Nonlinear sequence similarity between the and long noncoding RNAs suggests shared functions of tandem repeat domains.

The marsupial inactive X chromosome expresses a long noncoding RNA (lncRNA) called that has been proposed to be the functional analog of eutherian Despite the possibility that and encode related functions, the two lncRNAs harbor no linear sequence similarity. However, both lncRNAs harbor domains of tandemly repeated sequence. In , these repeat domains are known to be critical for function. Using -mer based comparison, we show that the repeat domains of and unexpectedly partition into two major clusters that each harbor substantial levels of nonlinear sequence similarity. Repeats B, C, and D were most similar to each other and to Repeat 1, whereas Repeats A and E were most similar to each other and to Repeats 2, 3, and 4. Similarities at the level of -mers corresponded to domain-specific enrichment of protein-binding motifs. Within individual domains, protein-binding motifs were often enriched to extreme levels. Our data support the hypothesis that and encode similar functions through different spatial arrangements of functionally analogous protein-binding domains. We propose that the two clusters of repeat domains in and function in part to cooperatively recruit PRC1 and PRC2 to chromatin. The physical manner in which these domains engage with protein cofactors may be just as critical to the function of the domains as the protein cofactors themselves. The general approaches we outline in this report should prove useful in the study of any set of RNAs.