Autism, De Novo Genetic Mutation and Environmental Mutagens

The genetic bases of autism dominated autism news the previous week with the publication of the Chromosome 16p11.2 study in the New England Journal of Medicine and three CNTNAP2 gene study reports, Alarcón et al., Arking et al.,and Bakkaloglu et al., in the American Journal of Human Genetics respectively. Various ideological, literary, anthropological and cultural perspectives on autism make for interesting chat, and occasionally heated debate, but add little to our real understanding of autism. It is very encouraging to see our science based understanding of autism growing in such dramatic fashion.

As a lay person heavily dependent upon credible interpretations of the science though I was struck by the references to genetic mutations and de novo genetic mutations. I tried to Google my way to a basic understanding of some of these concepts and some of the references that I found helpful follow:

The Genetics Home Reference web page provides some basic helpful information that indicates that environmental factors can play a role in some genetic mutations:

Gene mutations occur in two ways: they can be inherited from a parent or acquired during a person’s lifetime. Mutations that are passed from parent to child are called hereditary mutations or germline mutations (because they are present in the egg and sperm cells, which are also called germ cells). This type of mutation is present throughout a person’s life in virtually every cell in the body.

Mutations that occur only in an egg or sperm cell, or those that occur just after fertilization, are called new (de novo) mutations. De novo mutations may explain genetic disorders in which an affected child has a mutation in every cell, but has no family history of the disorder.

Acquired (or somatic) mutations occur in the DNA of individual cells at some time during a person’s life. These changes can be caused by environmental factors such as ultraviolet radiation from the sun, or can occur if a mistake is made as DNA copies itself during cell division. Acquired mutations in somatic cells (cells other than sperm and egg cells) cannot be passed on to the next generation.

At Learn. Genetics page of the Genetic Science Learning Center of the University of Utah an explanation is provided for how mutations occur:

There are two ways in which DNA can become mutated:

1. Mutations can be inherited. This means that if a parent has a mutation in his or her DNA, then the mutation is passed on to his or her children.
2. Mutations can be acquired. This happens when environmental agents damage DNA, or when mistakes occur when a cell copies its DNA prior to cell division.

The Learn. Genetics site indicates that environmental agents that can damage DNA include ultra violet radiation and certain chemicals. On the What Causes DNA Mutations page of the site the Center provides diagrams and further explanation of both the environmentally caused mutation process and the cell copying mistake process.

1. DNA damage from environmental agents

Modifying nucleotide bases

Ultraviolet light, nuclear radiation, and certain chemicals can damage DNA by altering nucleotide bases so that they look like other nucleotide bases.

When the DNA strands are separated and copied, the altered base will pair with an incorrect base and cause a mutation. In the example below a "modified" G now pairs with T, instead of forming a normal pair with C.

Breaking the phosphate backbone

Environmental agents such as nuclear radiation can damage DNA by breaking the bonds between oxygens (O) and phosphate groups (P).

Breaking the phosphate backbone of DNA within a gene creates a mutated form of the gene. It is possible that the mutated gene will produce a protein that functions differently.

Cells with broken DNA will attempt to fix the broken ends by joining these free ends to other pieces of DNA within the cell. This creates a type of mutation called "translocation." If a translocation breakpoint occurs within or near a gene, that gene's function may be affected.

In Mutation, Mutagens, and DNA Repair Beth A. Montelone, Ph. D., Division of Biology, Kansas State University, defined mutagen as "a natural or human-made agent (physical or chemical) which can alter the structure or sequence of DNA." In addition to radiation Dr. Montelone describes four categories of chemical mutagens and provides examples of some of the better known chemical mutagens in each category:

1. Base analogs

These chemicals structurally resemble purines and pyrimidines and may be incorporated into DNA in place of the normal bases during DNA replication:

• bromouracil (BU)--artificially created compound extensively used in research. Resembles thymine (has Br atom instead of methyl group) and will be incorporated into DNA and pair with A like thymine. It has a higher likelihood for tautomerization to the enol form (BU*)

• aminopurine --adenine analog which can pair with T or (less well) with C; causes A:T to G:C or G:C to A:T transitions. Base analogs cause transitions, as do spontaneous tautomerization events.

