They are relic hunters of a different kind. Soft-spoken Shanker Kalyana-Sundaram and ebullient Chandan Kumar-Sinha — young Indian scientists at the University of Michigan in the US — trawl the genomic wasteland for a living. They dig deep into the human genome scouting for molecular remains of ancient genes.

These genetic fossils, or pseudogenes as the scientists say, hold the key to several mysteries of life: how genes evolve or what triggers certain genetic defects which lead to life-threatening diseases such as cancer.

Since the human genome was mapped in 2000, pseudogenes have attracted a lot of scientific curiosity. Though they look very much like genes, they are unable to function normally because of lethal injuries to their structure. It is a mystery why the human genome has retained so many of them despite possessing a well-oiled, intrinsic mechanism to dispose of defective genetic material.

One of the major surprises thrown up by human genome sequencing was that only two per cent of the genome (numbering 20,000 to 25,000 genes) produce all proteins required for normal functioning. The rest is junk. Pseudogenes scattered all over the genome form a sizeable chunk of this so-called junk.

Geneticists are interested in pseudogenes as they offer unique insights into how genes have evolved. Subsequent studies have, however, suggested that they may even have functional roles, particularly in regulating the functions of normal genes.

One well-known study is on genes involved in the evolution of the sense of smell. Studies have shown there are nearly 1,000 genes that code for a diverse set of olfactory (smell) receptors. A study by researchers at Israel’s Weizmann Institute of Science showed that humans have lost a large number of olfactory genes as they evolved. Humans have fewer than 500 olfactory genes. Versions of nearly 300 human olfactory receptor genes are now pseudogenes. Though scientists have so far identified thousands of pseudogenes in the human genome, they have been able to confirm the expression of less than 200 and ascribed functionality for a few.

Recently, Shanker and Chandan — who work in the lab of Arul M. Chinnaiyan at the Michigan Center for Translational Pathology (MCTP), University of Michigan — hit a jackpot of sorts. Their combined effort has unraveled 2,000-odd expressed pseudogenes. “Strikingly, we observed that similar to normal genes, many pseudogenes were also specifically expressed in human tissues and cancers” said Shanker.

While Shanker, a bioinformatics expert was responsible for the sequence analyses that resulted in the discovery, Chandan validated and characterised the pseudogenes.

The scientists used approximately 300 samples from more than 10 tissue types collected from cancer patients. While 248 samples were cancer tissue, the rest were benign. Many of them display cancer-specific expression for various types of cancers including that of breast and prostate, say the MCTP scientists in a paper published in the June 22 issue of the prestigious Cell journal. Apart from Shanker, Chandan and Arul, many other researchers from MCTP also contributed to the study.

Chandan likens the Human Genome Project to understanding the lay of the land. “Earlier scientists working on the human genome project were looking for generalities. Now there is a huge rush to explore the uniqueness of individual genomes,” Chandan told KnowHow.

Before the quest for personal genomes takes off, there are some more pertinent questions to be answered. For instance, how a diseased genome is different from a healthy genome. This molecular understanding is vital for developing a new class of medicines, Chandan observes.

“Now that the human genome is sequenced, we have a reference frame. This is an attempt to see how a cancer genome is different from a normal genome,” says Chandan.

He admits that one of the reasons for their success in unveiling so many pseudogenes at once was the skill set brought in by Shanker who joined Arul’s lab eight years ago from the Institute of Bioinformatics in Bangalore. Shanker single-handedly developed analytical tools that can tap the next generation ultra fast sequencing technologies for the purpose, he says.

“Technology makes a huge difference. One needs to be clever to tweak the next generation sequencing technology to our advantage,” says Shanker, currently pursuing a PhD from the Bharathidasan University in Tamil Nadu.

Utpal Bhadra of the Centre for Cellular and Molecular Biology (CCMB) in Hyderabad agrees that the work is path-breaking. “This will hopefully help us to gain new insights into the role played by pseudogenes in cancer progression,” he says.