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Do curso por University of Geneva

Classical papers in molecular genetics

102 classificações

University of Geneva

Classical papers in molecular genetics

102 classificações

You have all heard about the DNA double helix and genes. Many of you know that mutations occur randomly, that the DNA sequence is read by successive groups of three bases (the codons), that many genes encode enzymes, and that gene expression can be regulated. These concepts were proposed on the basis of astute genetic experiments, as well as often on biochemical results. The original articles were these concepts appeared are however not frequently part of the normal curriculum of biologists, biochemists and medical students. This course proposes to read study and discuss a small selection of these classical papers, and to put these landmarks in their historical context. Most of the authors displayed interesting personal histories and many of their contributions go beyond not only the papers we will read but probably all their scientific papers. Our understanding of the scientific process, of the philosophy underlying the process of scientific discovery, and on the integration of new concepts is not only important for the history of science but also for the mental development of creative science.

Na lição

Session 6

Benzer and Champe studied the properties of deletions that cover the boundary between rIIA and rIIB. As expected, most of them cannot provide either function during infection of a non-permissive strain. One deletion however was highly unusual and was still able to provide rIIB function even though it lacks 10% of the rIIB sites. This deletion was instrumental in confirming the general nature of the genetic code proposed by Crick et al. In the discussion, the authors evoke the notion of bi-functional enzymes such as tryptophane synthase. In bacteria, the two catalytic activities are performed by individual proteins encoded by adjacent enzymes. In eucaryotes, both reactions are performed by a single protein: the product of the first reaction does not diffuse out but is “funneled” into the second active site. This is just one exception to the one gene one enzyme model discussed in the first session. Crick et al. start their paper by presenting the evidence that the code must be non-overlapping. One evidence, provided by Brenner, is the founding work of what will become bioinformatics. Starting with a single rIIB frameshift mutation, now known to involve the addition of a single base pair that displaces the reading frame of the mRNA, they isolate many intragenic suppressor mutations that restore rIIB function. The original mutation is given a + sign, and its suppressors a - sign. They then isolate suppressors of these suppressors that are themselves + mutants. All tested combinations of two + and two – mutations lack rIIB function. Most combinations of a + and a – mutations have rIIB function; the other combinations are proposed to generate a stop codon between the two frame shifts. Finally, a number of triple mutants were shown to have rIIB function. They use the unusual deletion that fuses the two rII genes to demonstrate that frameshift mutation located in the rIIA portion of the fused gene abolish its rIIB function. The simplest interpretation is that + mutants have one more (or one less) base pair and that – mutants have one less (or one more) base pair. Although the general nature of the code is 3n base pairs per amino acid, they belive that the code is a three rather than a six letters code.

Conheça os instrutores

Dominique Belin
Professor
Department of Pathology and Immunology University of Geneva Medical School

[MUSIC]

Last week we discussed the paper of Benzer on Gene Topography and

The Genetic Fine Structure.

Today we are going to discuss the paper by Craig, Adal, on the genetic code.

But, as a transition, I just would like to spend a few minutes on a paper by Champ

and Benzer, which is an introduction, basically to the Craig paper.

So, in this paper,

it's becoming clear now that amino acids sequence and

base sequence have a simple relationship.

We'll see later that this is a collinear relationship.

So in that paper, what Benzer did was to test a hypothesis.

The hypothesis is the following.

If a deletion covers the R2a and

R2b region, the phage have no R2a function,

have no R2b function, and so cannot grow on a lambda.

Now what happens with internal deletions in the locus?

On this slide you see internal deletions such as these which cover part

of the R2a gene for the first two and R2b gene for the last three.

These are internal deletion.

As expected, this deletion the first two don't have R2a function but

they can provide b function.

The last three cannot provide B function but can provide A function.

So, the prediction from this is that, if you had a deletion that would cover

the divide the limit between R2a and R2b gene or

sees from the way Benzer used to call them.

Such deletion should lose both a and b function.

And so, he checked among the several hundred deletions that he had, and

he found four, these four, that cover the divide between the two genes.

That's here.

And leave a little bit of R2a and a little bit of R2b on both sides.

So, these are internal deletion covering the two genes.

The prediction is that these deletion would

be incapable of providing R2a function and R2b function.

And this is exactly what he saw with the first three.

But 1589, which we will see later again, for several this weekend.

Next week 1589 is exceptional

because it can provide R2b function.

And this is surprising because usually we should delete part of a gene,

you delete, you remove the function.

Now, it's even more surprising because in the R2b gene,

on the part covered by 5089 here, there are point mutation sites.

So, how come you can have a mutation, a point mutation,

a single nucleotide change, that will abolish the function and

you can delete the region and keep the function.

They're essentially two ways of dealing with this paradox, or apparent paradox.

One way is to say that the R2a portion of 1589, somewhere here,

can compensate for the absence of the corresponding region in b.

The other more intriguing possibility is that

in fact the beginning of the R2b region, this region,

is not essential for the protein per se, for

the protein function but is essential to make the protein.

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