How to Make a Scientific Argument

The debate over the amount of junk in our genome is a genuine scientific debate. There are legitimate scientific points of view on both sides although the weight of evidence and logic is tilting heavily in favor of junk DNA. It looks more and more like most (~90%) of our genome is junk.

The problem with the debate is that the scientific literature is full of papers attacking junk DNA while there are very few papers promoting it. This is partly because there haven't been any new discoveries in favor of junk DNA. On the other hand, there have been quite a few discoveries showing that some small part of the genome that was thought to be junk might have a function. Even though these discoveries make an insignificant contribution to the big picture, they are often blown up out of all proportion and promoted as an end to junk DNA.

A recent paper in PLoS Genetics illustrates the problem.

Hangauer, M.J., Vaughn, I.W. and McManus, M.T. (2013) Pervasive Transcription of the Human Genome Produces Thousands of Previously Unidentified Long Intergenic Noncoding RNAs. PLoS Genetics 9, e1003569. [doi: 10.1371/journal.pgen.1003569]

Abstract
Much of the human genome is composed of intergenic sequence, the regions between genes. Intergenic sequence was once thought to be transcriptionally silent “junk DNA,” but it has recently become apparent that intergenic regions can be transcribed. However, the scope, nature, and identity of this intergenic transcription remain unknown. Here, by analyzing a large set of RNA-seq data, we found that >85% of the genome is transcribed, allowing us to generate a comprehensive catalog of an important class of intergenic transcripts: long intergenic noncoding RNAs (lincRNAs). We found that the genome encodes far more lincRNAs than previously known. A key question in the field is whether these intergenic transcripts are functional or transcriptional noise. We found that the lincRNAs we identified have many characteristics that are inconsistent with noise, including specific regulation of their expression, the presence of conserved sequence and evidence for regulated processing. Furthermore, these lincRNAs are strongly enriched with intergenic sequences that were previously known to be functional in human traits and diseases. This study provides an essential framework from which the functional elements in intergenic regions can be identified and characterized, facilitating future efforts toward understanding the roles of intergenic transcription in human health and disease.

Even if every one of their presumed lincRNAs has a biological function, it would only account for 2% of the genome. This hardly spells the end of the junk DNA debate.

Here's how the authors of this paper begin the introduction ...

A large fraction of the human genome consists of intergenic sequence. Once referred to as “junk DNA”, it is now clear that functional elements exist in intergenic regions. In fact, genome wide association studies have revealed that approximately half of all disease and trait-associated genomic regions are intergenic [1]. While some of these regions may function solely as DNA elements, it is now known that intergenic regions can be transcribed [2]–[7], and a growing list of functional noncoding RNA genes within intergenic regions has emerged [8].

I believe that this is very deceptive. It doesn't take into account the total evidence in the scientific literature and it ignores history. It seems to me that part of the problem with this debate is that we have become very lax in our standards of scientific discourse.

I'm quite fond of a quotation by Richard Feynman. He makes the same point made by dozens of other respectable scientists.

Details that could throw doubt on your interpretation must be given, if you know them. You must do the best you can — if you know anything at all wrong, or possibly wrong — to explain it. If you make a theory, for example, and advertise it, or put it out, then you must also put down all the facts that disagree with it, as well as those that agree with it.

Richard Feynman (1918-1988) "Cargo Cult Science" in Surely You're Joking, Mr. Feynman!

Let me restate Feynman's point in the context of the junk DNA debate. If you are going to argue for or against the presence of junk DNA then you owe it to your audience to present both sides of the issue. It's not good science to ignore all the evidence against your idea and only present the evidence that supports it.

This used to be the standard in scientific publications but, somehow, it isn't any more. Here's how that first paragraph should have been written. (I exaggerate a bit in order to make my point.)

The human genome contains about 25,000 known genes¹ that make up about 25% of the genome. Only a small fraction of this is present in mature functional RNAs of various sorts—the rest is mostly introns and most intron RNA is discarded during processing.

Intergenic regions have a variety of functions, most of which have been known for three or four decades. They include regulatory sequences, centromeres, telomeres, SARs, and origins of replication. No reputable group of scientists has ever claimed that all integenic DNA is junk in spite of the fact that this myth is widely promoted in the scientific literature.

Known functional regions of the genome make up less than 10% of the total and much of the rest is thought to be junk DNA—this includes most of the introns. The evidence is based on decades of work on genetic load, the C-value paradox (genome comparisons), modern evolutionary theory (population genetics), and the human genome sequence showing that 50% of our genome is composed of broken transposons and pseudogenes.

It has been known since the early 1970s that much of our genome is transcribed at some time or another during development or in some tissues. This "pervasive transcription" appears to be transcriptional noise based on the fact that the transcripts are very rare and on the known frequency of spurious binding of transcription factors and RNA polymerase. Such an interpretation is consistent with the evidence that most of our genome is junk.

However, the function of most of these low-level transcripts is still an open question and it is possible that they represent functional RNAs in which case a large fraction our genome may not be junk after all. If true, it would mean that the human genome contains tens of thousands of genes that have remained completely undetected in spite of decades of work in biochemistry and molecular biology labs over a period of forty years or more. This extraordinary discovery would revolutionize our understanding of gene expression.

We investigated this question by focusing our attention on possible lincRNAs that are present in at least one copy per cell and show signs of conservation and regulation. We confirmed that >85% of the genome is transcribed but discovered that only about 2% produces lincRNAs that meet our minimal criteria for potential function. Our results suggest that most pervasive transcription does not produce functional RNAs supporting the idea that it is transcriptional noise and that most of the genome is junk.

There, that's much better.

---

1. This includes many known genes that encode functional RNA such as ribosomal RNA, transfer RNA, and various other RNAs including regulatory RNAs, spliceosomal RNAs, microRNAs etc. etc.