New Genetics Theory for "Sporadic and Inherited" Autism

Our July 2007 IAN Research Report begins with major news: the first publication of a scientific paper based, in part, on IAN data.

The theory hypothesizes that there are two ways to "get" autism. The first way is by spontaneous mutation of a gene within a sperm or egg cell that leads to autism in a resulting child. The second way is when such a mutation has become part of the family genome, and is being passed down through generations.

The theory has the potential to link environmental and genetic concerns, because it says that most autism is caused by these spontaneous genetic mutations --which may in some cases be caused by some external factor-- not by a specific autism gene or genes that appear throughout the population.

You can read about the theory in our report here:
http://www.iancommunity.org/cs/ian_research_reports/ian_research_report_july_2007

What are your thoughts and opinions about this new theory?

The theory is based on a previous study published by Cold Spring Harbor that found 12 out of 129 (10%) of persons with an ASD from single incidence families had a copy number variation, but none of the CNV's were specific to a single gene or even chromosome. The study says nothing about what the CNV's actually do to 'cause' autism. The best researched report of CNV's associated with a specific gene comes from HIV research. CNV's in a specific gene was associated with resistance to infection after exposure to the HIV virus.

http://www.wellcome.ac.uk/doc_WTX034711.html

More problematic is that if the majority of cases are sporadic, with parents unaffected, the entire concept of the 'broad autism phenotype' would be discredited

I thought this study was really interesting, and it gives me a lot of hope that, as we have no history of autism in our family, we might have the same chance of having a second child with Autism as anyone else (as opposed to an increased risk).
However, with the millions of eggs and sperm and the probability of them interacting, are they saying that this sporatic mutation takes place pre-conception or post? If it is pre, wouldn't a LOT of sperm or egg cells have to have had these mutations in order to keep up with the numbers (meaning 1 out of 150 children effected). I appologize if I missed something in this study-- I am probably the farthest thing from a researcher!

Hi Drewsmom.

As Dr. Wigler, one of the authors of the study, explained to me, the spontaneous mutation would happen pre-conception. He said that mutations happen all the time for a variety of reasons, and we accumulate more of them as we age. When a spontaneous mutation occurs in a single random cell somewhere in the body, it may have very little effect. When it happens in a sperm or egg cell, however, it's tweaked the genetic blueprint for any child who might result from that sperm or egg.

Because each person will tend to have more cells with random mutations as they age, the theory does explain why older parents might be more likely to have a child with an ASD, as has been claimed in some studies.

One of the interesting questions that the theory raises is: are there more spontaneous mutations now than there used to be? If so, what explains this? (UV radiation because of a reduced ozone layer? Other environmental factors, like pollutants? Something else?)

For our write-up about the theory, I asked Dr. Wigler how a variety of different spontaneous mutations could all lead to some kind of autism spectrum disorder. His answer was incorporated into our Q&A #2 about the theory:

2. How can a variety of different spontaneous mutations all lead to autism in so many people?

Actually, the notion that spontaneous mutations cause autism would help explain why there is such great variation across the autism spectrum.

Genes have jobs. One of their most essential jobs is to make the proteins that run the millions of processes upon which the human brain and body depend. A mutated gene may not make a protein the way it is supposed to. It may not make it at all, or make too much of it, or make it incorrectly. If the problematic protein plays a critical role, it may disrupt normal development and cause disease.

Many different mutated genes may interfere with the same ultimate process, whether that be hearing, liver function, or brain function. A variety of genes, when working improperly, could lead to some kind of Autism Spectrum Disorder.

Think of cancer. Not so long ago, it was thought of as a single disease that probably had a single cause, but no single cause was found. Instead, many different variations of cancer were found, each with a different ultimate cause or causes.

There are additional Questions and Answers about the theory here:
http://www.iancommunity.org/cs/autism_spectrum_disorder_research/unified_genetic_theory

Hi Connie;
Here's a new study that may shed light on the original study about the theory for sporadic and inherited autism.

http://richarddawkins.net/article,1601,n,n

An entire genome scan of a single individual has been completed and reported that half of the subjects 23,224 genes contained variations or mutations.

Thank you, RAJ. This is a fascinating article. (Or, more accurately, a fascinating write-up about a scientific article. The article itself would be quite challenging for any non-geneticist such as myself to fully comprehend.)

One thing I had not realized is that our knowledge of the human genome was based upon two maps that were half maps --based on only one parent's chromosomes. This new study looks at a human's genetic material from both parents.

The other interesting point is how we are more diverse than first believed. Originally, it was estimated that humans were 99.9% genetically identical, while this new study finds we are only 99.5% genetically identical. (That may not sound like much difference, but it represents a jump by a factor of five in our diversity.) Keep in mind, though, that this entire analysis is based on one person's genetic material.

As you pointed out, they found many more variations and mutations than expected. To what extent these were inherited and to what extent they were the result of spontaneous mutations (such as were discussed in the Unified Genetic Theory for Inherited and Sporadic Autism) I do not know.

If anyone is feeling up to the challenge, you can find the full article, The Diploid Genome Sequence of an Individual Human (upon which the write-up RAJ provided is based), here:

http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0050254