Genetics and Health Health Article

GENETICS AND HEALTH

The role of genetics in medicine and public health came to broad public consciousness quite dramatically in June 2000, when President Bill Clinton and Prime Minister Tony Blair jointly sponsored the announcement by government, academic, and industrial scientists that a "first draft" of the human genome sequence had been completed. Then, in early 2001, the announcement of the full sequencing and a revised estimate of the number of genes in the human genome was released. No doubt many people were mystified by the term "genome," even if they had some idea about what genes and proteins are. The genome is the complete set of genes of each individual in any species. In humans, there are an estimated 30,000 to 100,000 genes in the forty-six chromosomes of, essentially, all human cells. In early 2001, the same scientific groups reported a nearly complete sequence for the human genome, with an estimated 30,000 to 40,000 genes distributed on twenty-three pairs of chromosomes.

THE MOLECULAR NATURE OF GENES

DNA (deoxyribonucleic acid) molecules carry the code for genetic information and its transmission from one generation to the next. For decades it was thought that DNA was a most unlikely candidate for this role, due to its presumed simplicity (compared with proteins). DNA consists of a string of just four different nucleotide bases (A, T, G, C—for adenine, thymine, guanine, cytosine) held together by a sugar (deoxyribose)—phosphate backbone. In contrast, proteins are polypeptide chains of twenty different amino acids, offering much more variation for coding. In a classic experiment in 1944, scientists at the Rockefeller Institute in New York City working with bacteria that cause pneumococcal pneumonia showed that inherited transformation of the surface characteristics of the bacteria could be accomplished with DNA and not with protein.

In 1953, James Watson and Francis Crick, at Cambridge University in England, published the stunning hypothesis that two intertwined strands of DNA, running in opposite directions, could be joined in a double helix through hydrogen bonds linking the nucleotide bases in the specific combinations of A-T and G-C (see Figure 1). This model was justified by available X-ray pictures of the molecular patterns of DNA. Linear sets of three nucleotide bases generate a "triplet code," with sixty-four combinations, more than enough to code for the twenty amino acids. We now know that the double helix of DNA can separate, through actions of enzymes that facilitate unwinding, so that one strand of the double-stranded DNA can be transcribed into messenger RNA (mRNA) molecules. The mRNA is then translated into polypeptides, which assume highly folded three-dimensional structures to function as enzymes, antibodies, and structural components of cells. Other RNA molecules are involved in supporting the formation of the polypeptides and in delivering the right amino acid to the growing polypeptide chain as directed by the triplet code in the mRNA.

This flow of information from DNA to RNA to protein is a general phenomenon throughout living organisms. There are exceptions, such as viruses (including HIV/AIDS [human immodeficiency virus/acquired immunodeficiency syndrome]) which use RNA as their genetic material. When these viruses infect human (or plant or animal) cells, they must first convert their RNA message into DNA to join the flow of information in the cell from DNA to RNA to protein. Similar "reverse transcription" can occur in cancer cells and during

Figure 1

embryological development. Experimental conversion of mRNA to DNA is utilized very extensively to clone and sequence individual genes, key techniques in the field of biotechnology.

THE BASIS FOR INHERITANCE

Long DNA molecules are carried on structures called chromosomes in the nucleus inside each cell. Human chromosomes occur in pairs, one derived from the mother and one from the father in sexual reproduction. Humans have twenty-three pairs of chromosomes, of which twenty-two are similar in males and females. These are numbered 1 through 22, according to chromosome size (1 is the largest). One chromosome pair is different between females and males: XX in females (one X from each parent) and XY in males (X from the mother and Y from the father).

When ordinary cells divide (during fetal development, normal growth, and the regeneration of skin, other organs, and cells lining the lung, intestine, and uterus), the chromosomes must be duplicated and then be distributed to daughter cells so that every cell gets a full set of twenty-three pairs of chromosomes. When the chromosomes are duplicated, the DNA must be replicated, as well.

Egg-forming cells in the ovary and sperm-forming cells in the testes are unique. They are duplicated in a more complex pattern so that they contain only one each of the twenty-three pairs of chromosomes; when egg and sperm then combine, their aggregate of chromosomes is the expected twenty-three pairs.

Something else important can happen during duplication of chromosomes and replication of DNA. There may be recombination across the pairs of chromosomes between the DNA strands, so that genes (information) from the mother are combined at the molecular level with information from the father, and vice versa. Also, there may be mistakes. Mistakes in an individual gene occurring during replication, or when triggered by X-rays, ultraviolet radiation, or chemical reactions, are called "mutations." The complementary double-stranded structure of DNA is a defense against loss of information when DNA is damaged or broken; the damaged strand is repaired using the complementary strand to direct the repair. Mistakes that occur when chromosomes are duplicated can lead to translocations of part of one chromosome onto another, loss of a chromosome or part of a chromosome, or failure of separation of duplicated chromosomes (gaining a third copy of that chromosome, as in Down syndrome, where there are three copies of chromosome 21). In addition, some genes are actually carried outside the nucleus in the energy factories called mitochondria; these can be passed on only by the mother, in the egg cell, and are associated with certain diseases of muscle and brain.