Clearer blueprint Scientists looking at life in reverse
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Clearer blueprint Scientists looking at life in reverse By Ronald Kotulak a
Tribune science reporter February 1, 2004
Say hello to Betty Bacteria, she's a far distant relative. Give a hearty
greeting to Rodney Rat, a cousin many times removed. Of course we all know George
the Gorilla, you can't miss the resemblance.
Unlike Charles Darwin, who was ridiculed in the mid-1880s for suggesting that
humans and monkeys are related, today's evolutionary geneticists don't expect
similar rebuke even though they are knocking our ancestral line down to the
bottom of the tree of life.
Using a new genetic language dictionary, scientists are translating the
incredible story of our evolutionary history all the way back to a time when we
were closer to rodents, and before that, to earlier relatives--headless, armless,
legless, undulating single-cell blobs.
The story of life on Earth is written in our genes, a convoluted script that
now lies all around us in its most up-to-date version. But it has remained as
stubbornly unreadable as Egyptian hieroglyphics until just a few years ago.
Now it is an open book, revealing how we got to be who we are, and why we are
not more like the chimpanzees with whom we share about 99 percent of our
genes. In chapter after chapter going back thousands, millions and even billions
of years, scientists are comparing human genes to those of our closest and most
distant relatives. Some of their genes changed little over time, their story
as simple as the day they were born. Others, more adventurous, changed in
different ways. Now they are all serve as milestones along the unpredictable path
evolution took to get to us.
Scientists are discovering what makes us so different: which genes, for
instance, make humans so much more intelligent than any other creatures. Tracking
the genealogy of human genes is packed with surprises: Humans, for example, are
more related to rodents than to our two favorite pets, dogs and cats, which
everyone had previously thought. Some of that history will likely always remain
murky because much of the earliest evidence has been wiped out.
Nevertheless, scientists are following the roll of the genetic dice. They are
discovering important clues to our existence--which genes, for instance,
trigger sexual attraction and why certain restless genes in male sperm sprout new
branches on the tree of life.
By flicking genes on and off, they are mastering the art of instant
evolution. Simply by adding a fat-metabolizing gene from a cold-climate fruit fly to a
tropical one, for instance, not only enables the hot-weather fly not only to
prefer the cold, but also drastically changes its sex appeal.
Life is thought to have started about 3.8 billion years ago, and it has left
a genetic record ever since. Scientists tracing its lineage are finding
mind-altering revelations. Perhaps the most enlightening and humbling: Humans are
genetically related to all creatures that have ever lived--from bacteria to
dinosaurs to mushrooms to monkeys to us.
One of the greatest discoveries from the ability to sequence genomes is that
there is a grand unity to life and that all forms of life on this Earth have a
common ancestor," said Martin Kreitman, a University of Chicago population
Scientists are deciphering the genetic code letter by letter--G, A, C, T, the
four nucleic acid chemicals breathing life into DNA--and learning how a
common ancestor gave rise to the great multitude of life forms. The letters are
crucial because a mutation in one can mean a new survival skill--walking
upright--or it can spell disaster--hemophilia. Most mutations, however, are neither
helpful nor harmful.
"Evolution is constantly tinkering with our genetic blueprint to figure out
ways to make things better or different," said Eric Green, scientific director
of the National Human Genome Research Institute. "We can now open up that
notebook and read its contents by sequencing the genes of other genomes and then
comparing them to each other and to the human genome.
"We are learning a tremendous amount about ourselves by exploring
evolutionarily diverse species," Green said. Comparing the genes of 13 vertebrate
species, Green confirmed a new tree of mammalian evolution showing that humans and
other primates are more closely related to mice and rats than to cats, dogs,
cows or pigs. Humans separated from rodents about 75 million years ago.
3 cell types
The common ancestor of life may actually have been a trio of founders, three
distinct cell types: one that produced bacteria, another that formed
multicellular complex organisms like mice and people, and a third domain of life called
archaea, according to University of Illinois microbiologist Carl Woese.
Archaea, which Woese discovered, are somewhere between bacteria and humans. They
are the most exotic forms of life, thriving in hot thermal vents at the bottom
of the ocean and other places once thought inhospitable to life. For his
discovery, Woese earlier this year won the prestigious $500,000 Crafoord Prize in
biosciences given by the Royal Swedish Academy of Sciences.
