Mutation intolerance – why some genes withstand mutations and others don’t

The river of genetic variants. The era of high-throughput sequencing has given us several unexpected insights into the human genome. One of these insights is the observation that mutations or variations can occur in parts of our genome without any major consequences. Every individual is a “knockout” for at least two genes in the human genome. This means that in every individual, both copies of a single gene are disrupted through mutations or small deletions or duplications. In addition, there are dozens, if not hundreds, of genes with disruptive mutations that affect only a single copy of the gene. Similar mutations in specific disease-associated genes, however, will invariably result in an early onset genetic disorder. This comparison already shows that the genes in the human genome differ with respect to the amount of disruptive genetic variation they can tolerate. A recent study in PLOS Genetics now tries to catalogue the genes in the human genome by assessing their mutation intolerance based on the genetic variation seen in large-scale exome datasets. Many genes for neurodevelopmental disorders are highly intolerant to mutations. Furthermore, some genes for monogenic epilepsies show surprising results in this assessment. Continue reading

A microscopic look at the 16p13.11 microdeletion

The patchwork chromosome. The human genome is a puzzle of duplications, duplications-within-duplications and more complex rearrangements.. Some of these duplications can misalign at meiosis and generate microdeletions and microduplications. The duplication architecture of the human genome is more pronounced in some chromosomes than in others. Chromosomes 15 and 16 are particularly rich in duplications, which is the reason several syndrome-associated microdeletions and microduplications are found there. One of these microdeletions is the 16p13.11 microdeletion. As a recent paper has looked as histological findings in brain tissue of patients with these deletions, it is time to review the only established genetic risk factor that contributes to wide range of epilepsy syndromes. Continue reading