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. 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 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)