Identity and Structure of Genetic Material (Genetics & Inherited Conditions)
Molecular genetics is the branch of genetics that deals with the identity of the molecules of heredity, their structure and organization, how these molecules are copied and transmitted, how the information encrypted in them is decoded, and how the information can change from generation to generation. In the late 1940’s and early 1950’s, scientists realized that the materials of heredity were nucleic acids. DNA was implicated as the substance extracted from a deadly strain of pneumococcal bacteria that could transform a mild strain into a lethal one and as the substance injected into bacteria by viruses as they start an infection. RNA was shown to be the component of a virus that determined what kind of symptoms of infection appeared on tobacco leaves.
The nucleic acids are made up of nucleotides linked end to end to produce very long molecules. Each nucleotide has sugar and phosphate parts and a nitrogen-rich part called a base. Four bases are commonly found in each DNA and RNA. Three— adenine (A), guanine (G), and cytosine (C)—are found in both DNA and RNA, while thymine (T) is normally found only in DNA and uracil (U) only in RNA. In the double-helical DNA molecule, two strands are helically intertwined in opposite directions. The nucleotide strands are held together in part by interactions specific to the bases, which “pair” perpendicularly to the sugar-phosphate strands. The...
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Copying and Transmission of Genetic Nucleic Acids (Genetics & Inherited Conditions)
James Watson and Francis Crick’s double-helical structure for DNA suggested to them how a faithful copy of a DNA could be made. The strands would pull apart. One by one, the new nucleotide units would then arrange themselves by pairing with the correct base on the exposed strands. When zipped together, the new units make a new strand of DNA. The process, called DNA replication, makes two double-helical DNAs from one original one. Each daughter double-helical DNA has one old and one new strand. This kind of replication, called semiconservative replication, was confirmed by an experiment by Matthew Meselson and Franklin Stahl.
Enzymes cannot copy DNA of eukaryotic chromosomes completely to each end of the DNA strands. This is not a problem for bacteria, whose circular genomes do not have ends. To keep the ends from getting shorter with each cycle of replication, eukaryotic chromosomes have special structures called telomeres at their ends that are targets of a special DNA synthesis enzyme.
When a cell divides, each daughter cell must get one and only one complete copy of the mother cell’s DNA. In most bacterial chromosomes, this DNA synthesis starts at only one place, and that starting point is controlled so that the number of starts equals the number of cell fissions. In eukaryotes, DNA synthesis begins at multiple sites, and each site, once it has begun synthesis, does not begin...
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Gene Expression, Transcription, and Translation (Genetics & Inherited Conditions)
DNA is often dubbed the blueprint of life. It is more accurate to describe DNA as the computer tape of life’s instructions because the DNA information is a linear, one-dimensional series of units rather than a two-dimensional diagram. In the flow of information from the DNA tape to what is recognized as life, two steps require the decoding of nucleotide sequence information. The first step, the copying of the DNA information into RNA, is called transcription, an analogy to medieval monks sitting in their cells copying, letter by letter, old Latin manuscripts. The letters and words in the new version are the same as in the old but are written with a different hand and thus have a slightly different appearance. The second step, in which amino acids are polymerized in response to the RNA information, is called translation. Here, the monks take the Latin words and find English, German, or French equivalents. The product is not in the nucleotide language but in the language of polypeptide sequences. The RNAs that direct the order of amino acids are called messenger RNAs (mRNAs) because they bring instructions from the DNA to the ribosome, the site of translation.
Multicellular organisms consist of a variety of cells, each with a particular function. Cells also respond to changes in their environment. The differences among cell types and among cells in different environmental conditions are caused...
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Small RNAs (Genetics & Inherited Conditions)
An additional level of control of gene expression is achieved via the presence of two classes of small RNAs, the microRNAs (miRNAs) and the small interfering RNAs (siRNAs). In 1993, Victor Ambrose and his coworkers discovered that in Caenorhabditis elegans, lin-4, a small 22-nucleotide noncoding RNA, was able to negatively regulate the translation of lin-14, which is involved in C. elegans larval development. Since then, these small RNAs have been found in plants, green algae, viruses, and animals. These small RNAs function as gene-silencers by binding to target mRNA sequences and preventing their translation or targeting the mRNAs for degradation in a process known as RNA interference (RNAi).
