Friday, January 30, 2015

Is Only 7% of the Human Genome Functionally Important?

ENCODE studies in 2012 (1) concluded that about 1% of the human genome codes for proteins and that about 80% of the genome is “biochemically active, and likely involved in regulating the expression of nearby genes.” These findings have produced a great deal of controversy and much hypothesizing among the scientific community. But a recent paper published in Nature Genetics (2,3) sheds doubt on those findings.

Researchers at Cold Springs Harbor created a computational method called fitCons which analyzes the changes in DNA letters that have occurred during long evolutionary periods across different species as well as during shorter periods between human individuals. In this way they hoped to identify which parts of the human genome were preserved and thus functionally important.

The present study showed that only about 7% of the letters in the human genome were preserved and are functionally important. Their conclusion is that “most of the sequences designated as ‘biochemically active’ by ENCODE are probably not evolutionarily important in humans,” and that “the much larger ENCODE-based estimates can’t be explained by gains of new functional sequences on the human lineage.”

Among the ENCODE papers, Kellis showed that 5% of the noncoding DNA is conserved across mammals and that an additional 4% is conserved among humans.

An obvious question that immediately arises if these findings are correct is what the activity shown by ENCODE in the other 73% of the genome that is not preserved by evolution is doing. Some of the critics of the ENCODE data have suggested that much of the ‘biochemical activity’ detected by their methodology is spurious and insignificant.

1.     Massachusetts Institute of Technology. "Biochemical functions for most of human genome identified: New map finds genetic regulatory elements account for 80 percent of our DNA." ScienceDaily. ScienceDaily, 5 September 2012.
2.     Cold Spring Harbor Laboratory. "Which 'letters' in the human genome are functionally important?." ScienceDaily. ScienceDaily, 20 January 2015.

3.     Brad Gulko, Melissa J Hubisz, Ilan Gronau, Adam Siepel. A method for calculating probabilities of fitness consequences for point mutations across the human genome. Nature Genetics, 2015; DOI: 10.1038/ng.3196