Genetics

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is the part of biology dealing with the rules and the mechanisms of inheritance. For a long time in the history of mankind it was only known in a very general way that the offspring resemble the parents. Until Gregor Mendel’s groundbreaking discovery, the passing on of inherited traits was believed to occur by „mixing“ without any recognizable natural laws. It was also known that somehow organisms can slowly change from generation to generation. This was observed by plant breeders (as noticed by Charles Darwin) who created new varieties by careful selection and crossing of different varieties of the same species. However, there was not the faintest idea how this was possible or what was the mechanism behind this phenomenon. Lamarck (1809) believed in an „invisible fluid“ which directs inheritance and which can be modified by environmental influences. This is the famous „inheritance of acquired traits“ which was discussed by biologists for decades but is now recognized as a wrong concept. It was interest in these questions that inspired the research of Charles Darwin, which was finally published in his famous book „On the origin of species by means of natural selection“ (1859). Darwin’s theory contained no assumption on the nature of inheritance. Also, the concept of „gene“ and of „mutation“ did not exist. The beginning of understanding these concepts even if they were called differently, had to wait for another six years when Mendel’s report on his systematic research of inheritance in carefully performed crosses of garden peas (Pisum sativum) was published. Johann Gregor Mendel (1822-1884) was an Augustynian monk in Brünn (at that time Austria and now Brno in the Czech Republic). To be accurate, Mendel’s paper did not use the terms „gene“ and „mutation“. What we call a gene, he called „particle of inheritance“, as the physical nature of this particle was completetly unknown and was discovered only many decades later. The concept of mutation was only implicitly, but still very clearly, described in his work, because he found that the difference between two characters (for example red flowers or white flowers) in his view was based on two forms of a gene, in modern language: two alleles differing by a mutation. As shown by Mendel’s crosses, these „forms of a gene“ remained stable and distinct over many generations, even if the character was not visible in the F1 (filial generation 1). Mendel’s paper for ever changed the scientific world, just like Darwin’s book, and was published in 1865 in the Verhandlungen des Naturforschenden Vereins zu Brünn under the title „Versuche über Pflanzenhybriden“ (experiments on plant hybrids). In the year 1900, Mendel’s laws were rediscovered independently by three groups in Vienna (Tschermak), Tübingen (Correns), and Amsterdam (de Vries) and in 1907, 42 years after Mendel’s discovery, Bateson suggested the term „Genetics“ for the science of inheritance.

Why could Mendel discover the laws of inheritance, although crosses had been performed by many plant and animal breeders throughout the centuries without noticing any specific quantifiable laws? Firstly, the planning of his experiments was extremely accurate and careful. For instance he carefully prevented selfing (self fertilization) in those plants as needed. Secondly, during his studies in Vienna he obtained excellent training in mathematics and he had a clear view of statistics, standard deviations of the mean, and statistical significance, which was necessary to interprete the ratios of mutant and wild-type plants that he found in his crosses. He had to perform a large number of crosses (typically, a few thousand) to be able to prove at the desired level of statistical significance the 3:1 ratio among the F2 progeny which he observed in every one of his experiments. Thirdly, he interpreted and explained this ratio on the basis of assumptions which were at the time guesses, but all of which proved to be true in the twentieth century. These were: somatic cells are diploid; when egg and sperm are formed the number of chromosomes is halved resulting in haploid cells (the gametes); fertilization results in the fusion of male and female gametes resulting in a diploid zygote, which by way of subsequent cell divisions produces all somatic cells of the organism; the genetic contribution of male and female gametes is equally important. The last statement could only be made because peas do not show sex-linked inheritance. It would not be generally true in humans for genes on the X chromosome. Individuals which harbor two different versions of the same gene were called of mixed inheritance, or in modern language, heterozygotes. Conversely, individuals which contain two identical versions of the same gene, were called pure breeding, or in modern language, homozygotes.

