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morfrain_encilgar
Friday, December 31st, 2004, 02:35 AM
Genes that control the size and complexity of the brain have undergone much more rapid evolution in humans than in non-human primates or other mammals, according to a new study by Howard Hughes Medical Institute researchers.

The accelerated evolution of these genes in the human lineage was apparently driven by strong selection. In the ancestors of humans, having bigger and more complex brains appears to have carried a particularly large advantage, much more so than for other mammals. These traits allowed individuals with "better brains" to leave behind more descendants. As a result, genetic mutations that produced bigger and more complex brains spread in the population very quickly. This led ultimately to a dramatic "speeding up" of evolution in genes controlling brain size and complexity.

"People in many fields, including evolutionary biology, anthropology and sociology, have long debated whether the evolution of the human brain was a special event," said senior author Bruce Lahn of the Howard Hughes Medical Institute at the University of Chicago. "I believe that our study settles this question by showing that it was."

Lahn and his colleagues reported their data in a research article published in the December 29, 2004, issue of the journal Cell.

The researchers focused their study on 214 brain-related genes, that is, genes involved in controlling brain development and function. They examined how the DNA sequences of these genes changed over evolutionary time in four species: humans, macaque monkeys, rats, and mice. Humans and macaques shared a common ancestor 20-25 million years ago, whereas rats and mice are separated by 16-23 million years of evolution. All four species shared a common ancestor about 80 million years ago.

Humans have extraordinarily large and complex brains, even when compared with macaques and other non-human primates. The human brain is several times larger than that of the macaque -- even after correcting for body size -- and "it is far more complicated in terms of structure," said Lahn.

For each gene, Lahn and his colleagues counted the number of changes in the DNA sequence that altered the protein produced by the gene. They then obtained the rate of evolution for that gene by scaling the number of DNA changes to the amount of evolutionary time taken to make those changes.

By this measure, brain-related genes evolved much faster in humans and macaques than in mice and rats. In addition, the rate of evolution has been far greater in the lineage leading to humans than in the lineage leading to macaques.

This accelerated rate of evolution is consistent with the presence of selective forces in the human lineage that strongly favored larger and more complex brains. "The human lineage appears to have been subjected to very different selective regimes compared to most other lineages," said Lahn. "Selection for greater intelligence and hence larger and more complex brains is far more intense during human evolution than during the evolution of other mammals."

To further examine the role of selection in the evolution of brain-related genes, Lahn and his colleagues divided these genes into two groups. One group contained genes involved in the development of the brain during embryonic, fetal and infancy stages. The other group consisted of genes involved in "housekeeping" functions of the brain necessary for neural cells to live and function. If intensified selection indeed drove the dramatic changes in the size and organization of the brain, the developmental genes would be expected to change faster than the housekeeping genes during human evolution. Sure enough, Lahn's group found that the developmental genes showed much higher rate of change than the housekeeping genes.

In addition to uncovering the overall trend that brain-related genes -- particularly those involved in brain development -- evolved significantly faster in the human lineage, the study also uncovered two dozen "outlier" genes that might have made important contributions to the evolution of the human brain. These outlier genes were identified by virtue of the fact that their rate of change is especially accelerated in the human lineage, far more so than the other genes examined in the study. Strikingly, most of these outlier genes are involved in controlling either the overall size or the behavioral output of the brain -- aspects of the brain that have changed the most during human evolution.

According to graduate student Eric Vallender, a coauthor of the article, it is entirely possible by chance that that two or three of these outlier genes might be involved in controlling brain size or behavior. "But we see a lot more than a couple -- more like 17 out of the two dozen outliers," he said. Thus, according to Lahn, genes controlling the overall size and behavioral output of the brain are perhaps places of the genome where nature has done the most amount of tinkering in the process of creating the powerful brain that humans possess today.

There is "no question" that Lahn's group has uncovered evidence of selection, said Ajit Varki of the University of California, San Diego. Furthermore, by choosing to look at specific genes, Lahn and his colleagues have demonstrated "that the candidate gene approach is alive and well," said Varki. "They have found lots of interesting things."

