How about some cool science as we head toward the weekend?
Let’s talk about long noncoding RNAs (lncRNA) – they are (somewhat arbitrarily) defined as stretches of DNA that are at least 200 base pairs in length that are transcribed into mRNA but have little potential to code for proteins. Determining the function (if one exists) of a particular lncRNA can often be difficult. In part, this may be due to the fact that lncRNA evolve much more quickly than protein-coding genes do and therefore exhibit a much smaller degree of sequence conservation, which can make identifying orthologs in other related organisms more difficult. Nevertheless, if a particular lncRNA is functionally important, we would usually expect to see copies of it in related organisms, so finding these homologs can be an important indicator of function.
A new paper in Genes and Development by Quinn et al. is a useful demonstration of this. The authors find evidence of 47 homologs of roX, an lncRNA involved in X chromosome dosage compensation, across 35 fruit fly species. The researchers identity roX homologs based on a combination of short regions of sequence conservation (“microhomology”), RNA secondary structure and synteny (i.e., similarity in location along a chromosome) Here is the abstract (I believe the paper itself is open access):
Many long noncoding RNAs (lncRNAs) can regulate chromatin states, but the evolutionary origin and dynamics driving lncRNA–genome interactions are unclear. We adapted an integrative strategy that identifies lncRNA orthologs in different species despite limited sequence similarity, which is applicable to mammalian and insect lncRNAs. Analysis of the roX lncRNAs, which are essential for dosage compensation of the single X chromosome in Drosophila males, revealed 47 new roX orthologs in diverse Drosophilid species across ∼40 million years of evolution. Genetic rescue by roX orthologs and engineered synthetic lncRNAs showed that altering the number of focal, repetitive RNA structures determines roX ortholog function. Genomic occupancy maps of roX RNAs in four species revealed conserved targeting of X chromosome neighborhoods but rapid turnover of individual binding sites. Many new roX-binding sites evolved from DNA encoding a pre-existing RNA splicing signal, effectively linking dosage compensation to transcribed genes. Thus, dynamic change in lncRNAs and their genomic targets underlies conserved and essential lncRNA–genome interactions.
I think it’s a neat demonstration of both the challenges and utility of using evolutionary conservation to help inform inferences regarding the functionality of non-coding genes. As we continue to get a better grasp of which non-coding sequences are important and which ones are less so, I expect to see many more studies like this.
Carl Zimmer also has an excellent write up of the paper here, which was the original inspiration for this post. Enjoy!
Edited to correct the number of species in which roX was detected.