Gene Transcription and Translation: The Central Dogma of Genetics
The central dogma of gene transcription and translation is that the DNA code is transcribed as mRNA code and then translated as amino acid code of the resulting protein (Fig 5-3). The trinucleotides that correspond with amino acids have some redundancy in the system, so that a nucleotide change may not necessarily result in a change in amino acid. The coding region of DNA is composed of exons, several of which are spliced together to make the full coding sequence of RNA. Although the central dogma specifies that DNA determines RNA sequence and that RNA determines amino acid sequence, there are feedback and regulatory mechanisms of gene expression that are both genetically and environmentally determined. These mechanisms, such as methylation and histone formation, can silence gene expression. In addition, small segments of RNA can block mRNA. The study of the influence of these regulatory mechanisms in gene and disease expression is known as epigenetics.
Figure 5-3 The central dogma of genetics, as represented schematically, is that DNA sequence codes are transcribed to the mRNA sequence, and then the mRNA transcription is translated into the amino acid sequence of the coded protein. However, proteins in the form of transcription factors and complementary short RNA sequences can modify translation and transcription. These proteins are being investigated as potential forms of therapy.
Genes control cellular activity through 2 processes:
transcription (expression), in which DNA molecules give rise to RNA molecules, followed by translation in most cases
translation, in which RNA directs the synthesis of proteins. Translation occurs in ribosomes, where mRNA induces transfer RNA (tRNA)–mediated recruitment of amino acids to “build” a protein. A more in-depth description of translation is beyond the scope of this chapter.
Transcription factors are proteins that bind to specific DNA sequences and thus control the flow (or transcription) of genetic information from DNA to mRNA. Transcription factors perform this function by promoting or repressing the recruitment of RNA polymerase to specific genes.
Approximately 10% of genes in the human genome code for transcription factors. They contain one or more DNA-binding domains, which attach to specific sequences of DNA adjacent to the genes that they regulate. There are numerous families of these genes, including the homeobox and paired box genes. PAX6 acts as a master control gene for the development of the eye, an example of the key role of transcription factors in embryogenesis.
Many ophthalmic diseases result from transcription-factor mutations. PAX2 mutations cause colobomas of the optic nerve and renal hypoplasia. PAX3 mutations cause Waardenburg syndrome with dystopia canthorum (types WS1 and WS3). PAX6 mutations are the basis of virtually all cases of aniridia, occasional cases of Peters anomaly, and several other rarer phenotypes, specifically autosomal dominant keratitis and dominant foveal hypoplasia.
Messenger RNA undergoes excision of the introns by a highly organized process called splicing, which leaves the mRNA composed of only exons, or coding segments. The exons can then undergo translation in the ribosomes. Splicing takes place in specialized structures called spliceosomes, which are composed of RNA and proteins. Errors of splicing can lead to genetic disease. Approximately 15% of point mutations that cause human disease do so by generating splicing errors that result in aberrations such as exon skipping, intron retention, or use of a cryptic splice site. For example, mutations in proteins that are vital in splicing can cause retinitis pigmentosa (RP).
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.