Two studies today Ignorance of nature, led by researchers at Boston Children ‘s Hospital, Brigham and Women’ s Hospital (BWH), and Harvard Medical School (HMS), causes mosaic mutations arising during embryonic development as a cause of autism spectrum disorder (ASD). The findings open up new areas for studying the genetics of ASD and could inform diagnostic tests.
Mosaic mutations affect only a fraction of a person’s cells. Instead of being possessed, they arise as an “error” introduced when cell gas divides. The resulting cells are not mutated into a gas cell, mismatching the mosaic pattern. When mosaic mutations occur during embryonic development, they can appear in the brain and affect the activity of neurons. The earlier a mutation develops, the more the cells carry it.
Identifying mosaic mutations in the brain
Both studies were part of the Brain Somatic Mosaicism Network, funded by the National Institute of Mental Health. The first study used full-length whole-genome sequences to measure and identify mosaic mutations in the facial cortex of people with and without ASD. It was led by Rachel Rodin, MD, PhD and Christopher Walsh, MD, PhD, of Boston Children, and Yanmei Dou, PhD and Peter Park, PhD, of HMS.
When the researchers examined samples of brain tissue from 59 people who died of ASD controls and 15 – the largest group of brain samples ever studied – they found that mosaic “point” mutations most of the brain (changes in a single “letter” of genetic code). They hypothesized that embryos receive several such mutations with each cell division, and they estimate that about half of us carry mosaic mutations that can be harmful in co-mutation. at least 2 percent of our brain cells.
In the brains of people with ASD, however, mosaic mutations were more likely to affect parts of the genome that play a critical role in brain function. In particular, they tended to land in “supplements,” chunks of DNA that do not code for genes but that regulate whether a gene is turned on or off.
“In the brains of people with autism, mutations accumulate at the same rate as normal, but are more likely to collapse in a therapist area,” says Rodin, the paper’s first author. “We believe this is because gene enhancers and promoters tend to be in DNA that is unopened and more exposed, which may make them more susceptible to mutations during cell division. “
“Variables in therapies are a hidden type of strain that you don’t see in normal exome diagnostic sequences, and may help explain ASD in some people,” notes Walsh, head of genetics and genomics at Boston Children and co-author of the paper by Park, who led the study’s computer analyzes. “We also need to better understand the effects of these mutations on neurons.”
Remove mosaic and duplicates
The second study is the first large-scale study of changes in copy number (CNVs) in people with ASD that occur in a mosaic pattern. In contrast to point mutations in a single gene, CNVn is the deletion or duplication of entire chromosome segments, which may be in several genes.
A team led by Maxwell Sherman, MS of BWH, Po-Ru Loh, PhD of BWH, Park, and Walsh examined blood samples from approximately 12,000 people with autism and 5,500 unaffected sisters donated by the Simons Simplex Collection and Simons Power Autism Research for Knowledge Datasets (SPARK). They used blood as a surrogate for brain tension and applied novel computational techniques to detect mosaic mutations that may arise at the time of initial development.
“People in CNVs have been interested in autism for a long time, and would occasionally notice that some of them were mosaic, but no-one had looked at them in a large study, “said Loh, co – author of the Walsh and Park paper.
From these large samples, the team identified 46 mosaic CNVs in the autism group and 19 in sisters. The CNVs affected 2.8 to 73.8 percent of blood cells sampled from each subject.
Size matters
In particular, those with ASD were particularly likely to have large CNVs, with some containing 25 percent or more of the chromosome. The CNVs span a median of 7.8 million centers in the ASD group, against 0.59 million centers in controls.
“This is one of the most interesting and fascinating aspects of our study,” said Sherman, the paper’s first author and a PhD student at MIT. “Children with ASD often had very large CNVs. affecting dozens of genes, and apparently including genes that were important for development. If the CNVs were in all their cells, rather than in a mosaic pattern, they would tend to be lethal. “
The study also suggested that the larger the CNVs, the greater the autism as assessed by standard clinical measurement. Another surprise was that smaller CNVs that were already known were not associated with ASD when detected in all cells, such as deletion or duplication of 16p11.2 or 22q11.2, which was not associated with autism when they occurred in a mosaic pattern.
“This suggests that, in order to get autism, you need to build a large number of brain cells in a very substantial way,” Walsh said. “We are pretty sure that these large CNVs will change the behavior of neurons that carry them. “
“We don’t know for sure which cell fraction is important, or which specific chromosomes are most likely,” notes Loh. “These events are still very rare, even in people with autism. As larger groups are gathered, we hope to gain some insight.”
Eventually the results of these studies could be fed into diagnostic tests in children with autism. Experiments could include the noncoding parts of the genome, such as gene enhancers and promoters, and introduce chromosomal analysis with a higher resolution to mosaic CNVs celebrate big. For now, the findings add to the growing autism puzzle, deepening the mystery of why so many different genetic mechanisms lead to the same manifestation of autism.
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Walsh is a Howard Hughes Medical Institute researcher. Other sponsors of the studies include the National Institute of Mental Health (F31MH124393, T32MH112510, U01MH106883, P50MH106933, R01MH104964), National Institute of General Medical Science (T32GM007753, R01GM108348), National Institutes of Health (K25HL00ome Research T32) R01HG00685), the Allen Discovery Center program through the Paul G. Allen Frontiers Group, the Stanley Center for Psychological Research, the National Science Foundation (DMS-1939015), and the Wellcome Burroughs Fund.
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