The first living organisms had a tenuous hold on life. To increase their
chances of survival, all three domains swapped genes, Woese says, lending each
other a hand like pioneers chipping in to build each other's farms, but then each
taking a separate evolutionary path. Along the way they left telltale genetic
"We are beginning to identify genes that appear to be relevant to the
evolution of humans, especially the human brain," said University of Chicago
molecular biologist Bruce Lahn.
Lahn studies genes involved in building brains. He's on the trail of a gene
that appears to be responsible for the expansion of the human brain's cerebral
cortex, the center for higher thinking. When the gene, called the Abnormal
Spindle-Like Microcephaly Associated (ASPM) gene, malfunctions, as it sometimes
does in newborns, the cortex does not develop.
Lahn found that the gene in humans has undergone astounding evolutionary
changes in comparison to the same gene in chimpanzees, the primate closest to us
on the evolutionary scale. Chimps are the brightest primates next to us.
Intellectual luminosity successively dims in other primates as they descend the
evolutionary ladder--gorillas, orangutans, gibbons, macaques and owl monkeys--as
their ASPM genes become more and more stunted.
The ASPM gene seems to control the multiplication of brain cells, which, in
humans, produces nature's biggest brain in relation to body size.
The human forebrain, for instance, responsible for executive functions,
language and other complex abilities, is twice as big as the forebrain of a
chimpanzee, relative to their sizes, and three times bigger than that of more
distantly related monkeys. Brainpower varies tremendously in the animal kingdom, and
the question of whether animals have thoughts and feelings has yet to be
answered. "It's possible that, when the human brain achieved a critical size,
intelligence became possible," Lahn said.
The human brain is unique, the epitome of the evolutionary process itself,
quick to adapt to any environment in which it finds itself and possessing an
unparalleled capacity to remember the past, deal with the present and plan for
Besides the brain, what makes humans and chimps look so different? The
numbers provide the answer. Human and chimp genomes each have about 3 billion
nucleic acid building blocks in their DNA. If they are 99 percent similar, that
means 1 percent are different. One percent of 3 billion is 30 million.
So about 30 million genetic differences between humans and chimps have
occurred since they separated from the same family stalk 5 million to 6 million
years ago. That's more than enough genetic disparity to account for their
appearances and capabilities.
Many of these changes resulted in mutations that gave the human branch new
powers, some of them relatively recently. Researchers from the Massachusetts
Institute of Technology and Washington University School of Medicine in St. Louis
compared hundreds of key genes that humans and chimps share, finding critical
mutations in the human version of the gene for speech, which may have changed
just 100,000 years ago. Similar mutations were found in human genes for
hearing, brain building and bone construction.
Today's evolutionary geneticists are going far beyond Darwin. Survival of the
fittest, or natural selection, was a revolutionary concept, but the mechanics
of how it worked were unknown.
That question can only be answered now with the powerful new tools of
molecular biology that recently decoded the human genome and are quickly spelling out
the genetic makeup of other species.
The genes of life are being compared for the first time. It is a remarkable
feat made possible in the late 1990s with the huge push to complete the Human
Genome Project, the $3 billion international effort to decipher all human
The first draft of the human genome was posted on the Internet on July 7,
2000, a river of G's, A's, C's and T's reciting the triumphs and tragedies of our
ancestors as they struggled to survive over billions of years.
"The sheer volume of data that can be generated now is astonishing," said
Green of the Human Genome Institute. "What used to be generated in the course of
several years in somebody's laboratory can now be generated in less than an
The same genes found in bacteria are found in humans, but we have many more.
Bacteria are admirably suited to survive anywhere just the way they have been
for billions of years, single-cell creatures that have taken over the world.
They make up the vast majority of Earth's biomass.
"Our planet is totally dependent upon the microbial world," said molecular
evolutionist Mitchell Sogin of the Woods Hole Marine Biological Laboratory.
"Microbes have always been important. The end point of evolution leading to us is
really something that happened in a twinkling of an eye in terms of geological
Complex creatures like humans are more at the mercy of environmental changes,
whether it's an ice age, tropics, jungle, savanna, meteor or predators.
Complex organisms had to move swiftly to find new uses for existing genes that
would endow them with better survival skills.
