A team of US and German scientists has found that we differ from each more because of the way our genes are regulated, such as which are switched on and which are switched off, than because of the differences among the genes themselves: furthermore there appears to be as much variation among humans as between humans and chimpanzees when it comes to gene regulation.

Researchers from the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, and Yale and Stanford Universities in the USA wrote about their findings in a paper that was published online in Science on 18 March.

After the human genome was sequenced and published nearly ten years ago, scientists have been searching for the genes that make individual humans unique.

The process is now so technologically advanced that scientists can obtain the genome of several people in a fraction of the time and cost it took for the first human genome, and we are now beginning to understand a lot more about how genes work.

But as we get to know more about how genes and DNA works, we realize that perhaps the picture is more complex than we imagined.

The team on this study, led by Jan Korbel at EMBL and Michael Snyder initially at Yale and now in Stanford, wrote that it is becoming increasingly apparent that:

“Differences in gene expression may play a major role in speciation and phenotypic diversity.”

So they decided to investigate genome-wide differences in a key component of gene expression called transcription factor (TF) binding.

While each of us inherits genes from our biological parents, those genes are effectively “switched off” in our DNA until they are transcribed into mRNA, the process that switches them on and thereby allows them to express control over the production of proteins.

However, the transcription of genes from DNA to mRNA is itself regulated by TF proteins, and a key part of how they work is they have special DNA-binding domains (DBDs) that attach to areas of DNA that lie next to the genes they are transcribing.

In a very crude sense it is like a TF protein has to “dock” next to the gene before it can start transcribing it. These “docking” area sections of DNA are not like genes: they don’t hold instructions for coding proteins, but they can vary from person to person and in this way influence whether genes are switched on or off.

As Korbel explained to the media:

“We developed a new approach which enabled us to identify cases where a protein’s ability to turn a gene on or off can be affected by interactions with another protein anchored to a nearby area of the genome.”

“With it, we can begin to understand where such interactions happen, without having to study every single regulatory protein out there,” said Korbel.

The team found that up to a quarter of all human genes are regulated differently in different people: this is more than the genetic variation among genes themselves.

Thus even if different people have exactly the same copy of a gene, for instance ORMDL3, thought to influence the development of asthma in children, the way their cells regulate the gene can vary among them.

They discovered that many of the differences are due to how TF proteins behave because of DNA sequencing differences in the “docking” areas between the genes: some of the differences comprising only a single-letter change in the DNA code.

They also found variations they could not explain, and proposed these might be used by TF proteins acting together in some way.

Finally, they compared the information they obtained on humans with that of a chimpanzee, and found that gene regulation seems to vary almost as much among humans as it does between humans and chimpanzees.

They concluded that:

“Our results indicate that many differences in individuals and species occur at the level of TF binding and provide insight into the genetic events responsible for these differences.”

Snyder said these discoveries may change the way we think about ourselves and diseases:

“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.”

“Variation in Transcription Factor Binding Among Humans.”
Kasowski M, Grubert F, Heffelfinger C, Hariharan M, Asabere A, Waszak SM, Habegger L, Rozowsky J, Shi M, Urban AE, Hong MY, Karczewski KJ, Huber W, Weissman SM, Gerstein MB, Korbel JO, Snyder M.
Science, 18 March 2010 (Epub ahead of print).
DOI: 10.1126/science.1183621

Source: European Molecular Biology Laboratory.

Written by: Catharine Paddock, PhD