The great brain gain
(appeared in Feb 2015)

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Tiny differences in an obscure part of the genetic code may have been the doorway for humans to get ahead of other primates, says S.Ananthanarayanan.

The early primates started walking on two legs some five to seven million years ago, after the earth became a cooler and drier planet, and forests began to give place to grasslands. This freed the primates' hands for manipulating tools and there is evidence to show that brain size grew rapidly, from the chimpanzee size of less than 400cc to about 600cc in the early humans of about two million years ago and the 1,300 cc of the present day humans.

Along with greater brain size, humans have evolved to display dramatically superior intelligence, with the capacity for language, abstraction, and social integration and organization not seen in other species. Although there are differences in the genes of humans and chimpanzees, like in the parts that control speech development or hearing, which can be linked to selection through language related behavior, the main genetic heritage is almost the same. How then does the human brain grow so much more than that of the chimp is a question of great interest.

J. Lomax Boyd, Stephanie L. Skove, Jeremy Rouanet, Louis-Jan Pilaz, Tristan Bepler, Raluca Gordan, Gregory A. Wray, Debra L. Silver, at Duke University, North Carolina report in the Journal, Current Biology, that they have discovered bits of DNA, which do not code for anything, but influence the expression of genes, and whose human version promotes cell division of neurons and hence a larger brain. The findings may lend insight into not only what makes the human brain special but also why people get genes, are able to spell out the specific proteins to be assembled and hence the role and function of the different kinds of cells.

But each of the groups can code for hundreds or thousands of amino acids, to lead to one protein, and there are many thousands of proteins. DNA also contains long stretches, often the longest of all, of non-coding sequences. Hence, although each unit in DNA is only nanometers long, the DNA molecule itself is nearly three metres long. And the whole length is folded and curled to fit inside the cell nucleus, just six microns in size. The result of this folding is that all parts of DNA are not always ready to get active, and ’expression’ or the actual action of genes, depends on other factors. Some of these factors are environmental and some are triggers within DNA itself, including regulator genes found in the ‘non-coding’ part of DNA.

It is these factors that set off gene action, either at times of stress, or even to decide what kind of cell the cell is to be. The main action of the DNA is brought about by enzymes called polymerases, which enable stretches of DNA to be copied and carried out into the cell, for assembly of proteins or to initiate cell division. Polymerase action is promoted or repressed by other agents, called activators or repressors, which help or interfere with polymerase binding to the relevant part, which is called the promoter. And then there are enhancers, which are found in non-coding parts of the DNA structure, which help DNA bend in a way that brings the promoter into the right position. And then, there are the silencers, which can bind to other factors, to prevent expression of a gene.

“Although a child can tell the difference between a chimpanzee and a human, identifying the molecular basis for the characteristics that make us human is one of the great challenges of biology,”

-Capra, Erwin, McKinsey, Rubenstein and Pollard of the University of California - Procedings of the Royal Society, Nov-Dec 2013

That the startling differences between humans and chimpanzees, when both species have such similarity in DNA, may lie in the regulatory mechanism of genes has been suspected for some time. Although there are enhancer segments that are unique to humans, none have been identified as affecting brain growth. But different groups of scientists have studied the non-coding sequences in DNA and extensive data has been collected of the parts that are conserved through the course of evolution of mammals and where there are changes in humans since the divergence from chimpanzees.

The Duke University team made use of these data bases and by a process of data mining, and imaginative analysis, they isolated enhancers in the DNA of humans and chimpanzees that expressed chiefly in brain tissue and early in development. They then separated the enhancers where there was a marked difference between humans and chimps and came down to a list of just 106. Of these, six appeared to affect genes that were involved brain development and they were named Human Accelerated Regulatory Enhancers, or HARE1 to HARE6. One of these, HARE5, was located physically close to a gene, FRIZZLED8, which was known to be involved in brain development and disease, and the team also found that HARE5 and Frizzled8 actually made contact in brain tissue

The team then introduced the human and chimpanzee versions of HARE5 into mouse embryos to see what effect they had on early brain development. What they found is that the human version of HARE5 actually promoted proliferation of stem cells maturing into neurons, leading to a 12% larger brain than mouse embryos that received chimpanzee HARE5. "What's really exciting about this was that the activity differences were detected at a critical time in brain development: when neural progenitor cells are proliferating and expanding in number, just prior to producing neurons," says researcher Debra L Silver.

The increased volume of brain is found to be in the neocortex, the region of the brain that is involved, in humans, in language and reasoning. The team of researchers now proposes to watch these two groups of new born mice into adulthood, to see what differences there were in full grow brains and behaviorof the adults. The team would also see what effect other HARE sequences may have on brain development. "What we found is a piece of the genetic basis for why we have a bigger brain," says Professor Gregory A. Wray, director of the Duke Center for Genomic and Computational Biology, “….this is probably only one piece, a little piece.”

Monkeys are smart too

Duke University appears to be active in studying simian intelligence. In 2007, Elizabeth Brannon and Jessica Cantlon of the Duke Center for Cognitive Neuroscience, reported in the journal, PLos Biology (Public Library of science) that macaque monkeys show ability to perform what appears to be basic arithmetic. A prevailing view about animal intelligence was that they do not actually think and any ability they show may arise from conditioned response rather than cognition.

Brannon, with Columbia professor Herbert S Terence, had first reported (in the journal, Science) that monkeys could rank the number of objects in computer generated pictures with as many as nine objects, which was evidence of thought process. She later showed, with Jessica Cantlon, that macaques were able to estimate the sum of two numbers with great accuracy and speed, which compared with the ability of college students!

Link to article on the 2007 paper

Getting smarter

Knowing what part of the human genome makes the brain grow may still not help us get much smarter. One limiting factor is that a large brain means a large head, which may be too much for the existing birth canal of the human mother. In the course of evolution, the larger human head has led to human females with wider hips, but there has been a limit, to allow rapid movement and safety. A price that has been paid is also that a good part of brain growth must take place after birth and the human infant is not independent for a few years!

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