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A Beginners' Guide to Molecular Biology



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What is a gene

  1. The "Beadle and Tatum" experiment
  2. The case of sickle cell disease

We shall assume the structure of the gene to be that of a huge molecule, capable only of discontinuous change, which consists in a re-arrangement of the atoms and leads to an isomeric molecule. The re-arrangement (mutation) may affect only a small region of the gene, and a vast number of different rearrangements may be possible.

Erwin Shrodinger, 1945

The definition of a gene came long before its structure was decipheredask Dr Chromo!. Chromosomesask Dr Chromo! consist of a protein framework with a long DNA molecule coiled round the framework. Several experiments which you should now be familiar with have shown it is the DNA part of the chromosome which controls the inherited characters. Sections of DNA constitute genes. Thus a gene is a specific length of the DNA double helix which codes for a protein, (or more strictly, a polypeptide chain).

A gene is a stable entity, but can suffer a change in sequence. A change is called a mutationask Dr Chromo!. When a mutation occurs, the new form of the gene is inherited in a stable manner, just like the previous form. The organism carrying the altered gene is called a mutant while the organism carrying the original form is the "wild type".

Experiments on Neurospora crassa by Beadle and Tatum (~1940).

You might need to refer to the Neurospora Page, and revise the spore formation.

The Beadle and Tatum experiment shows that a gene is responsible for the production of one single enzymeask Dr Chromo!.

The Beadle and Tatum experiment starts with creating mutant colonies of Neurospora crassa. There are several important reasons for using this fungusask Dr Chromo!. The main one is that the hyphaeask Dr Chromo! each have several nuclei, but each are in an haploidask Dr Chromo! state. Thus, if there is a mutation on one of the seven chromosomes it will be seen straight away in the new generation. What is the difference with diploid organisms? Why would they be difficult to use?

X-rays are the easiest mutating agents to use. After exposure to X-rays, a lot of the nuclei will have a mutation in them. Some of the nuclei will give rise to ascospores. The asci are dissected and individual spores are inoculated onto a rich medium which will cause all spores to grow. Figure 1 illustrates this first step in the experiment. Only eight tubes are shown in the illustration. Each tube contains a rich medium set in agarask Dr Chromo!, and a spore taken from the same ascospore. Of course, more than one ascus is dissected, and large numbers of tubes are used after this first step.
Step 2: when enough material is obtained, some is taken and inoculated onto a minimum medium. If the fungus develops on minimum medium, the colony is discarded because it means it has not mutated. If it doesn't, further tests are performed. Figure 2 illustrates this part of the experiment. The sample from tube 3 grows on minimal medium. The colony 3 is discarded. The sample taken from tube 7 doesn't grow on minimal medium. The colony 7 is taken into the next step of the experiment.

Step 3: Samples taken from the original colony 7 are inoculated onto minimal media in which one amino acid is added. The colony 7 does not grow on any of the media except on the one where the amino acid is Tyrosineask Dr Chromo! (Tyr). This mutant must therefore be deficient in a part of the synthesis that produces tyrosine. Further screening would help us to conclude which part. Can you imagine how? Use a chart of a metabolic pathway to design a similar experiment which would help you decide which part of the synthesis is affected.

Beadle and Tatum isolated a huge collection of mutants deficient in one aspect of their metabolism. They were shown not to be able to make one particular enzyme.

Think about these four basic questions about the experiment.

  1. Why have sloping agar tubes?
  2. Why do we need so many tubes at the end of the first step?
  3. In Step 2, colony 3 is discarded. Why?
  4. Colony 7 is kept. Why?

1) Why have sloping agar tubes?

A tube is easy to handle, and laying the tube down, at an angle, while cooling, allows the agar to set forming a larger surface than the circular surface obtained if the tube is held vertically while cooling. The fungi will grow on the larger surface.

2) Why do we need so many tubes at the end of the first step? It is important to have many tubes to be sure to pick up some interesting mutations.

3) In Step 2, colony 3 is discarded. Why? Colony 3 grows on minimal medium. It means it is similar to the wild type. It is therefore of no interest for this experiment.

4) Colony 7 is kept. Why? Colony 7 has lost it's ability to survive on minimal medium. It is a mutant worth keeping for further studies.

The case of sickle cell anaemia

Sickle cell anaemiaask Dr Chromo! is a world-wide health problem, affecting many races, countries and ethnic groups. The World Health Organisation estimates that each year more than 250,000 babies are born world-wide with this inherited blood cell disorder, which causes red blood cells to elongate and clog arteries.

Red blood cells from patients are less efficient in transporting oxygen than normal red cells. The shape of the red cell is deformed, and the haemoglobinask Dr Chromo! inside it forms long fibrous molecules. This kind of haemoglobin is called haemoglobin S, and is different from the normal haemoglobin just by one amino acid. The cause of this condition is a difference in one nucleotide in the gene of one of the components of the haemoglobin. As a result of the mutation, in the mRNA, a codonask Dr Chromo! GAA is replaced for a codon GUA. GAA codes for a glutamic acid, and GUA codes for a valine. These two amino acids differ greatly in their side chains, so the substitution has a dramatic affect on the overall structure of haemoglobin.

View of a normal molecule of haemoglobin

View of two sickle haemoglobin ,molecules stuck together.

(Click on an image to load it into Rasmol, and then manipulate it)

After releasing oxygen, haemoglobin molecules that contain the defect stick to one another instead of staying separate, forming long, rigid rods or tubules inside red blood cells. The rods cause the normally smooth, doughnut-shaped red blood cells to take on a sickle or curved shape and to lose their vital ability to deform and squeeze through tiny blood vessels. The sickle cells, which become stiff and sticky, clog small blood vessels, depriving tissues from receiving an adequate supply of oxygen. Most of the problems associated with sickle cell anaemia, including pain from ulcers, strokes and blindness, stem from this blockage.

Why did it spread to so many different parts of the world? The answer lies in a curious coincidence. It turns out that anyone who carries the inherited trait for sickle cell anaemia, but does not have the actual illness, is protected against the severe form of malaria. So in countries that had a problem with malaria, children born with sickle cell trait survived. They grew up, had their own children, and passed the gene for sickle cell anaemia on to these offspring. As populations migrated, the sickle cell trait and sickle cell anaemia moved throughout the world. This is called an heterozygote advantage.

A single mutation in a single gene is the cause of a succession of defects and problems. The discovery of the cause of sickle cell anaemia provided further evidence that the gene is a sequence of DNA, coding for a linear sequence of amino acids making up a single protein.

An example of diagnosis of sickle cell anemia has been included as part of the experiments provided for BioLab. Expt010.htm

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