I rarely blog about specific papers but felt moved to write about a new paper by Jonathan Mudge, Adam Frankish, and Jennifer Harrow who work in the Vertebrate Annotation group at the Wellcome Trust Sanger Institute.
Their paper, now out in Genome Research, is titled: Functional transcriptomics in the post-ENCODE era.
They brilliantly, and comprehensively, list the various ways in which gene architecture — and by extension gene annotation — is incredibly complex and far from a solved problem. However, they also provide an exhaustive description of all the various experimental technologies that are starting to shine a lot more light on this, at times, dimly lit field of genomics.
In their summary, they state:
Modern genomics (and indeed medicine) demands to understand the entirety of the genome and transcriptome right now
I'd go so far as to say that many people in genomics assume that genomes and transcriptomes are already understood. I often feel that too many people enter this field with false beliefs that many genomes are complete and that we know about all of the genes in this genomes. Jonathan Mudge et al. start this paper by firmly pointing out that even the simple question of 'what is a gene?' is something that we are far from certain about.
Reading this paper, I was impressed by how comprehensively they have reviewed the relevant literature, pulling in numerous examples that indicate just how complex genes are, and which show that we need to move away from the very protein-centric world view that has dominated much of the history of this field.
LncRNAs, microRNAs, and piwi-interacting RNAs are three categories of RNA that you probably wouldn't find mentioned anywhere in text books from a decade ago, but which now — along with 'traditional' non-coding RNAs such as rRNAs, tRNAs, snoRNAs etc. — probably outnumber the number of protein-coding genes in the human genome. Many parts of this paper tackle the issue of transcriptional complexity, particularly trying to address the all-important question how much of this is functional?
I found that so many parts of this paper touched on previous, current, and possible future projects in our lab. Producing an accurate catalog of genes, understanding alternative splicing, examining the relationship between mRNA and protein abundances, looking for conservation of signals between species...these are all topics that are near and dear to people in our lab.
Even if you have no interest in the importance of gene annotation — and shame on you if that is how you feel — this paper also serves as a fantastic catalog of the latest experimental techniques that can be used to capture and study genes (e.g. CAGE, ribosome profiling, polyA-seq etc).
If you have ever worked with a set of genes from a well curated organism, spare a thought for the huge amount of work that goes into trying to provide those annotations and keep them up to date. I'll leave you with the last couple of sentences from the paper...please repeat this every morning as your new mantra:
Finally, no one knows what proportion of the transcriptome is functional at the present time; therefore, the appropriate scientific position to take is to be open-minded. We thus do not claim that the annotation of the human genome is close to completion. If anything, it seems as if the hard work is just beginning.