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Monday, April 12, 2010

BDNF gene confirmed crucial in stress-caused brain damage

I have mentioned before that environmental stress such as
pollution, parental violence, mother-child separation, etc. are in fact behind most mental disorders, from low intelligence to schizophrenia and even Alzheimer syndrome.

While the effect is environmental and hence not really genetic but epigenetic, there is a gene that seems specially associated, known as BDNF (in particular polymorphism Rs6265).

It was already known that:

When normal mice are exposed to chronic stress (simulated by confinement in a wire mesh restraint), there is a significant retraction in the projections, or dendrites, of some of the neurons in the hippocampus, which shrinks in overall volume as well.

Left: healthy neuron, right: stress-damaged one

Now researches from New York have found that genetically altered mice with only one copy of the gene were stress-resistant and had brains apparently healthy even after prolonged stress.

However the research only seems to confirm the crucial role of this gene in stress damage in brain but does not explain why the mice with only one copy of BDNF managed to overcome neuronal stress damage.

Source: Science Daily, SNPedia

Ref. A. Magariños et al., Effect of brain-derived neurotrophic factor haploinsufficiency on stress-induced remodeling of hippocampal neurons. Hippocampus 2010. Pay per view.

Some thoughts on allele distribution:

The best researched SNP in humans within this gene seems to be the already mentioned rs6265, whose likely ancestral variant GG is very dominant among people of recent African ancestry but less so among Eurasians.

Eurasians have greater frequencies of the AA allele (not detected in Africans) and the heterozygous AG allele (only at very low frequencies in Africa), which would seem to have been affected by a marked selective sweep early on in human/hominin history. The AA allele seems to be quite negative for motor learning and favors introversion, however it also seems to provide resistence to depression and to some neurodegenerative diseases such as Parkinson syndrome. This variant is most concentrated in East Asia.

However all Eurasians have some of it and much more commonly the heterozygous AG allele, which has similar influences but not the depression resistance benefit.

Distribution of the r6265 alleles AA, AG, GG (from SNPedia)
Click here for the population codes

As most of the effects of this genetic variant seem negative (at best we could consider it to be neutral possibly, according to the described effects), I am in principle inclined to blame a founder effect for it. However, if the A allele has similar protective effects as the lack of one copy of the gene in the mice of the experiment (as the depression and neurodegenerative resistance may suggest), it might have been favored by selection in stressful conditions of some sort. This however is not at the moment demonstrated in any way and I mention only as a hypothetical scenario B.

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