Diverse autism mutations lead to different disease outcomes

autism
Quinn, an autistic boy, and the line of toys he made before falling asleep. Repeatedly stacking or lining up objects is a behavior commonly associated with autism. Credit: Wikipedia.

People with autism have a wide range of symptoms, with no two people sharing the exact type and severity of behaviors. Now a large-scale analysis of hundreds of patients and nearly 1000 genes has started to uncover how diversity among traits can be traced to differences in patients' genetic mutations. The study, conducted by researchers at Columbia University Medical Center, was published Dec. 22 in the journal Nature Neuroscience.

Autism researchers have identified hundreds of that, when mutated, likely increase the risk of developing (ASD). Much of the variability among people with ASD is thought to stem from the diversity of underlying genetic changes, including the specific genes mutated and the severity of the mutation.

"If we can understand how different mutations lead to different features of ASD, we may be able to use patients' genetic profiles to develop accurate diagnostic and prognostic tools and perhaps personalize treatment," said senior author Dennis Vitkup, PhD, associate professor of systems biology and at Columbia University's College of Physicians & Surgeons.

To investigate the links between genetic mutations and traits, Dr. Vitkup and a team of Columbia graduate students (Jonathan Chang, Sarah R. Gilman, and Andrew H. Chiang) analyzed genetic and clinical data on hundreds of patients with ASD from the Simons Simplex Collection.

IQ and gender differences in autism influenced by severity of mutations

The group found that more damaging usually lead to worse disease outcomes. "It looks as if high-IQ autism cases are usually triggered by milder mutations," Dr. Vitkup said.

Patients with low-verbal or nonverbal IQs usually had mutations in genes that are more active in the brain. And high-IQ individuals were less likely to have mutations that completely shut down genes. Instead, mutations that only partially damage normal gene function in the brain appear to be predominantly associated with high-functioning autism cases.

Gender differences in autism could also be traced to the types of genes mutated in the individual. Though ASD is far more common in males, females with ASD are more likely to fall on the severe end of the spectrum.

The Columbia researchers found that the genes mutated in females generally had greater activity throughout the brain than those mutated in males. Very damaging ASD mutations in girls on average are found in genes that are almost twice as active as typical genes in normal brains.

"These patterns are consistent with the idea that there are mechanisms that protect females," Dr. Vitkup said. "Most often, only when a mutation hits a highly active gene do we see symptoms in females. Given that the inherent differences in gene activity in male and female brains are typically on the order of a few percent, these findings are quite remarkable."

Autism mutations disrupt multiple cell types in brain

Behavioral variability in autism patients may also stem from the types of brain cells affected, and the Columbia researchers have taken the first steps in determining which cell types in the brain are most affected by autism mutations.

The team identified these cells by looking at the normal activity of autism-related genes in dozens of similar cell types in mouse brains. The analysis showed that many different types of neurons throughout the brain are affected by mutations in autism genes.

"The idea that eventually all autism would converge onto a single type of neuron or single brain area isn't what we see in the data," Dr. Vitkup said. "Instead, an autism mutation usually affects multiple brain areas simultaneously."

Certain neurons, however, appear to be more affected than others. The Columbia researchers found strong effects in cortical and striatal neurons that form a circuit that controls repetitive motions and behaviors, such as rocking, an insistence on sameness, and restricted interests, which are common in people with ASD.

"There are many hypotheses about the types of neurons and circuits involved in autism, but by using unbiased genome-wide approaches, like the one used in this study, one can understand which neurons are the most important and explain the core features we see in people with ASD," said Dr. Vitkup.

Identifying the circuits involved is the next step in understanding autism, he said. "Huge progress has been made in the last five years: We and our colleagues have now identified multiple affected genes, and we are coming to a consensus about how the genes work together in biological networks. Now, based on the affected genes, we are identifying affected and brains circuits and trying to connect them to disease outcomes in individual patients."


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More information: Genotype to phenotype relationships in autism spectrum disorders, Nature Neuroscience, http://nature.com/articles/DOI: 10.1038/nn.3907
Journal information: Nature Neuroscience

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JVK
Dec 22, 2014
See also: "...a comparative analysis of bacterial growth and gene deletion phenotypes using hundreds of genome-scale metabolic models." http://dx.doi.org...ure13827

The model that links metabolic networks to genetic networks in microbes has now been extended to human brain development by the same group.

In this report we see:
Excerpt 1) "...more damaging genetic mutations usually lead to worse disease outcomes."
Excerpt 2) "The idea that eventually all autism mutations would converge onto a single type of neuron or single brain area isn't what we see in the data," Dr. Vitkup said. "Instead, an autism mutation usually affects multiple brain areas simultaneously."

The theory that beneficial mutations link Lenski's E. coli to human brain evolution seems even more ridiculous. A model of nutrient-dependent pheromone-controlled amino acid substitutions that differentiate all cell types of all individuals of all species could become more popular.