One of the study's major surprises is the relatively large number of genes that have contributed to human brain evolution. "For a long time, people have debated about the genetic underpinning of human brain evolution," said Lahn. "Is it a few mutations in a few genes, a lot of mutations in a few genes, or a lot of mutations in a lot of genes? The answer appears to be a lot of mutations in a lot of genes. We've done a rough calculation that the evolution of the human brain probably involves hundreds if not thousands of mutations in perhaps hundreds or thousands of genes -- and even that is a conservative estimate."

It is nothing short of spectacular that so many mutations in so many genes were acquired during the mere 20-25 million years of time in the evolutionary lineage leading to humans, according to Lahn. This means that selection has worked "extra-hard" during human evolution to create the powerful brain that exists in humans.

Varki points out that several major events in recent human evolution may reflect the action of strong selective forces, including the appearance of the genus Homo about 2 million years ago, a major expansion of the brain beginning about a half million years ago, and the appearance of anatomically modern humans about 150,000 years ago. "It's clear that human evolution did not occur in one fell swoop," he said, "which makes sense, given that the brain is such a complex organ."

Lahn further speculated that the strong selection for better brains may still be ongoing in the present-day human populations. Why the human lineage experienced such intensified selection for better brains but not other species is an open question. Lahn believes that answers to this important question will come not just from the biological sciences but from the social sciences as well. It is perhaps the complex social structures and cultural behaviors unique in human ancestors that fueled the rapid evolution of the brain. "This paper is going to open up lots of discussion," Lahn said. "We have to start thinking about how social structures and cultural behaviors in the lineage leading to humans differed from that in other lineages, and how such differences have powered human evolution in a unique manner. To me, that is the most exciting part of this paper."

morfrain_encilgar
Friday, December 31st, 2004, 02:46 AM
Frans asked me to post that though I thought it was obvious that there was selection for a larger cranial capacity and different behaviour to other primates.

Frans_Jozef
Friday, December 31st, 2004, 02:58 AM
Frans asked me to post that though I thought it was obvious that there was selection for a larger cranial capacity and different behaviour to other primates.

How do you estimate this evolved brain growth? What do you think was the motor, the agent that made hominid brain larger, more complex and definitely more intelligent?

Premack showed that simians like chimpanzees have "symbolic capacity". He teached them random values that in tests, whereby these apes made surprising new, authentic combinations which expressed a faculty to express abstract thinking and linguistic prowness.

morfrain_encilgar
Friday, December 31st, 2004, 03:59 AM
How do you estimate this evolved brain growth? What do you think was the motor, the agent that made hominid brain larger, more complex and definitely more intelligent?

Premack showed that simians like chimpanzees have "symbolic capacity". He teached them random values that in tests, whereby these apes made surprising new, authentic combinations which expressed a faculty to express abstract thinking and linguistic prowness.

I dont know but most of the behavioural differences in the Homo lineage are associated with the shift in habitat from ecological apes like chimpanzees and orang utans which live in forest.

Triglav
Friday, December 31st, 2004, 08:27 AM
I dont know but most of the behavioural differences in the Homo lineage are associated with the shift in habitat from ecological apes like chimpanzees and orang utans which live in forest. It may appear off topic, but I read ages ago somewhere that bigger brains were sexual ornamentation, thus smaller brains were selected against. In plain English: a more ingenious and crafty guy was able to impress a potential mate with his architectural achievements and handiwork (parallels are found in the animal kingdom).

No comments about the current validity of this concept, please. ;)

morfrain_encilgar
Saturday, January 1st, 2005, 09:16 AM
How do you estimate this evolved brain growth? What do you think was the motor, the agent that made hominid brain larger, more complex and definitely more intelligent?

Premack showed that simians like chimpanzees have "symbolic capacity". He teached them random values that in tests, whereby these apes made surprising new, authentic combinations which expressed a faculty to express abstract thinking and linguistic prowness.

The study is called "Accelerated Evolution of Nervous System Genes in the Origin of Homo sapiens".

