Classical Papers Chihiro Fukami October 6, 2005

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) It is NOT the same as the sequence hypothesis, a positive statement saying that the (overall) transfer of nucleic acid to protein existed PROTEIN

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 “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 First antibiotic, penicillin, discovered by Alexander Fleming Phoebus Levene discovers the sugar deoxyribose in nucleic acids 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 X- chromosome 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 Chromosomes & Heredity (1902) Genes & Heredity (1933) Central Dogma (1958) Dominant and Recessive Factors in Crossbreeding (1858) Double Helix Structure of DNA (1953)