JVK
Dec 23, 2014
Some of my published works:

http://www.ncbi.n...ohl%20JV[Author]&cauthor=true&cauthor_uid=24693353

All of them link nutrient-dependent pheromone-controlled RNA-mediated cell type differentiation in species from microbes to man via conserved molecular mechanisms.

Dec 23, 2014
Aside from the somewhat patronising view that autism is purely a series of 'genetic mutations' as opposed to the more accurate view that is a completely different brain type - it is very disappointing that this article reproduces poorly-researched views about autistic women.

The sentence: "Though ASD is far more common in males, females with ASD are more likely to fall on the severe end of the spectrum" completely overlooks the emerging view that autistic women (this commenter included) are under-diagnosed as we generally have better communication skills than autistic men.

As clinicians diagnosing autism are trained to look for the 'male' traits associated with communication difficulties, women have to be 'very' autistic to be diagnosed as those who have very specific autistic traits yet can communicate more fluently do not 'fit' the stereotype of the 'male' autistic.

Let's hope future articles by this writer avoid such sweeping gender generalisations.

Dec 23, 2014
Some of my published works:

http://www.ncbi.n...ohl%20JV[Author]&cauthor=true&cauthor_uid=24693353

All of them link nutrient-dependent pheromone-controlled RNA-mediated cell type differentiation in species from microbes to man via conserved molecular mechanisms.



Jvk is a self proclaimed creationist that ignores and/or derides the sciences of geology, paleontology and the work of thousands of evolutionary biologist His Twitter account consist 25 creationist followers. His claim that mammals reproduction strategies is solely based on pheromones is laughably ignorant, though not surprising considering his pseudoscience based "perfume" business.

JVK
Dec 23, 2014
I am a medical laboratory scientist with 40 years experience as a generalist.

Exosomes: https://www.youtu...krsErbwI

See also: Secreting and Sensing the Same Molecule Allows Cells to Achieve Versatile Social Behaviors http://www.scienc...abstract with my comment at http://comments.s....1242782

What's been missing from most research is the understanding of RNA-mediated feedback loops that link experience-dependent de novo creation of odor receptors from ecological variation and nutrient-uptake to the metabolism of nutrients and species-specific pheromones that control the physiology of reproduction. The feedback loops link metabolic networks to genetic networks via RNA-directed DNA methylation and RNA-mediated amino acid substitutions that differentiate all cell types of all individuals of all species.

JVK
Dec 23, 2014
33 blog posts place what is currently known about autism and ASDs into the context of RNA-mediated amino acid substitutions and cell type differentiation. The focus on genes has led nowhere. The focus must change to what is known about how metabolic and genetic networks are linked via conserved molecular mechanisms in species from microbes to man.

http://perfumingt...bmit.y=0

Homology versus Convergence in Resolving Transphyletic Correspondences of Brain Organization http://www.karger...00356102

Genealogical Correspondence of Mushroom Bodies across Invertebrate Phyla
http://www.scienc...1401358X

Long-term phenotypic evolution of bacteria
http://dx.doi.org...ure13827

Genotype to phenotype relationships in autism spectrum disorders
http://dx.doi.org.../nn.3907

Dec 23, 2014
@khol

Except for referencing yourself you provided no support for your model. You must think readers at Phys.org don't bother reading the links you provide.

Dec 29, 2014
jvk, have any of your published works ever been peer reviewed?

JVK
Dec 29, 2014
Of course they have. Thanks for asking. For examples, see:

Human pheromones: integrating neuroendocrinology and ethology
JV Kohl, M Atzmueller, B Fink… - Neuroendocrinology …, 2001 - cogprints.org
The effect of sensory input on hormones is essential to any explanation of mammalian
behavior, including aspects of physical attraction. The chemical signals we send have direct
and developmental effects on hormone levels in other people. Since we don't know either ...
Cited by 80

From fertilization to adult sexual behavior
M Diamond, T Binstock, JV Kohl - Hormones and Behavior, 1996 - Elsevier
Research has established the broad mammalian developmental plan that genes on the sex
chromosomes influence gonad development which determines gonadal hormone
production (or its absence) leading to modification of the genitalia and simultaneously ...
Cited by 31

find others at http://scholar.google.com "James V. Kohl"

Dec 29, 2014
jvk, can you point me to one of your published works where I can read the peer review(s)?

Jan 01, 2015
jvk, why don't you want me to read your peer reviews?

JVK
Jan 01, 2015
Peer reviews are not typically included in published works. Your question indicates you are a science idiot. Thanks for asking.

Jan 02, 2015
So there is no evidence that you can show me that anything you have written has been peer reviewed?

Jan 06, 2015
Come on jvk at least you could help me out and give me something that actually proves you were peer reviewed. I am sincerely interested in what the peer reviews said or did they all discredit you? Is that why you will not show them to me?

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