Intrinsically Disordered Proteins Drive Emergence and Inheritance of Biological Traits

Abstract

Summary Prions are a paradigm-shifting mechanism of inheritance in which phenotypes are encoded by self-templating protein conformations rather than nucleic acids. Here we examine the breadth of protein-based inheritance across the yeast proteome by assessing the ability of nearly every open reading frame (∼5,300 ORFs) to induce heritable traits. Transient overexpression of nearly 50 proteins created traits that remained heritable long after their expression returned to normal. These traits were beneficial, had prion-like patterns of inheritance, were common in wild yeasts, and could be transmitted to naïve cells with protein alone. Most inducing proteins were not known prions and did not form amyloid. Instead, they are highly enriched in nucleic acid binding proteins with large intrinsically disordered domains that have been widely conserved across evolution. Our data thus establish a common type of protein-based inheritance through which intrinsically disordered proteins can drive the emergence of new traits and adaptive opportunities.

Multigenerational cohorts in patients with asthma and allergy

“…For example, in yeast both prion-like- proteins, and transient expression of non-prion proteins, have been shown to convey inheritance of traits independent of DNA. 26,27 In multicellular organisms, such as the nematode Caenorhabditis elegans, the RNA interference (RNAi) pathway results in non–DNA sequence–based heritable changes and environmental exposures can result in heritable phenotypic changes. 28 In mammalian models such as mice, a number of different types of non-genetic intergenerational or transgenerational inheritance have been observed.…”

“…28 In mammalian models such as mice, a number of different types of non-genetic intergenerational or transgenerational inheritance have been observed. 26,27 The most well-known examples being heritable non-genetic changes in expression of specific loci, such as at the Agouti viable yellow ( Avy ) locus affecting coat color and metabolic outcome, caused by methylation silencing of an insertional mutation that results in ectopic agouti expression, 29 which can be modified by maternal diet. 30 In another example, Manikkam et al demonstrated transgenerational inheritance of adult onset disease from exposure of gestating mice to an endocrine disruptor - the pesticide Methoxychlor.…”

Modifiers of the Genotype–Phenotype Map: Hsp90 and Beyond

“…For example, a number of studies have shown that genes involved in chromatin regulation and transcriptional repression uncover large amounts of cryptic variation when perturbed [7,25–27] and that prions [28–30] and proteins with regions of intrinsic disorder [31] can behave in a similar manner to Hsp90. Moreover, many genes buffer the effects of environmental variation; these genes might also modify the effects of genetic variation [32].…”

Phosphorylation-induced conformational dynamics in an intrinsically disordered protein and potential role in phenotypic heterogeneity

“…IDPs also participate in higher order phenomena, such as regulation of the cell division cycle (10)(11)(12), circadian rhythmicity (13,14), and phenotypic plasticity (15,16). Recent evidence suggests that several IDPs can act in a prion-like manner to create protein-based molecular memories that drive the emergence and inheritance of biological traits (17), further emphasizing their importance in state (or phenotype) switching. Moreover, if overexpressed, IDPs have the potential to engage in multiple "promiscuous" interactions with other proteins, which can lead to changes in phenotype and pathological states (18,19).…”