The Human Genome Contains Fewer Functional Genes Than Previously Thought

It's been a over a decade since the completion of the human genome project, and yet we still know very little about how much of that DNA is actually functional.  We have 23 pairs of chromosomes, with a total of 3 234.83 Mbp (that's 3 234.83 million base pairs), of which it was previously believed that 80% encoded functional proteins.  But since scientists like to argue, the word "functional" became contentious, since its definition was not made clear and it depended on experimental design.  The argument was that functional genes needed to contribute biochemical significance.  A new open access study recently set out to determine how much of the human genome contains functional genes.

Under the ENCODE (Encyclopedia of DNA Elements) definition of "functional" genes, the only important piece of information was whether or not the DNA was transcribed.  But the trouble with that definition is that genes contain both introns and exons which are transcribed, but only exons leave the nucleus to be translated into proteins.  Therefore, the DNA found in introns does not provide anything to the protein.  In that case, can we define it as functional simply because it is transcribed?  Drs. Chris Ponting and Gerton Lunter didn't think so.

To find out how much of the human genome is actually functional, the authors took advantage of evolution's screening process - namely, which genes are so important that they have not accumulated any changes over 100 million years of mammal evolution?  As we know, natural selection ensures that advantageous mutations and changes to the genome will prosper, but it also selects AGAINST disadvantageous changes to important genes, keeping useful genes intact.  By using bioinformatics to look at which genes were maintained throughout our evolutionary history, the authors were able to pinpoint which genes are therefore of the most biological and biochemical relevance to humans.



A diagram depicting how much of the human genome
contains non-coding DNA.  Source.

Using this technique, the authors estimate that only 7.1-9.2% of the human genome contains genes that are functional, a value that is 10-fold lower than the ENCODE estimate.  Of this amount, only 1% encodes proteins that carry out critical biochemical processes, the remaining 6-8% is thought to be responsible for turning on and off the genes that encode functional proteins.  This is done in regions of the DNA that are known as operators, enhancers, silencers, and promoters.  That means that a large amount of the "functional" DNA identified by ENCODE can actually be deleted from the human genome without impacting fitness.  That's not to say that ENCODE was completely wrong in their estimate, simply that their definition of functional may have been too liberal. 

So, what might be the evolutionary significance of having over 90% of the human genome be non-functional or non-crucial?  Some of this non-coding DNA contains sequences used as origins of replication, centromeres, and telomeres.  Further, up to 53% of the human genome is made up of remnants of retroviral sequences and "jumping genes" like transposons and retrotransposons.  As much as natural selection selects against mutations that would make important genes non-functional, it also has no reason to select for or against DNA sequences that just aren't useful, like these DNA remnants.  This large amount of non-coding DNA may also have a protective, since useful genes are kept very far apart, protecting genes from frameshift mutations in other parts of the chromosome.  Introns provide a similar level of protection.