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 .

autism