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I was reading the Wikipedia articles about genome-wide association studies (GWAS) and whole exome sequencing.

As I understand, GWAS is used to identify most common SNPs that are proved to be associated with a disease/disorder. On the other hand there is an article about whole exome sequencing method where it said that it is more sensitive to identify Mendelian mutations in contrast with the SNP genotyping methods used in GWAS.

As the graph shows below, there is a distinction between Mendelian mutations and common mutations. What exactly does Mendelian mutation mean (why do we call it Mendelian)? What makes a Mendelian mutation so rare but effective in contrast with common mutations? Aren't common mutations inherited with the same rules as Mendelian ones?

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I will focus more on the question of rarity, which the comments have not addressed. Recall that natural selection is operating on the human population. Because of this, bad mutations of large effect (disease mutations such as CFTR in your figure) are very rare, because selection is removing them at some rate from the population (people with cystic fibrosis are unfortunately very sick and are not as fertile as healthy people), whereas mutations with very little effect are not subject to much selection. Paper one and paper two are reviews describing the population genetics in more detail.

As suggested by commenters, Mendelian mutations are so named because they are single loci of large effect controlling traits (approximately). Common variants, by this logic, must have very little phenotypic effect, because they are not purged by natural selection (assuming that they are deleterious, or disease-causing).

Rule of thumb: 'Mendelian' alleles can easily be used to predict phenotypes (like disease) and are acted upon by natural selection. 'Common' alleles are individually not informative about phenotype and are thus mostly ignored by natural selection. Not exactly true, but close.

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In reality, Mendelian variants are very rare compared to non-Mendelian variants. Why would evolution evolve dominance or recessiveness? If you didn't learn about this in grade school, it would likely come off as a very weird and specific thing to evolve. More likely, there is an optimal value for whatever phenotype you are going for (enzymatic efficiency, height, disease, etc.), and it wouldn't make sense to want 25% of the population to have the trait completely turned off and the other 75% to have the trait completely turned on.

Mendelian alleles only account for a fraction of the variance in most diseases, because they are so rare, whereas common alleles, taken together, explain the bulk of the genetic variation in most diseases. However, when there is a Mendelian variant, its effect is so large that it is obvious. This makes them easy to study.

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  • $\begingroup$ I'd like to see some sources for your answer, specifically your claim that Mendelian variants are very rare. $\endgroup$
    – bob1
    Commented Feb 11 at 20:46
  • $\begingroup$ @bob1 There are certainly much fewer than 100,000 Mendelian variants. Even if we say there are only 10 million SNPs (some sources say 600 million), Mendelian variants are 100x rarer. $\endgroup$
    – BigMistake
    Commented Feb 11 at 21:54
  • $\begingroup$ "Why would evolution evolve dominance or recessiveness?" - recessiveness basically evolves from regulation that is useful whether or not a defective copy of a gene is present. Typically recessive alleles are recessive because they cause a defect in function and because the transcription/translation of the other copy happens to a level that doesn't depend strongly on the number of copies. Dominance similarly doesn't evolve directly, it's just a consequence of a gene product having an effect. $\endgroup$
    – Bryan Krause ♦
    Commented Feb 11 at 22:52
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    $\begingroup$ I think that "Mendelian" is being used by the OP due to confusion, not because they are interested in the population dynamics of dominance. I think that what you are talking about may be true in the context of the genetic architecture of traits and we have to some extent discussed that here. But they seem to be more interested in the dynamics that lead to the plot that they show, which is basically the result of selection. $\endgroup$
    – Maximilian Press
    Commented Feb 11 at 23:41
  • $\begingroup$ @MaximilianPress Yes, absolutely. I meant this more like a footnote to your answer $\endgroup$
    – BigMistake
    Commented Feb 12 at 0:03

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