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Now, after determining the genome sequence, the next step begins: locating all the genes and characterizing the proteins they encode

by Tamara Traubman

Last week, the scientists decoding the human genome came together and announced what many consider to be one of the greatest achievements in the history of science - the decoding of almost the entire human genome. The draft is incomplete. It has many holes that will not be easy to fill. And now scientists from all over the world are rushing to the next stage of the project, sometimes also known as the post-genomic era: identifying all human genes and their functions.

Decoding the genome, which means identifying the sequence of DNA units, is far from the end of the road. What is obtained from the decoding is a huge chain of about 3 billion DNA letters. The problem is that this genomic text is written in an incomprehensible language: it has no punctuation marks indicating where a gene begins and where it ends. Genes are separated by inconsequential DNA sequences, and the genes themselves are also divided into segments that contain the instructions for their production, called exons, and between them are segments of DNA sequences whose function is unknown, called introns.

Most of the genome is now known only at a first draft level. Only two chromosomes (the tiny packages in which the DNA is packaged) have been fully deciphered: chromosome 22 and chromosome 21. These are the two smallest chromosomes.

Next month, the scientists who are members of the association that finished deciphering the entire sequence of chromosome number 21 two months ago will gather, and will officially open the post-genomic era. The scientists - twenty research groups from seven different countries - will divide among themselves a hundred genes whose existence a computer program predicted on this chromosome based on clues scattered along the DNA sequence (for example, similarities to the DNA sequences of known genes). Each group of researchers will receive five genes and will have to verify their identity, discover their role and characterize the protein they are responsible for producing. There are 125 other known genes in the chromosome, which are known from studies that were done even before they finished deciphering.

Prof. Yoram Groner from the Weizmann Institute, the member of the union, says that they are expected to finish the work within a year. Then chromosome 21 will be the first human chromosome all its secrets are known to man.
Deciphering the complete set of genes in the chromosome, and understanding the interrelationships between them, is very important because most diseases are not the result of one gene, but of several genes. "This will give us a complete catalog of the genes that reside on the chromosome," says Prof. Gruner. This is the goal they want to reach in the genome project, but its completion, in all the other chromosomes, will certainly take decades more.

Chromosome 21 has only 225 genes, but it is biologically and medically fascinating because it contains genes associated with some of the most serious diseases, including Alzheimer's and Down syndrome.

Each group of researchers will also have to discover the characteristics of the proteins that the genes are responsible for producing. Some of the proteins are used to build the body, others are used as messengers that pass messages between the cells or that cause the cell to multiply, stop multiplying or carry out metabolism. When there is a defect in the gene, the instructions for the creation of its protein are wrong and it produces a defective protein. Today it is known about thousands of genetic defects that can cause diseases. Scientists and pharmaceutical companies are investing huge budgets in deciphering the structure of proteins, in what has come to be known as the proteomic industry. Their hope is that understanding the structure of the proteins will make it possible to design more precise drugs, which will inhibit the actions of the "bad" protein.

One of the interesting proteins on chromosome 21 is the one that is produced according to the detailed instructions in a gene called APP. Apparently, this gene is at the beginning of the chain of events that causes Alzheimer's. Other genes - including the BACE2 gene, which is also found on chromosome 21 - turn the protein into amyloid, which accumulates in the brain and causes nerve cell death, which characterizes the disease.

At the same time as the effort to identify all the genes, the scientists are trying to locate the small genetic differences between humans. These differences are the result of a change in a single DNA letter and are called "Single Nucleotide Polymorphism" or SNP for short. Most of them have no effect on the person (because they are found in areas that do not contain genes), but some of them affect a person's chance of developing a disease at some point in their life or their sensitivity to drugs. Because the branches are what differentiates one person from another, their identification is expected to lead to a revolution in medical care, to open an era in which it will be possible to check a person's genetic profile and choose, based on this profile, the most appropriate medical treatment.
{Appeared in Haaretz newspaper, 9/7/2000}

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