Introduction

The fruit fly Drosophila melanogaster has been extensively studied for over a century as a model organism for genetic investigations. It also has many characteristics which make it an ideal organism for the study of animal development and behavior, neurobiology, and human genetic diseases and conditions. Why? What makes it such a good model?

  • It's more like us than you think. To benefit medical studies, a good model organism needs to share, on the molecular level, many similar features and pathways with humans. It turns out that approximately 60% of a group of readily identified genes that are mutated, amplified, or deleted in a diverse set of human diseases have a counterpart in Drosophila. Studying these genes in Drosophila lets scientists bypass some of the ethical issues of biomedical research involving human subjects.
  • They're easy to keep, and work with. The fruit fly has many practical features that allow scientists to carry out research with ease:
    • A short life cycle,
    • ease of culture and maintenance, and
    • a low number of chromosomes
    • a small genome size (in terms of base pairs), but
    • giant salivary gland chromosomes, known as polytene chromosomes.

Let's explore these advantages a bit more, and then dive into how the fly has helped us understand a wide range of human conditions.

Image Source: Carolina Biological Supply Company.

The Life Cycle of Drosophila -- 12 Days, Lots of Offspring

The female fruit fly, about 3 mm in length, will lay between 750 and 1,500 eggs in her lifetime. The life cycle of the fruit fly only takes about 12 days to complete at room temperature (25°C). After the egg (at a mere half a millimeter in length) is fertilized, the embryo emerges in ~24 hours. The embryo undergoes successive molts to become the first, second, and third instar larva. The larval stages are characterized by consumption of food and resulting growth, followed by the quiescent pupal stage, during which there is a dramatic reorganization of the body plan (metamorphosis) followed by the emergence of the adult fly.

Easy to Grow, Easy to Keep, Easy to Study

Because the flies themselves are quite small (~1 mg), you can raise a lot of them at once. Traditionally flies have been raised in quarter-pint milk bottles, using a well-ripened banana as food, although more often a corn-meal agar mixture is now used. Genetic experiments can be done in a shell vial with just a few flies. Thus many different mutant stocks can be maintained, and numerous experiments carried out, in a small lab space. When large amounts of material are needed, large population cages, which hold up to 50,000 flies in a cage that is 1’ diameter x 1.5’ long, can be used. That means that scientists can collect and harvest hundreds of grams of embryos, larvae, or adults at a time. The material can be frozen in liquid nitrogen, and then used as the starting point for preparing enzymes such as RNA polymerase II, or for purifying chromosomal proteins such as the histones, or for analysis of chromatin structure (see Chromatin module).

Web Mission: Lifestyles of the Tiny and Numerous

Pete Geiger of the University of Arizona has developed several informational pages on the Drosophila life cycle and on the details of maintaining a stock of flies for the lab. First, visit the page on the Drosophila life cycle. Focus in particular on the short section at the end, under the heading "Life cycle of D. melanogaster," to get a handle on how the flies develop, and what can affect that development. Also, skim the separate page on culturing and maintaining Drosophila in the lab. What would you say are the important factors in the environment that researchers need to consider in setting up a fly lab?

A Manageable Number of Chromosomes

The giant polytene chromosomes found in the fly's salivary glands (compared here with the chromosomes from the fly's ovary) are another characteristic that makes the fruit fly an important organism for laboratory studies. These easily visualized chromosomes provided a road map for early geneticists.
Image source: Modified from T. S. Painter, J. Hered. 25, 465-476 (1934).

The genetic information (DNA) in all cells is carried in the chromosomes (literally "colored bodies") -- a complex of DNA plus specialized proteins (histones) packed in the cell's nucleus. As with humans, the chromosomes of Drosophila melanogaster come in pairs -- but unlike humans, which have 23 pairs of chromosomes, the fruit fly has only four: a pair of sex chromosomes (two X chromosomes for females, one X and one Y for males), together designated Chromosome 1, along with three pairs of autosomes (non-sex chromosomes) labeled 2 through 4. Chromosome 4 is the smallest and is also called the dot chromosome. It represents just ~2% of the fly genome.

The low, manageable number of chromosomes was a key attraction of this organism in early genetic studies. Indeed, some classic genetic analyses of mutations and mapping of mutants to specific chromosomes in Drosophila were used to determine the ground rules for the transmission of genes.

Web Mission: The Eyes Have It

Wondering about those amazing eyes? Red eyes are normal in "wild-type" Drosophila. But in 1910, the "Fly Lab" of Thomas Hunt Morgan at Columbia University discovered a mutant strain of flies that had white eyes, and, using that difference in phenotype as a jumping-off point, conducted an elegant series of experiments that ultimately led to fundamental discoveries about the physical basis of heredity in the bodies we call chromosomes. For that work, Morgan was awarded the 1933 Nobel Prize in Physiology and Medicine.

For this mission, go to the DNA Learning Center's short interactive exhibit on Morgan's work. Note in particular how Morgan and his team began with a simple difference in phenotype to construct a rigorous series of genetic rules, particularly for sex-linked inheritance. How do you think the characteristics of the fly -- particularly its short life span -- helped make these experiments possible?

Of course, there's more to a fly than its eyes. Go to the Exploratorium page showing the variety of phenotypes that scientists have used to tease out the fly's genetic map. In the diagram of fly chromosomes, notice where the yellow-body and white-eye genes are located. How does that line up with the observations from Morgan's lab?

