What are the relative roles of coding DNA versus regulatory DNA thought to be in evolution?

What are the relative roles of coding DNA versus regulatory DNA thought to be in evolution?

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Intuitively, once you have the idea that some DNA is responsible for turning on and off the DNA that codes for proteins, it's possible to imagine that the regulatory DNA is actually the most important part. In the ingredients list of a recipe, you might think the coding DNA gives you the list of ingredients, but the regulatory DNA gives you the amounts of each one, plus the order in which you add them to the bowl. If that's true, then different variants of regulatory DNA should be selected for and against, and evolutionary molecular biologists ought to be tracking those variants like they track alleles of genes. But evolution always is discussed as if it's just about different gene frequencies.

Is "regulatory evolution" a thing? If so, is there an understanding of how big a thing it is? Or, if not, why not?

Yes, a simple google search reveals millions of academic citations talking about "regulatory evolution".

But it's a little over-simplistic to divide coding vs. regulatory DNA. Indeed, some coding DNA is in fact also regulatory at the level of determining gene expression in cis (a well-known example of this would be codon usage).

It is moreover incorrect to think that coding DNA products don't do gene regulation. This was recognized very early on in the ideas of "structural gene" vs. "regulatory gene". These days we would call the latter transcription factors, we don't really use the structural/regulatory terminology anymore. Transcription factors do most of the actual active work of gene regulation in trans, in collaboration of course with regulatory DNA.

So in conclusion, yes it's important and there are tons of studies that you can google if you want to investigate these problems. I would suggest reading more about cis-regulatory and trans-regulatory elements. Of course, there isn't an exact mapping of coding<-->trans and noncoding<-->cis, it's just a helpful simplification.

Let's Recall an experiment described earlier and illustrated below.

Results of this experiment provided the evidence that even very different cells of an organism contain the same genes. In fact, in any multicellular eukaryotic organism, every cell contains the same DNA (genes). Therefore, the different cell types in an organism differ not in which genes they contain, but which sets of genes they express! Looked at another way, cells differentiate when they turn on new genes and turn off old ones. Thus, gene regulation produces different sets of gene products during differentiation, leading to cells that look and function differently in the organism.

Compared to prokaryotes, many steps in eukaryotes lie between transcription of an mRNA and the accumulation of a polypeptide end product. Eleven of these steps are shown in the pathway from gene to protein below.

Theoretically, cells could turn on, turn off, speed up or slow down any of the steps in this pathway, changing the steady state concentration of a polypeptide in the cells. While regulation of any of these steps is possible, the expression of a single gene is typically controlled at only one or a few steps. A common form of gene regulation is at the level of transcription initiation, similar to transcriptional control in bacteria, in principle if not in detail.

Stickleback genomes reveal path of evolution

Fish have used pre-existing genetic variation to colonize fresh water many times.

Scientists have pinpointed mutations that may help a tiny armoured fish to evolve quickly between saltwater and freshwater forms.

Since the last ice age ended about 10,000 years ago, ocean-dwelling threespine sticklebacks have repeatedly colonized streams and lakes worldwide. In as few as ten generations — an evolutionary blink of an eye — marine sticklebacks can swap their armoured plates and defensive spines for a lighter, smoother freshwater form.

David Kingsley, an evolutionary biologist at Stanford University in California, and his colleagues have now identified the DNA differences that distinguish ocean and freshwater sticklebacks around the world. Even though the switch has occurred on multiple separate occasions, it seems to involve many of the same genetic changes each time.

To trace the key DNA differences, the researchers sequenced the entire genetic code of 21 sticklebacks from ocean and freshwater sources on three continents. The results are published in Nature today 1 .

The researchers found that, over most of the genomes, freshwater sticklebacks were most similar to their nearest ocean-dwelling neighbours. But in about 150 DNA sequences, freshwater and saltwater populations were each more like their counterparts in the same environments across the globe. These sequences included genes affecting armour growth and salt processing in the kidney.

“It’s a series of adaptations that affect many aspects of the organism: the shape of the fish, its behaviour, diet and mating preferences,” says evolutionary biologist Greg Wray at Duke University in Durham, North Carolina, who was not involved in the study.

