Hartl, Jones - Genetics. Principlers and analysis - 1998, страница 13

Each codon specifying an amino acid matches with a complementarygroup of three adjacent bases in a single tRNA molecule, which brings the correct amino acid into line.The tRNA molecules used in translation do not line up along the mRNA simultaneously as shown in Figure 1.10.The process of translation takes place on a ribosome, which combines with a single mRNA molecule and movesalong it from one end (the 5' end) to the other (the 3' end) in steps of three adjacent nucleotides (codon by codon).As each new codon comes into place, the correct tRNA attaches to the ribosome, and the growing chain of aminoPage 15Figure 1.10The role of transfer RNA in the synthesis ofproteins. The sequence of bases in themessenger RNA determines the order in whichtransfer RNA molecules are lined up. Each groupof three adjacent bases in the messengerRNA attracts a transfer RNA containing acomplementary sequence of three bases.Each transfer RNA molecule carries aparticular amino acid, and the amino acids inthe protein join together in the same orderin which the transfer RNA molecules lineup along the messenger RNA.

Because thetransfer RNA molecules are aligned in this manner,the sequence of bases in the messengerRNA determines the sequence of amino acidsin the protein. Polypeptide chains aresynthesized by the sequential addition ofamino acids, one at a time. As each transferRNA molecule is brought into line, theincomplete polypeptide chain grows one aminoacid longer by becoming attached to theamino acid linked to the transfer RNA.acids becomes attached to the amino acid on the tRNA. As the ribosome moves along the mRNA, successiveamino acids are added to the growing chain until any one of three particular codons specifying "stop" isencountered.

At this point, synthesis of the chain of amino acids is finished, and the protein is released from theribosome. (Chapter 10 gives a more detailed treatment of translation.)Technically speaking, the chain of amino acids produced in translation is a polypeptide. The distinction between apolypeptide and a protein is that a protein can consist of several polypeptide chains that come together aftertranslation. Some proteins are composed of two or more identical polypeptide chains (encoded in the same gene);others are composed of two or more different polypeptide chains (encoded in different genes). For example, theprotein hemoglobin, which is the oxygen-carrying protein in red blood cells, is composed of four polypeptidechains encoded in two different genes: Two of the chains are β polypeptide chains translated from the β-globingene, and the other two are α polypeptide chains translated from the α-globin gene.1.5—MutationMutation means any heritable change in a gene.

The Watson-Crick structure of DNA also suggested that,chemically speaking, a mutation is a change in the sequence of bases along the DNA. The change may be simple,such as the substitution of one pair of bases in a duplex molecule for a different pair of bases. For example, an A—T pair in a duplex molecule may mutate to either T—A, C—G, or G—C. The change in base sequence may also bemore complex, such as the deletion or addition of base pairs. These and other types of mutations are discussed inChapter 13.One possible consequence of a mutation is illustrated in Figure 1.11.

Part A shows a region of duplex DNA and themRNA transcribed from the bottom strand. The tRNA molecules used in translation result in the amino acidsequenceMet—Phe—Gly—ValWhat happens if the T—A base pair marked with the "sunburst" mutates to become a C—G base pair? The result isshown in part B. The second codon in the mRNA is now CUU, which codes for leucine (Leu), instead of the codonUUU, which codes for phenylalanine (Phe). In translation, the CUU codon in the mRNA combines with theleucine-bearing tRNA, and the result is the mutant amino acid sequenceMet—Leu—Gly—ValPage 16Figure 1.11A mutation is a change in base sequence in the DNA.

Any mutation that causes the insertion of an incorrect aminoacid in a protein can impair the function of the protein. (A) The DNA molecule is transcribed intoa messenger RNA that codes for the sequence of amino acids Met—Phe—Gly—Val. In the DNA molecule,the marked T—A base pair results in the initial U in the messenger RNA codon UUU for Phe(phenylalanine). (B) Substitution of a C—G base pair for the normal T—A base pair results in a messengerRNA containing the codon CUU instead of UUU. The CUU codon codes for Leu (leucine), whichtherefore replaces Phe in the mutant polypeptide chain.1.6—How Genes Determine TraitsWe have seen that the key principle of molecular genetics is the central dogma:The sequence of nucleotides in a gene specifies the sequence of amino acids in a protein using messengerRNA as the intermediary molecule in the coding process.It is one of the ironies of genetics (and a consequence of the biochemical complexity of organisms) that whereasthe connection between genes and proteins is conceptually simple, the connection between genes and traits isdefinitely not simple.

