jueves, 9 de junio de 2016

Physicists confirm (what biologists have already konwn for years) there's a second layer of information hidden in our DNA

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Theoretical physicists have confirmed that it's not just the information coded into our DNA that shapes who we are - it's also the way DNA folds itself that controls which genes are expressed inside our bodies.

That's something biologists have known for years, and they've even been able to figure out some of the proteins responsible for folding up DNA. But now a group of physicists have been able to demonstrate for the first time through simulations how this hidden information controls our evolution.

Let's back up for a second here, because although it's not necessarily news to many scientists, this second level of DNA information might not be something you're familiar with.

As you probably learnt in high school, Watson and Crick discovered in 1953 that the DNA code that determines who we are is made up of a sequence of the letters G, A, C, and T. 

The order of these letters determines which proteins are made in our cells. So, if you have brown eyes, it's because your DNA contains a particular series of letters that encodes for a protein that makes the dark pigment inside your iris.

But that's not the whole story, because all the cells in your body start out with the exact same DNA code, but every organ has a very different function - your stomach cells don't need to produce the brown eye protein, but they do need to produce digestive enzymes. So how does that work?

Since the '80s, scientists have found that the way DNA is folded up inside our cells actually controls this process. Environmental factors can play a big role in this process too, with things like stress known to turn certain genes on and off through something known as epigenetics.

But the mechanics of the DNA folding is the original control mechanism. That's because every single cell in our body contains around 2 metres of DNA, so to fit inside us, it has to be tightly wrapped up into a bundle called a nucleosome - like a thread around a spool.

And the way the DNA is wrapped up controls which genes are 'read' by the rest of the cell - genes that are all wrapped on the inside won't be expressed as proteins, but those on the outside will. This explains why different cells have the same DNA but different functions.

In recent years, biologists have even started to isolate the mechanical cues that determine the way DNA is folded, by 'grabbing onto' certain parts of the genetic code or changing the shape of the 'spool' the DNA is wrapped around. 

So far, so good, but what do theoretical physicists have to do with all this?

A team from Leiden University in the Netherlands has now been able to step back and look at the process on a whole-genome scale, and confirm through computer simulations that these mechanical cues are actually coded into our DNA. 

The physicists, led by Helmut Schiessel, did this by simulating the genomes of both baker's yeast and fission yeast, and then randomly assigning them a second level of DNA information, complete with mechanical cues.

They were able to show that these cues affected how the DNA was folded and which proteins are expressed - further evidence that the mechanics of DNA are written into our DNA, and they're just as important in our evolution as the code itself.

This means the researchers have shown that there's more than one way that DNA mutations can affect us: by changing the letters in our DNA, or simply by changing the mechanical cues that arrange the way a strand is folded.

"The mechanics of the DNA structure can change, resulting in different packaging and levels of DNA accessibility," they explain, "and therefore differing frequency of production of that protein."

Again, this is confirming what many biologists already knew, but what's really exciting is the fact that the computer simulations open up the possibility for scientists manipulate the mechanical cues that shape DNA - which means they might one day be able to fold DNA to hide unwanted genes, like the ones that trigger disease.

We're a long way off doing that, but the more scientists understand about how our DNA is controlled and folded, the closer we get to being able to improve upon it. The research has been published in PLOS ONE. 


Abstract
Eukaryotic DNA is strongly bent inside fundamental packaging units: the nucleosomes. It is known that their positions are strongly influenced by the mechanical properties of the underlying DNA sequence. Here we discuss the possibility that these mechanical properties and the concomitant nucleosome positions are not just a side product of the given DNA sequence, e.g. that of the genes, but that a mechanical evolution of DNA molecules might have taken place. We first demonstrate the possibility of multiplexing classical and mechanical genetic information using a computational nucleosome model. In a second step we give evidence for genome-wide multiplexing in Saccharomyces cerevisiae and Schizosacharomyces pombe. This suggests that the exact positions of nucleosomes play crucial roles in chromatin function.

Fig 1. Nucleosomal DNA model with bp step dependent mechanical properties.
(A) The rigid base-pair model is forced, using 28 constraints (indicated by red spheres), into a lefthanded superhelical path that mimics the DNA conformation in the nucleosome crystal structure [4].
(B) Fraction of dinucleotides GC and AA/TT/TA at each position along the nucleosome model found in 10 million high affinity sequences produced by MMC at 100 K. The solid and dashed lines indicate minor and major groove bending sites; the nucleosome dyad is at 0 bp. The model recovers the basic nucleosome positioning rules [1, 3].
(C) Same as (B), but on top of 1200 coding sequences (produced by sMMC). The same periodic signals are found albeit with a smaller amplitude.
Fig 2. Mechanical energy landscape along a 500 bp stretch of the YAL002W gene of S. cerevisiae.
(A) Elastic energy of the nucleosome model as a function of position obtained from a Monte Carlo simulation at 50 K.
(B) Effective energy including excluded volume between nucleosomes. In both, (A) and (B), the vertical lines indicate experimentally determined nucleosome positions from the unique nucleosome map [25].
(C) The top graph shows a fraction of the original landscape from (A), the five landscapes below are produced via sMMC with the nucleosome positioned at the corresponding dashed vertical line. The minima can be shifted freely on top of genes, proving that multiplexing is possible. 

Fig 3. Mechanisms underlying multiplexing.
(A) Energy landscape (black dashed curve) of a sequence with highly optimized nucleosome affinity at −5 bp, produced by MMC at very low temperature (15 K). The colored curves are landscapes for three synonymous mutants (three different codon frames) that are optimized via sMMC for high affinity at position 0. The maximum cannot be turned into a minimum in this case, signaling that multiplexing would not be possible on genomes if they were selected for highest nucleosome affinity. 
(B) Distribution of AA, TT and TA dinucleotides around minor groove bending site −25 bp for the shifted nucleosome from Fig 2C bottom. Dashed blue curves: natural preferences (attained through MMC), red curves: distribution obtained from sMMC on that particular stretch of the YAL002W gene; both simulations are performed at 100 K. Though not optimal, sMMC brings in AA at a position close to its preferred position (amplitude almost 1) indicating the plasticity of the mechanical code.
Fig 4. Multiplexing in two eukaryotic genomes.
(A) Normalized Fourier amplitudes for the distribution of the synonymous codons for threonine along nucleosomes on top of genes (purple curve) and for the distribution of the corresponding trinucleotides along nucleosomes outside genes (green curve) [25]. The peaks at 10 bp (indicated by an arrow) are due to nucleosome positioning that appears weaker on top of genes but might signal multiplexing instead.
(B) Same as (A), but for S. pombe [26].
(C) The normalized 10 bp amplitude inside vs. outside genes of all 20 amino acids for the two yeast species. The arrows indicate threonine. All points below the line have smaller amplitudes inside genes, a hallmark of multiplexing.


ORIGINAL: Science Alert
FIONA MACDONALD
9 JUN 2016

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