NEUROPSIN II EXPRESSES A NEUROCHEMICAL INVOLVED IN LEARNING AND MEMORY

Neuropsin II: not all that separates us from chimps
May 10th, 2007 by Corey Tomsons

In a post a few days ago, I mentioned a recent paper which dates a mutation in human evolution. That mutation expresses a neurochemical involved in learning and memory - in mice. You can find the article here:

Zhi-xiang Lu, Jia Peng, Bing Su. A human-specific mutation leads to the origin of a novel splice form of neuropsin (KLK8), a gene involved in learning and memory. Human Mutation. (8 May 2007).
Linda MacDonald Glenn, at the Women’s Bioethics Blog, now writes about this under the headline: The gene/neurochemical that may separate human/ape brains: Neuropsin II.

Be cautious about oversimplifying this, however. Their research does not identify a ‘magic gene’ which separated humans from apes. It does show a neurochemical is present in human brains and not in the brains of other primates, but the mutation may have happened sometime after humans diverged from chimpanzees 5 million years ago.

Update: NewScientist reports this as Gene variant may be responsible for human learning.


A human-specific mutation leads to the origin of a novel splice form of neuropsin (KLK8), a gene involved in learning and memory
Zhi-xiang Lu 1 2 3, Jia Peng 1 2, Bing Su 1 2 *
1Key Laboratory of Cellular and Molecular Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
2Kunming Primate Research Center, Chinese Academy of Sciences, Kunming, China
3Graduate School, Chinese Academy of Sciences, Beijing, China

email: Bing Su (sub@mail.kiz.ac.cn)

*Correspondence to Bing Su, Kunming Institute of Zoology, Chinese Academy of Sciences, 32 East Jiao-Chang Rd., Kunming 650223, Yunnan, China

Communicated by David Cooper

Funded by:
Natural Science Foundation of Yunnan Province of China
Chinese Academy of Sciences; Grant Number: KSCX1-YW-R-34
National Natural Science Foundation of China; Grant Number: 30370755, 30525028, 30630013
National 973 Project of China; Grant Number: 2006CB701506

Keywords
neuropsin • kallikrein 8 • KLK8 • alternative splicing • cognition • human evolution


Abstract
Neuropsin (kallikrein 8, KLK8) is a secreted-type serine protease preferentially expressed in the central nervous system and involved in learning and memory. Its splicing pattern is different in human and mouse, with the longer form (type II) only expressed in human. Sequence analysis suggested a recent origin of type II during primate evolution. Here we demonstrate that the type II form is absent in nonhuman primates, and is thus a human-specific splice form. With the use of an in vitro splicing assay, we show that a human-specific T to A mutation (c.71-127T>A) triggers the change of splicing pattern, leading to the origin of a novel splice form in the human brain. Using mutation assay, we prove that this mutation is not only necessary but also sufficient for type II expression. Our results demonstrate a molecular mechanism for the creation of novel proteins through alternative splicing in the central nervous system during human evolution. Hum Mutat 0, 1-7, 2007. © 2007 Wiley-Liss, Inc.



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Received: 10 February 2007; Accepted: 26 March 2007

Led by Dr. Bing Su of the Chinese Academy of Sciences in Kunming, China, researchers analyzed the DNA of humans and several species of apes and monkeys. Their previous work had shown that type II neuropsin, a longer form of the protein, is not expressed in the prefrontal cortex (PFC) of lesser apes and Old World monkeys. In the current study, they tested the expression of type II in the PFC of two great ape species, chimpanzees and orangutans, and found that it was not present. Since these two species diverged most recently from human ancestors (about 5 and 14 million years ago respectively), this finding demonstrates that type II is a human-specific form that originated relatively recently, less than 5 million years ago.

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 identified a region of the chimpanzee sequence that has a weakening effect on the splicing site that also probably applies to humans. "It is likely that both the creation of novel splice form and the weakening of the constitutive splicing contribute to the splicing pattern changes during primate evolution, suggesting a multi-step process eventually leading to the origin of the type II form in human," the authors state.
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.

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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



Bing Su's Laboratory on Comparative Genomics
With the completion of human genome draft sequences, scientists are now facing the challenge of understanding the three billion genetic codes in the human genome, i.e. to establish the connections between genetic codes and their functional outputs. By conducting genome wide comparative genetic analysis among living primates including human beings who are the products of more than seventy million years of evolution, we are trying to dissect the human genome from the view of evolution by tackling the following questions:

1. How does genome structure change during primate evolution?

2. How do new genes carrying new functions emerge during primate evolution?

3. What are the genes involved in the progressive changes of cognitive skills during primate evolution?

4. What genes are responsible for human mental disorders?