Genomic clues to DNA treasure sometimes lead nowhere
By Don Monroe, July 10, 2009, Science 325: 142-143
The first paragraph summarizes the basic findings that the existing paradigm has no clues about: “When a gene works, evolution holds on to it, keeping its sequence intact even as bases around it change over time. Genome researchers had come to depend on this conservation to steer them to critical regions in the genome: If a stretch of DNA remains unchanged across different species, that DNA is probably performing a vital function. But a growing number of examples show that not all conserved sequences are important and, worse, that not all important sequences are conserved. That second observation—which would have been considered heresy until about a decade ago—means that researchers who had typically relied on conservation to guide them could have missed critical genes or unknown regulatory regions. But even as they scramble to understand how the "conservation equals function" rule has failed them, they are uncovering profound new subtleties in how genes are controlled and how they adapt during evolution.”
The fact that non-conserved sequences can be just as lethal when knocked-out as conserved ones is precisely what would be predicted by the MGD hypothesis.
Let us consider two genes A and B in mouse. A is conserved or shows 90% identity between two strains of mice. B is less conserved or merely shows 40% identity between two strains of mice. Based on the MGD hypothesis, the bare bone function of A (minimal function that shows activity in a test tube) may require merely 40% of the residues rather than 90%. The high degree of conservation of A indicates a broader function associated with epigenetic complexity rather than with bare bone function. In terms of percentage residues needed for bared bone function, A and B may in fact be quite similar. However, B may not be needed for multiple cell types and encounter less epigenetic constraints, leading to less sequence conservation. But the bare bone function of B may be just as essential as that of A and neither could be knocked out without a lethal effect.
To distinguish the functional importance of conserved vs non-conserved sequences, knock out is not the way to do it but is unfortunately what has so far been done simply because it is easy to do. Mutation is affecting single base pair while knock out is often deleting the whole gene. The MGD makes the following testable prediction. If one does random mutagenesis one by one by knock in method for each of the base pairs of a gene, it is far more likely for a point mutation in a conserved gene than in a less conserved one to lead to an abnormal phenotype.
The fact that conserved sequences are not lethal when knocked-out is also precisely what would be predicted by the MGD hypothesis. Conservation may reflect epigenetic complexity rather than merely functional essentialness for viability.