Programmed Genome Rearrangements and the Genetic Consequences of Pluripotency

The sea lamprey (Petromyzon marinus: a vertebrate) undergoes reproducible programmed genome rearrangements (PGRs) that mediate the deletion of ~20% of its germline DNA during the development of somatic cell lineages. The genomic differentiation of germline and soma that results from PGR is intriguing from an evolutionary and developmental standpoint, because the germline plays a unique role in an organism’s biology. Specifically, germline must retain the ability to undergo meiotic recombination and the capacity to differentiate into every cell type (pluripotency), whereas these same factors can potentially disrupt genome integrity or cell fate specification if misexpressed in somatic cells. To test this idea and further define the molecular causes and genetic consequences of PGR in lamprey, we have undertaken several sequencing projects aimed at dissecting the lamprey genome and transcriptome. Computational analyses, coupled with empirical validation, indicate that thousands of genes are deleted via PGR and identify presumptive deletion breakpoints that mediate a few individual PGR events. Functional information from deleted regions indicates that PGR serves as a (perhaps ancient) biological strategy to ensure segregation of pluripotency functions to the germline, effectively eliminating the potential for somatic misexpression. Analyses of breakpoint regions identify potential consensus sites that are bound in a sequence-specific manner by proteins in rearranging embryos and are presumably recognized in the targeting of programmed deletions.  With its highly dynamic genome biology, lamprey presents a novel evolutionary and developmental model for studying biological functions that are unique to pluripotent cell lineages and fundamental genetic tradeoffs between germline and soma.