Neuron-building gene made us big-brained

Two studies published in Cell have identified a gene family, NOTCH2NL, that appears to play an important role in human-specific cortex development and may have been a driving force in the evolution of our large brains. NOTCH2NL genes delay the differentiation of cortical stem cells into neurons, resulting in the production of more neurons across the course of development. The genes are found exclusively in humans, are heavily expressed in neural stem cells of the human cerebral cortex and are located on a part of the genome implicated in neurodevelopmental disorders. The first study, out of the University of California, Santa Cruz, reconstructed the evolutionary history of NOTCH2NL genes revealing that a process called gene conversion was likely responsible for repairing a non-functional version of NOTCH2NL, which originally emerged as a partial duplication of an essential neurodevelopmental gene known as NOTCH2. This repair happened only in humans – and they estimate it happened 3–4 million years ago, around the same time that the fossil record suggests human brains began to expand. After it was repaired, but before we diverged from our common ancestor with Neanderthals, NOTCH2NL was duplicated two more times. The second study, led by the Université Libre de Bruxelles, arrived at NOTCH2NL from a related direction, searching for human-specific genes active during fetal brain development using primary tissue. The researchers developed a tailored RNA sequencing analysis for specific and sensitive detection of human-specific genes in human fetal cerebral cortex. This allowed them to identify a repertoire of 35 genes unique to humans that are active during development of the cerebral cortex, including NOTCH2NL genes. They zeroed in on NOTCH2NL in particular because of the importance of its ancestral gene, NOTCH2, in signaling processes that control whether cortical stem cells produce neurons or regenerate more stem cells. And they found that artificially expressing NOTCH2NL in mouse embryos increased the number of progenitor stem cells in the mouse cortex. To better understand what the genes do in humans, the team turned to an in vitro model of cortical development from human pluripotent stem cells to explore NOTCH2NL function. In this model, they found that NOTCH2NL can substantially expand the population of cortical stem cells, which in turn generate more neurons, a feature expected to distinguish between human and non-human cortical neurogenesis.

Common virus in healthy eyes causes long-standing inflammation

Researchers at the University of Western Australia’s Lions Eye Institute have discovered that contrary to expectations, a common virus triggers long-lasting inflammation in the eyes of hosts with a healthy immune system. Healthy eyes have been considered largely inaccessible to viruses, as well as “immune privileged”, meaning that exposure to a foreign antigen, such as a virus, should not trigger an inflammatory response. Outbreaks of viral diseases such as Ebola and Zika have raised the possibility that viruses can cause enduring infections in the eye, but this was thought to be a feature of exotic viral infections. Published in PLOS Pathogens, the study focused on cytomegalovirus. Cytomegalovirus infections are common, with more than half of the adult population carrying the virus, but clinical symptoms are usually seen only in patients with compromised immune systems. Once a person is infected, the virus enters a dormant state in organs such as the lung. In people with healthy immune systems, tissues like the eyes are thought to be inaccessible to the virus. However, the researchers discovered that infecting healthy mice with cytomegalovirus resulted in broad ocular infection, chronic inflammation and establishment of a dormant pool of virus in the eye. While more research is needed to determine whether these unexpected findings extend to humans, the authors suggested that researchers and doctors may need to rethink the effects of cytomegalovirus – and, potentially, other viruses – on the eyes. Some eye problems caused by dormant or reactivated cytomegalovirus in people with healthy immune systems may be misdiagnosed, leading to improper treatment that could damage vision.

Walking faster could make you live longer

Researchers from the University of Sydney have found that walking at an average pace was found to be associated with a 20% risk reduction for all-cause mortality compared with walking at a slow pace, while walking at a brisk or fast pace was associated with a risk reduction of 24%. A similar result was found for risk of cardiovascular disease mortality, with a reduction of 24% walking at an average pace and 21% walking at a brisk or fast pace, compared with walking at a slow pace. The protective effects of walking pace were also found to be more pronounced in older age groups. Average pace walkers aged 60 years or over experienced a 46% reduction in risk of death from cardiovascular causes, and fast pace walkers a 53% reduction. Published in the British Journal of Sports Medicine, the study linked mortality records with the results of 11 population-based surveys in England and Scotland between 1994 and 2008, in which participants self-reported their walking pace. The research team then adjusted for factors such as total amount and intensity of all physical activity taken, age, sex and body mass index. In light of the findings, the research team is calling for walking pace to be emphasised in public health messages.

What’s online first at the MJA

4 June Podcast with Professor John McNeil, Head of the Department of Epidemiology and Preventive Medicine at Monash University, talking about middle-aged mortality in Australia … OPEN ACCESS permanently.

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