Most visible traits of organisms are the net result of many genes acting together incombination with environmental factors. Therefore, the relationship between genes and traits is often complex forone or more of the following reasons:1. One gene can affect more than one trait.2. One trait can be affected by more than one gene.3. Many traits are affected by environmental factors as well as by genes.Now let us examine each of these principles, with examples.Page 17Pleiotropy: One Gene Can Affect More Than One TraitA mutant gene may affect a number of seemingly unrelated traits. The mutation is then said to show pleiotropy,and the various manifestations of the mutation are known as pleiotropic effects. An example of a mutation inhuman beings with manifold pleiotropic effects is sickle-cell anemia, which affects the major oxygen-carryingprotein of the red blood cells.

The major organs and organ systems affected by the pleiotropic effects of themutation are shown in Figure 1.12.The underlying mutation in sickle-cell anemia is in the gene for β-globin, which codes for the β polypeptide chainspresent in the oxygen-carrying protein of red blood cells. The molecular basis of the disease is shown in Figure1.13. Figure 1.13A shows the region of the β-globin gene that codes for amino acids 5 through 8 (the completepolypeptide chain is 146 amino acids in length).

The sickle-cell mutation changes the base pair marked with thesunburst. As shown in part B, the mutant form of the gene contains a T—A base pair instead of the normal A—Tbase pair. As a result of the mutation, the mRNA contains a GUG codon. Because GUG codes for valine (Val), thisamino acid is incorporated into the polypeptide in place of the normal glutamic acid (Glu) at position number 6.The defective β polypeptide chain gives the hemoglobin protein a tendency to form long, needle-like polymers.Red blood cells in which polymerization happens become deformed into crescent, sickle-like shapes.

Some of thedeformed red blood cells are destroyed immediately (reducing the oxygen-carrying capacity of the blood andcausing the anemia), whereas others may clump together and clog the blood circulation in the capillaries.The consequences of the GluVal replacement are a profound set of pleiotropic effects. All of these effects arerelated to the breakdown of red blood cells, to the decreased oxygen-carrying capacity of the blood, or tophysiological adjustments the body makes to try to compensate for the disease (such as enlargement of the spleen).Patients with sickle-cell anemiaFigure 1.12Sickle-cell anemia has multiple, seemingly unrelated symptoms knownas pleiotropic effects.

The primary defect is a mutant form of hemoglobinin the blood. The resulting destruction of red blood cells and the impairedability of the blood to carry oxygen affect the circulatory system, bonemarrow, muscles, brain, and virtually all major internal organs. Thesymptoms of the disease are anemia, recurrent pain, weakness,susceptibility to infections, and slowed growth.suffer bouts of severe pain.

The anemia causes impaired growth, weakness, and jaundice. Affected people are sogenerally weakened that they are susceptible to bacterial infections, which are the most common cause of death inchildren with the disease.Although sickle-cell anemia is a severe genetic disease that often results in premature death, it is relatively frequentin areas of Africa and the Middle East in which a type of malaria caused by the protozoan parasite Plasmodiumfalciparum is widespread. The association between sickle-cell anemia and malaria is not coincidental.

ThePage 18Figure 1.13Genetic basis of sickle-cell anemia: (A) Part of the DNA in the normal β-globin gene is transcribed into a messenger RNAcoding for the amino acid sequence Pro—Glu—Glu—Lys. The T in the marked A—T base pair is transcribed as the A in theGAG codon for Glu (glutamic acid). (B) Mutation of the normal A—T base pair to a T—A base pair results in the codon GUGinstead of GAG. The codon GUG codes for Val (valine), so the polypeptide sequence in this part of the molecule isPro—Val—Glu—Lys. The resulting hemoglobin is defective and tends to polymerize at low oxygen concentration.association results from the ability of the mutant β-hemoglobin to afford some protection against malarialinfection. In the life cycle of the parasite, it passes from a mosquito to a human through the mosquito's bite.

Theinitial stages of infection take place in cells in the liver, where specialized forms of the parasite are produced thatare able to infect and multiply in red blood cells. Widespread infection of red blood cells impairs the ability of theblood to carry oxygen, causing the weakness, anemia, and jaundice characteristic of malaria. In people with themutant β-hemoglobin, however, it is thought that the infected blood cells undergo sickling and are rapidly removedfrom circulation.