Chapter 062. Principles of Human Genetics (Part 4)

Flow of genetic information. Multiple extracellular signals activate intracellular signal cascades that result in altered regulation of gene expression through the interaction of transcription factors with regulatory regions of genes. RNA polymerase transcribes DNA into RNA that is processed to mRNA by excision of intronic sequences. The mRNA is translated into a polypeptide chain to form the mature protein after undergoing posttranslational processing. HAT, histone acetyl transferase; CBP, CREB-binding protein; CREB, cyclic AMP response element–binding protein; CRE, cyclic AMP responsive element; CoA, Co activator; TAF, TBP-associated factors; GTF, general transcription factors; TBP, TATA-binding protein; TATA, TATA box; RE, response...
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Chapter 062. Principles of Human Genetics (Part 4) Chapter 062. Principles of Human Genetics (Part 4)Figure 62-2 Flow of genetic information. Multiple extracellular signals activateintracellular signal cascades that result in altered regulation of gene expressionthrough the interaction of transcription factors with regulatory regions of genes.RNA polymerase transcribes DNA into RNA that is processed to mRNA byexcision of intronic sequences. The mRNA is translated into a polypeptide chainto form the mature protein after undergoing posttranslational processing. HAT,histone acetyl transferase; CBP, CREB-binding protein; CREB, cyclic AMPresponse element–binding protein; CRE, cyclic AMP responsive element; CoA,Co activator; TAF, TBP-associated factors; GTF, general transcription factors;TBP, TATA-binding protein; TATA, TATA box; RE, response element; NH 2,aminoterminus; COOH, carboxyterminus. The presence of four different bases provides surprising genetic diversity.In the protein-coding regions of genes, the DNA bases are arranged into codons, atriplet of bases that specifies a particular amino acid. It is possible to arrange thefour bases into 64 different triplet codons (4 3). Each codon specifies 1 of the 20different amino acids, or a regulatory signal, such as initiation and stop oftranslation. Because there are more codons than amino acids, the genetic code isdegenerate; that is, most amino acids can be specified by several different codons.By arranging the codons in different combinations and in various lengths, it ispossible to generate the tremendous diversity of primary protein structure. Replication of DNA and Mitosis Genetic information in DNA is transmitted to daughter cells under twodifferent circumstances: (1) somatic cells divide by mitosis, allowing the diploid(2n) genome to replicate itself completely in conjunction with cell division; and(2) germ cells (sperm and ova) undergo meiosis, a process that enables thereduction of the diploid (2n) set of chromosomes to the haploid state (1n) (Chap.63). Prior to mitosis, cells exit the resting, or G0 state, and enter the cell cycle(Chap. 80). After traversing a critical checkpoint in G1, cells undergo DNAsynthesis (S phase), during which the DNA in each chromosome is replicated,yielding two pairs of sister chromatids (2n →4n). The process of DNA synthesisrequires stringent fidelity in order to avoid transmitting errors to subsequentgenerations of cells. Genetic abnormalities of DNA mismatch/repair includexeroderma pigmentosum, Bloom syndrome, ataxia telangiectasia, and hereditarynonpolyposis colon cancer (HNPCC), among others. Many of these disordersstrongly predispose to neoplasia because of the rapid acquisition of additionalmutations (Chap. 79). After completion of DNA synthesis, cells enter G 2 andprogress through a second checkpoint before entering mitosis. At this stage, thechromosomes condense and are aligned along the equatorial plate at metaphase.The two identical sister chromatids, held together at the centromere, divide andmigrate to opposite poles of the cell (see Fig. 63-3). After formation of a nuclearmembrane around the two separated sets of chromatids, the cell divides and twodaughter cells are formed, thus restoring the diploid (2n) state. Assortment and Segregation of Genes during Meiosis Meiosis occurs only in germ cells of the gonads. It shares certain featureswith mitosis but involves two distinct steps of cell division that reduce thechromosome number to the haploid state. In addition, there is activerecombination that generates genetic diversity. During the first cell division, twosister chromatids (2n→ 4n) are formed for each chromosome pair and there is anexchange of DNA between homologous paternal and maternal chromosomes. Thisprocess involves the formation of chiasmata, structures that correspond to theDNA segments that cross over between the maternal and paternal homologues(Fig. 62-3). Usually there is at least one crossover on each chromosomal arm;recombination occurs more frequently in female meiosis than in male meiosis.Subsequently, the chromosomes segregate randomly. Because there are 23chromosomes, there exist 223 (>8 million) possible combinations of chromosomes.Together with the genetic exchanges that occur during recombination,chromosomal segregation generates tremendous diversity, and each gamete isgenetically unique. The process of recombination, and the independent segregationof chromosomes, provide the foundation for performing linkage analyses, wherebyone attempts to correlate the inheritance of certain chromosomal regions (or linkedgenes) with the presence of a disease or genetic trait (see below).