The similarities between freshwater populations worldwide suggest that the fish do not evolve new features from scratch each time, says Kingsley. Rather, a few ocean-dwelling fish may retain ancient genetic adaptations to freshwater living that allow them to colonize new sites. The first few generations display mixed or intermediate features, but eventually the genes that allow the fish to adapt to fresh water dominate.

“On a genome-wide scale, we’ve found a whole set of regions being used over and over to adjust to new environments,“ says Kingsley. “We’re able to study the molecular basis of vertebrate evolution.”

The stickleback’s freshwater adaptations had previously been mapped to broad regions of the genome 2 . But adaptive mutations had been identified for only a few genes.

Researchers have debated about the types of mutations that could enable species to adapt to new environments. Some have championed the importance of regulatory changes — mutations that affect when and where existing genes are expressed. Others have stressed a role for coding changes, mutations that alter the proteins produced from genes.

Kingsley’s group found that about 80% of freshwater adaptations are probably situated in regulatory DNA, with the remaining 20% affecting coding DNA.

Regulatory changes could speed the stickleback’s adaptation by controlling gene expression in multiple tissues with each mutation. The study also shows that stickleback evolution is accelerated by the use of pre-existing genetic variation, instead of waiting for new, random mutations to arise, Wray explains.

“I think the paper is really nice, and I’m convinced by the data,” says Hopi Hoekstra, an evolutionary biologist at Harvard University in Cambridge, Massachusetts. However, she adds, “it could be very different — in terms of the fraction of mutations that are coding or regulatory — in an organism that had a much simpler genome, or adapted much more slowly.”

The same method could be applied to other organisms that have evolved multiple times to similar environmental changes, says Wray. Mice, for example, have evolved different fur colors for deserts, woodlands, and grasslands worldwide.“I’m guessing that we’ll see a whole series of papers,” he says.

8.2 percent of our DNA is 'functional'

Only 8.2% of human DNA is likely to be doing something important - is 'functional' - say Oxford University researchers.

This figure is very different from one given in 2012, when some scientists involved in the ENCODE (Encyclopedia of DNA Elements) project stated that 80% of our genome has some biochemical function.

That claim has been controversial, with many in the field arguing that the biochemical definition of 'function' was too broad - that just because an activity on DNA occurs, it does not necessarily have a consequence for functionality you need to demonstrate that an activity matters.

To reach their figure, the Oxford University group took advantage of the ability of evolution to discern which activities matter and which do not. They identified how much of our genome has avoided accumulating changes over 100 million years of mammalian evolution - a clear indication that this DNA matters, it has some important function that needs to be retained.

'This is in large part a matter of different definitions of what is "functional" DNA,' says joint senior author Professor Chris Pointing of the MRC Functional Genomics Unit at Oxford University. 'We don't think our figure is actually too different from what you would get looking at ENCODE's bank of data using the same definition for functional DNA.

'But this isn't just an academic argument about the nebulous word "function". These definitions matter. When sequencing the genomes of patients, if our DNA was largely functional, we'd need to pay attention to every mutation. In contrast, with only 8% being functional, we have to work out the 8% of the mutations detected that might be important. From a medical point of view, this is essential to interpreting the role of human genetic variation in disease.'

The researchers Chris Rands, Stephen Meader, Chris Ponting and Gerton Lunter report their findings in the journal PLOS Genetics. They were funded by the UK Medical Research Council and the Wellcome Trust.

The researchers used a computational approach to compare the complete DNA sequences of various mammals, from mice, guinea pigs and rabbits to dogs, horses and humans.

Dr Gerton Lunter from the Wellcome Trust Centre for Human Genetics at Oxford University, the other joint senior author, explained: 'Throughout the evolution of these species from their common ancestors, mutations arise in the DNA and natural selection counteracts these changes to keep useful DNA sequences intact.'

The scientists' idea was to look at where insertions and deletions of chunks of DNA appeared in the mammals' genomes. These could be expected to fall approximately randomly in the sequence - except where natural selection was acting to preserve functional DNA, where insertions and deletions would then lie further apart.

