Harmful mutations and genomic malleability

I think this might be completely wacko, but I'll post it anyway. Read at your own risk.

I've argued before that mutations are nonrandom and that genomes are designed to be mutated and reorganized as part of the emergence of new species within baramins. I've also argued that most muations are not harmful but rather neutral. The latest Molecular Biology and Evolution has an intriguing article by Domazet-Lošo and Tautz that looks at mutations associated with genetic diseases. Here's the abstract:

An ancient evolutionary origin of genes associated with human genetic diseases

Several thousand genes in the human genome have been linked to a heritable genetic disease. The majority of these appear to be nonessential genes (i.e., are not embryonically lethal when inactivated), and one could therefore speculate that they are late additions in the evolutionary lineage toward humans. Contrary to this expectation, we find that they are in fact significantly overrepresented among the genes that have emerged during the early evolution of the metazoa. Using a phylostratigraphic approach, we have studied the evolutionary emergence of such genes at 19 phylogenetic levels. The majority of disease genes was already present in the eukaryotic ancestor, and the second largest number has arisen around the time of evolution of multicellularity. Conversely, genes specific to the mammalian lineage are highly underrepresented. Hence, genes involved in genetic diseases are not simply a random subset of all genes in the genome but are biased toward ancient genes.

To translate: They looked at how many genes associated with genetic diseases are found in just primates, just mammals, just vertebrates, etc. They identified these taxon-specific genes using a BLAST search with a pretty high cutoff (E<0.001), which would detect mostly taxon-specific protein domains rather than taxon-specific paralogues. Despite this drawback, they found a paucity of eutherian- and primate-specific genes in the disease-gene set. As far as I can tell, their results could mean one of three things:

1. Their methodology is not sufficiently discriminatory and therefore their results tell us little about the distribution of disease-causing mutations. In other words, their high BLAST cutoff picks up too much distant homology or paralogy and not enough informative orthology. There could be primate-specific disease-genes, but they are primate-specific paralogues of genes that occur in other taxa. I find this unconvincing, since it would theoretically hold for any taxon in their set, but the eutherian-specific genes are the ones under-represented in the disease gene set.

2. The lack of eutherian-specific disease genes is real and results from fewer mutations occurring in eutherian-specific genes. I find this ad hoc and hard to believe. It also strikes me as a poor design: Why create a genome wherein mutations occur more often in genes that are likely to cause genetic disease?

3. The lack of eutherian-specific disease genes is real and reflects a greater tolerance to mutation among the eutherian-specific genes. This is an interesting possibility. Think of it this way: If genomes were designed to be mutable in certain ways, it would make sense that the most mutable genes would be genes that mark off the most specific traits of each organism. Mutations that occur in these mutable genes would be unlikely to produce a harmful phenotype, but any changes to the more basic genes, found in many taxa, would result in a genetic disease.

At this point, I'm not sure if 1 or 3 is more likely correct. Possibility #2 (unequal mutations) could be tested by comparing the SNP distribution in the eutherian-specific to all genes. I really like the concept of a class of mutable genes, since that could open the door to understanding the "limits of variation," but I'm not convinced that the technique used in the article was sufficient to demonstrate a lack of disease genes among all eutherian- or primate-specific genes.

Domazet-Lošo, T. and D. Tautz. 2008. An ancient evolutionary origin of genes associated with human genetic disease. Mol. Biol. Evol. 25(12):2699-2707.