Drosophila Genetics Research Papers

Drosophila as a Model OrganismAn Introduction

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.

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 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.

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

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.

In this section, you will:

  • Learn about the fruit fly Drosophila melanogaster -- and, in particular, what has made it such a spectacular success as a model system for biological investigations.
  • Explore how studies of the fly have been used to investigate the roots of human diseases and disorders, from alcoholism to Alzheimer's, through a series of Vignettes.
  • Take a number of Web Missions to external sites to deepen your understanding.
  • Consider and answer a series of Thought Questions on key topics to test your understanding.

Glossary Terms

TEST Monocytes

A cell of the immune system, which circulates through the blood, bone marrow, and spleen, and plays an important role in antimicrobial defense.

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Agar

A gelatinous substance used to grow, or culture, microorganisms. Agar provides the microorganisms a surface to grow on and contains nutrients.

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Antibody

A protein in the immune system that recognizes a specific target, or antigen, on a foreign molecule, allowing these two structures to bind together with precision.

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Autosome

A chromosome for which there is an equal number of copies in males and females -- that is, a chromosome that is not a sex chromosome.

Activator

A protein which, by binding to an operator sequence, promotes transcription of a gene.

Base Pairing

The "genetic code" in a DNA molecule is written in four bases -- adenine (A), cytosine (C), guanine (G) and thymine (T) -- that are arrayed along each strand of the twisted, two-stranded molecule (the famous "double helix"). Each base is chemically tuned to pair, via hydrogen bonds, with a corresponding base on the opposite strand -- A with T, G with C. The size of an organism's genome is usually given by the number of base pairs.

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ChIP-Seq

A technique for analyzing interactions of proteins with DNA, consisting of chromosomal immunoprecipitation, followed by massively parallel DNA sequencing.

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Chromatin

The combination of DNA and proteins found in the nucleus of a cell, which makes up chromosomes. Chromatin helps fold DNA so it will fit into the cell and is involved in both gene expression and DNA replication.

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Chromosome

A structure of coiled DNA and proteins that organizes the genetic material in the cell's nucleus.

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Differentiation

The scientific term for cells becoming more specialized throughout development.

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DNA

DNA encodes the genetic blueprint of an organsim. This genetic material is composed of deoxyribonucleotides -- individual units combining a sugar, a base, and a phosphate group -- that each have different chemical properties, and are referred to by the different base names adenine (A), cytosine (C), guanine (G) and thymine (T). Combinations of these bases "spell out" the code of a given gene.

DNA-Binding Protein

Proteins with a specific or general affinity for DNA.

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DNA Sequencing

The process of determining the specific order of nucleotide bases in a DNA molecule.

Enzymes

Biological molecules (mainly proteins) that catalyze, or increase the rate of, a chemical reaction

Epigenetics

The study of changes in gene expression resulting from mechanisms other than changes in the underlying DNA sequence.

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Eukaryotes

The class of organisms, composed of one or more cells, containing a membrane-enclosed nucleus and packaging its DNA with histones in a nucleosome array. Eukaryotic cells typically have complex organelles, such as mitochondria.

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Exon/Intron

An exon is a contiguous segment of a gene found both in the initial transcript and in the final product; the introns are those segments found in the initial transcript which are removed during processing, and so are not found in the finished product.

Gene

In molecular biology, a gene is the molecular unit of inheritance for a single function or phenotype -- or, more precisely, the full sequence of bases within a section of the genome that is necessary and sufficient for the synthesis of a functional product. Usually that product is a polypeptide (a section of a protein), but in some cases it is an RNA molecule.

Genome

The full complement of genetic information recorded in the chromosomal DNA (or, for some organisms, RNA).

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Genome Annotation

Within a genome sequencing project, annotation is the process of identifying biologically relevant elements within the genome sequence (e.g., genes), and adding information to the sequence on how those elements function.

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Genotype

The specific genetic encoding, or allele of a gene, that leads to an observable characteristic in an organism.

