John Mattick still claims that most lncRNAs are functional

Most of the human genome is transcribed at some time or another in some tissue or another. The phenomenon is now known as pervasive transcription. Scientists have known about it for almost half a century.

At first the phenomenon seemed really puzzling since it was known that coding regions accounted for less than 1% of the genome and genetic load arguments suggested that only a small percentage of the genome could be functional. It was also known that more than half the genome consists of repetitive sequences that we now know are bits and pieces of defective transposons. It seemed unlikely back then that transcripts of defective transposons could be functional.

Part of the problem was solved with the discovery of RNA processing, especially splicing. It soon became apparent (by the early 1980s) that a typical protein coding gene was stretched out over 37,000 bp of which only 1300 bp were coding region. The rest was introns and intron sequences appeared to be mostly junk.

Dan Graur explains junk DNA

If you want to be a serious participant in the debate over junk DNA then you should watch this video. Dan Graur presents the standard arguments for junk DNA—most of which have been around for decades. He also destroys the main arguments against junk DNA. You are entitled to choose sides in this debate but you are not entitled to pose as an authority unless you know the best arguments from BOTH sides. It is not sufficient to just quote evidence for function as support for your bias. You must also refute the evidence for junk. You have to show why it is wrong or misleading.

---

Hat Tip: PZ Myers

ENCODE workshop discusses function in 2015

A reader directed me to a 2015 ENCODE workshop with online videos of all the presentations [From Genome Function to Biomedical Insight: ENCODE and Beyond]. The workshop was sponsored by the National Human Genome Research Institute in Bethesda, Md (USA). The purpose of the workshop was ...

1. Discuss the scientific questions and opportunities for better understanding genome function and applying that knowledge to basic biological questions and disease studies through large-scale genomics studies.
2. Consider options for future NHGRI projects that would address these questions and opportunities.

The main controversy concerning the human genome is how much of it is junk DNA with no function. Since the purpose of ENCODE is to understand genome function, I expected a lively discussion about how to distinguish between functional elements and spurious nonfunctional elements.

The pervasive transcription controversy: 2002

I'm working on a chapter about pervasive transcription and how it relates to the junk DNA debate. I found a short review in Nature from 2002 so I decided to see how much progress we've made in the past 15 years.

Most of our genome is transcribed at some time or another in some tissue. That's a fact we've known about since the late 1960s (King and Jukes, 1969). We didn't know it back then, but it turns out that a lot of that transcription is introns. In fact, the observation of abundant transcription led to the discovery of introns. We have about 20,000 protein-coding genes and the average gene is 37.2 kb in length. Thus, the total amount of the genome devoted to these genes is about 23%. That's the amount that's transcribed to produce primary transcripts and mRNA. There are about 5000 noncoding genes that contribute another 2% so genes occupy about 25% of our genome.

Using conservation to determine whether splice variants are functional

We've been having a discussion about function and how to recognize it. This is important when it comes to determining how much junk is in our genome [see Restarting the function wars (The Function Wars Part V)]. There doesn't seem to be any consensus on how to define "function" although there's general agreement on using sequence conservation as a first step. If some sequence under investigation is conserved in other species then that's a good sign that it's under negative selection and has a biological function. What if it's not conserved? Does that rule out function? The correct answer is "no" because one can always come up with explanations/excuses for such an observation. We discussed the example of de novo genes, which, by definition, are not conserved.

Let's look at another example: splice variants. Splice variants are different forms of RNA produced from the same gene. If they are biologically relevant then they will produce different forms of the protein (for protein-coding genes). This is an example of alternative splicing if, and only if, relevance has been proven.

How many lncRNAs are functional: can sequence comparisons tell us the answer?

A large percentage of the human genome is transcribed at some time or another during development. The vast majority of those transcripts are very rare transcripts that look very much like spurious products of accidental transcription initiation at sequences resembling true promoters. They have been rejected by genome annotators. They do not define genes. They are junk RNA. Pervasive transcription does not mean that most of the genome is functional.

Among the transcripts is a class called long non-coding RNAs or lncRNAs. These are usually defined as capped and polyadenylated transcripts longer than 200 nucleotides. Many of them are processed by splicing. They look a lot like mRNA except they don't encode any polypeptides.¹

We don't know how many of these RNAs exist because different labs use different criteria to describe them. Some databases exclude low abundance lncRNAs and some include non-polyadenylated RNAs. There is general agreement that they number in the tens of thousands. A common number in the scientific literature is 60,000 lncRNAs.