Scientific Method —

Autism mutations strike genes active in the developing brain

Changes in these regions of the genes are otherwise very rare.

Genome Wide Association Studies have identified tons of mutations associated with many different diseases. This information is undoubtedly powerful, but also severely limited, because it cannot reveal how—or even if—these mutations cause the disease state; only that they are associated with the disease state. This means that people who have these genomic variants are at a higher risk for developing a particular malady than those who do not. But it would be helpful if researchers could figure out which mutations actually cause problems.

Over a hundred genomic variants are associated with autism spectrum disorders (ASD), and several hundred more are estimated to be awaiting detection. Some of these are very rare, existing in only one family or even one individual. But since everyone has unique genetic variants, it is very difficult to know which are the ones that actually cause the disease and which just distinguish one person's genome from another's.

To begin to tease out the relevant ones, an international research group has turned the traditional reasoning upside down. Rather than first identifying genetic mutations and then determining if the genes they affect are important, instead they first identified genes that are highly expressed in the brain but have few rare mutations. They then looked for ASD-associated mutations found within them, figuring that those mutations are more likely to be causative than rare mutations elsewhere in the genome.

To perform this search, the team obtained expression data from the regions of genes that get made into proteins, known as the exons. They picked out 3995 'brain-critical exons' that are highly expressed in this organ. They then checked for correlations between this expression and the number of disease-associated mutations in the same exon (their search was limited to people with European ancestry).

They found that, at the population level, exons that are highly expressed in the brain have fewer rare mutations than other exons; these exons are somewhat protected from changes. Conversely, rare mutations associated with brain disorders—like ASD, schizophrenia, and intellectual disability—are clustered in highly expressed exons.

The effect was most pronounced for exons highly expressed in the prenatal brain, particularly the orbital frontal cortex, which is thought to be important for complex social and emotional behaviors as well as decision making.

So, by focusing on genes active in the brain first, the researchers biased their study towards identifying the mutations most likely to be relevant to mental disorders. Now they have susceptibility genes for ASD, as well as some idea of how mutations can damage them.

Nature Genetics, 2014. DOI: 10.1038/ng.2980  (About DOIs).

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