Debunking myths on genetics and DNA

Saturday, May 17, 2014

Viruses and bacteria could be the missing piece in the missing heritability puzzle

I've discussed the issue of the missing heritability before: in layman words, same mutations shared across people don't lead to the same phenotype. This is particularly true for diseases. Many whole genome studies have looked at possible associations between DNA mutations and diseases, but, alas, the mutations that have been found generally explain only 10% of the cases. This suggests that there's a lot more to who and what we are than genes alone, and that complex interactions between DNA, RNA and proteins come to play. If you've been following the blog for a while you know that I love to talk about epigenetics (so much so that \begin{plug} I wrote a detective thriller based on epigenetics \end{plug}): I do believe a good portion of the missing heritability puzzle relies on epigenetics, which studies the mechanisms that turn our genes "on" and "off". These mechanisms are not coded in our genes, yet they can be carried on for 2-4 generations.

There are other factors, besides epigenetics and complicated genetic interactions, that could explain the missing heritability. Bacteria and viruses for example could be playing a fundamental role. In a recent post I discussed a study that points at the gut bacteria as responsible for the inheritance of a propensity towards an obese phenotype rather than a lean one. Another example is Crohn Disease: there are some specific mutations that make an individual prone to the disease, yet not everyone with those mutations manifest the symptoms. A 2010 study [1] on a mouse model found that in the presence of the mutation, the disease manifested only after infection with a particular strain of MNV (murine norovirus), the mouse variant of norovirus, a family of viruses that cause viral gastroenteritis. So, rather than the mutation alone, it's an interaction between genetic predisposition and viral infection that seems to cause Crohn Disease.

In a recent study published in PNAS [2], Edwards et al. proposed an yeast model to study the interaction between chromosomal mutations and non-chromosomal elements. In the yeast case, the non-chromosomal elements were:
"... the presence or absence of the yeast killer dsRNA virus and the other was varying mitochondria among two backgrounds with distinct differences in their genome sequence. The two mitochondrial genomes we selected show considerable variation, with about two to three SNPs per kilobase between them and 10 times as many insertions and deletions per kilobase between them as found in the chromosomal genome [2]."
The researchers induced chromosomal changes in different strains of yeast expecting their phenotype to change accordingly: they examined 17 single gene deletions that induced growth defects, expecting to observe much smaller populations. It turns out that this didn't work as a "switch". In other words, the belief "you turn on the green eye gene, you get green eyes" (which, sadly, is a very common misconception that people have about genes) is a myth. Yeast bacteria don't have green eyes, of course, but the researchers saw that despite changing certain genes, they were still getting a broad spectrum of growth phenotypes. Despite having the induced mutations, whether the yeast colonies did or didn't grow depended on the presence or absence of the dsRNA virus and the variation in mitochondrial genes. With their experiment, Edwards et al. showed that
"the heritability of a trait can depend on nonlinear interactions between chromosomal and nonchromosomal information that is transmitted from generation to generation. The nonchromosomal information can interact with the various chromosomal alleles at a locus to modify phenotype significantly. [...] Our results show that the nonchromosomal contribution to heritability can be large and, in some cases, can completely mask the effect of a chromosomal mutation [2]."

[1] Cadwell K, Patel KK, Maloney NS, Liu TC, Ng AC, Storer CE, Head RD, Xavier R, Stappenbeck TS, & Virgin HW (2010). Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine. Cell, 141 (7), 1135-45 PMID: 20602997

[2] Edwards, M., Symbor-Nagrabska, A., Dollard, L., Gifford, D., & Fink, G. (2014). Interactions between chromosomal and nonchromosomal elements reveal missing heritability Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1407126111

No comments:

Post a Comment

Comments are moderated. Comments with spam links will be deleted and never published. So, if your intention is to leave a comment just to post a bogus link, please spare your time and mine. To all others: thank you for leaving a comment, I will respond as soon as possible.