According to the National Institute of Health, this 13-year project has resulted in the identification of over 1800 genes linked to diseases and the development of approximately 1000 genetic tests.

The project has further prompted extensive research into the use of gene therapy in which viruses are used to carry genes into the cells. For example, in two separate studies gene transfer therapy was found to be effective in halting retinal degeneration and improving visual acuity in young adults with Leber’s congenital amaurosis (optic neuropathy). Gene therapy is designed to replace missing or defective genes. As a result of the HGP, the HapNap project is now focusing on various diseases worldwide. As research continues, the focus will be on genomic scanning to prevent and/or diagnose early, perfecting gene therapy, and gaining more insight into drug discovery based on specific gene targets. Some predict that within 20 years, patients entering a medical facility will be subjected to a genomic scanning for pathogenic and “epistatic” genes. Epistasis refers to the tendency of some genes to interact and cross over with genes other than their allelic partners. Epistasis appears to affect certain diseases positively or negatively and has the potential to result in variable intensities of disease in different ethnicities and individuals.

One area of genomics that has progressed more slowly than anticipated is that involving drug discovery based on specific gene targets unveiled by the HGP. Progress in this area has been slow for a number of reasons. First, the complexity of the human physiologic system has proven to be a bit daunting, perhaps accounting for the fact that most of the highly effective drugs on the market today, such as aspirin, act on multiple gene systems rather than on single-gene disorders. The tendency of genes to experience epistatic interactions has also hindered the pace of drug production through gene targeting.

Results of the HGP will have enormous ethical implications for prenatal testing and selective abortion of defective embryos. Ethical implications are also involved in testing concerned adults who seek to know the likelihood of their developing a specific disease, such as Huntington disease, in the future. This is especially troubling if the identified disease is one for which there is no treatment or cure, or if testing involves children. For adults and children with disease-causing mutations, future childbearing choices, the ability to purchase health insurance or life insurance, and the ability to find future employment are important considerations. The HGP has dedicated funding and time to explore the ethical factors involved in gene mapping. In the fall of 2005, a study was initiated by the National Human Genome Research Institute among healthy adult volunteers to sequence 100 to 300 genes that have been associated with various disease phenotypes. The aim is to provide information to
individuals on potential genetic risk factors and to evaluate how this enormous amount of information is handled by the patients and their families.

There are approximately 25,000 genes in the human genome, with each gene containing a few hundred to a few thousand base pairs of DNA. This is a much smaller number of genes than expected, given the complexity of the human genome. The DNA of a given gene includes coding portions, called exons, and noncoding portions. The coding portions of a gene carry the information needed to make a protein, often an enzyme. Enzymes and other proteins control the synthesis and function of each and every cell or tissue of the body. The function of the millions of molecules of noncoding DNA is unclear. Many genes grouped together make up the chromosomes.

Chromosomes are made up of molecules of DNA, complexed with proteins called histones. Chromosomes carry the genetic blueprint of an individual. All human somatic (body) cells contain 23 pairs of chromosomes, one pair from each parent, for a total of 46 chromosomes. Of the 23 pairs of chromosomes, 22 are the same in both sexes. The 23rd pair consists of the sex chromosome, X or Y. The female has two X chromosomes and the male has one X and one Y. Each human sex cell, an egg or a sperm, contains 23 unpaired chromosomes. Each chromosome is nearly identical (approximately 99.9%) across the human species in the genetic information it contains. The remaining variations are subtle but enough to make each one of us unique.

Although each somatic cell contains the same 23 pairs of chromosomes, only certain genes are activated in any given cell; therefore, only certain proteins or enzymes are produced by that cell. Which genes are activated in which cell is determined during embryologic development and throughout life by circulating growth factors, hormones, and chemical cues produced by a given cell and its neighboring cells. In addition, methylation of certain regions of a gene (adding a CH₃ group) can turn off, or silence, that gene. Demethylating the region can activate that gene and lead to the production of the protein for which it codes. In general, cells that have similar genes turned on and off perform similar functions and group together as tissues.

It has recently become clear that many genes can code for more than one protein, a finding that helps explain how so few genes can result in so many
different proteins. Recent research suggests that a process known as “alternative splicing” is responsible for this phenomenon. Alternative splicing refers to different combinations of exons on one gene that become active at different times, with each combination resulting in the production of one protein.

Each chromosome is composed of hundreds of thousands of molecules of DNA. DNA is made up of phosphoric acid, a sugar molecule called deoxyribose, and one of four possible nitrogen bases: adenine, guanine, cytosine, or thymine. DNA molecules line up in the cell in the form of a double helix (Fig. 2-1) DNA, in which the phosphoric acid and the deoxyribose sugar form
the backbone of the helix. The base pairs from two molecules of DNA lie between the two strands of the helix, opposing each other. Adenine always bonds across the helix with thymine, and cytosine always bonds with guanine. The bonds are loose, so that the helixes can separate when cell division occurs or when protein synthesis is initiated.

To replicate, the DNA double helix uncoils and each strand of DNA serves as a template for a new strand. In the formation of a new strand of DNA, each adenine will bind only with a thymine and each cytosine will pair only with guanine. Therefore, only one strand, acting as a mirror-image template for the other, is needed to replicate the entire double helix.

