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Classical Papers Outline • Central Dogma of Molecular Biology • Chromosomes in Heredity • What is a Gene? CENTRAL DOGMA OF MOLECULAR BIOLOGY Francis Crick, 1958 Francis Crick (1916 – 2004) • one of the co-discoverers (w/ James Watson) of the double helix structure of the DNA molecule in 1953 • awarded the 1962 Nobel Prize for Physiology or Medicine Origins of Term • Put forward at a time when molecular genetics was not well understood • Principle problem: formulation of general rules for information transfer from one polymer to another Classes of Information Transfer • Class I – – – – DNA DNA DNA RNA RNA Protein RNA RNA (presumed to occur because of existence of RNA viruses) Classes of Info Transfer (cont’d) • Class II – RNA DNA – DNA Protein • Class III – Protein Protein – Protein RNA – Protein DNA Classes of Info Transfer (cont’d) • Generally believed that Class I almost certainly existed, Class II probably rare or absent, and Class III very unlikely Conclusions? • No overwhelming structural reasons why Class II should not be impossible • Good general reasons against all transfers in Class III • “Conservative” claim about transfer of information leads to… Central Dogma of Molecular Biology • Central dogma: “Once information has passed into protein, it cannot get out again” • “About class II, I decided to remain discreetly silent” Misunderstandings about CD • CD says nothing about what the machinery of transfer is made of, and nothing about errors (assumed that accuracy of transfer is high) • CD says nothing about control mechanisms (i.e. rate of processes) • Intended to apply only to present-day organisms Misunderstandings (cont’d) PROTEIN • It is NOT the same as the sequence hypothesis, a positive statement saying that the (overall) transfer of nucleic acid to protein existed THE CHROMOSOMES IN HEREDITY Walter Stanborough Sutton, 1903 Mendel in a Nutshell (1866) • Characteristics determined by discrete units of inheritance • Law of independent assortment • Law of segregation (allelomorphs, inheritance, dominance) The State of Genetics, c. 1900 • “Chromosomes are the physical basis of inheritance” seems reasonable • How to test hypothesis? ? Sea Urchin Chromosomes • 1902 – Theodore Boveri shows through experimentation with sea urchins that complete set of chromosomes necessary for normal development W.S. Sutton (1877 – 1916) • Worked under C.E. McClung at U of Kansas (grasshoppers!) • Moved to Columbia, where he wrote his two famous papers Chromosomal Basis of Inheritance • Published paper in 1902 on study of grasshopper chromosomes • Observed meiosis, number of chromosomes halved after division Grasshopper Chromosomes • Found 23 chromosomes in grasshopper spermatogonia • One “accessory” chromosome and 11 pairs • Fertilization of ovum (11) and sperm (11) restores diploid number of 22 Pertinent Cytological Data • Chromosomes exist in homologous pairs (one set from father, other from mother?) • As a result of meiosis, every gamete receives one chromosome of each pair • Distribution of members of each pair during meiosis is independent from each other The Chromosomes in Heredity, 1903 • Mendel’s results could be explained on the assumption that genes are part of the chromosomes Heredity (cont’d) • “We have seen reason…to believe that there is a definite relation between chromosomes and allelomorphs…but we have not inquired whether an entire chromosome or only a part of one is to be regarded as the basis of a single allelomorph.” Connection with Mendelian Principles • “The association of paternal and maternal chromosomes in pairs and their subsequent separation during the reduction division…may constitute the physical basis of the Mendelian laws of heredity” ! WHAT IS A GENE? Milislav Demerec, 1933 Biology c. 1933 • 1928 - First antibiotic, penicillin, discovered by Alexander Fleming • 1929 - Phoebus Levene discovers the sugar deoxyribose in nucleic acids • 1933 - Tadeus Reichstein artificially synthesizes vitamin C; first vitamin synthesis Biology Experiments: Back in the Day • “Our present information about genes is largely obtained by indirect, genetic methods” • X-ray technology (discovered in 1895) used to observe effects of photoelectrons on genes Definition of Gene • A minute organic particle • Capable of reproduction • Located in a chromosome • Responsible for the transmission of a hereditary characteristic Size of the Gene • Found by dividing the volume by the number of estimated genes • Estimates range from 10 – 70 millimicrons • An ultramicroscopic particle? • Single/multiple molecules? Capacity of Reproduction • Each gene must divide at every cell division • Little known about nature of gene reproduction ? Location of Genes • Genes are located in chromosomes • Arranged in a linear order • Definite order retained with great regularity, each gene has permanent locus on gene string • Gene may attain several forms, allelomorphs Studies of fruit-flies • Studied more intensively than any other species • Genes arranged in a definite order in the chromosomes • Relative positions of over 200 genes determined Fruit-fly chromosomes • Fruit fly has 4 pairs of chromosomes • For the gene located in the white locus of fruit fly, at least 11 different allelomorphs known, all of which affect eye color Transmission of Hereditary Characteristics • No single gene is solely responsible for appearance of any one character • Final effect produced through interaction of the whole complement of genes • Some genes have greater influence than others on expression of certain characteristics Example, chromosome map • Gene of fruit-fly located in the Xchromosome • Arranged in genetic “charting” order Stability of the Gene • Mutations occur in different frequency in different gene • No “sharp” division between stable and unstable genes • Rate of change in various genes may depend on tissue or stage of development Example, lavender/rose • Unstable genes change to purple • Change in color gene occur at definite stage for lavender, any time for rose Mutation Experiments Today • Maize (corn) • Study plant evolution, crop domestication, crop improvement • DNA sequencing allows understanding and selection of desirable traits Nature of Gene Changes • Evidence suggests changes in genes are chemical processes – End product of changes is always the same – Change is not always a random process, favored by or limited to certain tissues – Several genetic factors known to stimulate rate of change in certain unstable genes Importance of Genes • Whole complement of genes necessary for organism to live, and for cell to function properly • In other words, primary function of gene is to regulate life process of cell Physical Picture of a Gene Look familiar? Physical Picture (cont’d) • “Genes are not larger than a particle containing a few complex organic molecules” • “Molecular groups constituting this molecule (whatever these groups may be) would be arranged in chains and side chains.” (hmm…) The Big Picture Dominant and Recessive Factors in Crossbreeding (1858) Chromosomes & Heredity (1902) Genes & Heredity (1933) Double Helix Structure of DNA (1953) Central Dogma (1958)