The more we learn about the cell, the more and more sophisticated is becomes. In biochemistry and molecular biology, it has long been known that shape is a crucial feature of macromolecules such as proteins and RNA – the functional, phenotypic core of the cell. Change the shape of any particular protein or RNA and you are likely to change the function. But it is now time to take that insight to a new level.
When it comes to the genome, we have long focused on it in linear terms – a mere sequence of nucleotides. But thanks to some fascinating research, it is now becoming clear that we need to start thinking about the shape of the genome:
By breaking the human genome into millions of pieces and reverse-engineering their arrangement, researchers have produced the highest-resolution picture ever of the genome’s three-dimensional structure.
The picture is one of mind-blowing fractal glory, and the technique could help scientists investigate how the very shape of the genome, and not just its DNA content, affects human development and disease.
“It’s become clear that the spatial organization of chromosomes is critical for regulating the genome,” said study co-author Job Dekker, a molecular biologist at the University of Massachusetts Medical School. “This opens up new aspects of gene regulation that weren’t open to investigation before. It’s going to lead to a lot of new questions.”
By studying the pairs, the researchers could tell which genes had been near each other in the original genome. With the aid of software that cross-referenced the gene pairs with their known sequences on the genome, they assembled a digital sculpture of the genome. And what a marvelous sculpture it is.
“There’s no knots. It’s totally unentangled. It’s like an incredibly dense noodle ball, but you can pull out some of the noodles and put them back in, without disturbing the structure at all,” said Harvard University computational biologist Erez Lieberman-Aiden, also a study co-author.
In mathematical terms, the pieces of the genome are folded into something similar to a Hilbert curve, one of a family of shapes that can fill a two-dimensional space without ever overlapping — and then do the same trick in three dimensions.
How evolution arrived at this solution to the challenge of genome storage is unknown. It might be an intrinsic property of chromatin, the DNA-and-protein mix from which chromosomes are made. But whatever the origin, it’s more than mathematically elegant. The researchers also found that chromosomes have two regions, one for active genes and another for inactive genes, and the unentangled curvatures allow genes to be moved easily between them.
Lieberman-Aiden likened the configuration to the compressed rows of mechanized bookshelves found in large libraries. “They’re like stacks, side-by-side and on top of each other, with no space between them. And when the genome wants to use a bunch of genes, it opens up the stack. But not only does it open the stack, it moves it to a new section of the library,” he said.
Let me take this new knowledge and use it to propose a hypothesis that might explain a current anomaly. The proteins that package the DNA are known as histones and histones are among the most highly conserved proteins in eukaryotes. Yet many years ago, Michael Behe did some research that showed several of the highly conserved amino acids can be replaced in yeast without any detectable negative effect.
More recently, scientists have discovered non-coding DNA that is also very highly conserved, but when you remove it from the genome, nothing seems to be wrong.
These anomalies are currently explained by arguing that survival in a lab setting cannot be extrapolated to survival in the wild. That is, while such mutated lab mice or yeast might be able to survive just fine in the controlled and comfortable lab environment, out in the wild, there are likely to be some conditions that would put these mutated creatures at a distinct disadvantage.
While this explanation rings true, it doesn’t tell us how this happens. It doesn’t provide the possible mechanism. But now we have one. To see it, consider a commonly isolated mutant in the lab – a temperature sensitive mutant. To get such a mutant, scientists randomly mutate protein sequence and then select for mutants under elevated temperatures. As it turns out, many proteins can acquire mutations without any negative effect if kept at lower temperatures, but become non-functional if shifted to higher temperature. The thinking is that the protein structure has been weakened, but can remain intact at lower temps. Only when shifted to the higher temperature does the network of crucial chemical bonds break down.
So here is my hypothesis. We can propose that various environmental stresses have the potential to challenge the shape of a particular genome. We can thus extrapolate and propose that mutations in the highly conserved histone and non-coding DNA sequence are analogous to temperature sensitive mutants – they weaken the structural integrity of the genome and environmental stresses perturb genomic structure and with it, the regulatory networks. The weakened system collapses.
Regardless of the truth of this hypothesis, it would seem clear that the organizational shape of a genome is something we will have to consider when assessing non-coding (“junk”) DNA, along with its re-formatting during evolution.