Agrippa
Saturday, January 1st, 2005, 01:21 PM
Humans and macaques shared a common ancestor 20-25 million years ago, whereas rats and mice are separated by 16-23 million years of evolution.

Hmm, that sounds somewhat strange...

Rats and mice in the same time as macaques is absurd, or did I just misunderstood the sentence...

morfrain_encilgar
Saturday, January 1st, 2005, 01:35 PM
Hmm, that sounds somewhat strange...

Rats and mice in the same time as macaques is absurd, or did I just misunderstood the sentence...

The article is saying that rats and mice are more closely related to one another, than macaques and humans are related to each other.

Frans_Jozef
Thursday, May 12th, 2005, 01:24 AM
Plos Biology, Volume 3 | Issue 3 | MARCH 2005 (http://biology.plosjournals.org/perlserv/?request=get-toc&issn=1545-7885&volume=3&issue=3)

http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0030050


Molecular Insights into Human Brain Evolution

Jane Bradbury

Jane Bradbury is a freelance science news writer based in Cambridge, United Kingdom. E-mail: janeb@sciscribe.u-net.com

Published: March 15, 2005

DOI: 10.1371/journal.pbio.0030050

Copyright: © 2005 Jane Bradbury. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Citation: Bradbury J (2005) Molecular Insights into Human Brain Evolution. PLoS Biol 3(3): e50

As a species, we pride ourselves on the uniqueness of our brain. Relative to our body size, the human brain is bigger than that of any other animal. It may also contain unique structures and patterns of organisation that presumably underlie our intelligence and ability to manipulate our environment. But how did our unique brain originate, and under what selective pressures did it evolve? Some of the answers may lie in the genetic differences that researchers are now uncovering between us and our closest relatives.

What Is So Different about the Human Brain?

When we compare our brain to those of other animals, the first thing that strikes us is its size. Human brains weigh on average 1,300 grams; a squirrel brain weighs six grams. Some of this difference is because, as larger animals, we need more brain to run our bodies. However, the brains of our nearest relatives, the great apes, weigh only 300–500 grams, even though their body size is similar to ours (Figure 1 (http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0030050#JOURNAL-PBIO-0030050-G001)). “Humans sit on the top of the pile when it comes to relative brain size”, notes geneticist Bruce Lahn (University of Chicago, Illinois, United States) (see Box 1 (http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0030050#BOX1)).

Throughout mammalian and primate evolution, there has been a gradual increase in brain size, superimposed with “spikes” of fast growth such as the tripling in human brain size that occurred about 1.5 million years ago, 4 million years after the human lineage diverged from that of the great apes. “Even in the ape lineage, the brain has been expanding but along the human lineage it has really taken off”, says Lahn.

In addition, over time, different parts of our brain have increased in size at different rates. The cerebral cortex has expanded more than other areas, and within the cortex, some areas have expanded differentially while others have lagged behind.

“Humans sit on the top of the pile when it comes to relative brain size.”


Paleoanthropologist Ralph Holloway (Columbia University, New York, United States) uses endocasts to look for macroscopic differences in the brains of our human ancestors. “We fill human fossil skulls with vulcanised rubber and once it has set, we pull it out of the large hole at the base of the skull and the rubber snaps back into the shape of the skull”, Holloway explains. Endocasts are particularly useful for comparing brain sizes, but they also provide information on when the asymmetries that are present in our brain first appeared. These often reflect cerebral specialisation, and Holloway believes that some of the asymmetries he sees in human fossil skulls may indicate when our ancestors acquired language.

http://biology.plosjournals.org/archive/1545-7885/3/3/figure/10.1371_journal.pbio.0030050.g001-M.jpg (http://biology.plosjournals.org/perlserv/?request=slideshow&type=figure&doi=10.1371/journal.pbio.0030050&id=22688)Figure 1. (http://biology.plosjournals.org/perlserv/?request=slideshow&type=figure&doi=10.1371/journal.pbio.0030050&id=22688) Comparison of a Human and a Chimpanzee Brain Scale bar = 1 cm

