A decade after mapping the genome, scientists scramble for more imaging data to unravel its mysteries

When the human genome was first sequenced over a decade ago, it was widely hailed as one of the greatest scientific achievements of all time. With 3.2 billion combined A, C, G and T nucleotides that make up our genes, just one investigation – by 400 researchers analyzing the “pseudogenes” once thought to be dormant relics of our evolutionary past – produced such a wealth of results that in graphic form it would fill a poster 50 feet high and 10 miles long, figured the Associated Press.

In other words, sequencing the human genome merely showed us that we had an overwhelming number of mysteries yet to decode. We were like toddlers handed a giant encyclopedia as a means of learning the facts of life – not only could we not read the book, we didn’t even know how many entries it contained.

“Not only do we not know what all the genes are, we don’t even know how many there are,” Steven Salzberg of the University of Maryland said in a keynote address at the Beyond the Genome conference in Boston in 2010. At one point scientists thought we had a few million, but by 2007 this figure had shrunk down to 22,000 (less than a grape but more than a chicken), and has recently shrunk further, to 19,000 – ranking us below the nematode worm.

Of the genes we have been able to identify, scientists are still hard at work understanding the function they play. “More than 10 years since the publication of the human genome, the so-called ‘Book of Life,’ we still have no direct evidence of the function played by half the genes across all species whose genomes have been sequenced,” Dr. Carazo Salas of the University of Cambridge’s Department of Genetics said in a recent school press release.

So Salas’ team has turned to high-res 3D confocal microscopy, a type of fluorescent imaging that’s been around for roughly 20 years, and quite sophisticated computer-automated analysis of the resulting images to analyze three key cellular processes in the fission yeast genome. As it stands, he said, we have no “catalogue” of the cellular processes of genes.

These 3D images of cells and mutations are used to help understand evolution and genetics.

These 3D images of cells and mutations are used to help understand evolution and genetics.

By simultaneously imaging three processes – cell shape, microtubule organization and cell cycle progression – one gene at a time, they were able to link two-thirds of the genes to one of these processes for the first time, and found that a third are actually involved in more than one of the processes, the researchers reported in the journal Developmental Cell.

Microtubules are tiny tube-shaped structures that help maintain the cell’s structure and also play an important role in how it divides. Fission yeast is a single-cell organism whose genes often carry out the same function in humans. So by analyzing how the genes behaved when they were manipulated one at a time, the researchers were able to link, for instance, microtubule stability to how DNA damage is repaired. And because cancer therapies often target microtubule stability or DNA damage, understanding how they are linked could lead to more targeted cancer drugs.

Using confocal mircroscopy is “a cool way to get good information about cells,” Emory physics professor Eric Weeks told me, but he stressed that the data analysis is the major achievement. “You get a huge image that’s 100 slices and they’re all megapixel images, so there’s a lot of data about what’s going on in there … but the challenging part would have been really manipulating all these genes and somehow collating the data across them. That sounds hard – tedious, at least.”

Salas said the technique as well as the data should prove valuable to the scientific community in the coming years, and his team has made all the results available as an open resource online.

“It allows us to shine a light into the black box of the genome and learn exciting new information about the basic building blocks of life and the complex ways in which they interact,” Salas said.