Replication of the chromosome pairs and the DNA occurs in the nucleus of the cell. Various enzymes participate in DNA replication, which results in each chromosome being exactly copied or duplicated. The duplication is checked and double-checked by several proofreading enzymes to ensure that no mistakes are made. If a mistake is identified, proofreading or other enzymes remove the error and correct it, or the cell may initiate its own death in a process called apoptosis. If a mistake is not repaired, and the cell does not undergo apoptosis, a mutation in the DNA will exist.

The cell cycle (Fig. 2-2) refers to a sequence of stages that a cell goes through during its lifetime. During embryogenesis, all cells go through all stages, as
do adult cells that continue to reproduce. The rate at which a cell goes through its cell cycle depends on the given cell and the growth factors, hormones, and chemicals to which it is exposed. Cells that do not continue to reproduce after embryogenesis remain in a resting stage and do not cycle through the other stages. The cell cycle is divided into two parts: interphase and mitosis.

Meiosis is the process during which germ cells of the ovary (primary oocytes) or testicle (primary spermatocytes) give rise to mature eggs or sperm (Fig. 2-4). Meiosis involves DNA replication in the germ cell, followed by two cell divisions rather than one, which results in four daughter cells, each with 23 (unpaired) chromosomes. In males, all four daughter cells are viable and continue to differentiate into mature sperm. In females, only one viable daughter cell (egg) is formed; the other three cells become nonfunctional polar bodies. During fertilization, genetic information contained in the 23 chromosomes of the egg joins with genetic information contained in the 23 chromosomes of the sperm. This results in an embyro with a total of 46 chromosomes (two pairs of 23).

An interesting phenomenon occurs during DNA replication in the first meiotic stage. At this time, pieces of DNA may shift between the matched chromosome pairs, in a process called crossing over. Crossing over increases the genetic variability of the offspring, and is one reason why siblings within a family may vary considerably in genotype and phenotype.

To transcribe or make a copy of a gene, the area of the double helix on the chromosome where that gene is contained must unravel. Once unraveled, a special enzyme, called an RNA polymerase, attaches to a certain section at the start of the gene, called the promoter or controlling sequence. When the RNA polymerase attaches to this site, the gene is copied as a mirror image, in a manner similar to that described for DNA replication. The product is a similar molecule called ribonucleic acid (RNA). RNA, like DNA, contains phosphoric acid, but unlike DNA, it contains the sugar ribose instead of deoxyribose and the base uracil instead of thymine. When the gene is copied as RNA, each cytosine base in the gene becomes a guanine in the copy, each guanine becomes a cytosine, each thymine becomes an adenine, and each adenine becomes a uracil. The entire gene is transcribed by this procedure. After the gene is copied, the RNA polymerase will reach a special sequence on the DNA (called the termination sequence) and the process will stop. The RNA copy is released from the gene and moves into the cytoplasm. The RNA copy that carries the DNA message out of the nucleus is called the messenger RNA (mRNA). The mRNA then moves through the cytoplasm to the ribosomes (Fig. 2-5).

Adenine, guanine, cytosine, and uracil are carried as mRNA to the ribosomes in groups of three, called triplets or codons. Each triplet codes for one amino acid. There are 20 amino acids used in the human body that combine in various ways to make up all the proteins of the body. The long strand of mRNA triplets can be snipped at any point before the molecule leaves the nucleus, allowing different proteins to be made from one original gene.

Before the ribosomes make the protein from the mRNA template, another type of RNA, called transfer RNA (tRNA), binds to the mRNA by connecting mirror-image bases (called anticodons) to each triplet of mRNA bases. At the opposite end of the anticodon is the amino acid coded for by those three bases. There are at least 20 types of tRNA, each one carrying a certain amino acid on one end and the anticodon for that amino acid on the other end.

When the mRNA has found its matching tRNA, both molecules bind onto the ribosome, which is composed partly of a third type of RNA—ribosomal RNA. The amino acid carried by the tRNA is added to a chain of amino acids growing on the ribosome until the ribosome is signaled to stop adding to the chain by a special codon known as a stop codon. The protein is then complete and is freed from the ribosome.

Regulatory proteins block or activate the promoter section of each gene in the cell, determining which genes will be turned on, transcribed into mRNA, and made into a protein. If a regulatory protein blocks the promoter region of a gene, protein synthesis will not occur from that gene. If a regulatory protein binds to, or near, the promoter area in such a way that it makes the area accessible to the RNA polymerase, it will activate the gene’s transcription into mRNA. This type of protein would be considered a transcription factor or enhancer; if, on the other hand, a regulatory protein blocked the promoter area of a gene so that it was not transcribed into mRNA, the regulator protein would be a repressor.

Production and activation of regulatory proteins appear to be linked to other genes responding to feedback signals, chemical cues, and hormones such as thyroid hormone and growth hormone. These signals result in the production of proteins with repressor or activator functions. Other factors that alter the function of the histones responsible for folding and exposing different portions of the DNA may also affect DNA transcription. Methylation (adding a CH₃

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