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 X-rays 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/2001/021201humangenome/

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 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

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.

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 gene-predicting 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 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

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.

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 gene-dense 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 transposons, large segments of the genome seem to have duplicated over time, both within and between chromosomes. This duplication, researchers say, allowed evolution to play with different genes without destroying their original function and probably led to the expansion of many gene families in humans. Apart from the genome sequence, both the Human 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

Image: DOE Human Genome Program

HARDLY DONE. Only one billion base pairs (yellow, orange and blues, above), or a third of the total, in the public database are in a "finished" form.

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