Discovering how those skills evolved is the job of geneticists as they
reverse-engineer life to learn how it was put together. That brings up an intriguing
question: If they find out how the machine was built, can they build a better
It's a question scientists know they will soon have to face. It probably
holds more significance for humanity than the problem confronting physicists more
than half a century ago when they unleashed the might of the atom, opening the
door to abundant energy or unbelievable destruction.
Some scientists, even though they are exploring the foundation of life,
oppose using that powerful knowledge to tinker with people.
Others, like Lahn, think human control of life is the next step in the
progression of evolution. "If you understand it, if you know the key genes that are
important for human evolution, then there is a potential that that knowledge
could be used to further advance the species.
"It's fully conceivable that some years from now, maybe a hundred years,
evolution, at least in terms of the human species, would occur at a more
intelligent level," he said.
Actually, it may happen sooner than that. Researchers have already made what
some might call artificial life. Stringing together nucleic acids to form
genes, they produced the same DNA pattern of two different viruses. Both synthetic
viruses were infectious just like the real thing. Viruses are considered
marginal life forms because they cannot reproduce by themselves, needing to infect
a host and take over its genetic machinery.
Evolution, scientists are finding, can inch forward by making small mutations
in single genes, or it can leap ahead by the wholesale duplication of genes
that then undergo mutations to give them spanking new properties--thumb, toe,
More gene families
The reason complex species have 10 to 100 times more genes than simple ones
is not because they have more totally new genes. Rather, they have more gene
families--genes that came from common genetic ancestors through a biological
A human, for example, has about 12 varieties of the globin gene, which makes
an oxygen-carrying protein in the blood. They are all duplicates of a single
globin gene that originated in bacteria. The genes underwent mutations over
time, acquiring different properties that enabled humans to breathe oxygen in
Geneticists generally believe this kind of gene family expansion is a major
source of new genetic information, the engine of evolution. In humans, for
example, there are gene families that are very large, and a single gene family can
contain several thousand genes. That is not seen in simple organisms such as
"Mammals have evolved from bacteria that are still here," said the University
of Chicago's Wen-Hsiung Li, one of the first scientists to develop widely
used methods for comparing genomes of different species.
"As long as you have a good niche, the organism will continue to survive," he
said. "But some of them may be able to diverge, branch out to a new niche and
become a new organism.
"Mice are still mice because they have a good niche," Li said. "If you look
at the same genes in humans, chimps and gorillas--we all came from the same
origin--our genes have changed a lot. Gorillas have changed less because they
have been able to survive in their niche."
Searching the dark depths around superhot vents at the bottom of the ocean,
scientists discovered an organism long thought extinct. Its genes are so simple
and primitive that they may be the smallest number of genes necessary for
life. If so, N. equitans could be the closest relative of the first living
organism on Earth, said molecular biophysicist Dieter Soll of Yale University
N. equitans is a member of the archaea domain that thrives in superboiling
water. It has only 552 genes--compared to 2,000 to 5,000 genes in bacteria and
about 30,000 to 35,000 human genes--and it doesn't have many non-functional
genes, as do higher organisms.
It has the leanest genome known, suggesting that it has remained basically
the same since its astoundingly ancient beginning, neither gaining nor losing
much material. Ninety-five percent of N. equitans' DNA is made of working genes,
compared to only about 3 percent of the human genome. The vast non-functional
portion of our DNA contains a lot of DNA that once made up genes. But a lot
of our non-functional genome is simply DNA remnants that never made it to gene
status and now serve as scaffolding to keep working genes in their proper
So far, Yale scientists have discovered about 10,000 dead genes--genes from
long-distant relatives that pushed evolution forward but died off when they
outlived their usefulness. They are still hanging around our genome, silent
sentinels of a glorious past that extends millions of years back in time.
The amazing thing about N. equitans is that its genes are a stripped-down
model of the most fundamental machinery needed to make inanimate chemicals come
alive. "This is the machinery that makes DNA, RNA and proteins. It is
absolutely essential machinery, very old and very conserved," Soll said.
Discovering N. equitans is like finding the very first Tinkertoy. So
essential are its genes to life, in fact, that humans and other organisms still rely
on the same ones.
N. equitans may be living in a time warp, a primitive organism contented to
munch on hot sulfurous nutrients in a sunless niche that may resemble the
primordial conditions on Earth when life first began.
All other organisms climbed the tree of life, adorning themselves with genes
like apples that scientists can now pluck and study.
