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Q J Med 2003; 96:953–954
doi:10.1093/qjmed/hcg153
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What’s the difference
It is no longer fashionable to believe that Man has
dominion over all the animals; we are increasingly
made aware that we are only a particular branch
of the Animalia. However, we are clearly different
from even the great apes, and the fact that we have
around 60% of our genes in common with the
banana does not mean it is 60% as sentient (even if
first-year medical students are taken as a baseline).
So the inevitable comparisons and subsequent
brouhaha that will be made when the genome of
Pan troglodytes is published (98.5% of our genes in
common, rights for chimps, should chimps have the
vote, etc.) raises the question of what makes us
human. It is perhaps not surprising that the fact that
80% of mouse genes have a 1:1 orthologue in the
human genome and more than 99% have some
homologue has not aroused the same kind of
response: mice are not even nearly men.
The chimpanzee is our nearest relative among the
apes, and the lineages of Pan and Homo diverged
somewhere between 5 and 7 million years ago. In a
recent column, I discussed how the rates of genetic
change occurs over a period of time and how most
of the sequence changes that accumulate between
species are selectively neutral, in that they fail to
contribute to phenotypic or functional changes.
So what changes make the difference and how can
they be studied?
It seems that a relatively large number of potential
hominids evolved from our Pan ancestors, and that
most of these lines were unsuccessful, if Homo
sapiens is the desired endpoint. Our critical features
include a large brain, bipedalism (with consequent
skeletal adaptations), small canines, serious tool
making ability (dependent on opposable thumbs)
and language. Earlier hominids had small brains,
bigger teeth and shorter legs, but Neanderthal man
had a bigger brain and body than Homo sapiens;
form alone does not explain his failure, and clearly
form cannot confer such great advantages that
success as a species is assured.
These phenotypic changes that define us did not
follow a smooth ‘upward’ path of relentless
improvement driven by selection. As one example,
there was a period of around a million years
between the Early and Middle Pleistocene when
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brain size did not change significantly. In addition,
examination of the brains of chimpanzees and
gorillas using modern investigative techniques in
magnetic resonance imaging has shown that the
asymmetry of Broca’s area that is a feature of
the human brain is also found in the great apes. The
increase in size of this area on the left is a thus a
change that precedes the development of speech,
but the use of the hands in communication is
common to all of these animals—perhaps communication per se is the driver. The receptive area for
speech in the posterior part of the temporal lobe is
also larger on the left in Homo sapiens and appears
to have been in Neanderthals, Homo habilis and
Homo erectus, but it is also asymmetrical in
chimpanzees.1 Carroll2 has reviewed subtle
changes in cyto-architecture in the relevant areas
of cortex between Man and chimpanzee, and also
comments on the increase in size of area 10 of the
prefrontal cortex in H. sapiens, and its specialized
structure when compared with that of apes. This
type of quantitative change is not difficult to arrange
in genetic terms and may have required no new
genes.3
Our rounded cranial vault and flat face are, of
course, a product of how the facial and cranial
skeletons develop. Human infants have bigger
brains and less developed skulls than baby chimps
but the ultimate size of skull (human vs. chimp)
shows no real difference—of course, cranial capacity is greatly different. The relative pace of
development of various components of the skull
may be the critical step, a regulatory phenomenon
rather than the result of the working of a gene (or
genes) of large effect. Other articles in this series
have emphasized that most variations in traits are
polygenically determined and often involve changes
in the non-coding regulatory regions of genes, that
they are slow (the observed rates of change are
much slower than would be possible if all mechanisms of genetic change were exploited), and that
genes that affect transcription factors and members
of signal transduction pathways are most likely to be
involved. So it is unlikely that we will find genes of
large effect that differentiate us from the great apes,
and the discussion makes it clear (I hope) that we
Association of Physicians 2003; all rights reserved.
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might be looking for differences in timing of
expression or reading rates—changes in gene
function rather than gene product.
Recent observations on duplications provide
possible mechanisms for change in gene function.
When duplications between vertebrate genomes
are compared as we get more and more complete
data sets, it becomes clear that this mechanism of
genetic change produces non-identical repeats in
chromosomes (duplications are found in human
chromosome 16 and the apes, but not in an
identical form). Here is one difference that might
produce a genetic drive: closely related genes
may operate in a different way to produce different
outcomes as a result of this type of change.
However, perhaps more significant, in one major
respect, is that some genes have altered their
function after minor sequence change and are, for
example, specifically associated with speech. In
Man, FOXP2 mutations are associated with speech
and language disorders. This gene codes for a
transcription factor, but it differs from the homologous gorilla and chimpanzee gene in only two
sequences (and from the mouse by only four),
changes probably occurring in the last 200 000
years in hominids. Perhaps two changes are
enough! But we have not yet found the other
genes undoubtedly involved in linguistic skill
development, and so are unable to ‘weight’ the
effects of this particular change.
All of this suggests that what differences there are
between the genomes of various apes might be
considered to be trivial in some terms, smaller than
the range of variation that exist between individual
members of the same species, say. This misses
the point: it is almost certainly alteration of the
regulation of the activity of closely comparable or
identical structural genes during development that
produces the morphological changes that define
the differences between species. This is why, in
my view, the attempt of Craig Venter to make a
complete genome from scratch4 is doomed, even
for the proposed eco-tidying bacterium. If as few as
265–350 genes are all that is needed, it might be
possible in technical terms; the genome of the 7500
nucleotide poliovirus has been synthesized. The
problem is deciding what is necessary: you can’t put
all the possible combinations together in a testing
programme, and the function of most genes is
unknown. And how do you start it off? (the viruses
cheat—they use an existing set of starters in the cells
they infect).
Nevertheless, this exciting experiment is probably
indicative of the best way to resolve the problem
of what makes us human experimentally; it will
be possible in theory to construct a genome that
produces a defined phenotypic change in a defined
experimental system. Many of these exist (palatal
shelves, tooth buds, limb buds, liver anlage,
pancreas, nephrogenic buds, etc.). Add microarray
analyses, quantitative trait genetics, population
genetics and the comparative study of vertebrate
genomes, and we have many systems that may
identify genes that are important in producing
phenotypic change with time. But whether we
should look at skull development, bipedal adaptation, reduction in canine size, the development of
the hand or the acquisition of speech, is anyone’s
guess.
Colin Berry
References
1. Gannon PJ, Holloway RL, Broadfield DC, Braun AR. Asymmetry of chimpanzee planum temporale: Humanlike patterns
of Wernike’s brain language area homolog. Science 1998;
279:220–2.
2. Carrol SB. Genetics and the making of Homo sapiens. Nature
2003; 422:849–57.
3. Berry CL. The new mapping. Q J Med 2003; 96:459–60.
4. Zimmer C. Tinker, Taylor: Can Venter stitch together a genome
from scratch. Science 2003; 299:1006–7.