The human genome is the home of over 3 billion nucleotide base pairs packaged into 23 chromosome pairs. But despite the tremendous size of the human genome, only 1-2% of genome actually encodes for proteins.

What about the remaining 98% of the genome? At the time of Watson and Crick in the 1970s, scientists have regarded the non-coding parts of the genome as junk DNA that are remnants of evolution; including gene “fossils” that have lost their ability to be translated into functional proteins, as well as chunks of DNA that are derived from retrotransposition and duplications that occur over the course of evolution (Mighell et al., 2000). Regardless how these DNA sequences were derived, it was thought that these sequences are junk DNA produced by the natural sculpting of the genome in response to evolutionary pressures over time.

With the sequencing of the human genome this decade, scientists soon discovered that the non-coded regions of the human genome actually play a plethora of regulatory functions to control or modulate gene expression at both transcriptional and translational levels. Further studies have discovered that as much as half of the “junk” DNA sequences are transcribed, and that 50% of these actually play important roles in the protein synthesis assembly line (Huttenhofer et al., 2005). Among the transcribed products include transfer RNAs (tRNAs) that are actively involved in protein translation in ribosomes, as well as the newly identified microRNAs (miRNAs) or short 22-23bp RNAs involved in regulating protein translation; specifically by recognizing the 5’ untranslated region of messenger RNAs through sequence complementation, followed by the recruitment of RISC complex that either stops transcription or cause mRNA degradation. MicroRNAs are often dubbed as the new translation microregulators of protein expression, where changes in their expression levels have been implicated in the development of cancer.

Although the above progress could help explain the existence of about 25% of the genome (merely the tip of an iceberg), the function of the remaining 75% of the genome remains elusive. It wasn’t until recently that a group lead by Dr. Pier Paolo Pandolfi at Harvard Medical School, Boston, has made another big step in defining the functional role of the uncharted territories of the human genome.

Within the 75% uncharted junk regions of the human genome, the majority encode for pseudogenes; or non-functional genes that can no longer be translated into functional proteins. About 20% of these pseudogenes are actively transcribed, and as revealed in studies by Pandolfi, play a surprising role in regulating protein synthesis. Briefly, Pandolfi revealed that the pseudogene similar to the tumor suppressor PTEN (phosphatase and tensin homologue), dubbed the PTENp, is actively transcribed. Interestingly, the transcribed RNA product actively sequesters specifically the microRNAs that inhibit PTEN translation. Moreover, the aberrant depletion of this pseudogene PTENp is a key molecular signature in cancer cells, suggesting an important role of these pseudogenes in the biology of cancers.
This finding suggests for the first time that pseudogenes are a new class of regulatory switches in the protein synthesis machinery, providing a new molecular dimension for scientists to unravel the elusive mechanism underlying cancers and other diseases.

Although this study have unlocked another intriguing secret in the human genome, it is clear that the progress so far is only a tip of the iceberg. There remain a vast number of untranscribed pseudogenes and other DNA sequences for which their functions remain elusive to scientists. Could the transcription of these pseudogenes be turned on or off during the natural development or aging of an organism? Or can this occur over the course of evolution? More importantly, could these quiescent pseudogenes be accessories aiding evolutionary changes? Or could their aberrant expression or repression be the cause of cancers and other diseases?

Although there are many unanswered questions, the discovery of functional pseudogenes has nevertheless opened an exciting new chapter in various dimensions of life sciences research.


Mighell AJ, Smith NR, Robinson PA, Markham AF. FEBS Lett. 2000 Feb 25;468(2-3):109-14. Review
Hüttenhofer A, Schattner P, Polacek N. Trends Genet. 2005 May;21(5):289-97. Review
Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi PP. Nature. 2010 Jun 24;465(7301):1033-8.