(Image: Todd Preuss, Yerkes Primate Research Center)


More details about how the shape of our brain differs from that of our closest living relatives are emerging from the work of neuroscientist Karl Zilles (Institute of Medicine, Research Center Jülich, Germany). He prepares magnetic resonance images of monkey, ape, and human brains and then uses a nonlinear elastic algorithm to transform one brain into another (Figure 2 (http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0030050#JOURNAL-PBIO-0030050-G002)). “We know what forces we have to apply to the images to do this”, he explains, “which tells us which areas of the brain have changed most during primate evolution”. Zilles and his colleagues also are currently using molecular imaging techniques to update the existing maps of the different areas within our brains. Until we have this information, it is hard to make meaningful comparisons between our brain and that of chimpanzees. Already, Zilles has discovered that there is much more interindividual variation in human brain organisation than anyone suspected. This means, says Zilles, “that a general statement like ‘the neocortex is bigger in human brains than in ape brains’ actually tells us very little. It gives us the general direction that evolution has taken but not whether an ape brain is different because of its sensory, motor, or association areas.”

Box 1. Nothing like a Whale

Just how unique is human brain evolution? Neuroscientist Lori Marino (Emory University, Atlanta, Georgia, United States) and her colleagues have used computed tomography to estimate the body and brain size of 36 fossil whale species and have compared these data with those for modern toothed whales. Relative to body size, whales and dolphins have the next biggest brains to us, bigger even than chimpanzees, and, says Marino, “there have been dolphins swimming in the oceans with huge brains for more than 15 million years. We are really the new kids on the block.”

Like in humans and other primates, the neocortex in whale brains is huge, but its structure is very different to that of our neocortex. Whales have been independent of other lineages for about 60 million years, notes Marino, and haven't shared a common ancestor with primates for 94 million years. “Nevertheless, during evolution, whales have converged upon very similar capacities and behaviours to those of primates, including a highly developed social structure, which tells us that there is more than one way to evolve a complex intelligence.”


Scientists are also using other techniques to investigate more subtle changes in the organisation of the human brain compared to the brains of other mammals and primates. Indeed, says Holloway, the reorganisation of the brain during evolution has been at least important as its increase in size. Neurobiologist John Allman (California Institute of Technology, Pasadena, California, United States) and his collaborators, for instance, have discovered that a special type of large spindle-shaped neuron, first described in the early 20th century by Constantin von Economo, is unique to apes and humans and much more numerous in the latter. These neurons are found in brain areas that are implicated in decision making in uncertain situations so, Allman speculates, they may help humans to interact rapidly in complex social situations.

http://biology.plosjournals.org/archive/1545-7885/3/3/figure/10.1371_journal.pbio.0030050.g002-M.jpg (http://biology.plosjournals.org/perlserv/?request=slideshow&type=figure&doi=10.1371/journal.pbio.0030050&id=22692)Figure 2. (http://biology.plosjournals.org/perlserv/?request=slideshow&type=figure&doi=10.1371/journal.pbio.0030050&id=22692) Magnetic Resonance Imaging of Brains

Three-dimensional reconstruction of a reference bonobo (pygmy chimpanzee) brain (A) and a reference human brain (B) after magnetic resonance imaging and normalisation of absolute brain sizes. The virtual bonobo brain has been transformed into the virtual human brain using an elastic deformation algorithm. The local deformation vectors are colour-coded and projected onto the virtual human brain (C). The most dramatic changes in brain shape occur in (1) the ventro-orbital prefrontal cortex, (2) the ventral stream of the visual cortex, and (3) the hypothalamic neuroendocrine region.

