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Model organisms

Definition

Model organisms are a small number of species that have been extensively studied. What has been learnt from model organisms has been extrapolated to include other species in the hope of understanding developmental, metabolic and biological pathways that are conserved throughout evolution.

Why use model organisms?

Many of the things we study in Biology, such as disease, development and genetics needs to be studied in the body (in vivo), to see how pathways and signals, for example, really work. Realistically always studying these in humans would be extremely expensive, not to mention potentially unsafe and unethical. We use model organisms instead as they provide amazing insight that cannot be gained from lab equipment. What we learn about that animal can then be used to predict what happens in other animals. This is because all living organisms have evolved from the same ancestor and many pathways are the same across different species.

What makes a good model organism?

A model organism must be easy to look after in the laboratory. They are nearly always small and do not need a lot of space, have an easy feeding regime and they must not be dangerous to work with. There are many species that would make good model organisms, many of the model organisms used most frequently were selected because of the extensive knowledge we already have of them from previous research.

Choosing a model organism

Arabidopsis

A flowering plant with just five chromosomes and 27,000 genes this is the easiest plant used to make transgenic and is also very easy to gene map. The Arabidopsis species used is Arabidopsis thaliana and it is transformed using Arabidopsis tumefaciens, most commonly using the method floral dip. As plants and animals evolved to be multicellular from different ancestors, Arabidopsis has been used to find common features needed to create a multicellular organism and to try and discover common features that may have been present in a unicellular common ancestor. It was also used in research to discover the genetic basis of phototropism and chloroplast alignment.

Caenorhabditis elegans

Used as a model organism since the 1970s this nematode worm is one of the simplest animals to care for in the laboratory. Surviving in agar plates that have a covering of E. coli they are so small they can barely be seen without the aid of a microscope.

This was the first multicellular organism to have its genome sequenced and we know a lot about its different cell lineages. One of the most important discoveries about C. elegans is that due to the animal's transparency we know the cell lineage of every single cell in C. elegans body. All multi-cellular organisms start as a single cell which then divides and differentiates to form many cells of different types. In C. elegans we know the entire differentiation pathway that leads to the 959 cells in the adult. This knowledge has helped understand cell differentiation in other animals too. Most of the genetic markers that are used in C. elegans have the advantage of being easily visible: they affect the worms' morphology or its movement. Two common genetic markers are uncoordinated (unc) that affects how the worms move along the plate and dumpy (dpy) which causes the worms to be born short and fat. Another advantage to C. elegans is that it is transparent; this means that changes to the cells can be easily seen as well as cells that have been fluorescently tagged. Evolution is easily studied in C. elegans as they can be frozen and stored. Young larvae survive best and at 80 degrees celsius they can be kept for up to 10 years. This means that generations can be compared to see how they have evolved. With such a short life cycle 10 years is a long time. As hermaphrodites they also produce homozygous strains, so every individual within a population has the same genome. Unfortunately it is hard to target gene disruptions in C. elegans, instead double stranded DNA is injected into the nucleus and maintained as an extrachromosomal multicopy array. See a video if this microscopic worm in action

Drosophila melanogaster

This fruit fly only has four pairs of chromosomes and the fourth is so small is it often ignored. Of the fly's 13, 750 genes it only carries one important one, the eyeless gene, although it expected that there are up to 80 genes on the chromosome. It has been used to understand genetics for over a century which means there are a large number of different mutant lines available to work with. Mutations in Drosophila are very easy to spot as many affect their morphology.

The first mutation recorded was white eyes in 1908 and is now one of many genetic markers which includes Curly (Cy1), which causes the wings to curve away from the body, ebony (e1), which is identifiable by the black bodies of the flies, and stubble (Sb1) which results in the bristles on the body being shorter and thicker. Raised on agar and yeast the flies can undergo their life cycle, eggs to flying adults, in just 10 days. This means that entire generations can be seen within a month making it an excellent organism for genetic crosses. Although it is difficult to target a gene disruption in the fly it is easy to create a transgenic fly as P transposable elements can be injected and they will integrate into a random position in the genome. Many of the genes in Drosophila are equivalent (homologues) of the genes we have as well. They are a fairly complex animal and that means we can use them to study more complex processes such as behaviour. Their mating ritual, for example, was the first behavioural process to be understood using genetics. See a close up of Drosophila melanogaster here See a video that explains Drosophila courtship here 

Mus musculus

Its genome is a similar size to ours, with 30, 000 genes, and its small size and fast life cycle make it a great model organism when researching mammalian biology that must be extrapolated to humans. Mus musculus has been used in studies of immunology, embryology and cancer. Inbred lines are created in the lab by mating offspring from the same generation, then mating the offspring form the new generation with each other and so on and so forth until it can be almost guaranteed that each individual mouse has exactly the same genome.

