Control Altered by Deletion – is lost DNA behind our bigger brains and spineless penises?

Where genes are concerned, less is sometimes more. Cory McLean, Phillip Reno and Alex Pollen from Stanford University have found many stretches of DNA that are missing in our genomes but are otherwise shared by chimps and other mammals. They think that the loss of these sequences coincided with the evolution of our larger brains, and the loss of features like whiskers and penis spines. Our genome’s loss has been our gain.

The trio found 583 stretches of DNA in the chimp genome that are shared with a variety of different mammals, except for humans. They called these sequences hCONDELs (short for “highly conserved deletions”). Except for one, they are all “enhancers”, stretches of DNA that control other genes, but aren’t genes themselves. They are overlords that have managed the activity of genes throughout the mammal family tree, but that abruptly abandoned their posts in the human branch.

The team found that hCONDELs cluster next to two main groups of genes – one that affects our neurons, and another that controls how we respond to hormones like testosterone or oestrogen. “We chose to follow up on one gene in each of these two categories,” says Daivd Kingsley, who led the study.

One of the hCONDELs affects a gene called the androgen receptor (AR), which produces a protein of the same name. Think of the AR protein as a machine – it’s switched on by hormones like testosterone, and it drives the development of male physical features, everything from penises to facial hair. The AR gene contains the instructions for making this machine, and the enhancers tell the body where and when to build it.

In chimps and mice, one of these enhancers instructs an embryo to build the AR protein in specific parts of the face and genitals. As the embryo grows up, it develops facial whiskers and spines on its penis. Because we don’t have this enhancer, we don’t build AR in the same places, and we never develop these features that are normally found in other mammals.

We might have facial hair, but we lack the sensitive whiskers that many other mammals use. That’s understandable for vision is our main sense. But why did we lose penis spines, and why do other animals have them in the first place? The spines aren’t there to inflict injuries (as those of many insects are). They’re hair-like and sensitive. Without them, sex is probably a less stimulating activity for human men than for other male mammals, and it takes relatively longer.

It’s possible that by evolving to have less arousing sex, lengthy human intercourse creates a stronger social bond than chimp quickies. “Penile spines are often found in species with competitive mating systems, where multiple males [aggressively] compete for fertilization success,” says Kingsley. “Humans have evolved a more monogamous, long-term bonding system, which involves many changes. “

In both these cases – whiskers and spines – losing an enhancer meant losing a body part. But that’s not always the case as McLean, Reno and Pollen found when they looked at a second gene called GADD45G. Like AR, this gene is also missing an enhancer in the human genome.

In mice and chimps, GADD45G is active in the subventricular zone, a part of the brain where new neurons are created. It acts as a barrier that restrains the brain from producing too many neurons. By losing one of its enhancers, our ancestors lifted these restraints and that could have contributed to the evolution of our big brains. “Loss of DNA could lead to expansion of some human structures,” says Kingsley.

Shyam Prabhakar, who also works on enhancer evolution, is impressed by the study, but not quite  convinced about the effect of the missing enhancers. To him, the big question is whether the loss of these sequences benefited our ancestors – whether they were adaptive. He has good reason to ask – in 2008, he showed that an enhancer called HACNS1 may have contributed to the uniquely human aspects of our thumbs, wrists, ankles and feet. Since we diverged from chimps, HACNS1 has changed more rapidly than most other parts of the human genome. The speedy nature of this change provides strong evidence that it was adaptive.

The case is more ambiguous for the lost enhancers that McLean, Reno and Pollen identified. It’s possible, for example, that the loss of the AR enhancer drove the loss of penile spines. Maybe our ancestors has already lost the spines because of changes elsewhere in the genome, allowing them to jettison the AR enhancer without any ill effect. Maybe things happened gradually, and the enhancer’s disappearance was just one of many events that de-spined our genitals.

The only way to tell the difference between these possibilities is to remove the enhancers in mice and see what happens. “If the knockouts result in reduced penile spines and bigger brains, that would be wonderful,” says Prabhakar. That would also tell them if they’ve matched up the enhancers with the right genes – after all, these sequences can often sit a long way off from the genes that they control.

Meanwhile, McLean, Reno and Pollen have a long list of missing enhancers to work through. “We suspect other deletions on the list may be related to other human-specific traits (skeletal modifications, bipedalism, hairlessness, etc), and are beginning experiments to test some of these possibilities,” says Kingsley. It’s a fascinating concept – some of our most human traits could lie, not in the genes we still have, but in the missing shadows of their former companions.

This research has the potential to tell us about more than just the origins of human features. Prabhakar wants researchers to look at genetic changes that separate primates from other mammals.“Most of the time, biologists try to understand humans by studying mice, not chimpanzees,” he explains. “So from the standpoint of biomedical research, the fact that we are not mice is much more problematic than the fact that we are not chimpanzees.” We need to understand the parts of our genome that define us as primates, rather than specifically as humans. “This treasure hunt is only just beginning.”

Reference: McLean, Reno, Pollen et al. 2011. Human-specific loss of regulatory DNA and the evolution of human-specific traits. Nature http://dx.doi.org/10.1038/nature09774

More on the genetics of human evolution:

• Did a gene enhancer humanise our thumbs?
• RNA gene separates human brains from chimpanzees
• The secret history of X and Z – how sex chromosomes from humans and chickens found common ground
• Revisiting FOXP2 and the origins of language
• Scientists “humanise” Foxp2 gene in mice to probe origins of human language
• Elephants and humans evolved similar solutions to problems of gas-guzzling brains
• Genetic neoteny – how delayed genes separate human brains from chimps
• A burst of DNA duplication in the ancestor of humans, chimps and gorillas