The pathway by which the small RNAs’ are processed has been intensively studied. After transcription and processing in the nucleus, small RNAs’ precursors are exported into the cytoplasm, where they undergo further processing by an enzyme called Dicer, which produces a single-stranded 21-23-nucleotide RNA. This small RNA attaches to an RNA-induced silencing complex (RISC) and is directed to a specific mRNA to which it shares base pair complementarity. In the case of miRNA, slight imperfections in the match between the miRNA and its target lead to a bulge in the duplex, which blocks translation. In contrast, the perfect binding of the siRNA with its target mRNA forms a duplex, which is targeted for degradation by...
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Protein Processing and DNA Mutation (Genetics & Inherited Conditions)
The completed polypeptide chain is processed in one or more ways before it assumes its role as a mature protein. The linear string of amino acid units folds into a complex, three-dimensional structure, sometimes with the help of other proteins. Signals in some proteins’ amino acid sequences direct them to their proper destinations after they leave the ribosomes. Some signals are removable, while others remain part of the protein. Some newly synthesized proteins are called polyproteins because they are snipped at specific sites, giving several proteins from one translation product. Finally, individual amino acid units may get other groups attached to them or be modified in other ways.
The DNA information can be corrupted by reaction with certain chemicals, some of which are naturally occurring while others are present in the environment. Ultraviolet and ionizing radiation can also damage DNA. In addition, the apparatus that replicates DNA will make a mistake at low frequency and insert the wrong nucleotide.
Collectively, these changes in DNA are called DNA damage. When DNA damage goes unrepaired before the next round of copying of the DNA, mutations (inherited changes in nucleotide sequence) result. Mutations may be substitutions, in which one base replaces another. They may also be insertions or deletions of one or more nucleotides. Mutations may be beneficial, neutral, or harmful. They are the...
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Invasion and Amplification of GenesGenomesmechanisms of change (Genetics & Inherited Conditions)
Mutation is only one way that genomes change from generation to generation. Another way is via the invasion of an organism’s genome by other genomes or genome segments. Bacteria have evolved restriction modification systems to protect themselves from such invasions. The gene for restriction encodes an enzyme that cleaves DNA whenever a particular short sequence of nucleotides is present. It does not recognize that sequence when it has been modified with a methyl group on one of its bases. The gene for modification encodes the enzyme that adds the methyl group. Thus the bacterium’s own DNA is protected. However, DNA that enters the cell from outside, such as by phage infection or by direct DNA uptake, is not so protected and will be targeted for degradation by the restriction enzyme. Despite restriction, transfer of genes from one species to another (horizontal, or lateral, gene transfer) has occurred.
As far as is known, restriction modification systems are unique to bacteria. Gene transfer from bacteria to plants occurs naturally in diseases caused by bacteria of the Agrobacterium genus. As part of the infection process, these bacteria transfer a part of their DNA containing genes, active only in plants, into the plant genome. Studies with fungi and higher plants suggest that eukaryotes cope with gene invasion by inactivating the genes (gene silencing) or their...
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Genetic Recombination (Genetics & Inherited Conditions)
Recombination occurs when DNA information from one chromosome becomes attached to the DNA of another. When participating chromosomes are equivalent, the recombination is called homologous. Homologous recombination in bacteria mainly serves a repair function for extreme DNA damage. In many eukaryotes, recombination is essential for the segregation of chromosomes into gamete cells during meiosis. Nevertheless, aspects of the process are common between bacteria and eukaryotes. Starting recombination requires a break in at least one strand of the double-helical DNA. In the well-studied yeast cells, a double-strand break is required. Free DNA ends generated by breaks invade the double-helical DNA of the homologous chromosome. Further invasion and DNA synthesis result in a structure in which the chromosomes are linked to one another. This structure, called a half-chiasma, is recognized and resolved by an enzyme system. Resolution can result in exchange so that one end of one chromosome is linked to the other end of the other chromosome and vice versa. Resolution can also result in restoration of the original linkage. In the latter case, the DNA around the exchange point may be that of the other DNA. This is known as gene conversion.
