Worm Breeder's Gazette 11(5): 91

These abstracts should not be cited in bibliographies. Material contained herein should be treated as personal communication and should be cited as such only with the consent of the author.

"Synthetic Dominance": Dominant Mutations Dependent on a smg Mutant Background

Rock Pulak, Beth De Stasio and Phil Anderson

In the course of studying the effects of smg mutations on unc-54 
mRNA levels, we observed that four unc-54 nonsense mutations, which by 
all criteria are typical recessive mutations, are dominant in a smg 
mutant background.  The four mutations e1420 (UAA at codon 614), e1419 (
UAG at codon 631), r274 (UGA at codon 761), and r308 (UGA at codon 833)
] are loosely clustered in the carboxyl-terminal region of the myosin 
globular head.  The positions of these mutations predict the 
expression of truncated proteins that contain most (but not all) of 
the myosin head region with no attached rod segment.  
In smg(+) backgrounds, these nonsense mutations are recessive and 
accumulate very low levels of unc-54 mRNA (5-10% of the amount 
accumulated by wild type; see accompanying WBG article).  Thus, we 
anticipate that these mutants (either homozygous or heterozygous) 
produce very low levels of the truncated myosin proteins.  In smg(-) 
backgrounds, these mutants accumulate nearly wild-type amounts of unc-
54 mRNA.  We anticipate that these strains produce large quantities of 
the truncated protein.  We believe that the dominance of these four 
unc-54 alleles is due to disruptive effects that the truncated myosin 
proteins have on thick filament or sarcomere assembly.  
The strength of this smg-dependent dominance varies, depending on 
both the unc-54 and smg allele, but the effect can be quite striking.  
In the background of smg-1 through smg-5, unc-54(r274) is strongly 
dominant when heterozygous and lethal when homozygous.  In this 
situation, r274 resembles the strongly dominant missense alleles of 
unc-54 that have been previously described (Waterston et al., J.M.B.  
180:473; Bejsovec & Anderson, Cell 60:133).  smg-6(r896) does not 
confer dominance to any of the four unc-54 alleles, while smg-6(r886) 
causes each of them to be dominant.  Thus, we believe that r896 is a 
We have been unsuccessful in our attempts to identify the predicted 
premature termination polypeptides.  We have looked for proteins of 
the predicted sizes in total protein homogenates, in 
immunoprecipitates using polyclonal anti-actomyosin, and in Western 
blots using a scallop anti-myosin antibody that recognizes head 
epitopes of many different myosin heavy chains.  No proteins of the 
predicted sizes were detected.  This result is disappointing, but it 
is not entirely unexpected.  Bejsovec & Anderson (Cell 60:133) could 
not detect the mutant myosin of several strongly dominant unc-54 
missense alleles.  The mutant proteins are efficiently degraded, but a 
small amount of a strongly disruptive protein is sufficient to 
interfere with thick filament and/or sarcomere assembly.  
We suggest that smg-dependent dominance ('synthetic dominance', 
analogous to synthetic lethals) may be a common occurrence.  When the 
truncated protein product of a nonsense or frameshift mutation has a 
disruptive biological activity, then smg mutations should enhance or 
reveal these disruptive effects.  The four unc-54 mutations described 
above provide one example, but a number of others have been 
encountered.  The weak dominance of dpy-5(e61) is enhanced in a smg 
mutant background (Hodgkin et al., Genetics 123:301).  dpy-14(e188) is 
essentially recessive in a smg(+) background, but in a smg(-) 
background it is strongly dominant when heterozygous and lethal when 
homozygous (K.  Anders, personal communication).  The weak dominance 
of glp-1(q35) (a UGA nonsense mutation) is substantially enhanced by a 
smg mutation (J.  Kimble, personal communication).  We suggest that 
mutant hunts in a smg background will yield a wider variety of 
dominant mutations than might otherwise be obtained.