Do Rare Mutations Play Important Roles in Common Conditions Like Autism?

The common disease, common variant hypothesis (CD/CV) stated that a few common allelic variants could account for the genetic variance in disease susceptibility, whereas the rare variant (CD/RV) hypothesis stated that DNA sequence variation at any gene causing disease could encompass a wide range of possibilities, with the most extreme being that each mutation is only found once in the population (Iyengar & Elston, 2007).

Many hoped that the Human Genome Project would pinpoint risk genes for common human diseases, urged on by earlier successes identifying causal genes associated with specific monogenic (single-gene) disorders. Unfortunately, the Human Genome and HapMap Projects results showed us that genetics is not so simple. We have indeed found numerous examples of rare mutations that are highly penetrant for a single, usually rare disorder. However, we’ve also identified many mutations, some rare and some less so, that are linked with conditions such as autism, intellectual disability, and the like; however, because we’ve identified so many risk genes it’s a challenge to understand how they all may play roles in these conditions. Thus there has been an ongoing debate over whether, for example, autism is a hodge podge of rare monogenic disorders with overlapping behaviors (which is certainly the case for at least a sizable minority of the autism spectrum) or genetic risk for autism is significantly affected by common mutation variants, the so-called Common Disease/Common Variant Hypothesis.

The neuroscientist and science writer, Kevin Mitchell, for instance, is a proponent for the Common Disease/Rare Variant in autism:

Examples of single mutations causing disorders such as autism, schizophrenia, diabetes, epilepsy and many other common diseases have long been known. While these could be identified in only a small proportion of cases, they could, however, be disregarded as exceptions to the generality of the disease: they did not cause ‘real schizophrenia’ or ‘real autism’. But what if there is no such thing? What if all cases are due to some rare mutation? (Mitchell, 2012, p. 237).

Single nucleotide polymorphisms (SNP) are point mutations that can vary from person to person and are an excellent way to study the genetics of a given condition. For one, because they don’t typically affect large regions of DNA, like segmental rearrangements (e.g., copy number variations), their effects are often targeted to the function of a single gene instead of multiple genes. This allows us to draw more inferences as to the involvement of that gene in the phenotype we’re studying. In addition, we can also study the frequency of certain SNPs and determine whether a given allele is significantly related to our condition of interest. Unfortunately, if the SNP variations we’re studying are not extremely rare, it can sometimes be a challenge to study enough people to make sure that any effects we’re seeing are truly real.

In minor support of Kevin Mitchell’s stance on rare variants in autism and other neurodevelopmental conditions, a study by Gorlov et al. (2011) reported that while individual rare variants (whose frequency is defined as less than 5%) are indeed rare, as a whole they actually make up a small majority of total human SNPs.

In this study, we analyzed the relevance of rare SNPs to the risk of common diseases from an evolutionary perspective and found that rare SNPs are more likely than common SNPs to be functional and tend to have a stronger effect size than do common SNPs (p. 199).

Thus, at face value, these results lend potential credence to the Common Disease/Rare Variant hypothesis.

Usually, each SNP location has a major allele, which is the most prominent allele in the overall population (which can of course vary by race), and at least one minor allele, the less common of the variants. Minor Allele Frequency (MAF) is a number that represents the frequency of the minor allele in the population (e.g., 0.45 = 45%). According to the NCBI Variation Viewer, the average MAF for all available SNPs is 2%, reiterating exactly what Gorlov et al. reported.

In autism, there have also been reports of increased rates of rare (< 1%) copy number variants (CNV) linked with the condition [1]. Of course, CNVs are in and of themselves rarer than SNPs due to their potential for deleterious effects and therefore when one speaks of “rarity” with CNVs one is typically referring to the fact that a given CNV isn’t seen at all in the control population. However, once again, the idea of “rare variants” is rearing its head in the debate of autism etiology.

A huge number of genes have been linked with autism-risk, though there are considerable variations in the level of penetrance of a given gene (i.e., how frequently autism results due to its mutation). For instance, almost all individuals with a MAGEL2 mutation who develop Prader-Willi-like Syndrome develop symptoms of autism; meanwhile, only about 20% of individuals with Muscular Dystrophy-Dystroglycanopathy due to POMGNT1 mutations develop autism or autistic-like symptoms. These are examples of highly penetrant autism-related mutations and there are many many more gene mutations with even lower yet significant associations.

Will we find in future that autism is a hodge podge of rare mutations like Kevin Mitchell contends? Or will we find that, like most things in life, it’s complicated and is a combination of rare and common mutations both? Though I’m personally FASCINATED by the Gorlov et al. study and their findings, I still lean towards the latter. But time will tell.

3 responses to “Do Rare Mutations Play Important Roles in Common Conditions Like Autism?

    • The term “polymorphism” is usually used for a variant that occurs in 1+% of the population. I suppose that percentage is somewhat arbitrary, just as the 5% was probably more of a posthoc distinction in the Gorlov et al. article once they saw a large cluster of SNPs occurring in <5% of the population.

  1. I have a now old book by Lewontin -Lewontin, R. C. (1974). The genetic basis of evolutionary change. New York: Columbia University Press – where he argued that allelic variance was essentially the norm in non functional areas of the coding gene as there was little or less selective pressure to maintain an exact code. Thus evolution is eased in progression as there is innate population diversity.

    I carry the idea forward with me as so relevant in these days of “The Human Genome Sequence = the impression we’re all built to exactly the same tiny detail”

    We’re not.

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