The year 2020 should be marked as a half-century anniversary of the publication of much influential book “Evolution by Gene Duplication” written by Dr. Susumu Ohno. In the very last section of this book, Dr. Ohno discusses how intelligence would have evolved in the complex neural networks of the human brain, which should have been acquired due to a hidden mechanism of evolution to precede the future necessity. Dr. Ohno also mentioned that the intelligence, or the learning capacity at least, should be evolved in parallel with the given longevity of animals. Therefore, it would be possible that emergence of certain gene(s) and/or gene regulatory element(s) could have been a prerequisite to the expected co-evolution of human intelligence and longevity. In this Dr. Susumu Ohno memorial symposium, I would like to discuss the emerging interests on a master regulatory gene called NRSF/REST and a gene regulatory element NRSE/RE-1, which would have accelerated the evolution of our intelligence and longevity during the vertebrate and human evolution.
After spending two years in the laboratories of Dr. Susumu Ohno and Dr. Art Riggs at City of Hope during 1984-86, I moved to Caltech, where I had found NRSE and NRSF. NRSE, neural restrictive silencer element, is a transcriptional silencing element that determines neuron-specific gene expression. In the mouse and human genome, there are a thousand neuron-specific genes that are controlled by NRSE. NRSE is bound by NRSF, neural restrictive silencing factor. NRSE and NRSF are also called RE-1 and REST, respectively. The NRSE/RE-1 and NRSF/REST system was initially considered as a master regulatory machinery of the neuron-specific gene expression in neural development, but recent evidence suggests that the system functions for protecting neurons in the aged human brain. The NRSF/REST expression levels correlate with cognitive levels of aged humans. Moreover, the ortholog gene spr-4 in C. elegans is involved in the control of longevity. The loss of NRSF/REST in developing brain results in microencephaly. The amino acid analysis of primate NRSF/REST sequences revealed that the NRSF/REST sequence is under positive selection during human evolution. SNP data is consistent with the idea that the polymorphic repetitive region is selective for higher cognition. Database analysis indicates that NRSF/REST emerged in the metazoan evolution. Although further studies are awaited, I would like to propose that the NRSE-NRSF system being emerged in the dawn of metazoan evolution preceding the future necessity for the evolving intelligence and longevity in humans.