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Clearer blueprint Scientists looking at life in reverse

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    Click here: Chicago Tribune | Clearer blueprint Clearer blueprint Scientists looking at life in reverse By Ronald Kotulak a Tribune science reporter February
    Message 1 of 1 , Feb 1, 2004
      Click here: Chicago Tribune | Clearer blueprint
      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
      geneticist.

      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
      traces.

      "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
      the future.

      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
      genes.

      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
      hour."

      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
      time."

      Survival skills

      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
      machine?

      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,
      brain.

      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
      gene-copying machine.

      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
      air.

      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
      yeast.

      "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
      places.

      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
      cold-temperature males.

      "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
      females.

      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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