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Green Fluorescent Protein (GFP)

A protein first isolated from the jellyfish Aequorea victoria that exhibits bright green fluorescence when exposed to ultraviolet blue light. The GFP gene can be introduced into organisms and used by scientists to "see" gene expression.

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Hermaphrodite

An organism containing both male and female reproductive organs within the same individual.

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Histones

The small, basic proteins used to package the DNA in chromatin. The core histones (H2A, H2B, H3, and H4) are highly conserved over evolution, while histone H1 is more variable.

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Histone Code Hypothesis

The hypothesis that combinations of chemical modifications to histone proteins in the chromatin form a complex, separate mechanism for regulating transcription and, thus, gene expression.

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Histone Deacetylase

An enzyme that removes acetyl groups from the ends of histone proteins.

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Homolog

A gene found in an organism that shares an ancestral sequence with that of another organism. Homologs are often identified based on the retention of shared genetic or protein-level identities between two different species that share a common evolutionary history.

High-Occupancy Target (HOT) Region

Genomic regions where 15 or more independent transcription factors bind.

Immunoprecipitation

The process of isolating and concentrating a specific protein of interest by trapping an antibody that binds to that protein, using any of a number of lab techniques.

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Instar

The intermediate developmental stages that an insect (such as Drosophila) undergoes between molts until it reaches sexual maturity.

Micro-RNA (miRNA)

Post-transcriptional regulators that bind to complementary sequences on target messenger RNAs, usually leading to gene silencing.

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Model Organism

A non-human species used in experimental biology to study biological processes that might illuminate workings of the same processes in other organisms, for which the same experiments might be infeasible or unethical.

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Molting

Molting, or ecdysis, is the periodic shedding of the outer skeleton, or exoskeleton, that accompanies the growth of most arthropods, including insects.

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Next-Generation Sequencing (NGS)

A family of techniques for DNA sequencing that rely on massively parallel processing of many millions of DNA fragments, followed by analysis and re-assembly of those fragments using computer techniques.

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Nanometer

A unit of length equal to one billionth of a meter.

Null Hypothesis

The null hypothesis generally corresponds to what we expect if nothing "interesting" is happening. If you flip a coin many times, and generally get roughly 50% heads and 50% tails, that is consistent with the null hypothesis that the coin is fair. If you flip a coin many times and get 99% heads, the coin may be unfair, and hence you may have cause to reject the null hypothesis that it is fair.

Ortholog

A gene that has similar sequence in each species in which it's found because the species have a common ancestor during evolutionary time. For example, the alcohol dehydrogenase and Malic Enzyme 1 genes are similar in both Drosophila melanogaster and Homo sapiens. Normally, orthologous genes have the same function in each species in which they are found; therefore, studying the function of a gene in a model organism can provide good evidence for the function of the orthologous gene in humans

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Petri Dish

A shallow cylindrical dish, made of glass or plastic, used to grow, or culture, cells, bacteria, and other microorganisms.

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Phenotype

The observable characteristics or traits of an organism, resulting from the interaction of the expression of the organism's genes with the influence of environmental factors.

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Pheromone

A type of nonverbal communication, usually a chemical or hormone secreted by an animal, which often influences the behavior of other members of the same species. Pheromones are used to establish territory and attract mates.

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Polytene Chromosomes

Giant chromosomes formed by some cells that undergo multiple rounds of DNA replication without actual cell division. The salivary glands of Drosophila contain examples of such chromosomes. Their size makes them especially convenient for work in the lab.

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Posttranslational Modification

Any of a variety of additional changes to a protein after translation that can modify its behavior and thus affect in gene expression.

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Prokaryotes

The class of single-cell organisms, including the eubacteria and archaea, that lack a true membrane-limited nucleus and other organelles.

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Protein

Biological compounds made up of one or more polypeptides (a chain of amino acids) typically folded into a 3-D form. The sequence of amino acids in a protein is defined by the sequence of a gene.

