Intriguingly, it has been shown that some suppressors of PEV are recessive lethals, and their lethality depends on their interaction with the Y chromosome.
It seems to have several mechanisms of lethality depending on the tumor type and the drug concentration.
The number of identifiable mutations of relatively high lethality depends on the extensiveness of lines used in the allelism test.
In the case of MK5, the KO mouse model, displayed either no particular phenotype or embryonic lethality, depending on which genetic background the mice were bred [ 6, 7].
Homozygous loss of function of Gpr126 in the mouse results in mid-gestational or perinatal lethality (depending on the allele), with a few pups surviving to 1-2 weeks of age (Waller-Evans et al., 2010; Monk et al., 2011).
In addition, a number of other gene knockouts in mice have been shown to present considerable variation in the penetrance of lethality, depending on the genetic background in which the knockouts were made (Doetschman 2009).
For populations of mir-35 -41(nDf50 ) or mir-35 -41(gk262 ) embryos, the penetrance of lethality depends on the temperature at which the animals are grown, with lower frequency of lethality at 15° or 20° and nearly complete lethality at 25° (Alvarez-Saavedra and Horvitz 2010; Massirer et al. 2012).
However, viability of adult flies that carry a UAS-driven H1 RNAi transgene and a ubiquitous GAL4 driver varies over a wide range (from apparently normal viability to complete lethality) depending on the temperature and inversely correlates with the extent of H1 depletion (Lu et al. 2009).
Of note, the neomycin cassette is retained in this mutant; constitutive expression of neomycin in the homozygous state has been reported to contribute to various phenotypes, such as embryonic lethality, depending on the gene that it affects (Scacheri et al, 2001).
Moreover, lethality depends on the functions and essentialities of the affected genes – e.g. events affecting two genes might be avoiding one another (i.e. mutually exclusive) as a means to increase the number of possible paths to achieve distinct phenotypes, but their individual or simultaneous occurrence might not necessarily be lethal to the cells (see Discussion).
