The Sad paradox: Mutations with dominant and recessive phenotypes.

ABSTRACT

Robert Metzenberg (June 11, 1930 – July 15, 2007) was described as ‘a geneticist extraordinaire and “model human”’ (Selker 2008). Claudio Scazzocchio (28 July 1938 –), a colleague and friend of Bob Metzenberg, is since his retirement a visiting professor at Imperial College, London, ‘actively writing old work, spending quite a few hours a day in front of a computer; trying to learn some bioinformatics’ and ‘following quite closely everything that has to do with epigenetics of fungi’. In 2001, Metzenberg and colleagues reported the fascinating discovery, in Neurospora crassa, of meiotic silencing by unpaired DNA (MSUD). MSUD is a presumed RNAi-mediated dousing of the ascusexpression of any gene lacking a sequence homologue at the same allelic position on the homologous chromosome (e.g. the transposase gene of a transposable element inserted into a novel location; also see figure 1) (Shiu et al. 2001). Somewhat counter-intuitively, MSUD leads deficiencies (Df) to exert an ascus-dominant phenotype. In a Df × WT cross, genes uncovered by the Df on the WT chromosome remain unpaired in meiosis, and are silenced. Interestingly, the gene, suppressor of ascus dominance-1+ (sad-1+), which encodes a putative RNA-dependent RNA polymerase essential for MSUD, silences itself when opposite a deletion allele (Sad-1Δ), and, consequently, Sad-1Δ suppresses MSUD in heterozygous crosses (i.e. Sad-1Δ × WT) (figure 1). Such self-silencing is reminiscent of Bertrand Russell’s famous paradox about the village barber who shaves all those who don’t shave themselves Who shaves the barber? Additionally, the homozygous Sad-1Δ × Sad-1Δ cross is infertile. In 2002, I wrote a ‘Commentary’ article describing the findings of Metzenberg and colleagues, and in it I also made reference to the paradox (Kasbekar 2002). Chancing upon my article last year, Scazzocchio graciously emailed his appreciation of it, and very soon a cordial correspondence developed between us. This correspondence brought to my possession three emails exchanged by Metzenberg and Scazzocchio in 2004, together with permission from Scazzocchio and Stan Metzenberg to use this exchange in any way I see fit. Nothing could be fitter than to publish this exchange in a new ‘Sidelights’ section in Journal of Biosciences. Interestingly, Scazzocchio also refers to Russell’s paradox in this scientific correspondence, and Metzenberg seems to suggest the barber shaves himself, but so incompletely as to create doubt about whether he shaved or merely trimmed his beard.