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That effort, says Caltech research fellow Richard Wilson, "is analogous to going around and shaking hands with everyone on earth." The resulting string of code letters, according to the 1988 National Research Council report urging adoption of the genome project, would fill a million-page book. Even then, much of the message would be obscure. To decipher it, researchers would need more powerful computer systems to roam the length of the genome, seeking out meaningful patterns and relationships.
It was from the patterns and relationships of pea plants that a concept of heredity first arose in the mind of Gregor Mendel, an Austrian monk. In 1865, after studying the flower colors and other characteristics of many generations of pea plants, Mendel formulated the laws of heredity and suggested the existence of packets of genetic information, which became known as genes. Soon afterward, chromosomes were observed in the nuclei of dividing cells, and scientists later discovered a chromosomal difference between the sexes. One chromosome, which they named Y, was found in human males' cells, together with another, called X. Females' cells, on the other hand, had two copies of X.
But it was not until 1911 that a gene, only a theoretical entity at the time, was correctly assigned to a particular chromosome. After studying the pedigrees of several large families with many color-blind members (males are primarily affected), Columbia University scientist E.B. Wilson applied Mendelian logic and proved that the trait was carried on the X chromosome. In the same manner over the next few decades, several genes responsible for such gender-linked diseases as hemophilia were assigned to the X chromosome and a few others attributed to the Y.
Scientists remained uncertain about the exact number of human chromosomes until 1956, when improved photomicrographs of dividing cells clearly established that there were 46. This revelation led directly to identification of the cause of Down syndrome (a single extra copy of chromosome 21) and other ( disorders that result from distinctly visible errors in the number or shape of certain chromosomes.
But greater challenges lay ahead. How could a particular gene be assigned to any of the nonsex chromosomes? Scientists cleverly tackled that problem by fusing human cells with mouse cells, then growing hybrid mouse-human cells in the laboratory. As the hybrid cells divided again and again, they gradually shed their human chromosomes until only one -- or simply a fragment of one -- was left in the nucleus of each cell.
By identifying the kind of human protein each of these hybrid cells produced, the researchers could deduce that the gene responsible for that protein resided in the surviving chromosome. Using this method, they assigned hundreds of genes to specific chromosomes.