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Impact and ApplicationsGenetic engineering (Genetics & Inherited Conditions)
Molecular genetics is at the heart of biotechnology, or genetic engineering. Its fundamental investigation of biological processes has provided tools for biotechnologists. Molecular cloning and gene manipulation in the test tube rely heavily on restriction enzymes, other nucleic-acid-modifying enzymes, and extrachromosomal DNA, all discovered during molecular genetic investigation. The development of nucleic acid hybridization, which allows the identification of specific molecular clones in a pool of others, required an understanding of DNA structure and dynamics. The widely used polymerase chain reaction (PCR), which can amplify minute quantities of DNA, would not have been possible without discoveries in DNA replication. Genetic mapping, a prelude to the isolation of many genes, was sped along by molecular markers detectable with restriction enzymes or the PCR. Transposable elements and the transferred DNA of Agrobacterium, because they often inactivate genes when they insert in them, were used to isolate the genes they inactivate. The inserted elements served as tags or handles by which the modified genes were pulled out of a collection of genes.
The knowledge of the molecular workings of genes gained by curious scientists has allowed other scientists to intervene in many disease situations, provide effective therapies, and improve biological production. Late twentieth century scientists...
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Further Reading (Genetics & Inherited Conditions)
Bartel, D. P. “MicroRNAs: Target Recognition and Regulatory Functions.” Cell 136 (2009): 215-233. This recent publication reviews what is currently understood about prediction of miRNA target recognition.
Brown, Terence A. Genetics: A Molecular Approach. 3d ed. New York: Chapman & Hall, 1998. Solid text with bibliography, index.
Carroll, Sean B., Jennifer K. Grenier, and Scott D. Weatherbee. From DNA to Diversity: Molecular Genetics and the Evolution of Animal Design. Malden, Mass.: Blackwell, 2001. Discusses morphology and its genetic basis, and evolutionary biology’s synthesis with genetics and embryology. Illustrations (some color), figures, tables, glossary, bibliography.
Clark, David P., and Lonnie D. Russell. Molecular Biology Made Simple and Fun. 2d ed. Vienna, Ill.: Cache River Press, 2000. A detailed and entertaining account of molecular genetics. Bibliography, index.
Hancock, John T. Molecular Genetics. Boston: Butterworth-Heinemann, 1999. Covers the basics of molecular genetics, especially for advanced high school and beginning-level college students. Illustrations, bibliography, summaries of key chapter concepts.
Hartl, D. L. Genetics: Analysis of Genes and Genomes. 5th ed. Boston: Jones and Bartlett, 2001. An excellent introductory genetics textbook.
Hartwell, L. H., et al. Genetics: From Genes to Genomes....
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Web Sites of Interest (Genetics & Inherited Conditions)
Human Molecular Genetics. http://hmg.oup journals.org. The Web site for the online journal, with abstracts of articles available online and full text available for a fee.
Max Planck Institute for Molecular Genetics. http://www.molgen.mpg.de. Research institute focuses on molecular mechanisms of DNA replication, recombination, protein synthesis, and ribosome structure, and offers educational information and history.
miRBase. http://microrna.sanger.ac.uk. miRBase fulfills three functions: The miRBase Registry determines microRNA gene nomenclature, miRBase Sequences is the primary online repository for miRNA sequence data and annotation, and miRBase Targets is a comprehensive new database of predicted miRNA target genes.
National Center for Biotechnology Information. http://www.ncbi.nlm.nih.gov. Created in 1988, NCBI develops, distributes, supports, and coordinates access to a variety of databases and software for the scientific and medical communities and develops and promotes standards for databases, data deposition and exchange, and biological nomenclature.
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