In the sum of the parts there are only parts
The study of ”genes” turned from a statistical analysis to cell biology.
What problem was [[Thomas Morgan]] trying to solve? How do complex organisms arise out of a single cell. How was his research question related to genetics? Understanding how complex embryological information is stored inside the cell could explain how complex organisms arise out of a cell.
[[Thomas Morgan]] started his research from the assumption that genes are present in a chromosome. In order to discover how genes were arranged on a chromosome, he started studying mutations in fruit flies. He discovered that certain genes in fruit flies would always appear together as if they were “linked” suggesting that the individual genes were moving in groups. This is unlike [[Gregor Mendel]]’s peas, where the genes behaved like completely independent entities.
[[Thomas Morgan]] postulated that genes can appear together only and only if they are physically and permanently connected to each other on the chromosome itself.
[[Thomas Morgan]]’s newly discovered rule had one exception. Even though genes normally move in packs and stay close to their neighbours, sometimes, a gene may unlink from its neighbouring genes and swap places from one chromosome to another. Morgan imagined the genes literally crossing over from one chromosome to another.
The likelihood of two genes to unlink/cross over, is proportional to how far they are from each other on a chromosome. This means we can use the strength of genetic linkage to find out where genes are present relative to one another on a gene. [[Thomas Morgan]]’s student, Strutevant, created the first linear genetic map in 1911 using this technique.
Truths and reconciliation
For genes to be the carrier of biological information, they had to explain: variation of individuals within a specie, evolution of that specie and the development of an individual.
Variation in species
[[Ronald Fisher]], in 1918, wrote a paper titled, “The Correlation between Relatives on the Supposition of Mendelian Inheritance” where he explained how Mendelian inheritance can give rise to normally distributed traits in a population.
Evolution of species
Ukrainian geneticist, [[Theosodius Dobzhansky]], discovered that changes in the environment act as selection pressure, testing the fitness of different individuals in a group. The fitness depends on the individual’s genetic makeup because of naturally occurring variance.
Dobzhansky discovered that the phenotype was a combination of genotype + environment + triggers + chance.
Natural selection indirectly seeks the fittest genotype by applying selection pressure on the phenotype.
Dobzhansky also discovered how genetic variation in a natural population can lead to speciation.
Geographical separation which causes sexual separation which causes genetic separation which causes reproductive separation.
Transformations
Discoveries from [[Ronald Fisher]] and [[Theosodius Dobzhansky]] lead to the creation of the [[Modern Synthesis]].
[[Frederick Griffith]] was a British bacteriologist studying pneumonia causing bacteria. He noticed that a non-virulent strain of Streptococcus pneumoniae could be made virulent when exposed to heat-killed virulent strains.
[[Genetic Transformation|Transformation]] is a method of [[horizontal gene transfer]]. A bacteria can “ingest” the genetic material in its environment and incorporate it into its own genetic material.
[[Henry Muller]], a former student of [[Thomas Morgan]], was trying to produce mutant fruit flies. He discovered that X-rays in low dosages produced dozens of mutants.
Lives Unworthy of Living
[[Trofim Lysenko]] claims to have produced stronger wheat strains by putting them through “shock therapy”. He gave rise to “Lysenkoism” in the Soviet Union.
That stupid molecule
[[Oswald Avery]] was able to reproduce [[Frederick Griffith]]‘s result of horizontal gene transfer. He discovered that the hereditary information was stored in the chromosomes as DNA.
Important Biological Objects come in Pairs
A central theme in many of the scientists who worked in genetics seems to be [[Erwin Schrödinger]]‘s [[What is Life?]]. [[Maurice Wilkins]] came to King’s College to study the 3D structure of DNA. To study its structure [[Maurice Wilkins]] used [[Crystallography]] and [[X-ray diffraction]]. By crystalizing different biological molecules and using X-rays to generate shadows of the molecules, it was possible to determine the structure of the bio-molecule.
[[Rosalind Franklin]] was recruited by KCL to do the same.[[Maurice Wilkins]]‘s was unable to get clear images of DNA strands because their structure was dependent on the surrounding humidity. [[Rosalind Franklin]] figured this out and managed to produce clear images. [[James Watson]] moved from Copenhagen to Cambridge to study DNA. Upon arrival, he met [[Francis Crick]]. [[James Watson]] and [[Francis Crick]] were inspired by [[Linus Pauling]] to solve the problem of DNA’s 3D structure from first-principles. Given the constraints of the purpose, which atom’s molecules could sit next to each other to form DNA’s structure, using model building.
