Metabolome

Metabolome is the set of small molecules of a molecular weight of less than 1,500 Daltons (metabolites), which includes fats, amino acids, sugars, nucleotides, and vitamins. My work in metabolomics was focused on the human evolution - I used a comparative approach we search for human-specific features of the metabolome and for their relation to human phenotype.
My major finding is that, unlike genome, that seems to be changing steadily with time metabolome of certain tissues underwent substantial changes in the human species that might contribute to the human phanotype. We compared metabolomes of 5 tissues: prefrontal cortex (part of the brain neocortex where human abstract thinking resides), visual cortex (another part of neocortex), cerebellum (a fundamental brain region), kidney and muscle (two non-neural tissues) among human, chimpanzee, macaque and mice individuals. Unsurprisingly, we found excessive changes in the metabolome of human prefrontal cortex. Over the last 6 million years that separate us from our most recent common ancestor with chimpanzee, we accumulated four times as many metabolic changes as chimpanzees. These changes might have allowed the evolution of the energy-demanding human brain and were part of the processes responsible for human cognition.
More surprisingly however human muscle experienced more than eight times as much change as the chimpanzee's one. That is as much as mouse muscle did over more than 20 times longer time span! To ensure that human muscle metabolome does not simply reflect our couch potato lifestyle, we involved several macaques into such lifestyle. These macaques spent two months not moving much and high-fat diet. Their metabolome changed by 3% only.
So what is it so special about human muscle? There is some anecdotal knowledge of exceptional muscle strength of non-human primates but we failed to find systematic evidence to support this. To show this, we designed a muscle strength test and tested several chimpanzees, macaques and also students and even professional athletes. Despite their sweat and determination the human participants failed more than two-fold against their chimpanzee and macaque competitors.
So here is our hypothesis: human muscle evolved extensive metabolic changes that allowed the evolution of high-performing brain at the cost of weaker muscle.
Bozek K, Wei Y, Yan Z, Liu X, Xiong J, Sugimoto M, Tomita M, Pääbo S, Pieszek R, Sherwood CC, Hof PR, Ely JJ, Steinhauser D, Willmitzer L, Bangsbo J, Hansson O, Call J, Giavalisco P, Khaitovich P Exceptional evolutionary divergence of human muscle and brain metabolomes parallels human cognitive and physical uniqueness. PLoS Biol 2014 May 27;12(5):e1001871.

Lipidome

Lipids compose half of the brain in dry weight. Initially considered only as the building material of membranes or as a bioenergetic fuel, lipids are now recognized as signaling messengers in neural tissues. The distinct architecture of lipids is the necessary regulator for optimal communication in neural tissues. Then what is their role in the evolution of human brain function and cognition?
From the samples used in the metabolome study decribed above we separated hydrophobic fraction and measured the tissue lipid composition. We found a tremendous specificity of lipids to brain, 75% of the lipids are present uniquely either in brain or non-neural tissues suggesting an organizational specificity of the brain lipidome. Moreover, the number of differences in lipidome composition between brain and non-neural tissues increases in parallel with the increase in brain functional capacity: from mice to humans. In addition, we observed a three-fold acceleration of lipidome evolution in the neocortical regions, but not in cerebellum, on the human evolutionary lineage compared to chimpanzee. Therefore, not only is brain lipidome not present in non-neural tissues, but also its complexity increased throughout human evolution at an astounding pace in the brain regions where human cognition and abstract thinking reside. This suggests that lipids play important roles in evolution of brain functionality, including the cognitive capacities unique to the human brain.
Is our understanding of brain function, its human-specific features, as well as its dysfunctions, incomplete without further knowledge of the lipidome of neural tissue?

Bozek K, Wei Y, Yan Z, Liu X, Xiong J, Sugimoto M, Tomita M, Pääbo S, Sherwood CC, Hof PR, Ely JJ, Li Y, Steinhauser D, Willmitzer L, Giavalisco P, Khaitovich P Organization and evolution of brain lipidome revealed by large-scale analysis of human, chimpanzee, macaque and mouse tissues. Neuron 2015 Feb 18;85(4):695-702.

Bozek K, Khrameeva EE, Reznick J, Omerbašić D, Bennett NC, Lewin GR, Azpurua J, Gorbunova V, Seluanov A, Regnard P, Wanert F, Marchal J, Pifferi F, Aujard F, Liu Z, Shi P, Pääbo S, Schroeder F, Willmitzer L, Giavalisco P, Khaitovich P Lipidome determinants of maximal lifespan in mammals Sci Rep. 2017 Jan 31

Li Q, Bozek K, Xu C, Guo Y, Sun J, Pääbo S, Sherwood CC, Hof PR, Ely JJ, Li Y, Willmitzer L, Giavalisco P, Khaitovich P Changes in Lipidome Composition during Brain Development in Humans, Chimpanzees, and Macaque Monkeys Mol Biol Evol. 2017 May 1

Khrameeva EE, Bozek K, He L, Yan Z, Jiang X, Wei Y, Tang K, Gelfand MS, Prufer K, Kelso J, Pääbo S, Giavalisco P, Lachmann M, Khaitovich P Neanderthal ancestry drives evolution of lipid catabolism in contemporary Europeans Nature Communications 2014