Porth's Essentials of Pathophysiology, 4e

90

Cell and Tissue Function

U N I T 1

acid alanine (Table 5-1). Start and stop codons, which signal the beginning or end of a protein molecule, are also present. Although there are only 20 amino acids, plus the start and stop codons, mathematically, the four bases can be arranged in 64 different combinations. As shown in Table 5-1, several triplets code for the same amino acid; therefore, the genetic code is said to be redundant. For example, there are four codons for the amino acid valine. Codons that specify the same amino acid are syn- onymous. Synonymous codons usually have the same first two bases but differ in the third base. Because the genetic code is a universal language used by most living cells, the codons for an amino acid are the same whether that amino acid is found in a bacterium, plant, or human being. Also notice that AUG is the codon for the start sig- nal as well as the codon for the amino acid methionine. DNA Repair Accidental errors in the replication of DNA do arise. These errors are called mutations . Mutations can result from the substitution of one base pair for another, the loss or addition of one or more base pairs, or rearrange- ments of base pairs. Many of these mutations occur spontaneously through normal endogenous processes, whereas others occur because of exogenous or environ- mental agents such as chemical and radiation. Mutations may arise in somatic cells or in germ cells. Only those DNA changes that occur in germ cells can be inherited. Considering the millions of base pairs that must be duplicated in each cell division, it is not surprising that random changes in replication occur. Most of these defects are corrected by DNA repair mechanisms. Several

repair mechanisms exist, and each depends on specific enzymes called endonucleases that recognize distor- tions of the DNA helix, cleave the abnormal chain, and remove the distorted region. The gap is then filled when the correct nucleotides, identified by a DNA polymerase using the intact complementary strand as a template, are added to the cleaved DNA. The newly synthesized end of the segment is then joined to the remainder of the DNA strand by a DNA ligase. The normal regulation of these gene repair mechanisms is under the control of DNA repair genes. Loss of these gene functions renders the DNA susceptible to accumulation of mutations, which can play a role in cancer (see Chapter 7). Genetic Variability As the Human Genome Project progressed, it became evident that the human genome sequence is almost exactly (99.9%) the same in all people. It is the small DNA sequence variation (one in every 1000 base pairs) that is thought to account for the individual differ- ences in physical traits, behaviors, and disease suscep- tibility. These variations are sometimes referred to as single nucleotide polymorphisms (from the existence of more than one morphologic form in a population), or SNPs. An international effort has been organized to develop a genome-wide map of these variations as hap- lotypes (a combination of SNPs at adjacent locations which are inherited together) with the intent of pro- viding a link between genetic variations and common complex diseases such as cancer, heart disease, diabe- tes, and some forms of mental disease (the International HapMap Project is discussed in the section under gene technology).

Triplet Codes for Amino Acids

TABLE 5-1

Amino Acid

RNA Codons

Alanine Arginine

GCU CGU AAU GAU UGU GAA CAA GGU CAU AUU CUU AAA AUG UUU CCU UCU ACU UGG UAU GUU AUG UAA

GCC CGC AAC GAC UGC GAG CAG GGC CAC AUC CUC AAG UUC CCC UCC ACC

GCA CGA

GCG CGG

AGA

AGG

Asparagine Aspartic acid

Cysteine

Glutamic acid

Glutamine Glycine Histidine Isoleucine

GGA

GGG

AUA CUA

Leucine

CUG

UUA

UUG

Lysine

Methionine

Phenylalanine

Proline Serine

CCA UCA ACA

CCG UCG ACG

AGC

AGU

Threonine Tryptophan

Tyrosine

UAC GUC

Valine

GUA

GUG

Start (CI) Stop (CT)

UAG

UGA