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DEAD box 1 (DDX1) is a member of the DEAD box family of RNA helicases which are involved in all aspects of RNA metabolism. DDX1 has been implicated in a variety of biological processes, including 3’-end processing of mRNA, DNA repair, microRNA processing, tRNA maturation and mRNA transport. To study the role of DDX1 during development, we have generated mice carrying a constitutive  Ddx1  knock-out allele.  Ddx1  +/−  mice have no obvious phenotype and express similar levels of DDX1 as wild-type mice indicating compensation from the intact  Ddx1  allele. Heterozygote matings produce no viable  Ddx1 −/−   progeny, with  Ddx1  −/−  embryos dying prior to embryonic day (E) 3.5. Intriguingly, the number of wild-type progeny is significantly decreased in heterozygote crosses, with two different heterozygote populations identified based on parental genotype: (i) normal  Ddx1  +/−  mice which generate the expected number of wild-type progeny and (ii)  Ddx1 * /−  mice (with * signifying a non-genetically altered allele) which generate a significantly reduced number of wild-type mice. The transgenerational inheritance of wild-type lethality observed upon crossing  Ddx1 * /−  mice is independent of parental sex and occurs in  cis  through a mechanism that is different from other types of previously reported transgenerational epigenetic inheritance.

Ddx1 knockout results in transgenerational wild-type lethality in mice