DNA: Nature Celebrates Ignorance

Some freelance science writer named Philip Ball has published an article in the April 25, 2013 issue of Nature: Celebrate the Unknowns.

The main premise of the article is revealed in the short blurb under the title: "On the 60th anniversary of the double helix, we should admit that we don't fully understand how evolution works at the molecular level, suggests Philip Ball."

What nonsense! We understand a great deal about how evolution works at the molecular level. Perhaps Philip Ball meant to say that we don't understand the historical details of how a particular genome evolved, but even that's misleading.

I've commented before on articles written by Philip Ball. In the past, he appeared to be in competition with Elizabeth Pennisi of Science for some kind of award for misunderstanding the human genome.

SEED and the Central Dogma of Molecular Biology - I Take Back My Praise
Shoddy But Not "Junk"?

Let's look at what the article says ...

The more complex picture now emerging raises difficult questions that this outsider knows he can barely discern. But I can tell that the usual tidy tale of how 'DNA makes RNA makes protein' is sanitized to the point of distortion. Instead of occasional, muted confessions from genomics boosters and popularizers of evolution that the story has turned out to be a little more complex, there should be a bolder admission — indeed a celebration — of the known unknowns.

That little tidy tale was discarded forty years ago by all knowledgeable scientists. We've known for at least that long that many functional DNA sequences aren't even transcribed (e.g. origins of replication, centromeres). We've known for even longer that many genes make functional RNAs instead of proteins. There was even a Nobel Prize awarded in 1989 for some of these RNAs [Sidney Altman] [Tom Cech]. We've known about regulatory sequences for more than four decades. It's in all the textbooks.

Of course there are still unknowns, but I think we have a pretty good understanding of genes and gene expression and a pretty good understanding of the composition of our genome [see What's in Your Genome?].

A student referring to textbook discussions of genetics and evolution could be forgiven for thinking that the 'central dogma' devised by Crick and others in the 1960s — in which information flows in a linear, traceable fashion from DNA sequence to messenger RNA to protein, to manifest finally as phenotype — remains the solid foundation of the genomic revolution. In fact, it is beginning to look more like a casualty of it.

For the real meaning of the Central Dogma see: The Central Dogma Dies Again! (not). The original Sequence Hypothesis (DNA --> RNA --> protein) only applies to protein-encoding genes. No molecular biologist believes that this linear pathway explains all there is to gene expression and genome function. They haven't thought that for at least 30 years—longer if they are as old as me.

Although it remains beyond serious doubt that Darwinian natural selection drives much, perhaps most, evolutionary change, it is often unclear at which phenotypic level selection operates, and particularly how it plays out at the molecular level.

Most genetic change is due to the fixation of neutral alleles by random genetic drift. We've known that since the 1960s. We have a good understanding of genome evolution due to population geneticists like Michael Lynch. Anyone who wants to understand (or write about) this issue should have read his book. Philip Ball mentions Michael Lynch below but at this point in his article he seems to have forgotten it.

You don't have to agree with Lynch's view on the nonadaptive evolution of complexity but you do have to be aware of it. It will keep you from making foolish statements in Nature.

Philip Ball next mentions the ENCODE project, pointing out that pervasive transcription ended up "challenging the old idea that much of the genome is junk." To his credit, he shows that he is aware of the controversy ...

Some geneticists and evolutionary biologists say that all this extra transcription may simply be noise, irrelevant to function and evolution. But, drawing on the fact that regulatory roles have been pinned to some of the non-coding RNA transcripts discovered in pilot projects, the ENCODE team argues that at least some of this transcription could provide a reservoir of molecules with regulatory functions — in other words, a pool of potentially 'useful' variation. ENCODE researchers even propose, to the consternation of some, that the transcript should be considered the basic unit of inheritance, with 'gene' denoting not a piece of DNA but a higher-order concept pertaining to all the transcripts that contribute to a given phenotypic trait3.

Right. We know about regulatory RNA ... been in the textbooks since about 1980. No, we don't need to redefine a gene.

The ENCODE findings join several other discoveries in unsettling old assumptions. For example, epigenetic molecular alterations to DNA, such as the addition of a methyl group, can affect the activity of genes without altering their nucleotide sequences. Many of these regulatory chemical markers are inherited, including some that govern susceptibility to diabetes and cardiovascular disease. Genes can also be regulated by the spatial organization of the chromosomes, in turn affected by epigenetic markers. Although such effects have long been known, their prevalence may be much greater than previously thought.

Like the man says, nothing new here. And I don't think control of gene expression by chromatin remodeling is any more prevalent than we thought back in the 1970s when we assumed that almost every gene was controlled in this manner.

Another source of ambiguity in the genotype–phenotype relationship comes from the way in which many genes operate in complex networks. For example, many differently structured gene networks might result in the same trait or phenotype. Also, new phenotypes that are viable and potentially superior may be more likely to emerge through tweaks to regulatory networks than through more risky alterations to protein-coding sequences. In a sense this is still natural selection pulling out the best from a bunch of random mutations, but not at the level of the DNA sequence itself.

Is there any credible biochemist or molecular biologist who doesn't know that mutations in regulatory sequences can have big effects? I don't think so. Are there any science writers who think this is new stuff? Apparently there are. Why don't they buy a textbook?

Researchers are also still not agreed on whether natural selection is the dominant driver of genetic change at the molecular level. Evolutionary geneticist Michael Lynch of Indiana University Bloomington has shown through modelling that random genetic drift can play a major part in the evolution of genomic features, for example the scattering of non-coding sections, called introns, through protein-coding sequences. He has also shown that rather than enhancing fitness, natural selection can generate a redundant accumulation of molecular 'defences', such as systems that detect folding problems in proteins. At best, this is burdensome. At worst, it can be catastrophic.

In short, the current picture of how and where evolution operates, and how this shapes genomes, is something of a mess. That should not be a criticism, but rather a vote of confidence in the healthy, dynamic state of molecular and evolutionary biology.

Hmmm ... that's not bad, although I wish he would place more emphasis on what we do know and more emphasis on the fact that many scientists, including ENCODE workers, are not familiar with modern evolutionary theory.

Barely a whisper of this vibrant debate reaches the public.

Hmmm ... isn't that interesting? Why have science writers been so negligent about informing the public? Isn't that their job?

The answer is that almost all science writers have been unaware of the "vibrant debate" and most of them are still in the dark. That explains why the public hasn't heard a whisper.

There may also be anxiety that admitting any uncertainty about the mechanisms of evolution will be exploited by those who seek to undermine it. Certainly, popular accounts of epigenetics and the ENCODE results have been much more coy about the evolutionary implications than the developmental ones. But we are grown-up enough to be told about the doubts, debates and discussions that are leaving the putative 'age of the genome' with more questions than answers. Tidying up the story bowdlerizes the science and creates straw men for its detractors. Simplistic portrayals of evolution encourage equally simplistic demolitions.

The mechanisms of evolution have been known for decades. There's very little uncertainty among informed evolutionary biologists. I agree that it's about time we inform the public and other scientists about what happened to evolutionary theory in the 1970s.

Science writers can help but they first have to educate themselves. They could start by learning about the Central Dogma of Molecular Biology and how modern scientists really thought about genes and gene expression in the 20th century.

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