'We found that 8.2% of our human genome is functional,' says Dr Lunter. 'We cannot tell where every bit of the 8.2% of functional DNA is in our genomes, but our approach is largely free from assumptions or hypotheses. For example, it is not dependent on what we know about the genome or what particular experiments are used to identify biological function.'

The rest of our genome is leftover evolutionary material, parts of the genome that have undergone losses or gains in the DNA code - often called 'junk' DNA.

'We tend to have the expectation that all of our DNA must be doing something. In reality, only a small part of it is,' says Dr Chris Rands, first author of the study and a former DPhil student in the MRC Functional Genomics Unit at Oxford University.

Not all of the 8.2% is equally important, the researchers explain.

A little over 1% of human DNA accounts for the proteins that carry out almost all of the critical biological processes in the body.

The other 7% is thought to be involved in the switching on and off of genes that encode proteins - at different times, in response to various factors, and in different parts of the body. These are the control and regulation elements, and there are various different types.

'The proteins produced are virtually the same in every cell in our body from when we are born to when we die,' says Dr Rands. 'Which of them are switched on, where in the body and at what point in time, needs to be controlled - and it is the 7% that is doing this job.'

In comparing the genomes of different species, the researchers found that while the protein-coding genes are very well conserved across all mammals, there is a higher turnover of DNA sequence in the regulatory regions as this sequence is lost and gained over time.

Mammals that are more closely related have a greater proportion of their functional DNA in common.

But only 2.2% of human DNA is functional and shared with mice, for example - because of the high turnover in the regulatory DNA regions over the 80 million years of evolutionary separation between the two species.

'Regulatory DNA evolves much more dynamically that we thought,' says Dr Lunter, 'but even so, most of the changes in the genome involve junk DNA and are irrelevant.'

He explains that although there is a lot of functional DNA that isn't shared between mice and humans, we can't yet tell what is novel and explains our differences as species, and which is just a different gene-switching system that achieves the same result.

Professor Ponting agrees: 'There appears to be a lot of redundancy in how our biological processes are controlled and kept in check. It's like having lots of different switches in a room to turn the lights on. Perhaps you could do without some switches on one wall or another, but it's still the same electrical circuit.'

He adds: 'The fact that we only have 2.2% of DNA in common with mice does not show that we are so different. We are not so special. Our fundamental biology is very similar. Every mammal has approximately the same amount of functional DNA, and approximately the same distribution of functional DNA that is highly important and less important. Biologically, humans are pretty ordinary in the scheme of things, I'm afraid.

'I'm definitely not of the opinion that mice are bad model organisms for animal research. This study really doesn't address that issue,' he notes.

The study was funded by UK Medical Research Council and the Wellcome Trust.

About Oxford University's Medical Sciences Division

Oxford University's Medical Sciences Division is one of the largest biomedical research centres in Europe, with over 2,500 people involved in research and more than 2,800 students. The University is rated the best in the world for medicine, and it is home to the UK's top-ranked medical school.

From the genetic and molecular basis of disease to the latest advances in neuroscience, Oxford is at the forefront of medical research. It has one of the largest clinical trial portfolios in the UK and great expertise in taking discoveries from the lab into the clinic. Partnerships with the local NHS Trusts enable patients to benefit from close links between medical research and healthcare delivery.

A great strength of Oxford medicine is its long-standing network of clinical research units in Asia and Africa, enabling world-leading research on the most pressing global health challenges such as malaria, TB, HIV/AIDS and flu. Oxford is also renowned for its large-scale studies which examine the role of factors such as smoking, alcohol and diet on cancer, heart disease and other conditions.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

Gill Slits—Our Greatest Shared Innovation?

Acorn worms range in size from 3 ½ inches to over 8 feet, and though most species live in shallow brackish water, some live at the bottom of the sea. The acorn worm pokes its acorn-shaped proboscis around in sand or mud, stirring up debris. It directs the debris-laden water into its mouth using cilia and collects not only oxygen but also bacteria, algae, and other nutritious edible organics by filtering it through its pharyngeal slits, or gill slits. An acorn worm can have hundreds of gill slits, equipping it for a very efficient form of filter feeding.

