Tandem repeats drive variation of intrinsically disordered regions in budding yeast

Abstract

Copy-number variation in tandem repeat coding regions is more prevalent in eukaryotic genomes than current literature suggests. We have reexamined the genomes of nearly 100 yeast strains looking to map regions of repeat variation. From this analysis we have identified that length variation is highly correlated to intrinsically disordered regions (IDRs). Furthermore, the majority of length variation is associated with tandem repeats. These repetitive regions are rich in homopolymeric amino acid sequences but nearly half of the variation comes from longer-repeating motifs. Comparisons of repeat copy number and sequence between strains of budding yeast as well as closely related fungi suggest selection for and conservation of IDR-related tandem repeats. In some instances, repeat variation has been demonstrated to mediate binding affinity, aggregation, and protein stability. With this analysis, we can identify proteins for which repeat variation may play conserved roles in modulating protein function.

Defining the role of the polyasparagine repeat domain of theS. cerevisiaetranscription factor Azf1p

“…We therefore examined the homorepeat domains of Azf1p for length variation. Through a bioinformatic analysis of the genomes of 93 lab and wild isolates of S. cerevisiae (Strope et al 2015; Babokhov et al 2018), we determined that the polyN and polyQ domains of Azf1p vary in repeat copy number across strains of yeast. The polyN domain has 8 alleles ranging from 17 to 25 N residues (Figure 6A), and the polyQ domain has 3 alleles, 9Q, 12Q, and 17Q (Figure 6B).…”

“…Several eukaryotic TFs have been shown to phase separate with Mediator via their IDRs, and the formation of these droplets was demonstrated to be required for transcription (Boija et al 2018; Sabari et al 2018). The polyQ and polyN domains of Azf1p are both intrinsically disordered (Babokhov et al 2018), and length variation within these domains could impact the extent to which Azf1p can be incorporated into phase separated droplets.…”

“…Variation within AZF1 was measured using the data available from 93 recently sequenced S. cerevisiae genomes (Strope et al 2015) as described in Babokhov et al 2018.…”

Contractions of the C-Terminal Domain ofSaccharomyces cerevisiaeRpb1p Are Mediated by Rad5p

“…Repetitive sequences have generally been dismissed as inconsequential; however, it is becoming increasingly clear that repetitive regions can play important roles in modulating protein function. Repeat copy number in most repetitive coding regions often varies not only at the organismal level, but from generation to generation (Babokhov et al 2018). When found in open reading frames, variable repeats can lead to variable phenotypes, and repetitive sequences throughout the genome may serve as hotspots for evolution.…”

Template Switching Mediates Contractions of a Repetitive Coding Region inS. cerevisiae

“…Repetitive sequences have generally been dismissed as inconsequential; however, it is becoming increasingly clear that repetitive regions can play important roles in modulating protein function. Repeat copy number in most repetitive coding regions often varies not only at the organismal level, but from generation to generation (29). When found in open reading frames, variable repeats can lead to variable phenotypes, and repetitive sequences throughout the genome may serve as hotspots for evolution.…”