[[Rosalind Franklin]] correctly identified that the backbone of DNA was made of phosphates. Over time, she took crisper and crisper pictures essentially discovering the double helical structure of DNA. [[Maurice Wilkins]] without her permission shared her data with [[James Watson]]. It was already known that A and T and G and C bases were always present in almost identical proportions. [[Watson]] figured that this was possible if the A-T and G-C were opposing pairs.
“The helix contains two intertwined strands of DNA. It is “right-handed”—twisting upward as if driven by a right-handed screw. Across the molecule, it measures twenty-three angstroms—one-thousandth of one-thousandth of a millimeter.”
“The biologist John Sulston wrote, “We see it as a rather stubby double helix, for they seldom show its other striking feature: it is immensely long and thin. In every cell in your body, you have two meters of the stuff; if we were to draw a scaled-up picture of it with the DNA as thick as sewing thread, that cell’s worth would be about 200 kilometers long.”
That Damned, Elusive Pimpernel
[[George Beadle]] and [[Edward Tatum]] won the 1958 Nobel prize for proposing the [[One gene–one enzyme hypothesis]] in the 1940s.
“Instructions” were carried from the DNA into the ribosome to produce proteins.
The discovery of RNA acting as the messenger molecule was made by [[François Jacob]] and some others at Cal Tech through the process of [[transcription]].
They were carried over by some kind of “messenger” molecule, which was later discovered to be RNA and was called “messenger RNA” or (mRNA).
Proteins are made of amino acids and there are 20 unique amino acids. How could the 4 bases of RNA be converted into 20 unique amino acids? [[Francis Crick]] discovered that each amino acid is defined by a “triplet” of bases. Eventually we discovered all the combinations that created the 20 amino acids. The other combinations of the four bases, served as start and stop instructions.
Out of the 64 possible codon combinations, 61 represent different amino acids and 3 act as STOP signals. The codon for a START signal is an amino acid itself. This means that each amino acid can be represented by multiple codons, but each codon always represents only one amino acid. This “multiciplity” is called “degeneracy” or “redundancy”.
Regulation, Replication, Recombination
How do cells activate specific genes needed to perform their unique function?
[[Jacques Monod]] was studying the “smooth” exponential growth of [[Escherichia coli]]. One day, he decided to add from two different sugars: glucose and lactose to the culture. Glucose is a simpler sugar molecule (mono-saccharide) whereas, lactose (bi-saccharide) is a complex sugar and needs to be broken into simpler units before it can be digested.
He observed that the growth curve now had a “kink” in it contrary to his expectation of a smooth curve. He had assumed that both sugars would be metabolised in the same way. However, [[Escherichia coli]] should preference to glucose over lactose. The “kink” in the growth curve was the result of the bacteria switching from glucose to lactose as their food source, during which they had to pause growing. He called these two distinct growth phases “double growth” or [[diauxic growth]].
[[Jacques Monod]] wondered what was the relationship between:
- glucose+lactose culture (the environment of the bacteria)
- enzyme (the protein needed to process lactose) and
- genes (that produced the enzyme)
To Monod, diauxie suggested that genes could be regulated by metabolic inputs.
[[Jacques Monod]] assumed that the appearance and disappearance of metabolising enzymes inside bacteria when switching between glucose and lactose had to be because the genes were somehow being turned on and off.
[[Jacques Monod]] along with [[François Jacob]] discovered the following principles of [[gene regulation]]:
- The DNA master copy of genes always stayed inside the nucleus, whether it was turned on or off. The on or off state was only identifiable by the abundance or lack of the RNA produced by that gene.
- The production of RNA messages was coordinately regulated. All the genes necessary for a specific “metabolic pathway” were present physically next to each other. They are all activated simultaneously. [[Jacques Monod]] called this functional sequence of genes, an operon.
- Every gene has a specific regulatory DNA sequence appended to it that acts like a recognition tag.
The genes in the DNA that control the expression of the metabolic pathway are called “regulatory” genes. The genes that form the proteins that perform the metabolic function are called “structural” genes. The combination of “structural” and “regulatory” DNA sequences is called a gene.
Some regulatory proteins are called “transcription” factors.
- How are they related to [[transcription]]?