“What’s so great about having gill slits is the large volumes of water you can put through the animal to collect food they allow high-throughput filtering and feeding, whereas other animals take one gulp, deal with the food in that one gulp, expel the water out the mouth and take another gulp,” Rokhsar explains.12 But the significance of gill slits in this invertebrate goes far beyond these observable advantages to the acorn worm and to an evolutionarily minded scientist speaks volumes about the unobservable past history of many other kinds of animals, and even humans.

Evolutionists believe that gill slits evolved in animals like acorn worms to make filter feeding efficient and then later evolved into oxygen-capturing gills and even later into various parts of our throats that have no direct oxygen-gathering roles at all. As Rokhsar says, “The presence of these slits in acorn worms and vertebrates tells us that our last common ancestor also had them, and was likely a filter feeder like acorn worms today. The pharyngeal area of these worms and of all deuterostomes is their most significant shared innovation.”13

Neither humans nor other mammals have gills at any point in their development. Human embryos have several swellings along the neck, little mounds of cells that differentiate into parts of the jaw, face, ear, middle ear bones, thyroid and parathyroid glands, and voice box. Based on superficial appearance and evolutionary thinking, these folds and swellings were once called gill slits, gill pouches, gill arches, or branchial arches. Many embryology textbooks have abandoned this deceptive terminology in favor of pharyngeal arches—meaning “arches in the region of the throat.” But the authors believe genetic similarities confirm a gill slit origin for them. That’s why Rokhsar refers to the acorn worm’s gill slits as our “most significant shared innovation.”


Warren, W. C. et al. Nature 453, 175–183 (2008).

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Zhan, S., Merlin, C., Boore, J. L. & Reppert, S. M. Cell 147, 1171–1185 (2011).

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Cis-regulatory sequences, such as enhancers and promoters, control development and physiology by regulating gene expression. Mutations that affect the function of these sequences contribute to phenotypic diversity within and between species. With many case studies implicating divergent cis-regulatory activity in phenotypic evolution, researchers have recently begun to elucidate the genetic and molecular mechanisms that are responsible for cis-regulatory divergence. Approaches include detailed functional analysis of individual cis-regulatory elements and comparing mechanisms of gene regulation among species using the latest genomic tools. Despite the limited number of mechanistic studies published to date, this work shows how cis-regulatory activity can diverge and how studies of cis-regulatory divergence can address long-standing questions about the genetic mechanisms of phenotypic evolution.


We wish to thank the sequencing projects that have made their data publicly accessible, and in particular we thank Paul Cliften and Manolis Kellis for advance access to the data. Betty Gilbert and John Taylor provided genomic DNA for N. crassa strain, Takao Kasuga and Louise Glass provided N. crassa microarray data, and Dennis Wall provided assistance in the ortholog assignments, for which we are grateful. We also wish to thank Michael Kobor, Joe DeRisi, David Nix, and DYC for yeast strains and plasmids Gary Stormo, Dan Pollard, Justin Fay, and the members of the Eisen lab for helpful suggestions and critical reading of the manuscript Marv Wickens for insightful advice on searching for 3′UTR elements and Eric Kelley for much computer help. APG was supported by a National Science Foundation postdoctoral fellowship in Biological Informatics, MB was supported by National Institutes of Health SBDR grant #5P01CA092584-03, and MBE is a Pew Scholar in the Biomedical Sciences. This work was carried out under the United States Department of Energy contract ED-AC03-76SF00098.

Chimps and Humans Redux

The morphological differences between modern humans, human ancestors, and the great apes are the product of evolutionary changes in development. I have argued elsewhere [60] that the evolution of complex traits such as brain size, craniofacial morphology, cortical speech and language areas, hand and digit form, dentition, and body skeletal morphology must have a highly polygenic and largely regulatory basis. The great and difficult challenge, with the genome sequences of humans, chimps, and other mammals now available, is to map changes in genes to changes in traits. Many approaches are being taken, and a few intriguing associations of candidate genes and the evolution of particular traits have been discovered, such as the FOXP2 gene and the evolution of speech [61], and the MYH16 muscle-specific myosin pseudogene and the evolutionary reduction of the masticatory apparatus [62]. My concern here is not whether these specific associations did or did not play a role in human evolution rather, my concern is the exclusive focus, by choice or by necessity, on the evolution of coding sequences in these and more genome-wide population genetic surveys of chimp–human differences [63].

