“Backwards” DNA—HPRT1R
understanding the “default” state of the genome
Understanding default genome states would help interpret whether pervasive transcriptional activity has biological meaning. The genomes of extant organism have undergone billions of years of evolution, making it unclear whether observed genomic activities represent the effects of selection or “noise”. We addressed this question by introducing a novel 101-kb locus into the genomes of yeast and mouse cells, and characterizing genomic activity. The locus was designed by reversing, but not complementing, human HPRT1, including substantial flanking regions, retaining basic sequence features but ablating evolved coding or regulatory information. We observed widespread activity of both reversed and native HPRT1 loci in yeast, despite the lack of evolved yeast promoters. In contrast, the reversed locus displayed no activity at all in mouse embryonic stem cells, instead showing repressive chromatin signatures. The repressive signature was alleviated in a locus variant lacking CpG dinucleotides; nevertheless this variant too was transcriptionally inactive. These results show that novel genomic sequences lacking coding information are active in yeast, but inactive in mouse embryonic stem cells, consistent with a major difference in “default genomic states” between these two divergent eukaryotic cell types, with implications for understanding pervasive transcription, horizontal transfer of genetic information, and new gene birth.
Read more in Camellato et al., Nature 2024.
(cover image in Project Library page by Microsoft Copilot)