What Is a Gene?

Tuesday, November 13, 2012 // Uncategorized

Gene therapy was supposed to revolutionize medicine.  That has yet to happen.  Why not?  Not surprisingly, the answer is that it is a lot more complicated than previously thought. 



New Studies Ask, “What Is a Gene?”

The ENCODE project has determined that 80% of the human genome is important for normal gene expression.

The early achievements of molecular biology researchers might have spoiled us. The first identified “molecular disease,” sickle cell anemia, involved a single mutation in the globin gene. Then came the central dogma of molecular biology: DNA makes messenger RNA (mRNA), and mRNA makes protein. Therefore, the DNA segment that coded for a protein was a gene. Diseases would result from structural abnormalities in genes.

However, we soon realized that, unlike sickle cell anemia, most diseases probably didn’t derive from a structural abnormality in a single gene, but from the combined effects of abnormalities in multiple genes. Members of the Human Genome Project set out to determine the sequence of every gene — every stretch of DNA that coded for a protein. The Project achieved that goal but also produced a rude surprise: Less than 2% of the human genome coded for proteins. What did the rest of the DNA do? At first, it was called “junk DNA” — the presumed detritus of evolution, with no role in current human biology.

More than 400 investigators working together as part of the ENCODE project have just published 30 papers that tell a very different story:

  • Disease can occur when structurally normal genes are not controlled properly (i.e., turned on or off or “expressed” correctly).
  • Eighty percent of human DNA is transcribed — not into mRNA that makes protein, but into small RNA segments that control gene expression.
  • Many stretches of DNA do not code for proteins but are landing zones for proteins that control gene expression.

Comment: The ENCODE project is a landmark event in human genetics. But its message is daunting: Human disease is a function not just of the structure of one or more genes but also of many different forces that control gene expression. Indeed, a gene might be better defined as a stretch of DNA that is transcribed at all — not just stretches of DNA that code for mRNA and, hence, protein. Or we could define a gene as the DNA that codes for a particular mRNA plus the other DNA that affects expression of that mRNA. Understanding the molecular pathology that leads to human diseases has become much more complicated than we once thought it would be.

Anthony L. Komaroff, MD

Published in Journal Watch General Medicine October 25, 2012


Pennisi E. Genomics: ENCODE Project writes eulogy for junk DNA. Science 2012 Sep 7; 337:1159. (


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