Genetic analysis of individuals with autism finds gene deletions

Using powerful genetic sequencing technology, a team of investigators, led by researchers at the Icahn School of Medicine at Mount Sinai, scanned the genome of hundreds of individuals, and discovered those diagnosed with autism spectrum disorder (ASD) were more likely to have gene deletions than were people without the disorder. That means those individuals—seven percent of the study group—had one copy of one or more genes when they should have had two.

The scientists further report, in the American Journal of Human Genetics, that their analysis suggests the deletions may result in the miswiring and altered activity of brain neurons.

"This is the first finding that small deletions impacting one or two appear to be common in autism, and that these deletions contribute to risk of development of the disorder," says the study's lead investigator, Joseph D. Buxbaum, PhD, Professor of Psychiatry, Genetics and Genomic Sciences and Neuroscience at the Icahn School of Medicine at Mount Sinai.

"This conclusion needs to be expanded in other independent samples of ASD so that we can truly understand how the risk manifests," he says.

That process is now ongoing, Dr. Buxbaum adds. The Autism Sequencing Consortium, a group of over 25 institutions, was awarded a $7 million grant from the National Institutes of Health to continue analyzing the genomes of thousands of ASD individuals at Mount Sinai.

First look for missing genes in autistic population

Autism, which affects about one percent of the population, is a developmental disorder thought to be caused by a complex interplay between genetic and environmental factors. Although the disorder is highly heritable, the majority of autism cases cannot be attributed to known inherited causes, Dr. Buxbaum says.

While research has indicated that there might be as many as 1,000 genes or genomic regions that contribute to ASD, most studies have looked for either single point mutations—a change in a single letter of DNA on a gene—or for large areas of the genome, encompassing many genes, that is altered.

In this study, the researchers looked for small copy number variation —deletion or duplication of genes— between ASD individuals and a "control" population without the disorder.

To conduct the study, they used exome sequencing to look at all 22,000 human genes in the sample set, and analyzed that data using the eXome Hidden Markov Model (XHMM) program. Together, the tools are the first that can find single gene-sized deletions or additions in the genome.

"This gives us the power, for the first time, to run one test from a blood sample and compare it to a reference genome to search for mutations and small copy number variation in patients," Dr. Buxbaum says.

They applied this method to analyze a databaseconsisting of 431 ASD cases and 379 matched controls, totaling 811 individuals. They found 803 in the ASD group and 583 deletions in the control group, and the ASD population had a greater likelihood of having multiple small deletions.

Gene deletions not due to genetic inheritance.

"It is now known that imperfect gene copy number is one of the major sources of variability between people. One of the reasons we are different from each other is because of gene additions or deletions which are often inherited," he says. "But of the extra deletions we see in ASD not all are due to genetic inheritance. Some occur during the development of the egg or sperm, and deletions that develop in this way tend to be associated with the disorder."

The researchers then examined the deletions they found in the autistic group and found that a significant proportion of them related to autophagy, a key process that keeps cells healthy by replacing membranes and organelles.

"There is a good reason to believe that autophagy is really important for brain development because the brain produces many more synapses than it needs, and the excess needs to be pruned back," Dr. Buxbaum says. "Too many, or too few, synapses have the same effect of not making communication work very well. It could mean that some synaptic connections come in too late and may not solidify properly."

The researchers believe the findings will have clinical significance. "Key copy number variations—those that consistently appear in an autistic population—can impact genetic testing," Dr. Buxbaum says.

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julianpenrod
1.3 / 5 (12) Oct 03, 2013
Too many people tend to take reports such as this too shallowly, with too little questioning. They come away with the "conclusion" that autism must be real because there is a gene deletion present, and it must be caused by the gene deletion. They too casually ignore fundamental invalidating facets of the article.
Among other things, it is including people with "autism Spectrum Disorder", which covers a wide variety of manifestations, some so minor that many might not even notice it at all at least at first blush. Yet the article suggests that the entire spectrum derives from the lack of one gene. They have to suggest that or else they have to admit it's all a phony, an ever expanding artificial and fabricated collection of claimed manifestations, grounded in a single described serious condition.
But a gene deletion can cause the worst forms of autism. So how could the same deletion cause only minor symptoms and even not cause any symptoms in others?
JVK
1 / 5 (11) Oct 03, 2013
"Gene deletions not due to genetic inheritance." Mutations are not fixed in the genome http://www.nature...417.html "The result of these complex dynamics is that genetic diversity could be maintained indefinitely, without one allele or the other ever being fixed in the population."