"We used to ask such questions as: `Are there any genetic determinants for
sexual preference?' And all we got were blank stares," said Chung-I Wu, chairman
of U. of C.'s department of ecology and evolution.
"You had people who studied genes and those who studied sexual preference.
But the people who studied sexual preference could never find the genes, and the
people who studied genes never were quite sure what the genes really could do
at that level," he said.
Wu and his colleagues found a sexual attraction gene in fruit flies. It is
the same fat-metabolizing gene that, when turned on in hot-climate flies, allows
them to survive in cold temperatures. The gene also changes the makeup of
waxy aromatic compounds coating the abdomen of female flies, which give off a
scent that attracts males. The genetically manipulated females were no longer
appealing to the hot-climate males, but they suddenly became irresistible to
"Now, everything we are looking at--your brain size, your body size, your
hypertension, your diabetes, your sexual attractiveness--is under a network of
gene control," Wu said. "Now there is the possibility of connecting complex
biology with complex genetics. That's the future."
Exploring the future, the Chicago team overturned a long-held dictum: that
mutational changes in genes take place at a constant rate over evolutionary
time, the so-called molecular clock.
Li and Wu found instead that the genetic clock runs at different
speeds--faster in organisms like mice that have short generation times, and longer in
humans and other organisms that have greater life spans.
Li, the newest recipient of the $709,000 Balzan Prize in genetics, referred
to as the Italian Nobel, was instrumental in setting off another genetic
bombshell, discovering a surprisingly high mutation rate in males compared to
Unlike the eggs a female is born with, which carry her genetic contribution
to offspring, sperm are made by the millions every day. Each sperm requires the
replication of half of a male's genes, a process known to lead to genetic
errors or mutations.
Comparing the genes of humans, monkeys and mice, Li found that the male
mutation rate was phenomenally higher, more than 5 times greater than that of
females. "That tells you that most mutations were due to the male germ line," or
sperm cells, he said. "We call that male-driven evolution."
The mutation rate may be male driven, but females have an equal say in the
final product. Natural selection--determining which offspring have the best
chance of survival--is a joint effort of the two sexes.
X vs. Y
Take the sex chromosomes --X in females and Y in males. The U. of C.'s Lahn
showed earlier that they were derived from two regular chromosomes 200 million
to 300 million years ago when evolutionary pressures made it necessary to have
a new method of determining sex in changing environments.
Back then, when our mammalian ancestors were more like reptiles, sex
chromosomes did not exist. Sex was determined by temperature at the time a brood was
hatched, and still is in reptiles. Depending on the temperature, they could all
be female, all male or half-and-half.
Sex chromosomes gave evolution a big boost, freeing mammals to explore and
reproduce in new niches not dependent on temperature.
"The Y chromosome lost most of its ancestral genes, but the few it does carry
are involved in male-specific functions, such as making sperm," Lahn said.
"Just by virtue of having a male chromosome, which carries genes beneficial only
for males, that may have further exaggerated the sex differences between
males and females." (Males have an X and a Y sex chromosome, females two Xs.)
Although the male mutation rate is higher, it rarely produces significant
genetic changes within a few generations. But over millions of years, these
mutations can add up to major evolutionary advances.
According to the U. of C.'s Wu, male mutations are also largely responsible
for the formation of new species.
"Male reproduction represents the most fascinating aspect of biology," he
said. "The reason is very simple: In animals there are so many sperm chasing so
few eggs. So the competition among males is really intense. Evolutionary
changes tend to affect males because the male reproductive system has to be retooled
constantly in order to stay ahead of the curve."
Speciation is usually defined as the inability of species to cross-breed, an
evolutionary device to ensure the survival of a species in a new niche.
Experimenting with fruit flies, Wu discovered the first speciation gene in
sperm, called Odysseus. The gene is harmless in one species but causes sterility
when transplanted into another species.
When two species are crossed, the first thing that usually occurs is male
sterility. Male sterility plays the central role in animal speciation because it
reduces gene flow between diverging populations, thereby allowing a new
species to form.
More than a million species thrive above, on or below Earth's surface. Many
more have come and gone, faded chapters of the unfinished book of life.
"I look at life as a piece of art," Wu said. "You put all the pieces together
and you see how nature weaved a thing together and how it created from the
same thing two very different-looking species. And each one is elegant and
beautiful in its own right."
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