The danger of "non-genetic" mutations
DNA mutations outside of genes may be the cause of malformations of the nervous system
Marina Astvatsaturyan, Echo of Moscow
This is evidenced by the results of the first large-scale study of its kind.
New mutations, or de novo mutations, arising in a particular embryo, rather than inherited from parents, affecting certain genes, can cause defects such as brain dysfunction in 42 percent of children. This leads to problems with learning and speech. But until now it remained unclear how many people, including patients with undiagnosed malformations, may be carriers of "non-genetic" mutations, that is, mutations located in DNA regions that do not encode proteins. Scientists from The Wellcome Sanger Institute in Cambridgeshire decided to explore an unfamiliar genomic territory – sections of human DNA that consist of regulatory elements. They suggested that these non-coding segments may play some role in the occurrence of malformations of the nervous system.
Analyzing the genomes of almost 8,000 children and their both parents, the researchers paid close attention to the non-coding part with regulatory elements that control the switching on and off of genes. These regulatory elements are highly conservative, that is, they have hardly changed during the evolutionary history of mammals, therefore, they could play a decisive role in the early development of the brain. A group of Sanger Institute in collaboration with geneticists from the National Health Service (NHS Regional Genetics) The UK has established that this is indeed the case: extragenic mutations affecting regulatory elements can cause neurological developmental disorders, and an article in Nature (Short et al., De novo mutations in regulatory elements in neurodevelopmental disorders) is devoted to this discovery.
The authors estimate that from one to three percent of patients who do not have mutations in their genes are pathologically causing de novo mutations in regulatory elements that are usually active in the embryonic brain. Among the undiagnosed malformations of the nervous system in children are mental retardation, epilepsy and autism, and new data may contribute to clarifying their nature. In 2010, a project on genomic diagnostics of children with unknown developmental disorders (Deciphering Developmental Disorders) was launched in the UK.
To date, it has been possible to establish the origin of developmental defects in 13,000 children, but this is one third of the sample, and two thirds of the violations have not yet been recognized, that is, they are not related to any protein-coding genes. The Sanger Institute study involved children with brain dysfunction affecting learning and speech, and 140 examined children from 8000 families were found to have new mutations not in genes, but in regulatory elements.
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