Early Studies of Drosophila
By the early 1900s, scientists had discovered chromosomes inside cells and knew that they occurred in pairs, that one partner of each pair was provided by each parent during reproduction, and that fertilization restored the paired condition. This behavior of chromosomes paralleled the observations of Austrian botanist Gregor Mendel, first published in 1866, which showed that traits in pea plants segregated and were assorted independently during reproduction. This led geneticists Walter Sutton, Theodor Boveri, and their colleagues, in 1902, to propose the chromosome theory of inheritance, which postulated that Mendel’s traits, or “genes,” existed on the chromosomes. However, this theory was not accepted by all scientists of the time.
Thomas Hunt Morgan
was an embryologist at Columbia University in New York City, and he chose to study the chromosome theory and inheritance in the common fruit fly, Drosophila melanogaster. This organism was an ideal one for genetic studies because a single mating could produce hundreds of offspring, it developed from egg to adult in only ten days, it was inexpensively and easily kept in the laboratory, and it had only four pairs of chromosomes that were easily distinguished with a simple microscope. Morgan was the first scientist to keep large numbers of fly “stocks” (organisms that are genetically similar), and his laboratory became known as the Fly Room.
After one year of breeding flies and looking for inherited variations of traits, Morgan found a single male fly with white eyes instead of the usual red, the normal or wild-type color. When he bred this white-eyed male with a red-eyed female, his results were consistent with that expected for a recessive trait, and all the offspring had wild-type eyes. When he mated some of these offspring, he was startled to discover a different inheritance pattern than he expected from Mendel’s experiments. In the case of this mating, half of the males and no females had white eyes; Morgan had expected half of all of the males and females to be white-eyed. After many more generations of breeding, Morgan was able to deduce that eye color in a fly was related to its sex, and he mapped the eye-color gene to the X chromosome of the fruit fly. The X chromosome is one of the sex chromosomes. Because a female fly has two X chromosomes and a male has one X and one Y chromosome, and because the Y chromosome does not carry genes corresponding to those on the X chromosome, any gene on the male’s X chromosome is expressed as a trait, even if it is normally recessive. This interesting and unusual example of the first mutant gene in flies was called a sex-linked trait because the trait was located on the X chromosome. Genes in flies are named for their mutant characteristics; therefore, because the mutant version of this gene conferred white eyes, it was named the white gene.
This important discovery attracted many students to Morgan’s laboratory, and before long they found many other unusual inherited traits in flies and determined their inheritance patterns. One of the next major discoveries by members of the fly lab was that of genes existing on the same chromosome, information that was used to map the genes to individual chromosomes.
Linked Genes and Chromosome Maps Many genes are located on each chromosome. Genes, and the traits they specify, that are situated on the same chromosome tend to be inherited together. Such genes are referred to as linked genes. Morgan performed a variety of genetic crosses with linked genes and developed detailed maps of the positions of the genes on the chromosomes based on his results. Morgan did his first experiments with linked genes in Drosophila that specified body color and wing type. In fruit flies, a brown body is the wild type and a black body is a mutant type. In wild-type flies, wings are long, while one mutant variant has short, crinkled wings referred to as vestigial wings. When Morgan mated wild-type females with black-bodied, vestigial-winged males, the next generation consisted of all wild-type flies. When he then mated females from this new generation with black-bodied, vestigial-winged males, most of the progeny were either brown and normal winged or wild-type black and vestigial winged, in about equal proportions. A few of the offspring were either just black bodied (with wild-type wings) or vestigial winged (with wild-type body color), trait combinations found in neither parent, thus referred to as nonparentals. Because of the equal distribution of these mutant traits between males and females, Morgan knew the genes were not sex linked. Because the traits for body color and wing length generally seemed to be inherited together, he deduced that they existed on the same chromosome.
As Morgan and his students and colleagues continued their experiments on the inheritance of body color and wing length, they observed a small but consistent percentage of offspring with nonparental trait combinations. After repeating these experiments with many different linked genes, Morgan discovered that chromosomes exchange pieces during egg and sperm formation. This exchange of chromosome pieces occurs during a process called meiosis,which occurs in sexually reproducing organisms and results in the production of gametes, generally eggs and sperm. During meiosis, the homologous chromosomes pair tightly and may exchange pieces; since the homologous chromosomes contain genes for the same trait along their length, this exchange does not present any genetic problems. The eggs or sperm produced through meiosis contain one of each pair of chromosomes.
