Philipp Khaitovich, from the Max-Planck-Institute for Evolutionary Anthropology and the Shanghai branch of the Chinese Academy of Sciences, led a collaboration of researchers from Cambridge, Leipzig and Shanghai who investigated brains from healthy and schizophrenic humans and compared them with chimpanzee and rhesus macaque brains. The researchers looked for differences in gene expression and metabolite concentrations and, as Khaitovich explains, "identified molecular mechanisms involved in the evolution of human cognitive abilities by combining biological data from two research directions: evolutionary and medical".
The idea that certain neurological diseases are by-products of increases in metabolic capacity and brain size that occurred during human evolution has been suggested before, but in this new work the authors used new technical approaches to really put the theory to the test.
They identified the molecular changes that took place over the course of human evolution and considered those molecular changes observed in schizophrenia, a psychiatric disorder believed to affect cognitive functions such as the capacities for language and complex social relationships. They found that expression levels of many genes and metabolites that are altered in schizophrenia, especially those related to energy metabolism, also changed rapidly during evolution. According to Khaitovich, "Our new research suggests that schizophrenia is a by-product of the increased metabolic demands brought about during human brain evolution".
The authors conclude that this work paves the way for a much more detailed investigation. "Our brains are unique among all species in their enormous metabolic demand. If we can explain how our brains sustain such a tremendous metabolic flow, we will have a much better chance to understand how the brain works and why it sometimes breaks", said Khaitovich.
genomebiology/
"By measuring protein levels, we could illustrate that microRNAs fine-tune gene expression rather than simply working as a switch to turn a gene on or off," says Daehyun Baek, co-lead author on the paper and a postdoctoral fellow in Bartel's lab. "The knockout mouse model enabled us to more accurately gauge the interactions of microRNAs with their regulatory targets, and to confirm what we found earlier in human cells."
"Surprisingly, the protein levels of cells missing microRNA-223 nearly matched those of normal cells," adds Gygi. "This microRNA changed the expression level of hundreds of proteins, but only by a small amount."
Identifying the proteins influenced by the presence of miR-223 also enabled the researchers to evaluate different predictions that scientists had made regarding which genes are regulated by each miRNA.
"We still cannot predict perfectly which genes are targeted by a particular microRNA, but at least now we know which of the proposed prediction methods are most useful," says Bartel.
By comparing protein levels and measuring RNA levels, the researchers demonstrated that microRNAs are more likely to change gene expression by destabilizing messenger RNAs rather than simply fouling up the protein translation process.
"There had been a suspicion that the majority of microRNA regulation would happen in a manner that doesn't really change the amount of messenger RNA," says Bartel. "We found that this wasn't true, at least for this particular microRNA."
Cristin Carr.
wi.mit