2. Chemicals which alter structure and pairing properties of bases

There are many such mutagens; some well-known examples are:

• nitrous acid--formed by digestion of nitrites (preservatives) in foods. It causes C to U, meC to T, and A to hypoxanthine deaminations. [See above for the consequences of the first two events; hypoxanthine in DNA pairs with C and causes transitions. Deamination by nitrous acid, like spontaneous deamination, causes transitions.
• nitrosoguanidine, methyl methanesulfonate, ethyl methanesulfonate--chemical mutagens that react with bases and add methyl or ethyl groups. Depending on the affected atom, the alkylated base may then degrade to yield a baseless site, which is mutagenic and recombinogenic, or mispair to result in mutations upon DNA replication.

3. Intercalating agents

acridine orange, proflavin, ethidium bromide (used in labs as dyes and mutagens)

All are flat, multiple ring molecules which interact with bases of DNA and insert between them. This insertion causes a "stretching" of the DNA duplex and the DNA polymerase is "fooled" into inserting an extra base opposite an intercalated molecule. The result is that intercalating agents cause frameshifts.

4. Agents altering DNA structure

We are using this as a "catch-all" category which includes a variety of different kinds of agents. These may be:

• --large molecules which bind to bases in DNA and cause them to be noncoding--we refer to these as "bulky" lesions (eg. NAAAF)
• --agents causing intra- and inter-strand crosslinks (eg. psoralens--found in some vegetables and used in treatments of some skin conditions)
• --chemicals causing DNA strand breaks (eg. peroxides)

What these agents have in common is that they probably cause mutations not directly but by induction of mutagenic repair processes .

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"House Autistic" Or More Neurodiversity Trash Talk

One of the unspoken truths about the neurodiversity "movement" is the extent to which ND adherents engage in Trash Talk in the form of offensive terminology like "curebie" "idiot" and even "retard" when referring to people whose views challenge their ND ideology.

Yesterday I posted about an autistic blogger named Jonathan Mitchell who wrote an article on his site urging other autistic persons and persons with an interest in autism to reject ND ideology to Just Say No to neurodiversity. I received a heated, and somewhat confused, response from someone who identified himself as "Robert Montgomery" although he provided no email address, link or url to confirm that name and I learned for the first time that autistic persons who disagree with the ND ideology are dismissed by neurodiversity adherents as "house autistics". They are also, apparently, dismissed as being liars about their past.

This particular "Robert Montgomery" seemed very upset that I had posted a comment about an autistic individual, Jonathan Mitchell, who dared reject the neurodiversity ideology. In fact he was so upset he posted his comment in response to the wrong article, posting incorrectly under my CNTNAP2 Gene And The Unravelling Of Autism Spectrum Disorders article. This alleged Robert Montgomery accuses Mr Mitchell of being a "house" autistic and declares that "sadly, like most house autistics, they lie about their past."

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Robert Montgomery said...

There's one serious flaw to Jonathan's argument. Not many special education opportunities were available in the 1960's. I think Jonathan needs to change his story. The majority of students with recognized disabilities, and I would presume feces smearing would have been considered a disability even in the 1960's, were in segregated institutions. The IDEA wasn't passed into law until Jonathan would have been 22 years of age. Nice try though Jonathan.

This is from the Georgetown University Press:

As the United States entered the 1960s, American public schools faced challenges in several areas. Discussions regarding social and economic inequality led to intense national soul-searching, with the sweeping implications of the Supreme Court’s 1954 Brown vs. Board of Education of Topeka decision affecting developments in law, politics, social policy, and certainly education. The federal government under President John F. Kennedy determined that much greater involvement on its part was necessary to stimulate action and ensure the enforcement of law, the protection of civil rights for all Americans, and the fulfillment of the promise of public schooling. Among educational professionals, questions about the rigor and direction of curriculum and instruction dominated educational discourse after the launch of the Sputnik satellite by the Soviet Union in 1957, leading to reform efforts in the teaching of most subject areas, science and mathematics. As deliberations about the appropriate purposes, character, and methodology of education intensified, special education found itself linked, directly and indirectly, to changes in the teaching of content and subject matter, the organization and structuring of schools, and the classification and categorization of students.