(Image: Karl Zilles, Hartmut Mohlberg, and Peter Pieperhoff, Research Center Jülich)


Costs and Benefits

A bigger, more complex brain may have advantages over a small brain in terms of computing power, but brain expansion has costs. For one thing, a big brain is a metabolic drain on our bodies. Indeed, some people argue that, because the brain is one of the most metabolically expensive tissues in our body, our brains could only have expanded in response to an improved diet. Another cost that goes along with a big brain is the need to reorganise its wiring. “As brain size increases, several problems are created”, explains systems neurobiologist Jon Kaas (Vanderbilt University, Nashville, Tennessee, United States). “The most serious is the increased time it takes to get information from one place to another.” One solution is to make the axons of the neurons bigger but this increases brain size again and the problem escalates. Another solution is to do things locally: only connect those parts of the brain that have to be connected, and avoid the need for communication between hemispheres by making different sides of the brain do different things. A big brain can also be made more efficient by organising it into more subdivisions, “rather like splitting a company into departments”, says Kaas. Overall, he concludes, because a bigger brain per se would not work, brain reorganisation and size increase probably occurred in parallel during human brain evolution. The end result is that the human brain is not just a scaled-up version of a mammal brain or even of an ape brain.

For natural selection to work, the costs of brain evolution must be outweighed by the advantages gained in terms of fitness. For many years, explains ecological psychologist Robin Dunbar (University of Liverpool, United Kingdom), “people thought that the ability to hunt or forage better was what drove the evolution of our brains. But a better diet had to come before we could grow a bigger brain.” Dunbar believes instead that brain evolution in primates and more generally in mammals “has been driven by the need to manage social relationships, and in primates, in particular, to coordinate coherence in social groups through time and space”. More complex social interactions, he says, mean that individuals are better able to pool resources to solve problems like finding food, and so they survive better.

This theory, says Dunbar, is supported by a correlation between social group size and neocortex size across primates and modern humans. Furthermore, during primate brain evolution, the trend has been to add more material to the front than the back of the brain. The front of the brain is where information from the rest of the brain is interpreted, and the capacity to interpret information underlies social interactions, says Dunbar. The number of problem-solving cognitive tasks you can do may well depend on how much frontal lobe volume you have and how it is organised. Just think of how few moves you can run a chess game into the future with a 1980s personal computer compared to a 21st century mainframe machine, he suggests.

The human brain is not just a scaled-up version of a mammal brain or even of an ape brain.


The Genetics of Human Brain Evolution

Selective pressures like those considered by Dunbar and, before him, by scientists like Holloway work on the raw material of random gene mutations, and molecular biologists now have some clues to the gene changes that may underlie brain evolution. Take brain size, for example (Figure 3 (http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0030050#JOURNAL-PBIO-0030050-G003)). Research groups, including those led by Lahn, neurologist Christopher Walsh (Harvard Medical School, Boston, Massachusetts, United States), and clinical geneticist Geoffrey Woods (University of Leeds, United Kingdom), wondered whether the genes that cause microcephaly, an inherited human disorder in which brain size is greatly reduced, might include genes involved in human brain evolution. In 2002, mutations in the genes ASPM (abnormal spindle-like microcephaly associated) and microcephalin were identified as two causes of microcephaly. Three groups have since reported that both these genes have been under selective pressure during primate evolution. ASPM encodes a protein involved in spindle formation, so it is tempting to think that changes in its sequence might result in an increased rate of cell division and hence brain size. But, cautions Walsh, “we really have no idea yet how or even if ASPM is involved in brain evolution”.

Both Lahn and Walsh believe that ASPM and microcephalin may be only the tip of the iceberg when it comes to genes that have helped to shape our brains. For example, Walsh has recently reported that deletion of a gene called Nde1 produces mice with very small brains. “Our experiments indicate that the loss of Nde1 causes neurons to mature prematurely. This stops them dividing so the mice end up with small brains”, explains Walsh, who is now investigating whether human NDE1 variants have been positively selected during human evolution.

Lahn is also searching for additional candidate genes that might help to explain how our brains evolved. In a recent Cell paper, Lahn and his colleagues identify several hundred genes that are involved in nervous system biology and show that, as a group, there are significantly higher rates of protein evolution in these genes in primates than in rodents. Protein evolution rates are particularly high in the lineage leading from ancestral primates to humans, notes Lahn, “so some of these genes may regulate brain size and behaviour”. However, he warns, as with ASPM and microcephalin, “definitive proof for this will only come from functional studies, which are difficult to do”.

