BASIC CONCEPTS IN GENETICS
Knowledge of the basic principles of genetics and an under-standing of their application are essential in current med-ical practice. These principles form the basis for screening, diagnosis, and management of genetic disorders.
Genes, the basic units of heredity, are segments of deoxyri-bonucleic acid (DNA) that reside on chromosomes located in cell nuclei. DNA is a double-stranded helical molecule. Each strand is a polymer of nucleotides made up of three components: (1) a “base,” which is either a purine (adenine [A] or guanine [G]) or a pyrimidine (cytosine [C] or thymine [T]); (2) a 5-carbon sugar; and (3) a phospho-diester bond. The strands of the DNA helix run in an antiparallel fashion, adenine binding to thymine and cyto-sine binding to guanine. These base pairs, in their nearly limitless combinations, constitute the genetic code.
The information in the DNA must be processed before it can be used by cells. Transcription is the process by which DNA is converted to a messenger molecule called ribonucleic acid (RNA). During transcription, the DNA molecule is “read” from one end (called the 5-prime [5′] end) to other end (called the 3-prime [3′] end). A mes-senger RNA (mRNA) molecule is formed that is exportedfrom the cell nucleus into the cytoplasm. This mRNA contains a translation of the genetic code into “codons.” Transcription is regulated by promoter and enhancer sequences. Promotor sequences guide the direction of translation, from 5′ to 3′, and are located on the 5′ end. Enhancer sequences have the same function, but arefound further down the 5′ end of the DNA molecule.
After transcription is complete, mRNA is used as a template to construct the amino acids that are the build-ing blocks of proteins. In this process, called translation, each codon is matched to its corresponding amino acid. The amino acid strand grows until a “stop” codon is encountered. At this point, the now completed protein undergoes further processing and is then either used inside the cell or is exported outside the cell for use in other cells, tissues, and organs. Errors in the DNA replication process can occur in a variety of ways and lead to a mutation, a change in the normal gene sequence. Most DNA replica-tion errors are rapidly repaired by enzymes that proofread and repair mistakes.
Replication errors are of four basic kinds: (1) missense mutations, in which one amino acid is substituted for another; (2) nonsense mutations, in which premature stop codons are inserted in a sequence; (3) deletions; and (4) insertions. An example of a replication error causing a recognized disease is Huntington disease, in which an abnormal number of CAG repeats occurs in the Huntington gene. DNA can also be damaged by environ-mental factors, such as ultraviolet light, ionizing radiation, or chemicals.
The genetic information in the human genome is packaged as chromatin, within which DNA binds with several chromosomal proteins to make chromosomes. A karyo-type reveals the morphology and number of chromo-somes. Somatic cells are all the cells in the human body that are not gametes (eggs or sperm). Germ cells, or gametes, contain a single set of chromosomes (n= 23) and are described as haploid in number. Somatic cells contain two sets of chromosomes, for a total of 46 chromosomes.These cells are diploid, signifying that they have a 2n chro-mosome complement (2n = 46). These chromosome pairs consist of 22 pairs of autosomes, which are similar in males and females. Each somatic cell also contains a pair of sex chromosomes. Females have two X sex chromosomes; males have an X and a Y chromosome.