IT鈥橲 not how many genes you鈥檝e got, it鈥檚 what you do with them that counts.
That鈥檚 one of the key revelations about the human genome announced this
week.
The first look at our genetic panorama, the result of a massive effort by
both public and private groups, fills more than 100 pages in Nature and
Science. 鈥淚t鈥檚 the first time we鈥檝e stood back to look at the landscape
of our own human biology,鈥� says Francis Collins, head of genome research at the
National Institutes of Health near Washington DC. 鈥淚t鈥檚 a milestone of the
highest order.鈥�
The nuggets that scientists are eager to find in this new territory are our
genes, regions of DNA that are copied to make RNA templates for producing
proteins. The most surprising revelation of the two reports is that our genes
are rarer treasures than nearly anyone guessed. Ten years ago, most researchers
predicted that our cells harboured about 100,000 genes.
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But the two independent genome groups, using different strategies to sift
through the sequence, discovered a mere 27,000 to 40,000 human genes. 鈥淭he small
number of genes has tremendous implications,鈥� says Craig Venter of Celera. 鈥淭he
fruit fly genome has only 13,000 or so genes, and we鈥檙e so much larger and
smarter that we thought we should have a lot more genes.鈥�
Also humbling is the discovery of 223 genes that our ancestors appear to have
acquired directly from bacteria. This must have occurred when wayward bacterial
DNA became integrated into the DNA inside the sperm or egg of a distant
vertebrate forebear. Today, many of these genes appear to play a crucial role in
our biology.
But about 22 per cent of vertebrate genes aren鈥檛 found in worms or flies.
In fact, vertebrates can lay claim to a certain amount of innovation
when it comes to protein design, such as the invention of new structural
elements that many proteins share. Our proteins also tend to have more complex
arrangements of these elements.
But the secret of our complexity may lie not in the numbers of our genes, but
how we use them, says Richard Myers of Stanford University. 鈥淎 fine sports car
and a junker may have the same number of pieces,鈥� he says. 鈥淭he difference is
the quality of parts and the sophistication with which we put them
迟辞驳别迟丑别谤.鈥�
For example, genes usually come in segments. By 鈥渟plicing out鈥� some segments
of the RNA templates for proteins, or using one segment rather than another, a
single gene can yield many different proteins. The same gene can be used to make
one protein in, say, muscle, and another in the brain. Up to 60 per cent of our
genes produce these 鈥渟plice variants鈥�.
Another key finding from both public and private genome efforts is that many
human 鈥渢ranscription factors鈥� are unique and a cut above those of the fly and
the worm. Transcription factors and other regulatory proteins dictate which
genes are switched on at vital stages of development, as embryos form and organs
take shape. It is they that orchestrate such amazing complexity from so few
genes.
Venter thinks all higher vertebrates have roughly the same genes. What鈥檚
important is when they are switched on and off, he says. 鈥淲e have the same
number of genes as cats and dogs, but differently regulated.鈥�
If we don鈥檛 have as many genes as some hoped, no one can be disappointed by
our vast collection of clutter. It turns out that the coding regions of genes
fill a scant 1.5 per cent of our genome, while repetitive copies of 鈥渏umping
genes鈥�, or transposons, claim about half our DNA real estate.
While transposons appear to be just junk, they may have helped us to evolve.
Most are now inactive, but when they first arrived they were able to hop from
place to place in our genome. This helped to rearrange the DNA in chromosomes,
creating new genes. Indeed, one newly discovered transposon, MER85,
appears to contain an active gene that is switched on in the brains of
fetuses.
Our chromosomes also turn out to be remarkably variable. Genetic oases are
often surrounded by vast geneless deserts. And Rogier Versteeg at the University
of Amsterdam in the Netherlands and his colleagues report that highly active
genes are often grouped together in what he calls regions of increased gene
expression, or RIDGEs, where the transcription of genes zooms along at 200 times
the rate found elsewhere. 鈥淭hese are like factories just churning out RNA,鈥� says
Versteeg.
Another property that is unevenly distributed through the genome is
recombination鈥攖he exchange of DNA segments between pairs of chromosomes
during the formation of sperm and eggs. James Weber of the Marshfield Medical
Research Foundation in Wisconsin and his colleagues found that there are dead
spots for recombination, as well as 鈥渏ungles鈥�, where chromosomes switch pieces
100 times as often.
Nothing that has been found so far in the DNA sequence predicts where
recombination is likely to occur. Another twist is that the preferred sites of
recombination differ substantially between men and women.
A final enigma is how cavalier we are about where we keep genes. Most
biologists had bet that the ends of chromosomes, or telomeres, would be
gene-free zones because telomeres shorten throughout our lifetime.
But when Robert Moyzis of the University of California, Irvine, searched for
genes near telomeres, he found 500 candidates. Putting precious genes in
telomeres is like building homes on an earthquake zone. 鈥淚 frankly can鈥檛 come up
with a good reason to do that,鈥� he says. Intriguingly, this suggests that some
aspects of ageing could be caused by genetic changes triggered by telomere
shrinkage.
The work is only just starting. 鈥淭he important thing to realise is that some
of us are already using this sequence every day to solve problems in biology,鈥�
Myers adds. 鈥淎nd people will be doing that for decades, if not millennia.鈥