In some of Morgan’s genetic crosses, flies carried one chromosome with alleles (alternate forms of a gene at a specific locus) for black bodies and vestigial wings. The homologous chromosome carried wild-type alleles for both traits. During meiosis, portions of the homologous chromosomes exchanged pieces, resulting in some flies receiving chromosomes carrying genes for black bodies and normal wings or brown bodies and vestigial wings. The exchange of chromosome pieces resulting in new combinations of traits in progeny is referred to as recombination. Morgan’s students and colleagues pursued many different traits that showed genetic recombination. In 1917, one of Morgan’s students, Alfred Sturtevant, reasoned that the farther apart two genes were on a chromosome, the more likely they were to recombine and the more progeny with new combinations of traits would be observed. Over many years of work, Sturtevant and his colleagues were able to collect recombination data and cluster all the then-known mutant genes into four groupings that corresponded to the four chromosomes of Drosophila. They generated the first linkage maps that located genes to chromosomes based on their recombination frequencies.
The chromosomes in the salivary glands of the larval stage of the fruit fly are particularly large. Scientists were able to isolate these chromosomes, stain them with dyes, and observe them under microscopes. Each chromosome had an identifying size and shape and highly detailed banding patterns. X-rays and chemicals were used to generate new mutations for study in Drosophila, and researchers realized that in many cases they could correlate a particular gene with a physical band along a chromosome. Also noted were chromosome abnormalities, including deletions of pieces, inversions of chromosome sections, and the translocation of a portion of one chromosome onto another chromosome. The pioneering techniques of linkage mapping through recombination of traits and physical mapping of genes to chromosome sections provided detailed genetic maps of Drosophila. Similar techniques have been used to construct gene maps of other organisms, including humans.
Control of Genes at the Molecular Level This seminal genetic work on Drosophila was unparalleled in providing insights into the mechanisms of inheritance. Most of the inheritance patterns discovered in the fruit flies were found to be applicable to nearly all organisms. However, the usefulness of Drosophila as a research organism did not end with classical transmission genetics; it was found to provide equally valuable insight into the mechanisms of development at the level of DNA.
Drosophila were discovered to be ideal organisms to use in the study of early development. During its development in the egg, the Drosophila embryo orchestrates a cascade of events that results in the embryo having a polarity, a head and a tail, with segments between each end defined to become a particular body part in the adult. Edward Lewis, Christiane Nüsslein-Volhard, and Eric Wieschaus were awarded the Nobel Prize in Physiology or Medicine in 1995 for their research on the genetic control of Drosophila development. Nüsslein-Volhard and Wieschaus studied the first step in this process: pattern formation in the early embryo. Lewis studied the next step in this process: genes that further specialized adult structures.
Developmental instructions from the mother fruit fly are sequestered in the egg. When the egg is fertilized, these instructions begin to “turn on” genes within the fertilized eggs that begin to establish the directionality and segment identity within the embryo. Working together at the European Molecular Biology Laboratory in Heidelberg, Germany, Nüsslein-Volhard and Wieschaus identified fifteen such genes that are “turned on” to pattern the Drosophila embryo. To identify these genes, they performed a genetic screen in which they treated flies with chemicals, mutating their genes at random, and then searched for mutations resulting in defective embryonic segmentation (for example, embryos with reduced numbers of segments or embryos that no longer had a distinct head and tail). Segmentation genes similar or identical to those in the fruit fly also exist in higher organisms, including humans, and perform similar functions during embryonic development.
These segments originally defined during embryonic development remain established during the larval stages, and each becomes specific body segments in the adult fly. For example, the second segment of the thorax will support one pair of wings and one of the three pairs of legs. Mutations in genes controlling this process resulted in the transformation of one body segment into another and showed bizarre appearances as adults, such as having two sets of wings or legs replacing the normal antennae on the head. By studying these homeotic mutants, Lewis was able to elucidate some of the mechanisms that control the overall body plan of nearly all organisms in early development. He also found that the homeotic genes are arranged in the same order on the chromosomes as the body segments that they controlled—the first genes controlled the head region, genes in the middle controlled abdominal segments, and the last genes controlled the tail region. Like the segmentation genes, scientists found that the Drosophila homeotic genes directly corresponded to similar genes in all animals studied. Vertebrate homeotic genes are not only closely related to the insect genes but also found in the same order on the chromosomes and have the same essential function in time and space during embryonic development as in the fly.