[A note on gene names: Remember that when Morgan and his colleagues were working out the rules of fly genetics, they did not have any information on the structure of DNA, or how the information used by the organism might be coded; hence they did not know the actual functions of the genes they studied. Their knowledge of a gene was based simply on the inherited phenotype. The white gene is required to have a fly with red eyes, so you might have named the gene red, but the name always refers to the mutant phenotype – here, white eyes – so the name given to the gene was white.]

Structure and Organization of the Drosophila Genome

As we've already seen, we have learned a tremendous amount about general genetic rules from studies analyzing fly phenotypes across multiple generations, and tying those phenotypes to specific locations on chromosomes. But to make the leap to using the fly as a model for other organisms, we need to drill down deeper, to the actual sequence of base pairs within the DNA itself. Sequencing of the genome lets us make direct comparisons between organisms at the molecular level, and puts us in the realm of molecular biology -- where things really start to get interesting.

Image Source: Science

The genome sequence of Drosophila melanogaster was published in the journal Science in March 2000. Studies of the sequence, and comparisons with the sequence of the human genome, published around a year later, have uncovered some key facts in thinking about Drosophila as a model organism:

  • In terms of base pairs, the fly genome is only around 5% of the size of the human genome -- that is, 132 million base pairs for the fly, compared with 3.2 billion base pairs for the human.
  • In terms of the number of genes,, however, the comparison isn't nearly so lopsided: The fly has approximately 15,500 genes on its four chromosomes, whereas humans have about 22,000 genes among their 23 chromosomes. Thus the density of genes per chromosome in Drosophila is higher than for the human genome.
  • Humans and flies have retained the same genes from their common ancestor (known as homologs) over about 60% of their genome.
  • Based on an initial comparison, approximately 60% of genes associated with human cancers and other genetic diseases are found in the fly genome.

Use of Drosophila for Studying Human Behavior, Development, and Disease

Image Source: J. Craig Venter Institute

The parallels between the genomes of Drosophila and humans are central to using these tiny flies to explore human development, behavior, and genetic diseases. Often, the genes associated with these attributes in humans have closely matched fly counterparts -- and there are many examples of "conditions" in Drosophila that parallel human conditions, and that can provide an opportunity to study the function of these genes and, perhaps, help in the development of valuable drugs. Genes associated with neurological diseases, cancer, the hypoxic response, infectious disease, etc., are currently under study. (A searchable database of such genes is available on UCSD's "Superfly" server.)

The number of human conditions for which Drosophila has been used as a model for study is surprising, and the story of these explorations can be fascinating. Each of the following Vignettes digs deeper into the role of Drosophila in revealing the genetic basis of a common (or uncommon) human disorder or condition. In several of the Vignettes, try to answer the Thought Questions to measure your understanding of the main themes.

Vignettes

Web Mission: Drosophila Development

The final Web Mission in this segment is all about development. Much of what is known about animal development comes from the studies on Drosophila -- and, though the products of the developmental process are obviously quite different, many of the genes and activation pathways in development are the same in human and the fly.

To start out, visit the chapter on Drosophila development from an online textbook for a genetics-and-development introductory course at Kenyon College. Note here the initial point that human and fly development are homologous processes -- that is, much of the genetic machinery under the hood of development for both organisms derives from genes inherited from a common ancestor. That's a key to the ability to use something as seemingly different as a fruit fly to study aspects of embryonic development in humans.

Work through the Kenyon page, and note the discussion toward the end of the so-called Hox (homeobox-containing) genes. These genes encode for transcription factors -- proteins that regulate the expression of genes, in this case in development. As is suggested here, certain details of the Hox genes' organization and function are conserved across a huge swath of evolutionary time -- for example, the Hox gene order is the same in the fruit fly and the mouse, even though the last common ancestor of these two organisms existed hundreds of millions of years ago. Evolution, of course, operates by natural selection on genes that have mutated or changed over time -- that's why mice don't look much like fruit flies. Why would the process of evolution be so disinclined to mess with these genes in particular?

In development, a picture is worth a thousand words, and a moving picture worth many thousands. So next, head over to the FlyMove Web site, an online project gathering information, images, and movies about Drosophila development. First, click on the "Stages" tab, and open up the table showing the 17 stages of Drosophila development from fertilization to the hatching of the first instar larva. With that table still open, open up the movie immediately below, showing a time-lapse view of the development of a fly embryo across all 17 stages. At what stage do you start to see visible changes in the movie? What is the name of that stage? Find out what is going on by drilling deeper into the stage-number links at the left.

All of these stages are controlled by the action of specific genes. To get a glimpse of the richness of this genetic blueprint, head to the final stop, The Interactive Fly, a project hosted by the Society for Developmental Biology. In particular, read the discussion of gastulation and morphogenetic movements -- the processes beginning at stage 6. (Warning: There is a fair amount of difficult terminology on the page.) The links on the page give an idea of some of the key steps and genes involved in this intricate process.

Other Web Resources

From Fly to Worm

Now that we have explored the fly as a model organism and seen something of how fly studies have paid off in biology, let's move on to the other model organism investigated by modENCODE -- the roundworm C. elegans.