Like son like…mother? Macro problems with a recent paper on microchimerism

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Gene found on Y chromosome detected in females brains.

A recent Plos One article found expression of a male-specific gene in a high proportion of female brains, providing the first evidence for microchimerism in the human brain (it’s been shown in mice). Furthermore, researchers reported that the brains of women who had Alzheimer’s disease were less likely to harbor male DNA.

Microchimerism refers to the persistence of a small number of genetically distinct cells – or just the DNA – within a host. During pregnancy, cells are exchanged between mother and fetus via the placenta and can reside in a variety of organs for the lifespans of mother and child. Studies have established that microchimerism can have either detrimental or beneficial effects for mother and offspring, as in the case of autoimmunity or cancer, respectively. Imagine the fascinating implications of a child’s cells living in his mother’s brain.

Back up a minute. Before we’re overcome with the warm and fuzzies thinking about nature’s nod to the amazing bond between mother and child, let’s first consider the primary article in question. One glaring problem: we don’t know how many of the women were, in fact, mothers.

Pregnancy history was largely unavailable to the researchers, but let’s look at the cases for which they knew maternal status: in 5/9 cases of women who had had sons, male DNA was detected. In 1 female who had no history of having a son, male DNA was detected. To be fair, the presence of the male DNA could reveal an unknown miscarriage. However, male DNA can also be transferred via mechanisms that are not dependent on maternal status, such as from a twin brother or even an older brother who previously took up residence in his mother’s uterus and made her microchimeric. This limitation is an even bigger problem when the researchers seek to compare brains of control females and those with Alzheimer’s disease (AD) – what if mothers were unequally distributed across groups? If maternal history were available, it would have been interesting to know if there was a dose-dependent effect (more sons = greater concentration of male DNA?) or how failed pregnancies may contribute to microchimerism compared to successful pregnancies.

Because Alzheimer’s disease (AD) has been reported to be more prevalent in mothers than women who do not have children, researchers compared male DNA levels in neurologically normal women and AD patients. I mentioned the potential complication that the control group may have included more mothers, but beyond that there are flaws in the study’s design. Postmortem brain studies face many challenges, particularly when scientists wish to apply molecular techniques to the tissue. After a patient dies, it’s a race against the clock to section the brain and immerse it in fixative. The so-called post mortem interval (PMI) is a crucial factor for preserving the integrity of proteins and genetic material. To deal with the inevitable uncontrolled variables that pop up during tissue processing, researchers try to get all their ducks-in-a-row by matching subjects beforehand. This means that one would compare a 70-year-old woman with AD whose brain was fixed after 18 hours with a woman of a similar age and PMI. While the researchers in this study used statistical methods to correct for subject differences, the subjects were not matched, and the AD group was significantly older. Therefore, tissue quality could be reduced in the AD group, making it more difficult to detect the male genetic material.

Despite drawbacks, it is still striking that 18/26 control female brains had detectable levels of the male gene in at least one brain section of brain sampled – suggesting that microchimerism is prevalent. However, the case is not strong that there is any difference between control and AD patients. When the researchers analyzed the concentration of male microchimerism they did not find a statistical difference after excluding an outlier in the control group who had 10 times more male DNA than the next highest sample (did she have a brood of boys?!). They also had a wonky design whereby they measured male DNA in whatever brain samples were available – a bit of hippocampus, a little pons here.. without regard for comparing similar samples across groups. Therefore, when they report the proportion of positive samples across all regions, it isn’t a fair comparison. Add in some uncertainty as to how many mothers were in each group, and it seems that any conclusion regarding differences between AD and control subjects is shaky at best.

I could let my imagination run wild with follow-up questions like, “Are there fewer positive samples in AD patients because chimeric cells are more vulnerable to AD-induced cell death?” but these findings first require further validation in patients whose maternal status is documented. Still, studies like this that suggest widespread microchimerism open up fascinating avenues of research into the role that these “immigrant” cells play in normal health.

*EDIT: I wanted to point out that chimerism isn’t unique to males. This study chose to look at the Y chromosome because females are XX, so it would be easy to detect chimerism due to the fact that there shouldn’t be any extra Y chromosomes hanging around.

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