Shedding new light on how deleterious mutations can compensate for each other

Scientists at the University of Iceland Biomedical Centre, together with international colleagues, have published an article in the journal EMBO Reports, discussing how deleterious mutations in a certain protein can have a positive impact on the visible characteristics of an organism. 

This study was completed by the Vietnamese PhD student Hong Nhung Vu, under the supervision of Eiríkur Steingrímsson, professor at the UI Biomedical Centre and a scientist who has devoted many years to researching the regulator protein Microphthalmia-associated Transcription Factor (MITF). MITF binds to DNA and regulates gene production. It is a key protein for the development of melanocytes, the cells that produce the pigment melanin that determines the colour of skin, hair and eyes. MITF increases production of the pigment when the body is exposed to UV rays. It is therefore important as a defence against the harmful effects of the sun. MITF also plays a significant role in melanoma, a kind of cancer that develops from melanocytes. Research has shown that MITF mutations increase the chances of melanoma in families that carry the mutation.

This study was designed to identify genetic factors that regulate or influence MITF activity by inducing random mutations in mice that already carried a mutation in the MITF gene. The goal was to explore whether it would be possible to induce new mutations that would affect the phenotype of the first mutation. Similar studies are commonly carried out on bacteria and fruit flies and have yielded knowledge about the processes by which proteins work and which other proteins they work with. This kind of research is, however, rarely conducted on mice.

Identified a mutation that changes the colour of mice as well as shortening the protein 

For this study, the scientists started with MITF mutated mice with white coats and attempted to find out whether it was possible to induce mutations that corrected the phenotype and made them darker again. A mutation was identified that made the mice darker in colour and the scientists were surprised to discover that the mutation was in the MITF protein itself, removing a quarter of the protein. Mice that carry this mutation on one of their chromosomes and an MITF mutation that impairs the function of the protein on the other chromosome therefore have a more normal coat colour than those with full-length MITF protein.

How can a protein missing a quarter of its length cause a more normal phenotype? The study revealed that the MITF protein was less stable when missing a quarter of its length, but could still bind to DNA and form doublets. The scientists were interested to observe that when the shorter, mutated MITF protein formed a doublet with another MITF protein (mutated or not), the stability of the shorter protein increased. The fact that the mutated protein caused a more normal phenotype can probably be explained by its stability in a doublet with other MITF proteins, meaning that it is stored in the cell for longer before being released and able to bind to DNA and regulate gene expression. Deleterious mutations such as this one can therefore have a positive impact on an organism’s phenotype.

The scientists claim that this discovery sheds new light on MITF regulation and how mutations in the protein can affect its role in pigment production and melanoma. They also point out that these findings provide one explanation for how people carrying mutations on both chromosomes which knock out the function of a gene (so-called human knockouts) can be healthy. The mutations compensate for each other in some way, resulting in a normal phenotype. 

Link to article in EMBO Journal.