Firstly, I think I should clarify, for the readers, who I am and why I wrote the paper. I am the creator and curator of the Cytochrome P450 Homepage http://drnelson.utmem.edu/CytochromeP450.html, a gene family database in existence since 1995. This database contains nomenclature and sequence information for almost 5,000 cytochrome P450 genes, from hundreds of species. I have been involved in cytochrome P450 research since 1985 and I have been naming these genes since 1987. I am not opposed to gene databases because this is how I spend much of my time. This paper arose from the fact that my wife was diagnosed with breast cancer in 2003. She had her BRCA1 and BRCA2 genes sequenced, and a variant of uncertain significance was found.

This sparked my interest in the human gene mutation databases, and led me to write the paper.

The final paragraph, which triggered the reply, raises a point about the cost of a making a set of data, such as mutation data, comprehensive by obtaining by mutagenesis every single point mutant and analysing it. In 1998, Ronald Kaback's laboratory used Cys-scanning mutagenesis and mutated every amino acid in the lacY permease protein and assayed each one for function [1]. This feat was extraordinary, and as far as I know, it has not been repeated on other genes, due to the high cost.

With 30,000 or more human genes, I was trying to ask: should we make comprehensive gene mutation datasets? I am not opposed to diagnostic sequencing, nor to placing the results in mutation databases. These are valuable tools, with considerable benefits. But there is a cost associated with knowledge, and complete knowledge has a very high price.