March 13, 2013 § Leave a comment
It very well may be possible that compromised leukotriene signaling is one of the reasons Neanderthals are not among us today. In a recent paper in the Journal of Lipid Research, investigators compared the genome sequences of Homo neanderthalensis and Homo sapiens to see if the two hominid subspecies shared genes for the biosynthesis of leukotrienes and other inflammatory mediators. The investigators, led by Hartmut Kuhn at the University Medicine Berlin-Charité, found that the Neanderthal genome contained six genes encoding for six different lipid-peroxidizing isoenzymes called lipoxygenases (LOXs). Previous work has shown that we too have six LOX genes. However, the cDNA for two of the enzymes contained premature stop codons in the Neanderthal sequence, suggesting that expression of these enzymes was compromized.
Neanderthals are our closest evolutionary relatives. The youngest Neanderthal fossils have been dated to some 30,000 years ago, but there is evidence that Neanderthals may have survived in southwestern Europe until about 25,000 years ago.
A draft sequence of the Neanderthal genome was recently published. Global comparison of the genomic sequences of H. sapiens and H. neanderthalensis hinted that a number of genomic regions were different between the two subspecies of hominids. “Among them was the gene encoding the cysteinyl leukotriene receptor 2, which was mutated in the Neanderthal genome,” says Kuhn. “Although no direct functional studies have been carried out, the sequence data suggest that Neanderthals might have suffered from compromised leukotriene signaling.”
Leukotriene signaling, in which cysteinyl leukotriene receptor 2 is involved during processes of inflammation, requires the biosynthesis of leukotrienes. These molecules are made by LOXs. LOXs are lipid peroxidizing enzymes that have been implicated in cell differentiation and in the pathogenesis of inflammatory, hyperproliferative and neurodegenerative diseases. “Except from a large number of genomic LOX sequences that have been deposited in the publically available databases, virtually nothing is known is know about the evolution of this enzyme family,” says Kuhn.
Kuhn and colleagues carried out a series of bioinformatic experiments and protein biochemical assays to compare and contrast the LOX genes of Neanderthals and modern humans. They established that the genomes of H. sapiens and H. neanderthalensis contained six LOX genes – nALOX15, nALOX12, nALOX5, nALOX15B, nALOX12B and nALOXE3 – and one functionless pseudogene. “Since this pseudogene is functional in mice, it appears to have been corrupted later on in mammal evolution,” says Kuhn.
The sequences of the LOX genes confirmed that the two subspecies were related closely in evolutionary terms. But nALOX12 and nALOXE3 had two premature stop codons, hinting that the expression of these two LOX isoforms in Neanderthals might have been compromised. But Kuhn cautions that this conclusion should be interpreted carefully because there may be sequencing artifacts and problems with sample collection.
Nonetheless, Kuhn and colleauges are pressing ahead with doing more sequence comparisons. The complete genomic sequence of another ancient human ancestor, the Denisovan, recently was released. The Denisovan hominids share a number of anatomical similarities with Neanderthals. “We are about to apply the combined research strategy of our Neanderthal study to these sequences to find out of whether or not the take-home messages we concluded from the Neanderthal genome may also be applicable for Denisovan individuals,” says Kuhn. He says the hope is the sequence comparison will help to confirm or reject that there are premature stop codons in nALOX12 and nALOXE3.