Tag: genetic mutation

Genomic ‘Butterfly Effect’ Explains Risk for Autism spectrum Disorder

Photo by Sangharsh Lohakare on Unsplash

Researchers in Japan discovered that a special kind of genetic mutation works differently from typical mutations in how it contributes to autism spectrum disorder (ASD). In essence, because of the three-dimensional structure of the genome, mutations are able to affect neighbouring genes that are linked to ASD, thus explaining why ASD can occur even without direct mutations to ASD-related genes. This study appeared in the scientific journal Cell Genomics.

ASD is a group of conditions characterised in part by repetitive behaviours and difficulties in social interaction. Although it runs in families, the genetics of its heritability are complex and remain only partially understood. Studies have shown that the high degree of heritability cannot be explained simply by looking at the part of the genome that codes for proteins. Rather, the answer could lie in the non-coding regions of the genome, particularly in promoters, the parts of the genome that ultimately control whether or not the proteins are actually produced. The team led by Atsushi Takata at in the RIKEN Center for Brain Science (CBS) examined de novo gene variants (new, non-inherited mutations) in these parts of the genome.

The researchers analysed an extensive dataset of over 5000 families, making this one of the world’s largest genome-wide studies of ASD to date. They focused on TADs – three-dimensional structures in the genome that allow interactions between different nearby genes and their regulatory elements. They found that de novo mutations in promoters heightened the risk of ASD only when the promoters were located in TADs that contained ASD-related genes. Because they are nearby and in the same TAD, these de novo mutations can affect the expression of ASD-related genes. In this way, the new study explains why mutations can increase the risk of ASD even when they aren’t located in protein-coding regions or in the promotors that directly control the expression of ASD-related genes.

“Our most important discovery was that de novo mutations in promoter regions of TADs containing known ASD genes are associated with ASD risk, and this is likely mediated through interactions in the three-dimensional structure of the genome,” says Takata.

To confirm this, the researchers edited the DNA of stem cells using the CRISPR/Cas9 system, making mutations in specific promoters. As expected, they observed that a single genetic change in a promotor caused alterations in an ASD-associated gene within the same TAD. Because numerous genes linked to ASD and neurodevelopment were also affected in the mutant stem cells, Takata likens the process to a genomic “butterfly effect” in which a single mutation dysregulates disease-associated genes that are scattered in distant regions of the genome.

Takata believes that this finding has implications for the development of new diagnostic and therapeutic strategies. “At the very least, when assessing an individual’s risk for ASD, we now know that we need to look beyond ASD-related genes when doing genetic risk assessment, and focus on whole TADs that contain ASD-related genes,” explains Takata. “Further, an intervention that corrects aberrant promoter-enhancer interactions caused by a promotor mutation may also have therapeutic effects on ASD.”

Further research involving more families and patients is crucial for better understanding ASD’s genetic roots. “By expanding our research, we will gain a better understanding of the genetic architecture and biology of ASD, leading to clinical management that enhances the well-being of affected individuals, their families, and society,” says Takata.

Source: RIKEN

Gene Identified for Rare Disorder Involving Extra Fingers and Toes

Photo by Jonathan Borba on Unsplash

A rare disorder which causes babies to be born with extra fingers and toes and a range of birth defects has been identified in new research published in the American Journal of Human Genetics. The disorder, which has not yet been named, is caused by a genetic mutation in a gene called MAX.

As well as extra digits – polydactyly — it leads to a range of symptoms relating to ongoing brain growth, such as autism. The research marks the first time this genetic link has been identified. It has also found a molecule that could potentially be used to treat some of the neurological symptoms and prevent any worsening of their condition. However, more research is needed to test this molecule before it can be used as a treatment.

Co-led by the University of Leeds, the study focuses on three individuals with a rare combination of physical traits, namely polydactyly, and a much larger than average head circumference – known as macrocephaly.

The individuals share some other characteristics, including delayed development of their eyes which results in problems with their vision early in life.

The researchers compared the DNA of these individuals and found they all carried the shared genetic mutation causing their birth defects.

The latest research was co-led by Dr James Poulter from the University of Leeds; Dr Pierre Lavigne at Université de Sherbrooke in Québec and Professor Helen Firth at Cambridge University.

As with many rare disorders, the disorder currently has no treatments – but in this case, the researchers identified one already undergoing clinical trials which might reverse some of the mutation’s effects.

The study team has highlighted the importance of interdisciplinary research into rare diseases in giving understanding and hope of a treatment to families who often face many years of uncertainty about their child’s condition and prognosis.

The researchers now plan to look for additional patients with mutations in MAX to better understand the disorder and investigate whether the potential treatment improves the symptoms caused by the mutation.

Source: University of Leeds