There exists some disconnect between what studies in model species have underscored—the ability or sufficiency of regulatory sequences to account for the evolution of physical traits—and which models of evolution are implicitly or explicitly being tested when only coding sequence divergence is considered. Two stories concerning the FOXP2 gene illustrate the dramatically different conclusions one might draw, depending upon the methodologies and assumptions applied.

The human FOXP2 gene encodes a transcription factor, and mutations at the locus were discovered to be associated with a speech and language disorder [64]. The human FOXP2 protein differs from the gorilla and chimp protein at just two residues, raising the possibility that the two replacements that occurred in the human lineage might be significant to the evolution of speech and language. Furthermore, population genetic analysis indicates that the FOXP2 locus has undergone a selective sweep within the last 200,000 years of human evolution [61]. While it would certainly be convenient if the two changes in the FOXP2 protein were functional, the additional hypothesis must be considered that functional regulatory changes might have occurred at the FOXP2 locus. In weighing alternative hypotheses of FOXP2 or any gene's potential involvement in the evolution of form (or neural circuitry), we should ask the following questions. (i) Is the gene product used in multiple tissues? (ii) Are mutations in the coding sequence known or likely to be pleiotropic? (iii) Does the locus contain multiple cis-regulatory elements?

If the answers are yes to all of these questions, then regulatory sequence evolution is the more likely mode of evolution than coding sequence evolution. For FOXP2, this appears to be the case. FOXP2 is expressed at multiple sites, not just in the brain, but in the lungs, heart, and gut as well [64,65]. Patients with the FOXP2 mutation do have multiple neural deficits [66]. And, because FOXP2 is expressed in different organs and different regions of the brain, it is certain to possess multiple regulatory elements. Furthermore, it is an enormous, complex locus, spanning some 267 kb. Based upon a simple average base pair divergence of 1.2%, there should be over 2,000 nucleotide differences between chimps and humans in this span. Because there is much more potential for functional divergence in non-coding sequences, there is no specific reason to favor coding sequence divergence over regulatory sequence divergence at FOXP2.

The discovery of FOXP2 and its association with human speech has inspired consideration of the potential role of FOXP2 in the evolution of vocalization in other animals, and here is where strikingly different conclusions were reached depending upon the hypothesis tested and the methodology used. Song learning has evolved in three orders of birds. There are some behavioral and neural similarities between bird song and human speech in terms of their being learned at critical periods and the involvement of auditory and motor centers and specialized brain centers. A standard comparative analysis of the FOXP2 coding sequences of humans and song-learning and non-learning birds did not reveal any amino acid substitutions that were shared between song-learning birds and humans, nor any fixed differences between song-learning and non-learning birds. The study concluded there was “no evidence for its [FOXP2] role during the evolution of vocal learning in nonhuman animals” [67].

In great contrast, when FOXP2 mRNA and protein expression in the developing and adult brains of a variety of song-learners and non-learners were examined, a striking increase in FOXP2 expression was observed in Area X, a center necessary for vocal learning that is absent from non-learners [68] (Figure 3A–3C). This increase occurs in zebra finches over the developmental period when vocal learning occurs. Furthermore, in adult canaries, seasonal changes in FOXP2 expression were observed in Area X, associated with changes in the stability of the bird's song (Figure 3D–3F). Thus, remarkable changes in the regulation of FOXP2, but not the protein sequence, are correlated with the development and evolution of vocal learning in birds. These changes could arise through the evolution of FOXP2 cis-regulatory sequences, or of the regulatory or coding sequences of transcription factors that control FOXP2.

Author information


Department of Computational Biology, School of Medicine, University of Pittsburgh, Fifth Avenue, Pittsburgh, PA, 15260, USA

Shaun Mahony & Panayiotis V Benos

Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, DeSoto Street, Pittsburgh, PA, 15261, USA

David L Corcoran, Eleanor Feingold & Panayiotis V Benos

Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, DeSoto Street, Pittsburgh, PA, 15261, USA

University of Pittsburgh Cancer Institute, School of Medicine, University of Pittsburgh, Centre Avenue, Pittsburgh, PA, 15232, USA


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