Many other aspects of Drosophila were also useful in understanding the structure and function of the DNA of all organisms. It was found that in Drosophila, large pieces of DNA will, under certain circumstances, pop out of the chromosome and reinsert themselves at another site. One such element, called a P element, was used by scientists to introduce nonfly DNA into the fruit fly embryo, thus providing information on how DNA is expressed in animals. This work also provided early clues into the successful creation of transgenic animals commonly used in research. Many additional genetic tools developed over the years allow scientists to “turn on” or “turn off” genes in particular tissues and at particular times in fly development. Such tools also enable genes to be “turned on” at levels higher than normal, “knocked down” to levels lower than normal, or deleted from the fly’s DNA completely. This precise manipulation of gene expression makes the fly a powerful genetic system for studying the control
of genes at the molecular level in an entire organism.
Impact and Applications Genetic studies of Drosophila melanogaster have provided the world with a fundamental understanding of the mechanisms of inheritance. In addition to the inheritance modes shown by Mendel’s studies of pea plants, fruit fly genetics revealed that some genes are sex linked in sexually reproducing animals. The research led to the understanding that while many genes are linked to a single chromosome, the linkage is not necessarily static, and that chromosomes can exchange pieces during recombination. The ease with which mutant fruit flies could be generated led to the development of detailed linkage maps for all the chromosomes and ultimately to the localization of genes to specific regions of chromosomes. With the advent of molecular techniques, it was discovered that Drosophila provided a wealth of information concerning the molecular control of genes in development.
Although all these breakthroughs were scientifically interesting in terms of the flies themselves, many of the breakthroughs helped identify fundamental principles consistent among all animals. Most of what is known about human genetics and genetic diseases has come from these pioneering studies with Drosophila. Historically, Drosophila was considered a model of embryogenesis. However, completion of its full genome sequence in March of 2000 led to an emphasis on Drosophila as a model of human disease. Analyses of the fly’s nearly 14,000 genes revealed that approximately 75 percent of known human disease genes have related sequences in the fly. This high level of conservation further supported the search for additional disease-causing genes in Drosophila.
Novel genes can be identified using genetic screens. Because of the sheer numbers of offspring from any mating of flies, their very short life cycle, and large numbers of traits that are easily observable, fruit flies have become an ideal system to screen for mutations in genes with previously unknown functions. In one type of screen, flies are exposed to a chemical mutagen and mated; then their offspring are analyzed for any abnormal appearances or behaviors, or for low numbers of offspring. Should a mutation cause any variation in the expected outcome of a cross, it is then subjected to more rigorous research, beginning by mapping the mutation to a particular gene locus on the chromosome.
The versatile, easy-to-care-for, inexpensive fruit fly is often a fixture in classrooms around the world. Indeed, many geneticists have traced their passion to their first classroom encounters with fruit flies and the excitement of discovering the inheritance patterns for themselves. Drosophila is routinely used in the study of many aspects of biology and disease conditions, including cancer, muscle and neurological disorders, cardiology, diabetes, aging and oxidative stress, innate immunity, drug addiction, learning patterns, behavior, and population genetics. Because of the ease of study and the volumes of information that have been compiled about its genetics, development, and behavior, Drosophila will continue to be an important model organism for biological study.
Key Terms
homeotic genes
:
a group of genes responsible for transforming an embryo into a particular body plan
linked genes :
genes, and traits they specify, that are situated on the same chromosome and tend to be inherited together
model organism
:
an organism well suited for genetic research because it has a well-known genetic history, a short life cycle, and genetic variation between individuals in the population
sex chromosomes
:
The X and Y chromosomes, which determine sex in many organisms; in
Drosophila, a female carries two X chromosomes and a male carries one X and one Y chromosome
Bibliography
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