Showing posts tagged genetics

Beadle, GW and Ephrussi, B. 1936. The differentiation of eye pigments in Drosophila as studied by transplanation. Genetics 21(4) 225-247.

Beadle & Tatum are basically the Cheech & Chong of biology, in that they are complete geniuses who were way ahead of their time. These were the two heroes who showed up in the 1940s when everyone was wildly speculating about the physical nature of these mysterious things called “genes” and showed that each gene gives rise to one single protein product (the so-called “one gene - one enzyme” hypothesis). Their famous experiments were done by inducing x-ray mutations in a fungus called Neurospora, and then showing that each individual mutation could be rescued by supplying a single, specific nutrient - in other words, that a single genetic mutation causes a single, specific fuck-up in a single enzyme. They even went the extra step of confirming that each of these mutations is inherited like a Mendellian recessive and was therefore a single gene.

The spine-tingling thing about the Beadle and Tatum experiments, though, is that they are so outrageously perfect and beautiful that it is truly terrifying to anyone who has ever tried to do an experiment one’s self. When I read the first Beadle and Tatum pape, it makes me feel like I’m a particularly stupid and tone-deaf 6-year old banging on some pots and pans, hearing the congo playing on “Life’s a Gas” for the first time -  i.e. that it is time to throw in the towel because I’ll never achieve anything even approaching that level of perfection.

But buddy, if you are lucky enough (and have access to enough adderall) to have read Beadle’s Noble Prize acceptance speech, you will see that the elegance and clarity of his most famous work is largely the result of a set of earlier experiments done with Boris Ephrussi, which themselves are a LOT more like experiments most of us have attempted: insanely technically challenging, time-consuming and labor intensive, and although really suggestive of something potentially important, never really coming anywhere close to actually proving that potentially awesome thing because that goal won’t be attainable for decades.

Beadle and Ephrussi worked together at Caltech, studying the genetic control of eye-color in fruit flies. Fruit flies were already a powerful system for experimental genetics, so many different mutations had been isolated which gave rise to unusual eye-colors. Working with these different mutant lines, Beadle and Ephrussi physically transplanted the eye primordia from these different mutants into host larvae of different genotypes, making three-eyed flies (this was the psychotically difficult technical part). By reciprocally transplanting between these genotypes, they showed that two of the eye-color mutants (cinnabar and vermillion) were “non-autonomous,” meaning that it was the genotype of the host rather than the donor tissue that controlled the eye color. 

The next part, though, is where the scary-genius shit happens. When a cinnabar eye is transplanted into a vermillion hosts, the eye remains cinnabar-colored. But when a vermillion eye is put in a cinnabar host, the eye becomes normal colored! Although this typically shouldn’t make sense to anyone who isn’t on Peyote, Beadle and Ephrussi came up with the idea that perhaps vermillion and cinnabar represent mutations in different genes within a single biochemical pathway that ultimately produce eye pigment. In other words, their idea was that the eye color pathway would be: “Precusor Substance -> Vermillion substance -> Cinnabar substance -> Pigment.” where the substances are diffusible throughout the host body, but interpreted locally within organs, and ultimately control eye color. Even when you know the answer it’s still confusing to think clearly about how this works, so it’s really jaw-dropping how these dudes were able to figure it out from scratch, before anybody else in the entire world understood what it might mean.

These experiments and their interpretation are so hot that my computer battery starts smoking every time I open the PDF. It’s like Beadle and Ephrussi stepped into an ancient temple completely brimming with confusing symbols and death-traps, yet were instantly able to shine the laser on the one specific key symbol that opens the trap door to all the gold coins. And its particularly cool to realize that from these really complex reciprocal eye transplantations, Beadle and the boys were already thinking that genes give rise to distinct biochemical entities, and that because of this, he could design the Beadle and Tatum experiments precisely to prove what he already suspected: that each gene encodes one specific product. 

Contributed by benewencampen

The majority of animal genes are required for wild-type fitness.
Ramani AK, Chuluunbaatar T, Verster AJ, Na H, Vu V, Pelte N, Wannissorn N, Jiao A, Fraser AG. Cell. 2012 Feb 17;148(4):792-802.

In this age of inflatable pillows and personal seltzer machines, it is easy to forget that we are engaged in a constant and horrific war against nature. This is a war that we will not win. The overwhelming chaos of entropy will inevitably smother each of us in turn, leaving behind only a fleetingly stinky husk and whatever genetic code we manage to propagate in the form of pathetic progeny.

In this hopeless battle against thermodynamics, man’s only defense is the 3 billion base pairs that constitute his meager genome (as well as whatever epigenetic mumbo-jumbo he might be harboring). An even more sobering thought is that the human genome contains the code for only ~20,000 proteins, a mere 1.5% of our DNA. The rest is either bullshit or (more likely) regulatory, “non-coding” DNA. The genome represents the zenith of violence and despair. It is the scroll upon which is written the curse of our miserable existence.

Given the stakes of the battle, and the precarious nature of existence, you might guess that even a small loss of genetic armor would be catastrophic. However, disrupting expression of a single protein produces measurable consequences in only a very small minority of cases. For the most part, knocking out a random gene in a worm or a fly has no detectable phenotype. This finding is at odds with the high levels of genetic conservation across species, which suggests that each and every gene is essential for survival. To resolve this, it has been proposed that many genes are functionally redundant, or required under only highly specific environmental conditions.

However, the problem with these type of genetic loss-of-function experiments is that humans are hopelessly shitty at measuring functional consequences. Although we can easily notice if a genetic manipulation leads to underdeveloped genitalia, we would never notice if it resulted in a slight propensity to produce inside-out sperm. To overcome our observational inadequacies, the Canadian authors of a recent sick pape used a more ambiguous but perhaps more sensitive measure of phenotypic consequence: the ability of an animal to pass on its genes. This is also known as fitness.

Ramani et al studied how fucking with expression of individual genes affected the fitness of nematode worms. They disrupted the expression of 300 random genes using RNA interference, and measured (1) how many worms survived after 2-3 reproductive generations, and (2) the rate at which a surviving population consumed a meal of bacteria. They found that mucking with a single gene resulted in decreased fitness in most cases (~70%). So it turns out that the majority of genes are relatively necessary for the development and function of an animal, if measured under the correct circumstances.

Although this approach might not provide specific insight into the function of individual genes, it serves as a firm reminder that real animals live in a world of hellish and ceaseless competition. Every one of our genes, as well as those belonging to our brother worm, has been struggling for billions of years to overcome the hulking abyss of nonexistence. The point of animals is to kill each other and fuck and transmit genetic code on to some hapless ungrateful child beasts. Let us not forget that survival and propagation is the ultimate arbiter of biological function.

Contributed by butthill
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