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So, what is DNA, anyway?
DNA is a long fiber, like a hair, only thinner and
longer. It is made from two strands that stick
together with a slight twist.
Proteins attach to the DNA and help the strands
coil up into a chromosome when the cell gets ready to
divide.
The DNA is organized into stretches of genes,
stretches where proteins attach to coil the DNA into
chromosomes, stretches that "turn a gene on" and
"turn a gene off", and large stretches whose purpose
is not yet known to scientists.
The genes carry the instructions for making all
the thousands of proteins that are found in a cell.
The proteins in a cell determine what that cell will
look like and what jobs that cell will do. The genes
also determine how the many different cells of a
body will be arranged. In these ways, DNA controls
how many fingers you have, where your legs are
placed on your body, and the color of your eyes.
So, what's the difference between DNA and a
chromosome?
A chromosome is made up of DNA and the
proteins attached to it. There are 23 pairs of
chromosomes in a human cell. One of each pair was
inherited from your mother and the other from your
father. DNA is a particular bio-molecule. All of the
DNA in a cell is found in individual pieces, called
chromosomes.
So, why do you want to learn about DNA?
If you have gotten this far, you already have some
curiosity about DNA. That curiosity may have come
from hearing about it in the news or in the movies. A
revolution has occurred in the last few decades that
explains how DNA makes us look like our parents and
how a faulty gene can cause disease. This revolution
opens the door to curing illness, both hereditary and
contracted. The door has also been opened to an
ethical debate over the full use of our new
knowledge. In the end, curiosity is the reason to
learn about DNA. Fittingly, curiosity is the driving
force behind science itself.
Many genes have more than two alleles
A, B, O blood groups are an example of multiple
alleles. Blood types are determined by the presence
of different glycoproteins on the surface of human
red blood cells.
Some traits are controlled by more than one gene
People arenot either 160 cm or 180 cm tall.
Codominant alleles are both expressed
Blood type AB.
Gene Expression can be affected by external
factors
Especially if a trait is controlled by a single gene, the
gene can be mutated or affected by external factors.
Many genes are active throughout life, but some are
not. An example in humans is the gene that causes
Huntington disease. This disorder which is controlled
by a single dominant gene, is active between the ages
30 and 50 years. Affected individuals undergo a
progressive degeneration of the nervous system,
causing uncontrolled movements of the head and
limbs as well as mental disorder. Research on
molecular genetics has now made it possible to
identify those who will develop the disorder.
Genes are located on chromosomes
Chromosomes: are long strands of dna double helix,
with the strand wrapped around a series of proteins.
DNA: a strand of nucleotides with alternating
phosphate and sugar molecules in along chain, and
with base molecules. Adenine, guanine, cytosine and
thiamine at the side. It is a ladderlike double helix.
Gene: a section of long dna molecule. One gene
carries the information needed to assemble one
protein.
Human genome project:
The sum of all information contaned in the DNA for
any living thing –the sequence of all the bases in all
the chromosomes is known as the organism’s genome.
The Human Genome Project (HGP) is an international
13-year effort formally begun in October 1990 to
discover all the estimated 30,000-35,000 human
genes and make them accessible for further
biological study. Another project goal is to determine
the complete sequence of the 3 billion DNA subunits
(bases in the human genome). As part of the HGP,
parallel studies are being carried out on selected
model organisms such as the bacterium E. coli to help
develop the technology and interpret human gene
function. The DOE Human Genome Program and the
NIH National Human Genome Research Institute
(NHGRI) together make up the U.S. Human Genome
Project.
READING THE BOOK OF LIFE
Journey to the Genome
1866
Gregor Mendel, an Austrian monk,
proposes that discrete, hereditary
units he calls "factors" are passed down
along family lines to produce
recognizable traits. The factors are
later termed "genes."
Gregor Mendel
1910
In studies of the fruit fly, Drosophila,
Dr. Thomas Hunt Morgan, a Columbia
University researcher, proves that
genes are carried on chromosomes.
Later, he determines that genes lie in a
linear order on chromosomes and that
their positions can be mapped.
