Allelic variants of hereditary prions: The bimodularity principle

Abstract

Modern biology requires modern genetic concepts equally valid for all discovered mechanisms of inheritance, either "canonical" (mediated by DNA sequences) or epigenetic. Applying basic genetic terms such as "gene" and "allele" to protein hereditary factors is one of the necessary steps toward these concepts. The basic idea that different variants of the same prion protein can be considered as alleles has been previously proposed by Chernoff and Tuite. In this paper, the notion of prion allele is further developed. We propose the idea that any prion allele is a bimodular hereditary system that depends on a certain DNA sequence (DNA determinant) and a certain epigenetic mark (epigenetic determinant). Alteration of any of these 2 determinants may lead to establishment of a new prion allele. The bimodularity principle is valid not only for hereditary prions; it seems to be universal for any epigenetic hereditary factor.

The mechanisms of epigenetic inheritance: how diverse are they?

“…Some authors (Jablonka & Lamb, ) suggested expanding this term to cover all chromatin‐related heritable forms of a gene with an unchanged DNA sequence. Moreover, different variants of the same hereditary prion (see Sections IV.8, V, VI) were recently considered to be prion alleles (Tikhodeyev, Tarasov, & Bondarev, ). The list of allelic EHFs also includes lyonized and active X chromosomes in some cell lineages in mammalian females (Clerc & Avner, ), alternative expression states of bistable networks in bacteria (Gardner, Cantor, & Collins, ; Tchuraev et al, ), irreversibly inhibited and normal plastid translation in plants (Zubko & Day, ), and alternative orientations of a particular ciliary row in ciliates (Beisson, ), among others.…”

“…Nevertheless, all mechanisms of SAEI display a fundamental similarity. Each EA is a bimodular unit, the features of which depend on two principal determinants (Tikhodeyev et al, ): a DNA determinant (DNA sequence) and an epigenetic determinant (epigenetic mark on the DNA sequence or its product). The best model to illustrate this bimodularity is the yeast amyloid prion [ PSI + ] which has hundreds of known allelic variants.…”

“…The best model to illustrate this bimodularity is the yeast amyloid prion [ PSI + ] which has hundreds of known allelic variants. To perpetuate a particular [ PSI + ] allele the cell must possess both: ( i ) a specific epigenetic mark as a ‘seed’, and ( ii ) the corresponding SUP35 sequence, in the absence of which the allele will not be reproduced because of the absence of the necessary protein (see Tikhodeyev et al, ). Multiple [ PSI + ] and [ psi − ] alleles have been described (see Table ).…”

“…Designation of a prion allele is bimodular: ( i ) a DNA determinant reflecting the amino acid sequence of Sup35p, and ( ii ) the epigenetic state of this protein (Tikhodeyev et al, ).…”

“…At present, clear bimodular nomenclature is given only for amyloid hereditary prions (see Tikhodeyev et al, ).…”