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Thursday, September 6, 2012

Our methylomes make us human

It’s been a longstanding puzzle as to how humans and chimpanzees can be so different when our genomes are so similar. Now, researchers from the Georgia Institute of Technology (GIT), the University of California, Los Angeles and Emory University may have found an answer. Our genes may be similar, but the DNA methylation of those genes is different.

I’ve written before (here and here) about DNA methylation and the strides scientists have made in deciphering exactly when and where it occurs. Suffice it to say that this ‘after-factory’ alteration does not affect the sequence of DNA but does affect the expression of that DNA. In general, more highly methylated stretches of DNA have lower levels of expression. Improper methylation is correlated with a host of illnesses including neurological problems and many kinds of cancer.

The researchers, led by Jia Zeng of GIT, compared the ‘methylomes’ (methylation maps) of the prefrontal cortex of three humans and three chimps. These samples all had to be obtained from deceased subjects, but none were killed for the purposes of this experiment. In addition, the scientists compared the human prefrontal cortex methylomes with those of three other human tissues (embryonic stem cells, neonatal fibroblasts and peripheral blood mononuclear cells).

It turns out that human brain DNA is more highly methylated than other human tissues. In addition, within each species, younger individuals have more methylated brain DNA than older individuals. It gets more interesting when you compare across species, though.

Chimpanzee brains showed higher methylation levels than human brains. In fact, the authors identified over a thousand genes that were significantly less methylated in the human than in the chimp brain. Remember, lower DNA methylation means higher levels of gene expression. In other words, there are a host of genes that, while sequentially nearly identical between the two species, may have very different levels of expression. We humans make far more of those gene products than chimps do. Not surprisingly, many of these same genes are associated with neurological defects and brain function.

So, has this answered the question of why we’re humans and not chimps? Possibly. All three of the chimp brains had very similar methylation patterns, yet, despite the fact that none of the humans had any known neurological problems, one of the humans was almost as different from the other two humans as it was from the chimps. This implies that methylation is only one part of a complex story.

Illustration by Kayla Orlinsky, 10/27/2011.
Jia Zeng, Genevieve Konopka, Brendan G. Hunt, Todd M. Preuss, Dan Geschwind, & Soojin V. Yi (2012). Divergent Whole-Genome Methylation Maps of Human and Chimpanzee Brains Reveal Epigenetic Basis of Human Regulatory Evolution AJHG DOI: 10.1016/j.ajhg.2012.07.024