That also means mutations cannot be responsible for mutation-driven evolution, which means that adaptive evolution is nutrient-dependent and pheromone-controlled in species from microbes http://stke.scien...291/pe28 to man. http://www.socioa...ew/20553
mathari
3 / 5 (2) Oct 03, 2013
Lead and Mercury damage DNA and micronuclei formation. Cell culture studies support an epigenetic mechanism or co-mutagenic effects. Proteins depending upon sulfur-containing side chains for maintaining conformity or activity are vulnerable to inactivation by lead because of its strong sulfur-binding affinity. The enzyme, ALAD, a 280 kDa protein, is inducible and is the major Pb-binding protein within the erythrocyte. In human brain, Pb-binding proteins include thymosin β4 and an unidentified protein of 23 kDa. Animal toxicology studies demonstrated a role for metallothionein as a renal Pb-binding protein.
JVK
1 / 5 (10) Oct 03, 2013
Epigenetically caused color changes in the context of industrial melanism and ingestion of lead and manganese by moth larva, was reported as an example of predator-driven selection of mutated color. Are you trying to say something similar in the context of animal toxicology studies? Is the role for metallothionein as a renal Pb-binding protein somehow involved in the physiology of nutrient-dependent reproduction and adaptive evolution? Or are you simply addressing lead toxicity out of that context?
Sinister1811
1 / 5 (2) Oct 04, 2013
julianpenrod has a point. How can gene deletion be responsible for the diversity of people with the condition? I wish they would just stop messing around, and wasting everybody's time and money, and just find new ways of treating or curing health conditions (like this, MS, Alzheimers and cancer). But I guess, then they won't get any money from research grants and donations.
JVK
1 / 5 (9) Oct 04, 2013
Sinister1811: It snot just the loss of grant money and money from donations. It's the embarrassment of being forced to admit that adaptive evolution is nutrient-dependent and pheromone-controlled in species from microbes http://stke.scien...291/pe28 to man. http://www.socioa...ew/20553 People will be asking: "How could you have missed something so obvious?" I'm not sure an acceptable answer can be "spun." And attempts to do that may make the embarrassment worse.
roguetech
1.5 / 5 (8) Oct 04, 2013
Too many people tend to take reports such as this too shallowly... They come away with the "conclusion" that autism must be real...
... it is including people with "autism Spectrum Disorder"... Yet the article suggests that the entire spectrum derives from the lack of one gene...

The article does not suggest the entire spectrum is due to the lack of one gene. Indeed, it doesn't even suggest that ANY of the spectrum is due to lack of any genes. What you THINK the article SUGGESTS is just your own denialist bias (read: stupidity).

What the article STATES is that "the ASD population [has a statistically] greater likelihood of having multiple small deletions." As stated, it's your own stu... bias that leads you to the conclusion this is causal. In other words, "[You] take reports such as this too shallowly, with too little questioning. [You] come away with the 'conclusion' that autism must [not] be real because [you make up a bunch of crap that's never stated]."
roguetech
1 / 5 (9) Oct 04, 2013
julianpenrod has a point. How can gene deletion be responsible for the diversity of people with the condition?
Nothing in this suggests causality. It also only looks at broad trends, at least from the article (not having read the actual study).

To more directly address the question, the article suggests gene deletions may lead to more or fewer neural connections. Your question amounts to, "How can parts missing from one specific area of the engine in a broad range cars result in similar performance problems?"

The "range of people" are all very very similar... Because they're PEOPLE. We aren't comparing autism in koala bears and humans! The article states the gene deletions are concentrated in one area, and different internal outcomes can result in the same external results.

Your last comment about not liking science, but preferring science, is unsurprising given your blanket disagreement with facts, while not addressing how the study may be flawe