Enter Glutamate Dehydrogenase

For one gene, evidence for an effect on brain function may be emerging. Geneticist Henrik Kaessmann (University of Lausanne, Switzerland) studies the origin of new genes in primates, in particular genes that arise when a DNA copy of an mRNA transcribed from an existing gene is integrated back into the genome. Usually this new “retrocopy” is not expressed, but if the DNA inserts near an active promoter, it can become a transcribable “retrogene”. This is the origin of GLUD2, a retrogene derived from GLUD1, which encodes glutamate dehydrogenase. GLUD2, which first appeared 18–23 million years ago in hominoids, probably immediately picked up a brain-specific promoter and then over the next few million years acquired two critical amino acid changes, explains Kaessmann. These allow GLUD2-encoded glutamate dehydrogenase to work better in the brain than the GLUD1-encoded enzyme. Because glutamate dehydrogenase recycles the neurotransmitter glutamate, the presence of GLUD2 may permit a higher neurotransmitter turnover and greater neuronal activity in hominoid brains than is possible in monkey brains, which lack GLUD2, suggests Kaessmann.

http://biology.plosjournals.org/archive/1545-7885/3/3/figure/10.1371_journal.pbio.0030050.g003-M.jpg (http://biology.plosjournals.org/perlserv/?request=slideshow&type=figure&doi=10.1371/journal.pbio.0030050&id=22696)Figure 3. (http://biology.plosjournals.org/perlserv/?request=slideshow&type=figure&doi=10.1371/journal.pbio.0030050&id=22696) Primate Brain Sizes

These skulls are from the Harvard Museum of Comparative Zoology.

(Image: Christopher Walsh, Harvard Medical School)


Gene Expression

Kaessmann plans to search his extensive database of retrocopies in the human genome for other functional genes that could, like GLUD2, be implicated in brain evolution. By contrast, evolutionary neurobiologist Todd Preuss (Yerkes Primate Research Center, Emory University, Atlanta, Georgia, United States) hopes to identify genes involved in human brain evolution by comparing gene expression patterns in different primates. Preuss, who began training as a paleoanthropologist before turning to neuroscience, has been comparing post-mortem human and chimpanzee brains since the mid 1990s, believing that “if we want to understand human brain evolution, we really have to compare humans with chimpanzees, our nearest relatives”, even though chimp brains have been evolving separately from ours for 5–7 million years. But, warns Preuss, “we have to do these studies now. There are few chimps left and if we lose the opportunity to study them and their brains, we will lose forever a fundamental source of insight into our own species.”

To begin with, Preuss used staining techniques that exploit antibodies to examine the neural components of chimpanzee and human brains. Then in 1998, he was asked to collaborate in a microarray project. “My antibody approach was very labour intensive so I jumped at the opportunity to screen 10,000 genes at once”, he says.

Preuss and his collaborators now know that more than 100 genes are differentially expressed in chimpanzee and human brains. “Importantly, when we go back into tissue with probes for these gene products, in some cases there are remarkably different spatial patterns of expression in humans, chimps, and macaques”, notes Preuss. “We don't know yet what these differences mean in terms of functional organisation in these different brains but our results open up new and exciting vistas”, particularly since many of the differentially expressed genes have not previously been considered as being potentially involved in brain evolution. The microarray data produced by Preuss and other researchers also indicate that many of the gene expression changes that have occurred during brain evolution involve gene upregulation. For example, there is increased expression of genes involved in metabolism, synaptic organisation, and synaptic function. “All told, it seems that the human brain may be more dynamic than ape or monkey brains”, says Preuss. “The human brain seems to be running hot in all sorts of ways.”

Scratching at the Surface

As far as understanding how our brains evolved, more questions remain than have been answered. One problem is that we don't really know enough about how our brains differ from those of other mammals and primates, although work by Zilles and others is helping here. We also know very little about how the areas of our brain are physically linked up, and we need to understand that before we can see how we differ from our nearest relatives. And as far as identifying the gene changes that were selected during evolution, although we have several candidates, we don't know how or if these gene variants affect our cognitive abilities. It is one thing, concludes Dunbar, to identify genetic or anatomic differences between human and ape brains, but quite another to know what they mean in terms of actual cognitive processes.

