Gene regulation, not just genes, make us unique

The scientific world was surprised when the sequencing of the first human genome revealed we have only 22,000-odd protein coding genes. Many corals possess more genes. And we share 50 per cent of our genes with a banana.

So how to account for the unique complexity of our species? And how to account for the vast amount of diversity between individual humans with such a relatively small number of genes?

The answer appears to be in the complex regulatory mechanisms that switch individual genes on and off, according to a paper recently published in the journal Science.

Researchers at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, and Yale and Stanford Universities in the US, found that up to a quarter of all human genes are regulated differently in different people.

The researchers, led by Jan Korbel at the EMBL and Michael Snyder at Yale (now at Stanford), compared individual genome sequences from 10 individuals to look for differences in gene regulation.

They specifically looked at two common transcription factors, RNA polymerase II and NFkappaB, to examine the variability from one individual to the next.

RNA polymerase II, which is active in all cells, transcribes DNA into RNA. NFkappaB is activated by stress, plays a key role in immune responses to infections, and has been implicated in several diseases, including cancer.

They found that even a difference of one letter of the genetic code can result in changes in regulation, while other individuals exhibited large changes in DNA sequences that influenced gene regulation.

The researchers also found a large number of binding sites for each transcription factor: around 19,000 for RNA polymerase II and 15,500 for NFkappaB.

It's the difference between these binding sites that plays a role in determining the number of a particular gene product produced by an individual, thus accounting for some variation between two individuals.

The study also reports differences in binding of RNA polymerase II and NFkappaB near genes implicated in many major diseases, including type 1 diabetes, lupus, chronic lymphatic leukemia, schizophrenia, asthma, Crohn’s disease, and rheumatoid arthritis.

They also looked at a how two individual with the same gene, such as ORMDL3, which is implicated in asthma, differ in regulation, finding the gene may be regulated in very different ways in different people.

Another surprising finding was that even these differences in the genetic code couldn't account for the all the differences between two individuals, leading the researchers to suspect that the regulatory proteins interact with each other in a complex way.

"Our findings may help change the way we think of ourselves, and of diseases", said Snyder in a statement.

"As well as looking for disease genes, we could start looking at how genes are regulated, and how individual variations in gene regulation could affect patients' reactions."

They also compared the data on human gene regulation to that of a single chimpanzee and found that there is almost as much variation between humans as there is between us and chimps. Yet the slight differences could hold tremendous significance in explaining our unique traits.

"We know there are differences in gene expression between people.” Kasowski said in a statement.

"Understanding the differences in how genes are regulated could help us understand human diversity. But identifying the regulatory DNA that controls expression is much more difficult than looking for differences in the regions of the genome that code for genes."

According to Snyder, these studies open a new genomic frontier for biologists.

"Only about two per cent of our DNA codes for genes," he said. "Studying the rest of the genome, including gene regulation and transcription factors, is the next wave in understanding human variation."

This finding parallels work done by Professor John Mattick at the University of Queensland, a leader in the field of RNA and gene regulation.

"This result is unsurprising, in the sense that it's been obvious that the difference between individuals and species is down to the difference in regulation," he said.

According to Mattick, much of the focus to date has been on proteins - the building blocks of life - as the source of differences between individuals, and certainly, a single monogenetic disorder that yields a faulty protein can have a dramatic effect.

However, these days more and more researchers are focusing on regulation as the source of differences between individuals and as the cause of complex diseases.

In an article in the upcoming March/April edition of Australian Life Scientist, Mattick details some of his findings about the significance and complexity of gene regulatory networks and the epigenome.