The two most obvious advantages to using mice over other model organisms is the similarity in their genomes to us and the fact that genes can be disrupted by deletion or insertion very specifically by using embryonic stem cells. There are few limitations to the research that can be conducted on mice however the ethics guidelines are much stricter. There are many regulations for animal research using vertebrates whereas there are practically none for invertebrates. Cephalopods (octopus and squid) are classed as vertebrates when it comes to research as they are considered to be very intelligent and have complex nervous systems. These regulations can affect the use of mice, and other vertebrates, in the lab. See a mouse with a genetic hyperactivity disorder here See a close up of a much calmer Mus musculus here 

Other examples of model organisms

Techniques used in the study of model organisms

Random Mutagenesis Now we have techniques to make very specific changes to animals' genomes but we did not always have them. In the past the most common method for causing mutations was to expose cells to mutagens.  These are substances that cause mutations in the genome. The cells may be exposed to UV radiation, certain chemicals, or even carcinogens. Any mutations are completely random, changes in the phenotype are identified and then researchers will try and find the changes in the genome that could be the cause. This method is referred to as reverse genetics. 

Marker Mutations The majority of mutations are recessive and homozygous lethal. This means that if they have one copy of the mutated gene they cannot be identified, and if they have two the foetus will not survive. This makes it difficult to track where the allele is within a population.  This is why the mutations are often linked to balancer chromosomes which have a marker mutation. These genes are dominant and homozygous lethal. If an individual has one copy of the balancer chromosome it will be identified just by looking at the phenotype and no individuals will have two copies. The balancer chromosomes are inserted into the genome near to the gene of interest. They suppress recombination and this ensures that an individual has a balancer chromosome and a recessive mutation. In Drosophila balancer chromosomes are used (as described above) which are often homozygous lethal like the mutations. This means that the flies can be left to mate and only individuals who have balanced chromosomes will survive. Another method is to insert the green fluorescent protein (GFP) onto the chromosome and use it as a reporter gene. This allows the embryos carrying a mutation or specific gene to be identified; the homozygous wild-type, homozygous mutation and heterozygote individuals can then be separated at an earlier stage. It is often used in mice.

Gene Knockout This is a technique that renders a gene inoperable. By seeing how this affects the phenotype the gene's function can be determined. It takes a number of techniques to create a knockout animal and it all starts with a plasmid.  Using gene knockouts changed mouse genetics; it can be used in place of random mutagenesis (although this still has its uses) and target mutations to specific genes of interest. Often if both alleles of a gene are knocked out then a lethal phenotype occurs; this is why often the knockouts are heterozygous and the mutated gene is paired with a genetic marker so it is identifiable. Some knockouts can even be conditional, so produce the wild-type phenotype under certain temperatures for example. Conditional mutations are a very common technique in Drosophila. To produce a knockout mouse a gene construct, very similar to the gene of interest, is created. It is then inserted into embryonic stem cells via electroporation. Homologous recombination will occur and some of the stem cells will have incorporated the gene construct. The stem cells are then inserted into a blastocyst and implanted into a female's uterus. Some of the offspring will now carry the knockout gene. Here is a video of a knockout mouse that now has a little too much energy...

Knockdown Some genes when knocked out of the genome create a lethal phenotype. This means that the foetus will not survive to full term or the offspring will die soon after birth and the function of the gene cannot be identified. Knockdown mutations are often engineered in mice, reducing the function of a gene to discover what that function is. One method of knocking down a gene is to use RNA interference (RNAi): double stranded RNA is inserted into living cells. Here it will be separated and one strand will bind to a complementary sequence in mRNA and induce its cleavage from the rest of the mRNA sequence. To knockdown a gene the RNA is simply designed to be complementary to the sequence of interest; once inserted into the cell it will be incorporated into the RNAi pathway. This technique is used in C. elegans and mice embryos.

Mice under UV light expressing the GFP protein

Mice under UV light expressing the GFP protein

Credits and further reading

Arabidopsis image owned by Benjamin ZwittnigC. elegans image owned by Zeynep F. AltunDrosophila image owned by Andr‚ KarwathMus musculus image owned by Aaron LoganGFP image owned by Ingrid Moen

References For Further Reading:

A good textbook that goes into lots of detail about the different model organisms. Meneely P., (2009) Advanced Genetic Analysis: Genes, Genomes and Networks in Eukaryotes, Oxford, Oxford University Press, chapter 1.2

A good website for seeing other kinds of model organism and why they are used. http://developmentalbiology.de/en/modelorganisms.php 

 How do we choose new model organisms? Jenner, R. A. and M. A. Wills (2007). "The choice of model organisms in evo-devo." Nat Rev Genet 8(4): 311-314.

Why model organisms will be used in research for years to come. Fields, S. and M. Johnston (2005). "Whither Model Organism Research?" Science 307(5717): 1885-1886.

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