Loss-of-function mutations

A study by the Welcome Trust Sanger Institute and Yale University released in Science this month set out to determine on average how many genuine loss-of-function mutations do humans carry and how many genes are inactivated because of the mutations.  Depending on what definition you use, humans carry ~20,000 genes.  These loss-of-function mutations cause the protein to lose its structure or function.   For example, one of the most common cancer genes, TP53, is called a tumor-suppressing gene because it controls the cell cycle.  When TP53 is mutated, tumor cells can replicate uncontrollably because TP53 has lost its ability to control (or suppress) the cell cycle properly.

Using the three pilot phases of the 1000 Genomes Project, the researchers suggest humans carry ~100 loss-of-function (or deleterious) mutations and ~20 genes that have been inactivated (that's ~.1% of your genes)!  This is such an interesting topic because up till now whenever researchers have found these loss-of-function mutations, they normally assumed it is somehow disease-causing.  This is no longer the case.  This news article from GenomeWeb states "as more and more apparently healthy individuals have their genomes and exomes sequenced, he added, investigators have unearthed a raft of apparent loss-of-function variants that are both intriguing and puzzling. "  The article in Science is suggesting that we should expect humans to have a given number loss-of-function mutations (~100).   What is still unclear is how to differentiate between the loss-of-function mutations that are disease-causing and the ones that are more benign.  As personalized medicine is becoming an increasingly important topic, this type of research will be critical when whole-genome sequencing becomes cost effective.