From 1960 through 1968, special education would continue its dramatic evolution, encountering significant challenges to its assumptions, structures, and operations. It maintained its remarkable expansion in terms of its number of programs offered and students served, even while special educators constantly maintained that an unacceptably low percentage of students who needed special education services were actually receiving them. The introduction and solidification of learning disabilities as a recognized category of disability rearranged and expanded the identified population of children with disabilities; the linking of disability with poverty, cultural deprivation, and minority status substantially altered views on the etiology and diagnosis of disability, especially in the area of mental retardation, shifting the ways in which discussions of special education services and purposes were framed. The number of people with disabilities housed in residential institutions kept increasing, leading to severely overcrowded conditions and serious charges that care and treatment of the residents all too frequently was cruel and inhumane. Such developments took place in the context of rapidly expanding federal involvement as well as heated debate about the propriety of segregated schools and settings, including those for students with disabilities.

Harold, really, a cursory knowledge of the disability movement in the US would have tipped you off that this man could have never spent 8 years in special education.

But like John Best, your not really interested in facts and I my guess would be that this comment too will never be posted on your website. That's ok, because I'm taking screen shots of them to show the world that your a dishonest person not interested in truth.

I'm sure you think your clever because you found a "house" autistic who supports your hatred of autism and autistic people who disagree with you. But sadly, like most house autistics, they lie about their past.

7:33 PM

I personally don't know what Mr. Mitchell meant by his reference to Special Education or whether, as Mr. Montgomery contends. no such "Special Education" could have existed at the time Mr. Mitchell would have attended school but I assume that Mr. Mitchell is telling the truth about a non-controversial matter of that nature. Obviously Mr. Montgomery, at least in whatever state of mind he was in at the time he posted the above note, is very quick to jump to conclusions about other peoples' honesty and character.

I have long known of, and been on the receiving end of, the heated nature of many internet autism debates. Mr. Montgomery's post though seems beyond the pale even by those standards. Hopefully his views of Mr. Mitchell and any other autistic person who presume to disagree with Neurodiversity doctrine are not shared by other Neurodiversity adherents.

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CNTNAP2 Gene And The Unravelling Of Autism Spectrum Disorders

If anyone doubted that we are living in the era of the Autism Knowledge Revolution they should doubt no longer. The January 10 2008 edition of the American Journal of Human Genetics includes reports of three studies which separately validate the March 2006 study led by Dr. Dietrich A. Stephan, that identified a gene called CNTNAP2 which, when mutated, suggested a predisposition to autism. In Unravelling Autism Dr. Stephan comments on the three studies and states:

In this issue of AJHG, Alarcón et al.,¹ Arking et al.,² and Bakkaloglu et al.³ identify a series of functional variants in the CNTNAP2 gene that unequivocally implicate this gene as causing Type 1 autism in the general population. ...... The modern technologies and strategies derived from the Human Genome Project, coupled with the elegant sample banking, phenotyping, and data dissemination resources of groups like AGRE, are resulting, finally, in the unraveling of Autism Spectrum Disorder.

Dr. Stephan offers characteristics of Type 1 autism which many parents will recognize in their autistic children:

The three studies herein^{1, 2, 3} have moderate sample overlap and use different strategies to narrow the phenotype of the ASD cohorts to relative homogeneity before performing genotyping/resequencing across the CNTNAP2 gene locus. Nevertheless, the three studies together identify a set of common and rare variants that provide unequivocal evidence that the CNTNAP2 gene, when disrupted, leads to a subtype of ASD. This genetic subtype can be clinically characterized by ADOS/ADI-R-defined autism with language deficits and potential gender bias and parent-of-origin effects. Type 1 autism may also be associated with seizures.

The gender bias referred to by Dr. Stephan is the male gender bias associated with autism which sees from 3 to 1 to 4 to 1 male to female ratios amongst persons with autism. On the practical side Dr. Stephan indicates that the CNTNAP2 information might be of assistance in early detection and intervention in the 12 to 24 month period.

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