Section 1. Fundamentals

Chapter 2. Genetics

Topics: Introduction | Gene Abnormalities | Gene Technology | Gene Therapy

Introduction

The body's genetic material is contained within the nucleus of each of its cells, which in an adult person number over 5 trillion. The genetic material consists of coils of DNA (deoxyribonucleic acid) arranged in a complex way to form chromosomes. Human cells each contain 22 pairs of nonsex (autosomal) chromosomes, and one pair of sex chromosomes, for a total of 46 chromosomes.

See the figure Structure of DNA.

Each DNA molecule is a long double helix that resembles a spiral staircase. The steps of the staircase, which determine a person's genetic code, consist of pairs of four types of molecules called bases (nucleotides). In each step, adenine (A) is paired with thymine (T), or guanine (G) is paired with cytosine (C). The genetic code is written in triplets, so each group of three bases codes the production of one of 20 possible amino acids, which are the building blocks of proteins. For example, "GCT" codes for the amino acid alanine, while "AAA" codes for the amino acid lysine.

A gene consists of the code required to construct one protein. Thus, a gene is a collection of DNA in sequence. Genes vary in size, depending on the size of the protein they code for. All inherited characteristics (traits) are encoded by genes (although many traits are governed by more than one gene). Some genetically determined characteristics, such as hair color, simply distinguish people from one another; variations in hair color are not considered abnormal. However, other genetically determined characteristics are important for the body's normal structure or function; variations in the genes controlling such characteristics may result in a hereditary disease.

A chromosome is a collection of genes. Genes are arranged in a precise sequence on the chromosomes; the location of a particular gene on a chromosome is called its locus.

Telomeres are like tiny caps at the ends of each chromosome and protect the chromosome from damage. Before a cell divides, it must replicate all its DNA. However, the cell has difficulty replicating the telomeres (which are also made of DNA), and each time it does so the telomeres get slightly shorter. Eventually, on any given chromosome, the telomeres disappear completely. The disappearance of the telomeres seems to lead to cell death, thus one cause of aging might be the gradual shortening of the telomeres. Curiously, some cancer cells either manage to preserve the length of the telomeres or manage to survive despite loss of the telomeres.

A person's genetic makeup is called the genotype. The genotype is a complete set of instructions on how the body is "supposed" to be built. The body's response to having these genes--that is, the expression of the genotype (how the body is actually built)--is called the phenotype.

Many genetically determined characteristics are the result of more than one gene. For example, a person's height is likely to be determined by genes affecting growth, appetite, muscle mass, and activity level along with myriad nongenetic influences. Susceptibility to disease is often the combination of multiple genetic influences as well. Thus, it is not always easy to determine which hereditary influences most affect phenotype.

Transferring Information From DNA

When a part of the DNA molecule is actively controlling some function of the cell, the DNA helix splits open along its length. One strand of the open helix is inactive; the other strand is active and acts as a template against which a complementary strand of RNA (ribonucleic acid) forms. The RNA bases are arranged in the same sequence as bases of the inactive strand of the DNA, except that RNA contains uracil (U) instead of thymine (T). The RNA copy, called messenger RNA (mRNA), separates from the DNA, leaves the nucleus, and travels into the cytoplasm of the cell. There, it attaches to a ribosome; ribosomes are the cell's factories for manufacturing proteins. The messenger RNA instructs the ribosome as to the sequence of amino acids for constructing a specific protein. Amino acids, which are floating free in the cytoplasm, are brought to the ribosome by transfer RNA (tRNA), a much smaller type of RNA. Each molecule of transfer RNA brings one amino acid to be incorporated into the growing chain of protein, which is folded into a precise shape under the influence of nearby "chaperone" molecules.

When cells divide (either for growth or for replacing cells that die), DNA replicates itself. The DNA helix unravels, and through a stepwise process, a new molecule of DNA forms. If all goes as planned, each new cell has DNA that is identical to what was in the cell from which it derived. If a mistake occurs, a mutation develops. Often, a mutation is lethal to the cell, and the cell dies. In some cases, a mutation is trivial and there is no noticeable consequence. In other cases, the mutation does not kill the cell but introduces a change that is either detrimental or advantageous to the cell.

Sex Chromosomes

The two sex chromosomes determine whether a fetus becomes male or female. Males have one X and one Y chromosome; females have two X chromosomes, only one of which is active.

There are other genes on the X and Y chromosomes besides those that control sex. However, the Y chromosome carries relatively few genes other than the ones that determine male sex. The X chromosome contains many more genes than the Y chromosome. Genes on the X chromosome are referred to as sex-linked, or X-linked, genes. In males, virtually all of the genes on the X chromosome, whether dominant or recessive, are expressed, because there is no second X chromosome to offset the instructions of recessive genes on the one X chromosome.

Because a female has two X chromosomes, she has twice as many X-chromosome genes as does a male. This would seem to result in an overdose of some genes. However, one of the two X chromosomes in each cell of the female--except in the eggs in the ovaries--is thought to be inactivated early in the life of the fetus. The inactive X chromosome (the Barr body) is visible under a microscope as a dense lump in the nucleus of the cell.

See the figure Inheriting Abnormal Recessive Genes.

The inactivation of the X chromosome explains certain observations. For example, extra X chromosomes cause far fewer developmental abnormalities than extra nonsex (autosomal) chromosomes, because no matter how many X chromosomes a person has, all but one seem to be inactivated. Women with three X chromosomes (triple X syndrome) are often physically and mentally normal (see Section 23, Chapter 266). In contrast, an additional nonsex chromosome can be fatal during early fetal development or can lead to many severe physical and mental abnormalities (for example, Down syndrome (see Section 23, Chapter 266)). Similarly, the absence of a nonsex chromosome is invariably fatal to the fetus, but the absence of one X chromosome usually results in relatively minor abnormalities (Turner syndrome (see Section 23, Chapter 266)).