Grade school prodigy but downhill from there? Blame your methyltransferase variant.

A recent report out of Scotland points to epigenetic regulation of the IGF2 gene in the womb as relating to child intelligence, but not adult intelligence.

Haggarty P, Hoad G, Harris SE, Starr JM, Fox HC, et al. 2010.  Human Intelligence and Polymorphisms in the DNA Methyltransferase Genes Involved in Epigenetic Marking. PLoS ONE 5, e11329. doi:10.1371/journal.pone.0011329.

Now, we know quite a few people who showed tremendous promise in  5th grade, but, through lifestyle decisions,  ended up in a halfway house.  So it looks like epigenetics do soften the blow of genetic karma, but it can only work for so long.

Let’s review: Unless you are the product of virgin birth, you contain two sets of chromosomes, one set each from the male and female biological parent. So, much like people in Hawaii buy two used cars, driving one and keeping a beater of the same model up on blocks in the driveway for hard-to-get parts, there are duplicate genes, but frequently only one allele is actually ever transcribed.   For instance, you only express your biological father’s insulin growth factor 2 (IGF2), a protein upregulating growth hormone in utero, and having a lot to do with fetal development. When you get old, you may begin to express both your mother’s and your father’s allelic variants, and that could lead to cancer. Issa et al. 1996. Switch from monoallelic to biallelic human IGF2 promoter methylation during aging and carcinogenesis. PNAS-USA 93, 11757-11762. (There are also lots of reports about IGF2 partial or improper imprinting in utero causing tragic congenital problems.)

Genetic imprinting, or silencing of one allele, however, isn’t as binary, on-off, 0 or 1, as all that, and recent work points to the vagaries of epigenetics.  It is sort of like wearing a kilt – one is not totally unclothed, but not totally clothed, either.  And so IGF2 imprinting is sort of wearing a kilt, in being regulated with at least one particular  methyltransferase (DNMT1, Weaver JR, Sarkisian G, Krapp C, Mager J, Mann MR, Bartolomei MS. 2010. Domain-specific response of imprinted genes to reduced DNMT1. Mol Cell Biol. Jun 14.).

And so, it is now reported that a little extra IGF2 in utero, determines whether you will work as a burger flipper or get a Nobel prize for smarts. OK, not that dramatic, but still, a particular epigenetic configuration for IGF2 expression in the womb resulted in doing decidedly better on a grade school intelligence test.

The study began in 1936, when knowledge of genetics was sketchy, and the prevailing eugenic theories were in a downward spiral toward evil.

In Scotland, 1936 was a year most school children took an intelligence test.  Some 74+ years later, with a genetic toolkit in hand and eleemosynary intent, Scottish researchers checked the epigenetic markers for  the children who were then 11 from Aberdeen and Lothian ( now 70+ years old, about 1500+ people in total). They found a gene associated with childhood intelligence, or at least how well the children did on the test. This was a methyltransferase genetic variant , the DNMT3L 11330C>T variant .  Some of the people were kind enough to re-take an intelligence test, apparently, but the gene wasn’t strongly associated with adult intelligence.  (Haggerty et al 2010) .

Haggarty et al also report that this particular variant  hypomethylates (under methylates) IGF2 regulatory regions ( manuscript in press.) Possibly this results in extra IGF2 during a particularly important fetal developmental period (a guess) and so some extra brain cells packed in. That would get you through the grade school intelligence exams. Presumably, if both alleles stayed stuck in the “on” position there would be perhaps a lethal mutation in utero, due to cell growth (this is presumed from the many in utero studies reported).

So, the key is to have methyltransferases that are kilt-like, able to open at appropriate times, to give a perhaps unfortunate Scottish visual.

But, of course, lots of lifestyle decisions can mess with epigenetics, as possibly Mr. Osbourne’s DNA analysis may reveal.