This means that Mendel logically derived the laws which are today named after him with the help of assuming many details about cells and gametes, chromosomes, mitosis, meiosis and (indirectly) the structure of nucleic acids, which were unknown at his time. He formulated two rules (or laws): the first one considered „monohybrid“ crosses, meaning crosses in which just one gene is different between the two purebreeding partners in the cross. In that case, the progeny in the first filial generation is uniform, and intercrossing those F1 progeny resulted in the since famous 3:1 ratio of mutant and wild type plants in the F2 (second filial generation). The second law considered „two factor crosses“ („dihybrid crosses“) meaning crosses in which the pure breeding parents differed in two genes. In all seven cases that he studied, the corresponding genes did not influence each other and behaved independently. Therefore, the second law is also called the law of independent segregation or independent assortment of genes. In our modern interpretation, this independence rests on and is true only if the two genes are either on separate chromosomes or, if they are on the same chromosome, but sufficiently separated. In modern language, they are „unlinked“ and will be separated by meiotic recombination in 50% of the crosses. If two genes are closely spaced (linked) on a chromosme, their genetic distance is defined by the frequency with which they are separated in meiosis. These ideas constituted another milestone in the history of genetics and were proposed by the group of T.H. Morgan in the United States in 1911. To the present day, genetic maps are constructed using recombination frequencies.

Around the middle of the 20th century the foundations of what is nowadays molecular genetics were laid. It became clear that DNA is the molecule which contains and transmits genetic information (Avery 1944; Hershey and Chase 1952). Further, the structure of the double helix (Watson and Crick 1953) and the way in which this information is duplicated through the process of replication (Meselsohn and Stahl 1958) were discovered. The relationship between genes (DNA) and gene products (RNA and protein) was elucidated and the „central dogma“ was formulated, stating that protein synthesis occurs in two steps, the first one being transcription of the coding sequence in DNA into a messenger RNA strand (which follows the principle of base pairing) while the second one is translation, which is immensely more complicated and is based on decoding the nucleotide sequence of mRNA with the help of ribosomes and tRNA. The phenotype of a cell is based on its proteins, and the genotype is nothing else than its complement of genes (DNA). Although Mendel knew nothing of these biochemical facts about genetics, it was Mendel’s work which inspired the moleuclar genetic research of the 20th century.

Starting in 1949 a problem came into focus that had completely escaped the pioneers of of molecular biology (the „phage group“ in the United States, and others whom we have already named). The very low frequency of spontaneous mutations – necessary for survival of organisms and at the same large enough for the slow process of evolution through mutation and selection – was not entirely based on chemical stability alone, which would be hardly possible because of the constant environmental chemical and physical insult which DNA suffers. A second principle is necessary to explain this low frequency of mutation, about one mutation in one thousand million base pairs replicated. This principle is DNA repair (Kelner 1949). Multiple biochemical mechanisms of repair do exist and we do not have the space here to describe all of them. Mostly these faithfully repair DNA, but some can introduce errors. One of the many pioneers in this field was Miroslav Radman who discovered the concept of SOS repair in bacteria in 1974.

At around the same time (1976) another completely unexpected revolution took place. Through the collaboration of many molecular biologists in The United States and in Europe the era of „reverse genetics“ and „genetic engineering“ was started. Key discoveries were bacterial restriction enzymes, enabling the construction of circular small DNA plasmids, and the development of vectors that could through transformation techniques deliver recombinant DNA generated in the test tube to many different bacterial and eukaryotic cells. The result of these new techniques was that genes could be changed at will, reintroduced into living cells and the phenotypic consequences could then be studied. Alternatively, genetically modified organisms could be constructed which were useful for the production of pharmacological or other substances or for the improvement of crops for agriculture. To give just one example, an „antifreeze“ gene of an antarctic fish was transferred into strawberries and frost-resistant strawberries were indeed obtained. Experiments like this started an entirely new era of genetic engineering which was greeted with enthusiasm on the one side and with hostility and fear on the other side. In agriculture and in the growing of vines, these methods can be applied along with the classical plant breeding methods.


Michael Breitenbach University of Salzburg Austria

Ian W. Dawes University of New South Wales Sydney Australia

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