Mendelian puzzles

A Mendelian disorder is a disease caused by a single-gene mutation that's usually inherited according to Mendel's laws. Despite being for the most part quite debilitating, they persist in the population, though at a very low prevalence. This is due in part to the effect called heterozygote advantage. Recessive mutations bear no symptoms and are carried on from one generation to the next until an individual with both mutated alleles is born.

A Perspective in the latest issue of Science [1] gives a good review of Mendelian disorders and the puzzles yet to unravel around them. The mystery is two-fold: first, given a disorder, not all subjects carry the specific mutation; second, given the specific mutation, not all subjects are affected in the same way, and in fact, some aren't affected at all.

The first puzzle (an affected person who doesn't carry the mutation) can easily be attributed to the fact that the specific disease could indeed have many causes. Just because it has been found to be monogenic (caused by one gene), it doesn't mean that it has one cause only. Environmental factors could be playing a role too, for example, as well as additional interactions between genes. Different environmental exposures could also explain the other side of the puzzle, i.e. why carriers of the same mutations can be affected in such different ways, from no symptoms at all to severe conditions. Ultimately, things like gene-to-gene interactions and variation in an individual's regulatory sequences could explain both puzzles.

DNA transcription is controlled by proteins called transcription factors. These proteins bind to the region "upstream" from the gene, and this is the non-coding region called "regulatory sequence" because it affects whether the gene is silenced or expressed.

"For an autosomal dominant disorder in which individuals harbor one normal (wild-type) and one mutant gene copy (allele), additional variants at a physically close silencer or enhancer can modulate the wild-type versus mutant transcripts so as to yield more or less mutant transcript and protein, thus leading to more severe or less severe disease. The specific outcomes depend on the function of the regulatory sequence and whether the regulatory variant is physically linked to the wild-type or the mutant allele.

In the Science review, Chakravarti and Kapoor hypothesize that mutations in the regulatory sequences are far more common than mutations in the adjacent structural gene that code for the affected transcript or protein, and it is the combination of the two that could explain the wide range of disease penetrance we observe. Furthermore, while disease mutations are kept at a low prevalence by strong selection, selection is much weaker on regulatory sequences. As a consequence, mutations that arise in these regions have a higher chance to become common in the population.

"The combination of rare coding mutations with common regulatory variants can lead to complex patterns of inheritance and thus provide a singular mechanistic explanation of Mendelian families that do not carry a mutation in the coding gene associated with the disease, as well as variable disease penetrance in individuals that carry the Mendelian gene mutation."

Photo: waves in La Jolla, CA.

[1] Chakravarti, A., & Kapoor, A. (2012). Mendelian Puzzles Science, 335 (6071), 930-931 DOI: 10.1126/science.1219301