Pseudogenes lose their ability to encode proteins and natural selection stops to notice them, as no mutations in such genes can be harmful. A study conducted with the participation of the specialists from the Faculty of Bioengineering and Bioinformatics, MSU (Lomonosov Moscow State University) confirms this fact but shows that natural selection still has certain influence on some of such genes. An article about it was published in Genome Biology and Evolution journal.
Sometimes a protein stops playing a key role in an organism's adaptation and survival (e.g. due to environmental changes). Therefore, any mutations in the gene that codes this proteins become irrelevant for the organism in general.
"Scientists have known for a long time, that after a gene undergoes a harmful mutation, e.g. a nonsense mutation, it stops working and turns into a pseudogene. In this case negative selection (the one that removes harmful mutations from the population) stops applying to it, and nonsynonymous mutations (the ones that cause the replacement of one amino acid in a protein with another) start to accumulate in the gene at the same speed as synonymous ones (the ones in which amino acids are not replaced). Previously this was indirectly referred to in many works with individual examples, but no full-scale research of the effect of nonsense mutations has been ever conducted before," says Nadezhda Potapova, a co-author of the work, postgraduate of the Faculty of Bioengineering and Bioinformatics, MSU.
A human genome contains 53-100 non-functioning alleles, and 21 to 27 of them have been switched off due to nonsense mutations. This type of mutations got its name due to its ability to deprive the gene of its sense (a functioning protein). Nonsense mutations are a type of mutations causing the occurrence of a terminating codon at which protein synthesis stops. Such mutations may occur due to different reasons: replacements, insertions, or even deletions of the "letters" in the genetic code.
The big number of alleles with nonsense mutations (or nonsense alleles in short) made the scientists think there were not so nonsense after all. Several molecular mechanisms which allow the function of an apparently broken gene to remain at least partially preserved have already been described.
Nonsense alleles differ from nonsynonymous mutations by their harmfulness. They cause diseases three times more often, are observed less frequently, and often have additional copies in the genome (paralogs) making the elimination of just one of them irrelevant.
Biologists studied the genomes of Zambian populations of Drosophila melanogaster that on average contain 35 nonsense mutations. They focused only on the nonsense alleles that occurred due to the replacement of one nucleotide.
It turned out, that negative selection (i.e. the selection reducing the frequency of a certain feature within a population) did not influence those parts of the flies' coding genes) that contained nonsense mutations. However, the selection still had slight impact on some of them. The reason for it may be alternative splicing - different ways of reading the same DNA region due to the shifting of their start and end points. Biologists believe that alternative splicing is reason why some genes preserve their functions and are at least partially making them visible for the negative selection.
"We used Drosophila melanogaster genomes. Based on it, we managed to confirm that nonsense mutations actually switch off single exon genes (i.e. the genes that contain no introns cut out during protein synthesis), and they start to accumulate both synonymous and nonsynonymous mutations at the same speed. In multi exon genes (genes with several introns) only the exon with the mutation seems to be left out, and the others remain under the influence of negative selection, though slightly weakened," explains Nadezhda Potapova.
The study was conducted by the scientists of the Faculty of Bioengineering and Bioinformatics, MSU together with colleagues from Kharkevich Institute for Information Transmission Problems of the Russian Academy of Sciences, Skolkovo Institute of Science and Technology, and the University of Michigan (USA).