Further Reading


Burki F, Kaessmann H (2004) Birth and adaptive evolution of a hominoid gene that supports high neurotransmitter flux. Nat Genet 36: 1061–1063. Find this article online (http://biology.plosjournals.org/perlserv/?request=get-citation-links&doi=1061-4036%282004%29036%3C1061:BAAEOA%3E2.0.CO ;2&id=JOURNAL-PBIO-0030050-B1&sitename=PLOSONLINE)
Dorus S, Vallender EJ, Evans PD, Anderson JR, Gilbert SL, et al. (2004) Accelerated evolution of nervous system genes in the origin of Homo sapiens. Cell 119: 1027–1040. Find this article online (http://biology.plosjournals.org/perlserv/?request=get-citation-links&doi=0092-8674%282004%29119%3C1027:AEONSG%3E2.0.CO ;2&id=JOURNAL-PBIO-0030050-B2&sitename=PLOSONLINE)
Dunbar RIM (2003) The social brain: Mind, language, and society in evolutionary perspective. Annu Rev Anthropol 32: 163–181. Find this article online (http://biology.plosjournals.org/perlserv/?request=get-citation-links&doi=0084-6570%282003%29032%3C0163:TSBMLA%3E2.0.CO ;2&id=JOURNAL-PBIO-0030050-B3&sitename=PLOSONLINE)
Feng Y, Walsh CA (2004) Mitotic spindle regulation by Nde1 controls cerebral cortex size. Neuron 44: 279–293. Find this article online (http://biology.plosjournals.org/perlserv/?request=get-citation-links&doi=0896-6273%282004%29044%3C0279:MSRBNC%3E2.0.CO ;2&id=JOURNAL-PBIO-0030050-B4&sitename=PLOSONLINE)
Holloway RL, Broadfield DC, Yuan MS, Schwartz JH, Tattersall I (2004) Brain endocasts—The paleoneurological evidence. 3: The human fossil record. New York: Wiley-Liss. 315 p.
Kaas JH (2004) Evolution of somatosensory and motor cortex in primates. Anat Rec 281A: 1148–1156. Find this article online (http://biology.plosjournals.org/perlserv/?request=get-citation-links&doi=0003-276X%282004%29281A%3C1148:EOSAMC%3E2.0.C O;2&id=JOURNAL-PBIO-0030050-B6&sitename=PLOSONLINE)
Marino L, McShea DW, Uhen MD (2004) Origin and evolution of large brains in toothed whales. Anat Rec 281A: 1247–1255. Find this article online (http://biology.plosjournals.org/perlserv/?request=get-citation-links&doi=0003-276X%282004%29281A%3C1247:OAEOLB%3E2.0.C O;2&id=JOURNAL-PBIO-0030050-B7&sitename=PLOSONLINE)
Preuss TM, (2004) What is it like to be a human? In: Gazzaniga MS, editor. The cognitive neurosciences III, 3rd ed. Cambridge (Massachusetts): MIT Press. pp 5–22.
Preuss TM, Cáceres M, Oldham MC, Geschwind DH (2004) Human brain evolution: Insights from microarrays. Nat Rev Genet 5: 850–860. Find this article online (http://biology.plosjournals.org/perlserv/?request=get-citation-links&doi=1471-0056%282004%29005%3C0850:HBEIFM%3E2.0.CO ;2&id=JOURNAL-PBIO-0030050-B9&sitename=PLOSONLINE)
Vallender EJ, Lahn BT (2004) Positive selection on the human genome. Hum Mol Genet 13: R245–R254. Find this article online (http://biology.plosjournals.org/perlserv/?request=get-citation-links&doi=0964-6906%282004%29013%3CR245:PSOTHG%3E2.0.CO ;2&id=JOURNAL-PBIO-0030050-B10&sitename=PLOSONLINE)