Today’s Nature

14 09 2006

The differences in brain size and
function that separate humans from other mammals must be reflected in
our genomes. It seems that the non-coding ‘dark matter’ of genomes
harbours most of these vital changes.

The human brain is supposed to set us apart from other animals. If so,
our genome must retain the imprint of our brain’s recent evolution. So
which parts of our genome have seen the most change, and are these
genomic innovations linked directly to our unique brain structure and
function? On page 167 of this issue, Pollard et al.1 describe how they have clocked the speed at which various human genome regions have changed in recent times*.
The clear winner of this race is human accelerated region 1 (HAR1),
part of an RNA gene whose pattern of expression is suitably poised to
influence the migration of neurons in the developing cortex. The
authors’ second and equally important finding is that all but two of
the most-accelerated regions lie outside protein-coding sequences — in
the enigmatic ‘dark matter’ of the human genome.
The brains of humans and chimpanzees are anatomically not so different2, except in scale. … Size matters, but it is equally likely that alterations in cellular
structures contribute to the cognitive differences between the two
species. … Yet evidence directly linking DNA differences to anatomical or
behavioural differences between these two species has been, at best,
fragmentary3.
What was needed, instead, was an unbiased genome-wide scan to pinpoint
the few regions — of whatever type — where the DNA has remained
essentially static over tens and hundreds of million years in diverse
species, yet which, in the past few million years of human evolution,
have altered especially rapidly.
Pollard and colleagues’ computational scan of the human genome1 reveals a set of 49 regions (HAR1–HAR49), each with a
sequence that is highly evolutionarily conserved among many mammals,
but that has diverged rapidly in humans since our last common ancestor
with chimpanzees
. The fastest among them, HAR1, has accrued 18 changes
in sequence in this time, when only one or no substitutions would be
expected to occur by chance.
In particular, HAR1F is also expressed in the ovary and testis
of adult humans, and sexual selection of genes expressed in these
tissues has often driven unusual sequence changes7.
Furthermore, the authors show that HARs are often associated with
regions that undergo a high rate of recombination — the process by
which an offspring obtains a blend of parental genes. Recombination,
and its associated process, biased gene conversion, are thought to
favour the inclusion of G and C nucleotides over the other two possible
nucleotides, A and T (ref. 8). As all of the nucleo-tide substitutions observed in HAR1 are of this type, high (and biased) mutation rates might explain part of the rapid evolution of HAR1.
Nevertheless, this process cannot explain the authors’ other
observations, such as the pairs of substitutions that together further
stabilize the structure of HAR1 RNA. Clearly, much work on the function and evolution of HAR1, and indeed of all HARs, remains to be done.
In our hotfoot pursuit of the biology that is unique to
humans, we should remember that each species will have winners of their
own genome race. Could it be, for example, that accelerated regions in
chimpanzees, mice or dogs are linked to the adaptive evolution of their
brains, too?
HARs seem to be particularly rare in protein-coding sequences. Instead,
they often lie near protein-coding genes that have neuro-developmental
functions, perhaps within regions that are involved in regulating when
and where these genes are turned on. The pattern of highly biased substitutions extends well beyond the
predicted RNA structure in a 1.2-kb region overlapping the first exon
of HAR1F (34 W S substitutions out of 44 total human–chimpanzee differences, with no S W substitutions).
The last sentense is most important; Now it would seem that searches within the functional non-coding ‘dark matter’ might be more enlightening.

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3 responses

16 09 2006

好深奥啊,崇拜一下吧:)

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