Is The Third Splice the Charm?

Neuropsin is a serine protease that plays an important role in memory formation in the mammalian hippocampus. Scientists at the Chinese Academy of Sciences have discovered that type II Neuropsin, a longer form of the enzyme, exists in human brains but not in the brains of great apes, lesser apes, or monkeys.

The human and chimpanzee genomes vary by just 1.2 percent, yet there is a considerable difference in the mental and linguistic capabilities between the two species. A new study showed that a certain form of neuropsin, a protein that plays a role in learning and memory, is expressed only in the central nervous systems of humans and that it originated less than 5 million years ago. The study, which also demonstrated the molecular mechanism that creates this novel protein, will be published online in Human Mutation, the official journal of the Human Genome Variation Society. The journal is available online via Wiley InterScience at http://www.interscience.wiley.com/journal/humanmutation.

....Gene sequencing revealed a mutation specific to humans that triggers a change in the splicing pattern of the neuropsin gene, creating a new splicing site and a longer protein. Introducing this mutation into chimpanzee DNA resulted in the creation of type II neuropsin. "Hence, the human-specific mutation is not only necessary but also sufficient in creating the novel splice form," the authors state.

The results also showed a weakening effect of a different, type I-specific splicing site and a significant reduction in type I neuropsin expression in human and chimpanzee when compared with the rhesus macaque, an Old World monkey. This pattern suggests that before the emergence of the type II splice form in human, the weakening of the type I splicing site already existed in the common ancestor of humans and chimpanzees, implying a multi-step process that led to the dramatic change of splicing pattern in humans, the authors note.

...They note that further studies should probe the biological function of type II neuropsin in humans, as the extra 45 amino acids in this form may cause protein structural and functional changes. They note that in order to understand the genetic basis that underlies the traits that set humans apart from nonhuman primates, recent studies have focused on identifying genes that have been positively selected during human evolution. They conclude, "The present results underscore the potential importance of the creation of novel splicing forms in the central nervous system in the emergence of human cognition."

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Neuropsin protease modifies the extracellular matrix in its interaction with synaptic membranes, in LTP and learning. The interaction is complex, and relies upon the activation and de-activation of Neuropsin at the proper times in proper concentrations. Read this study by Tamura et al for more information.

The progressive changes in Neuropsin splicing from monkeys to chimpanzees to humans, suggests that relatively simple epigenetic changes leading to the longer Neuropsin II protease in humans may be partially responsible for the much greater ability of human brains to learn complex systems of knowledge, including language.

You may be wondering the same thing that I am wondering. If the first change in splicing to Neuropsin I led to the CNS of Chimp/Human precursors, and the second change in splicing that created Neuropsin II led to uniquely human brain changes, what will the next splicing change in the Neuropsin gene lead to? Will the third splice be the charm?