Porth's Essentials of Pathophysiology, 4e

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Genetic Control of Cell Function and Inheritance

C h a p t e r 5

Metaphase chromosome

Looped domains

Supercoiled fiber in chromatin

Histone core

Linker DNA

Semiconservative Model

Conservative Model

original strand of DNA newly synthesized strand of DNA

Nucleosomes

FIGURE 5-2. Semiconservative versus conservative models of DNA replication as proposed by Meselson and Stahl in 1958. In semiconservative DNA replication, the two original strands of DNA unwind and a complementary strand is formed along each original strand.

DNA double helix

FIGURE 5-3. Increasing orders of DNA compaction in chromatin and mitotic chromosomes. (From Cormack DH. Essential Histology. Philadelphia, PA: J.B. Lippincott; 1993.)

acid (RNA). These and other current findings have put to rest the old hypothesis of “one gene–one protein.” Packaging of DNA The genome is distributed in chromosomes, discrete bundles made up of one continuous, linear DNA helix. Each human somatic cell (cells other than the gam- etes) has 23 pairs of different chromosomes, with one chromosome of each pair derived from the individual’s mother and the other from the father. One of the chro- mosome pairs consists of the sex chromosomes. Genes are arranged linearly along each chromosome. When unraveled, the DNA in the longest chromosome is more than 7 cm in length. If the DNA of all 46 chromosomes were placed end to end, the total DNA would span a distance of about 2 m (more than 6 feet). Because of their enormous length, the DNA double helices are tightly coiled in a complex called chroma- tin , which consists of proteins called histones along with other less well-characterized proteins that appear to be critical for ensuring normal chromosome behavior and appropriate gene expression. The histones play a criti- cal role in proper packaging of chromatin. They form a core around which a segment of DNA double helix winds, like thread around a spool (Fig. 5-3). About 140 base pairs of DNA are associated with each histone core, making about two turns around the core. After a short “spacer” segment of DNA, the next core DNA complex forms, and so on, giving chromatin the appearance of beads on a string. Each complex of DNA with a histone core is called a nucleosome, which is the basic structural

unit of chromatin. Each chromosome contains several hundred to over a million nucleosomes. Although solving the structural problem of how to fit a huge amount of DNA into the nucleus, the chro- matin fiber, when complexed with histones and pack- aged into various levels of compaction, makes the DNA inaccessible during the processes of replication and gene expression. To accommodate these processes, chroma- tin must be induced to change its structure, a process called chromatin remodeling . Several chemical interac- tions are now known to affect this process. One of these involves the acetylation of a histone amino acid group that is linked to opening of the chromatin fiber and gene activation. Another important chemical modification involves the methylation of histone amino acids, which is correlated with gene inactivation. Genetic Code Four bases—guanine, adenine, cytosine, and thymine— make up the alphabet of the genetic code. A sequence of three of these bases forms the fundamental triplet code for one of the 20 amino acids used in protein synthe- sis in humans. This triplet code is called a codon . The molecular link between the DNA code of genes and the amino acid sequence of proteins is RNA, a macromol- ecule similar in structure to DNA, except that uracil (U) replaces thymine (T) as one of the four bases. An example is the nucleotide sequence GCU (guanine, cyto- sine, and uracil), which is an RNA codon for the amino

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