Protein Purification

A variety of processes used to isolate a particular protein from a biological tissue or culture, and thereby to allow the further characterization of the protein's structure and function.

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Proteome

The full complement of proteins expressed by a genome, cell, tissue, or organism.

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Repressor

A protein which, by binding to an operator sequence, prevents transcription of a gene.

Reference Genome

A genome sequence assembled from the experimentally obtained sequences of a number of individuals in a species, designed to serve as a representative example of the "typical" gene sequence of that species.

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Regulatory Region

Segments of DNA where transcription factors bind preferentially.

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Reverse Transcriptase

An enzyme that uses RNA as a template to transcribe single-stranded DNA -- thereby reversing the more familiar information flow from DNA to RNA. In addition to its use in the lab, RT has been extensively studied in retroviruses (particularly HIV) that have an RNA genome but must produce double-stranded DNA that becomes integrated into the host cell genome as part of their replication cycle.

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Ribosome

The complex molecules that catalyze protein synthesis within the cell.

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RNA

RNA is composed of nucleotides, just like DNA -- three major differences between the two: (1) RNA contains the sugar ribose, while DNA contains the slightly different sugar deoxyribose (2) RNA has the nucleobase uracil, while DNA contains thymine; (3) unlike DNA, most RNA molecules are single-stranded.

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RNA Interference (RNAi)

The silencing or reduction of RNA expression (which generally correspondes to protein production) for a given gene in a cell or organism. It occurs as a natural process within living cells, but is also a powerful technique for studies of gene expression in the lab.

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RNA Polymerase I, II, and III

Enzymes in eukaryotic cells that manage the synthesis of a strand of RNA based on the sequence encoded in the DNA.

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RNA-Seq

A high-throughput technique for sequencing an organism's "transcriptome" -- the RNA transcribed from the genome under investigation.

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Sequence Read

The sequence of a small fragment of DNA, obtained as part of a high-throughput sequencing experiment.

Sex Chromosomes

A pair of chromosomes, usually designated X or Y, in the germ cells of most animals and some plants, that combine to determine the sex and sex-linked characteristics of an individual.

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Small Interfering RNA (siRNA)

Short, 20-to-25-nucleotide, double-stranded RNA fragments that interfere with the expression of a specific gene.

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Single-nucleotide polymorphism (SNP)

A difference in a single base pair in a given gene sequence, between two or more individuals, or between an individual and a reference genome, that is associated with a difference in phenotype or expressed trait.

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Stasis

The state of equilibrium or inactivity, analogous to hibernation.

Transcription

During transcription, a DNA sequence is read by RNA polymerase and a complementary RNA copy of the DNA sequence is created.

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TATA Box

A consensus sequence, TATA(A/T)A, found about 25 base pairs upstream from the start site of a group of eukaryotic genes encoding messenger RNA -- often those that can be transcribed at a high rate. The TATA box binds the TATA box binding protein (TBP), a subunit of TFIID, initiating the process of RNA polymerase II assembly at the promoter in vitro, and plays a key role as a recognition sequence for RNA polymerase II in eukaryotic organisms.

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Transcription Factor

A protein that binds to a DNA sequence and controls (increases or decreases) the rate of transcription (the flow of genetic information from DNA to RNA).

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Transcriptome

The full complement of RNA molecules produced in a given cell or cell population.

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Transcription Preinitiation Complex

A group of proteins necessary for the start of protein transcription in eukaryotic organisms.

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Translation

The process in which RNA, produced during transcription, is decoded to produce an amino acid chain (polypeptide) that will then fold into an active protein.

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Wet Lab

Slang term for the domain of classic lab experiments handling actual and analyzing actual biological materials, as opposed to experiments and work performed using computer analysis.

Wild-Type

This is the typical or most common form, appearance, or strain of an organism that exists in the wild, as opposed to the lab. It can also refer to the normal, non-mutated form of a gene that's common in nature.

Zygote

The earliest developmental stage of the embryo, occurring when two gamete cells are joined by means of sexual reproduction.

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