Thomas Hunt
Morgan
1926
Hermann J. Muller discovers that Xrays induce genetic mutations and
hereditary changes in fruit flies.
1944
Researchers at the Rockefeller
Institute prove that genes are made of
deoxyribonucleic acid by mixing
pneumonia bacteria (pneumococcus)
with foreign DNA to induce inheritable
traits. It had been thought that
proteins were the probable genetic
material.
1953
Dr. James D. Watson and Dr. Francis
Crick, aided by the work of Rosalind
Franklin and Dr. Maurice Wilkins,
discern the structure of the DNA
molecule: two strands of nucleotides
(sugars, phosphate groups and bases)
spiraling around each other in a double
helix. The molecule's shape allows it to
unwind and act as a template for
replication and transcription.
1960
Dr. Sydney Brenner, with Dr. Matthew
Meselson and Dr. Francois Jacob,
proves the existence of messenger
RNA, the transcript that carries the
genetic message from DNA to the cell's
protein-making factories.
Sydney Brenner
1961
Dr. Brenner and Dr. Crick determine
how DNA instructs cells to make
specific proteins. The code is the same
in organisms as diverse as viruses,
bacteria, plants and animals (people).
The universality of the code will
ultimately allow scientists to transfer
DNA from one organism to another.
1970
A new class of molecule is discovered.
These restriction enzymes cut DNA in
specific locations.
1973
A restriction enzyme is used to cut
animal DNA, which is then spliced into
bacteria where the gene's function is
carried out.
1973
Genes are transferred to bacteria,
which reproduce, generating multiple
copies. This cloning allows genes to be
studied in detail.
1977
Dr. Frederick Sanger and Dr. Walter
Gilbert independently develop a
technique to read the chemical bases of
DNA, adenine (A), thymine (T), guanine
(G) and cytosine (C). The technique
increases, by a thousand times, the rate
at which DNA information can be
sequenced.
1977
A virus (bacteriophage) is the first
organism to have its entire genome
sequenced.
1983
Kary Mullis develops the polymerase
chain reaction P.C.R., which allows
scientists to generate billions of copies
of a DNA strand in a matter of hours.
1984 – 1986
Department of Energy officials present
the idea for a large-scale effort to
learn the sequence of the entire human
genome. At a separate conference to
discuss the project, Dr. Gilbert
declares, "The total human sequence is
the grail of human genetics."
1988
Dr. Watson becomes director of the
Office of Human Genome Research at
the National Institutes of Health. He
pledges to decode the genome by 2005
at a cost of $3 billion.
1990
Dr. J. Craig Venter, an N.I.H.
researcher, develops a shortcut method
to find fragments of human genes.
Based on the fragments, whole genes
can be identified.
J. Craig Venter
1995
Dr. Hamilton O. Smith and Dr. Venter
sequence the genome of a bacterium
(Haemophilus influenzae). To do it, they
employ Venter's "shotgun" method in
which Dr. Smith prepares a library of
clones, or chopped-up and amplified
pieces of DNA, which he gives to Dr.
Venter's laboratory. All the pieces of
the genome are sequenced at once and
reassembled later.
1997 - 1998
Dr. Venter meets with Dr. Michael W.
Hunkapiller of PE Biosystems to review
an unreleased technology that greatly
accelerates large-scale sequencing.
Hunkapiller proposes the idea of a
separate human genome project.
May 1998
Dr. Venter joins a new company that
plans to complete the human genome in
three years, well ahead of the
government's target date. The company
is later named Celera.
December 1998
The first full genome of an animal, the
roundworm C. elegans, is sequenced by
two teams of biologists headed by Dr.
John E. Sulston and Dr. Robert H.
Waterston. The project's success
shows that large-scale sequencing is
possible.
March 1999
The publicly financed consortium,
including the Sanger Center in England,
several universities and the N.I.H.,
announces it will move up its target for
the first draft of the human genome to
the spring of 2000. N.I.H.'s
contribution is led by Dr. Francis
Collins.
Francis Collins
March 2000
Two groups led by Dr. Venter and Dr.
Gerald M. Rubin sequence the genome
of the fruit fly, Drosophila, using Dr.
