Newly discovered family of genes played key role in human brain evolution
Errors by the molecular machinery involved in DNA replication, repair or recombination can lead to gene duplication, a well-established driver of evolution. The duplicated genes can either be active, or truncated and inactive, what we call pseudogenes (Note that pseudogenes can arise by other mechanisms too, like a loss-of-function mutation in a proper gene). The human genome, for example, is estimated to have around 10000 pseudogenes (and approximately 20000 "normal" genes for comparison). Once locked in the genome, pseudogenes and duplicated functioning genes are fertile ground for evolution: the original, intact gene can carry on its perhaps essential function but the duplicate is free for natural selection to select mutated versions of, versions which may turn into a very different new gene as time goes by. In two new studies published in the Cell journal, scientists describe how one such family of duplicated genes may have driven the evolution of the human brain.
The NOTCH2NL gene family regulates brain tissue expansion during development
Primates stand out from most other mammals in that our brain size exceeds what would be expected relative to our body mass. And even within our group, one of the characteristics separating us from our non-human primate cousins is, again, our brain size (see figure below). In the span of two million years our brain tripled in size from australopithecines (averaging around 500 ml) to Neanderthals and modern humans (1500 ml and 1300 ml, respectively). In the two new studies—led independently by Dr David Haussler at the University of California Santa Cruz and Dr Pierre Vanderhaeghen at the Free University of Brussels—researchers have characterized the NOTCH2NL gene family, finding it’s involved in the expansion of cortical neurons during development.
Cortical neurons are the key constituents of the neocortex, the newest area of the brain in evolutionary terms, having evolved around 200 million years ago in the earliest mammals. The neocortex is involved in, among other things, somatosensory perception, voluntary motor control, processing of visual information and the higher cognitive functions we associate with humans such as language, reasoning and planning.
After identifying NOTCH2NL as a human-specific gene expressed during development, the team led by Dr Vanderhaeghen found that inserting said gene into mouse neural tissue increased the number of cortical stem cell progenitors, the same thing they found in human tissue cultures. “From one stem cell, you can either regenerate two progenitor cells, generate two neurons, or generate one progenitor stem cell and one neuron,” Dr Vanderhaeghen explains. “What NOTCH2NL does is bias that decision in a slight way towards regenerating progenitors, which can later go on to make more neurons. It's a small early effect with large late consequences, as often happens with evolution."
The team led by Dr Haussler independently identified NOTCH2NL also as a human-specific gene and conducted similar experiments. One of their key findings was that deleting NOTCH2NL from human neural tissue cultures results in stem cells differentiating faster into cortical cells, leading to smaller patches of tissue compared to control tissue cultures.
The NOTCH2NL gene family evolved by multiple duplication events
By analysing the previously published genomes of archaic humans (including extinct species such as Neanderthals), the teams led by Dr Haussler also reconstructed NOTCH2NL evolutionary history. A gene known as NOTCH2 first got duplicated around 10 million years ago in the ancestor to all African apes (modern gorillas, chimps and humans) but remained a non-functional pseudogene until around 4 million years ago. It was then that a new mutation event in the common ancestor to all humans turned the pseudogene on. But that wasn’t the end of the story, the new gene would go on to be duplicated again not once, but twice (the three genes are now known as NOTCH2NLA, NOTCH2NLB and NOTCH2NLC), all three variants being confirmed in modern humans and Neanderthals too.
Size is not all that matters
While it can be generally assumed that bigger brains mean more neurons, and more neurons mean more computational power, it's not all about size. Brain architecture also comes into play. For example, analysis of Old World monkeys' fossils has revealed the appearance of more complex neocortex structures before increases in brain size and bonobos have very similar brain sizes to chimps but differences in brain architecture and behaviour. In fact, it stands to reason that as much as bigger brains may have had an evolutionary advantage, there was only so much that the pelvis and vaginal canal could give. This is why around 3 million years ago our ancestors evolved cranial bones that are still not fused at birth, an adaptation that helps the disproportionately big skull of our babies to be more plastic and squeeze through the birth canal.
But natural selection didn't stop there, favouring other ways to increase human intelligence independent of brain size. One strategy was to increase surface area relative to volume, which is why our neocortex has so many and pronounced folds compared to other mammals, allowing more of the neocortex's particular six-layered architecture to fit per unit of volume. Furthermore, bigger brains means more energy consumption (modern human brains require around 20% of our caloric intake but make up only around 2% of our bodymass) which would have severely hindered the fitness of our species before supermarkets and junk food. This is why we believe the taming of fire, and cooking in particular, may have helped us evolve big brains. Cooking food made calories from the meat we hunted more readily available to be absorbed, in essence starting the digestive process outside of our bodies, which not only meant we could then extract more energy per unit of food consumed but also allowed us more time free from hunting and foraging.
Consequences for health too
The new study has also linked the NOTCH2NL gene family to neurodevelopmental disorders. The presence of duplications or deletions in the same area of chromosome 1 that carries all three NOTCH2NL genes had been linked in the past to microcephaly, macrocephaly, schizophrenia and autism. For example, the authors note that out of nine cases consistent with deletion of NOTCH2NLA and/or NOTCH2NLB, all had microcephaly, while in two cases consistent with duplication of the same genes, both patients had macrocephaly.
Further reading and sources:
"Trio of genes supercharged human brain evolution" at Science News
"The Human Fossil Record: Brain Endocasts—The Paleoneurological Evidence" 2005, Wiley-Blackwell
"A Companion to Paleoanthropology" 2013, Wiley-Blackwell