Written by Isobel Young, Science Writer
Research focusing on neurological disorders has become more frequent in recent years. However, there is still much to be explored. A team of researchers from Yale University, the Lieber Institute for Brain Development (LIBD), and Harvard University have analysed frozen brain tissue in the hope of determining the frequency of somatic mutations in the general population, and to gain a better understanding of whether these mutations lead to neurological disorders.
The study, published in Science, involved the whole genome sequencing of tissue from 131 frozen brains from neurotypical individuals or from individuals with neurological disorders (Tourette’s syndrome, schizophrenia, or autism spectrum disorder (ASD)). The frequency of different somatic mutations were identified, along with their location.
Throughout a lifetime, genetic mutations are common. Somatic mutations are mutations that occur in any cell of the body except germ cells; this means the mutations are not hereditary and so will not be passed down the generations. In some cases, an individual may have a much higher frequency of mutations compared to the rest of the population. This is known as hypermutability.
While not a primary aim of this study, the researchers found that 6 of the brains they analysed were what they termed “hypermutable brains”. Their results showed that although hypermutability was not found to be linked to the neurological disorders they were studying, it was linked with age. It was found that there was a 3% population frequency of hypermutability in the brains of individuals over 40 years of age.
Somatic mutations and neurodivergence
The team found that the brains of individuals on the autism spectrum had deleterious mutations, missense mutations and splice mutations. The missense mutation detected in ASD brains was in the PCDH15 gene, which the authors explain is responsible for “encoding a protein mediating calcium-dependent cell-cell adhesion”. The splice mutation was found on the MTOR gene, which has been linked to the IGF1-PI3K signalling pathway. These results support findings of previous studies that link the pathway to ASD development.
The study also found that the brains of individuals with autism had mutations that the researchers believe resulted in transcription factor binding motifs (TFBMs) in enhancer-like regions. TFBMs are genetic sequences that bind to transcription factors, aiding in the regulation of gene expression. The team found that the TFBMs caused by these mutations were linked to myeloid ectopic viral integration site transcription factors; a key regulator involved in embryonic development, as well as cancer. This new data allows scientists to infer that there may be a connect between these genes and autism, however future studies will be required to truly understand the link.
When analysing the brains from individuals with Tourette’s syndrome, the researchers identified a missense mutation in a gene associated with X-linked intellectual disability- the ARHGEF6 gene. This gene has implications for the development of cell polarity, supporting earlier research that has suggested a significance of cell polarity in of Tourette’s syndrome.
While the number of brains belonging to schizophrenic individuals was small in this study, the researchers were able to obtain some valuable data. They found that in one of these brains, (which was also hypermutable), there was an abnormal number of chromosomes in hippocampal cells; this is known as genomic aneuploidy. The small sample size is a limitation of this study. To truly determine if there is a link between somatic mutations and neurological disorders, further studies with larger sample sizes are needed.
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