Genetic ScreensIf mutating a certain gene causes abnormal development of a certain organ,
then we conclude that the function of the protein coded by this gene
must be part of the control system by which that organ is built.
A systematic search for as many different mutations as can be found that
Sometimes, researchers just have to look at thousands or millions
Other times, it can be arranged for the special organisms to find themselves.
For example, if you were looking for mutations with defective phototaxis,
A good screen will save you 99% + of the effort.
Some biologists' reputations (and professorships) have been earned largely by inventing a new genetic screen. Many are fiendishly clever!!
It is a huge stimulus to your cleverness to search for mutants, one by one! You get a lot of time to think of better & more powerful screens.
When you hear geneticists talking about "screens", it's probably not wire mesh.
With a good screen, plus a lot of effort, one can hope to identify ALL the different proteins that participate in some process, or development of some organ!
For about the last 15 years, a large percentage of researchers follow this approach.
Even when a "knock out" is an eventual part of proving the function of a gene & protein, there almost always had to be a screen to find the mutation in the first place! Elementary textbooks and courses tend to mislead about this, because it' so easy to visualize eliminating a gene (which is really done by inserting a big block of DNA into the middle of it) and then seeing the effect.
It's as if a history book said that X was discovered to be a spy because
after his execution not so many secrets reached an enemy.
In brief: Geneticists developed several fiendishly clever tricks by which to "recover" recessive lethal mutations.
The first key idea is that those genes that code for proteins that control early stages of embryonic development are especially likely to be lethal when mutated.
So how do you breed dead flies?
Even harder, how do you screen for lethals that die with consistent anatomical (geometrical) abnormalities.
You want genes whose mutation produces two tails and no head,
Christine Nusslein-Volhard (a West German woman scientist) and Eric Weischaus (a Yale Biology PhD) and several others spent ~10 years finding 140 such genes .
Incidentally, the great majority of these genes code for transcription factors.
In situ hybridization was then used to map the times & locations in developing embryos where these various genes get transcribed?
What result would you guess? If organ X fails to form as a result of mutating gene Y, then don't be surprised if messenger RNA of the normal Y gene appears in stained embryos at higher concentrations at the normal location of organ X. That's the pattern!
If your in situ stain gives that sort of result: submit a paper about it to Nature.
If you get a different result, try to make sense of it, or submit it to a lesser journal.
Mostly, results have fallen into these patterns, plus genes with very similar base sequences were then discovered in mammals, and worms, etc. even though mutating the mammal homologs produces different phenotypes Embryology is never going to be the same! It is morphing into a game of figuring out how to explain normal development is accomplished by particular combinations of normal (wild-type) alleles of these genes.
For example, the gene-that-when-mutated-causes-two-tails-and-no-heads (Bicoid) gets transcribed in the fly's mother's cell ("maternal effect"!), gets put in the front end of the fly embryos, and its translation there results in a diffusion gradient through syncytial cytoplasm that activates transcription of a series of other genes for transcription factors, different ones depending on its concentration (making it a morphogen, in Lewis Wolpert's sense of that word, and fitting theories that go back a century), and then those transcription factors bind to DNA and selectively stimulate other genes, according to which combinations of other transcription factors are present at each location (a combinatorial alternative category of morphogen!) [which some other people had hypothesized]
One family of transcription factors controls where and when transcription will be stimulated in the next (of five) families of transcription factors will be activated, much like dominos knocking over dominos, and somewhat like a cuckoo clock, designed by a cuckoo clockmaker.
But it's all true.