Venter's decoding strategy. The
completion validates Celera's methods.
June 2000
In what President Clinton calls "a day
for the ages," Celera and the public
consortium say they have a working
draft of the genome.
http://www.sciam.com/explorations/2001/021201humangenom
e/
Reading the Book of Life
We have only about twice as many genes as a worm or fly—far fewer
than anyone guessed. So now what?
Last summer the world celebrated when
scientists from the Human Genome Project, an
international consortium of academic research
centers, and Celera Genomics, a private U.S.
company, both announced that they had
finished working drafts of the human genome. It
was an important first step toward deciphering
the entire genome, one of the greatest scientific
undertakings of all time. But these drafts
revealed only the beginning of the story—the
scrolls containing the instructions for life. Now
both teams have started reading—gene after
gene—the actual scriptures within the scrolls.
Today they will announce the results of their
analyses, which will appear in separate papers
in this week’s Nature and Science.
Among other surprises, both papers agree that
Image: DOE Human Genome Program
GENES are encoded in DNA by
four bases, the letters of the genetic
alphabet (A,G,T,C), and can be very
difficult to identify. Chromosomes,
located in the cell's nucleus, contain
the DNA.
humans have a mere 26,000 to 40,000 genes—which is far fewer than many people
predicted. For perspective, consider that the simple roundworm Caenorhabditis
elegans has 18,000 genes; the fruit fly Drosophila melanogaster, 13,000. As of last
summer, some estimated the human genome might include as many as 140,000
genes. It will be several more years before scientists agree on an absolute total, but
most are confident that the final number won’t fall out of the range reported today. "I
wouldn’t be shocked if it was 29,000 or 36,000," says Francis Collins, director of the
National Human Research Institute at the NIH. "But I would be shocked if it was
50,000 or 20,000."
An error margin of some 10,000 genes may not seem impressive after so many years
of work, but genes—the actual units of DNA that encode RNA and proteins—are very
difficult to count. For one thing, they are scattered throughout the genome like
proverbial needles in a haystack: their coding parts constitute only about 1 to 1.5
percent of the roughly three billion base pairs in the human genome. The coding
region of a gene is fragmented into little pieces, called exons, linked by long stretches
of noncoding DNA, or introns. Only when messenger RNA is made during a process
called transcription are the exons spliced together.
To identify functional genes, Collins explains, the
scientists had to "depend upon a variety of bits of
clues." Some clues come from comparisons with
databases of complementary DNAs (cDNAs), which are
exact copies of messenger RNAs. So, too,
comparisons with the mouse genome help because
most mouse and human genes are very similar; their
sequences are conserved in both genomes, whereas a
lot of the surrounding DNA is not. And when such clues
aren’t available, scientists rely exclusively on genepredicting computer algorithms.
Because these algorithms are not totally reliable—
sometimes they see a gene where there is none or
miss one altogether—a few scientists doubt the new
human gene count. For instance, William Haseltine of
Image: DOE Human Genome Program
CLUES BY COMPARISON.
The mouse genome can
help scientists identify
human genes because
most mouse and human
genes are very similar; their
sequences are conserved
in both genomes.
Human Genome Sciences—a company that specializes
in finding protein-encoding genes only on the basis of
cDNA—thinks that "the methods that have been used
are very crude and inexact." He believes that there are
more than twice as many genes as reported thus far by
the two groups.
But many others do accept the current estimates and
are asking what it means that humans should have so
few genes. According to Craig Venter, president of
Celera Genomics, "the small number of genes, means
that there is not a gene for each human trait, that these come at the protein level and
at the complex cellular level." As it turns out, at least every third human gene makes
several different proteins through "alternative splicing" of its pre-messenger-RNA.
Also human proteins have a more complicated architecture than their worm and fly
counterparts, adding another level of complexity. And compared with simpler
organisms, humans possess extra proteins having functions, for example, in the
immune system and the nervous system, and for blood clotting, cell signaling and
development.
Scientists are also puzzling over the significance of the discovery that more than 200
genes from bacteria apparently invaded the human genome millions of years ago,
becoming permanent additions. Today, the new work shows, some of these bacterial
genes have taken over important human functions, such as regulating responses to
stress. "This is kind of a shocker and will no doubt inspire some further study," Collins
says. Indeed, scientists previously thought that this kind of horizontal gene transfer
was not possible in vertebrates.
Another curious feature of the human genome is its overall landscape, in which genedense and gene-poor regions alternate. "There are these areas that look like urban
areas with skyscrapers of gene sequences packed on top of each other," Collins
explains, "and then there are these big deserts where there doesn’t seem to be
anything going on for millions of base pairs." Moreover, such differences are
apparent not only within but also between chromosomes. Chromosome 19, for
example, is about four times richer in genes than the Y chromosome.
So what’s going on in gene deserts? More than half the human genome consists of
repeat sequences, also known as "junk DNA" because they have no known function.
Vertebrates can live well without them: the puffer fish, for example, has a genome
with very few of these repeats. In humans, most of them derive from transposable
elements, parasitic stretches of DNA that replicate and insert a copy of themselves at
another site. But now almost all the different families of transposons seem to have
stopped roaming the genome, and only their "fossils" remain. Still, nearly 50 genes
appear to originate from transposons, suggesting they played some useful role
during the genome’s evolution.
One type of transposon, the so-called Alu element, is
found especially often in regions rich in G and C
bases. These areas also harbor many genes, and so
Alu’s might somehow be beneficial around them.
Overall, the human genome once seemed to be "a
complex ecosystem, with all these different elements
trying to proliferate," says Robert Waterston, director
of the Genome Sequencing Center at the University
of Washington, a member of the public consortium.
Today the mutations they have accumulated provide
an excellent molecular fossil record of the
evolutionary history of humankind.
In addition to repeat sequences caused by
Image: DOE Human Genome Program
transposons, large segments of the genome seem to HARDLY DONE. Only one
have duplicated over time, both within and between billion base pairs (yellow,
chromosomes. This duplication, researchers say,
orange and blues, above), or a
allowed evolution to play with different genes without third of the total, in the public
destroying their original function and probably led to database are in a "finished"
the expansion of many gene families in humans.
Apart from the genome sequence, both the Human
form.
Genome Project and Celera have identified a multitude of base positions in the DNA
that differ between individuals and are called single polynucleotide polymorphisms, or
SNPs (pronounced "snips"). The public consortium discovered 1.4 million SNPs, and
Celera announced it had found 2.1 million of them. Scientists are hoping to learn from
them how genes make people different and, in particular, why some are more
susceptible to certain diseases than others. "It will certainly take us a long time to
figure out what they all mean, if they all mean anything, but I think the process is
already beginning," Waterston notes.
To be sure, much work remains. Only one billion base pairs, a third of the total, in the
public database are in a "finished" form, meaning they are highly accurate and
without gaps. Both the Celera and the public data contain numerous gaps at the
moment. In addition, large parts of the heterochromatin—a gene-poor, repeat-rich
part of the DNA that accounts for about 10 percent of the genome—has yet to be
cloned and sequenced. By the spring of 2003, the public project is hoping to finish
that task, except for sequences that turn out to be impossible to obtain using current
methods.
The next big challenge will be to find out how the genes interact in a cell. According
to Collins, researchers will "begin to look at biology in a whole-genome way,"
studying, for example, the expression of all genes in a cell at a given time. Proteins,
the products of the genes, will also be studied "not just one at a time, but tens of
thousands at a time," Collins says, speaking of a fast-growing research field that
goes by the name of proteomics. In the end, however, genes may provide only so
many answers. "The basic message," Venter concludes, "is that humans are not
hardwired. People who were looking for deterministic explanations for everything in
their lives will be very disappointed, and people who are looking for the genome to
absolve them of personal responsibility will be even more disappointed." —Julia
Karow
RELATED LINKS:
Webcast of Genome Symposium at NIH, Feb. 12, 2:30-5:30 pm E.S.T.
Profile of Francis Collins
Profile of Craig Venter
The Human Genome Race
The Bioinformatics Goldrush
Beyond the First Draft
Personal Pills
SNPs of Disease
Pink Slip in Your Genes
Mapping Chromosome 21