A male gene for a male brain

Male and female brains are different in important ways — not just in generating distinct sexual behaviours, but also in terms of cognition and other key functions. Until recently, these differences were thought to arise from the effects of sex hormones during brain development, but there have been several hints lately that genes in the adult brain have a role in maintaining this male–female divide. Work from Eric Vilain and colleagues now shows that the Y-chromosome gene Sry directly influences the function of the brain in adult males.
Sry is a transcriptional regulator and is best known as the master controller of male sexual development. However, previous studies have shown that, intriguingly, this gene is also expressed in the adult male brain. Vilain and colleagues confirmed this, showing that Sry mRNA is present at a low level throughout the brain cortex in male mice, and at higher levels in two regions: the mammillary bodies and the substantia nigra (SN). Focusing on the SN, which controls voluntary movement, the authors showed that the SRY protein colocalizes with tyrosine hydroxylase (TH), an enzyme that is involved in the synthesis of the neurotransmitter dopamine, which is essential for the functioning of this region.
To investigate the functions of SRY in TH-expressing cells, male rat SNs were microinfused with antisense oligonucleotides targeted against Sry. This led to reduced TH expression in the SN and in regions that are usually innervated by TH-expressing neurons, showing that SRY directly regulates the expression of this enzyme. The authors were also able to show that SRY expression in the SN has a functional consequence. Microinfusion of Sry antisense oligonucleotides into the SN on one side of the brain reduced the stepping activity of rats using the forelimb on the corresponding side of the body.
The fact that SRY functions in the adult male brain in a way that doesn't rely on hormones indicates that we should think differently about sexual dimorphisms in the brain, taking direct genetic effects into account. This will be important for many reasons, not least for understanding the differing susceptibilities of men and women to psychiatric disorders and other neurological diseases.
Nature Reviews Genetics 7, 244-245 (April 2006)

New genetic discovery explains 74 percent cases of age-related macular degeneration

A new study, led by researchers at Columbia University Medical Center, pinpoints the role that two genes – Factor H and Factor B – play in the development of nearly three out of four cases of age-related macular degeneration (AMD), a devastating eye disease that affects more than 10 million people in the United States.
Findings indicate that 74 percent of AMD patients carry certain variants in one or both genes that significantly increase their risk of this disease.
Published in Nature Genetics, the research is a continuation of work published last year by the same team in the Proceedings of the National Academy of Sciences (PNAS, April 30, 2005 issue, see Columbia press release: http://www.cumc.columbia.edu/news/press_releases/AMD-Allikmets.html). Led by Rando Allikmets, Ph.D., the Acquavella Associate Professor in Ophthalmology, Pathology and Cell Biology at Columbia University Medical Center, the research team included collaborating groups headed respectively by Gregory Hageman, Ph.D., professor of ophthalmology and visual sciences at the University of Iowa Roy J. and Lucille A. Carver College of Medicine, and by Michael Dean, Ph.D., at the National Cancer Institute of the National Institutes of Health.
The PNAS study showed that several variants in the Factor H gene significantly increase the risk of developing AMD. Factor H encodes a protein that helps shut down an immune response against bacterial or viral infection, once the infection is eliminated. People with these inherited risk-increasing variations of Factor H are less able to control inflammation caused by infectious triggers, which may spark AMD later in life.
Though the effect of Factor H on AMD is large, variation in this gene alone does not fully explain who gets AMD and who doesn't. As described in the PNAS paper, about one-third (29 percent) of people with a Factor H risk variant had not been diagnosed with AMD.
The investigators decided to look for additional culprits and focused on genes in the same immune response pathway that contains Factor H.
Their genetic analysis of 1,300 people quickly identified Factor B as the major modifier of the disease. The discovery makes good biological sense: while Factor H is an inhibitor of the immune response to infection, Factor B is an activator. Because of the complementary roles of the these two genes, a protective Factor B variation can protect against AMD, even if one carries a risk-increasing variant of Factor H, and vice versa.
As described in Nature Genetics, the two genes explained nearly three out of four AMD cases: 74 percent of the subjects with AMD had either the Factor H or Factor B risk variant (or both), but no protective variants of either gene.
"I am not aware of any other complex disorder where nearly 75 percent of genetic causality has been identified," said Dr. Rando Allikmets, who is senior author of the paper.
"These findings are significant because they absolutely confirm the roles of these two genes and, consequently, the central role of a specific immune response pathway, in the development of AMD. We confirmed this association not just statistically and genetically but, most importantly, pinpointed the biological origin of the disease," added Dr. Allikmets. "In just a few short years, we've gone from knowing very little about what causes AMD to knowing quite a lot. We now have clear targets for early therapeutic intervention."
Though the new paper explains much of the genetic risk, the specific triggers that set off the immune response and subsequent inflammation are still unknown. Researchers at Columbia University Medical Center and the University of Iowa are now searching for specific viral and bacterial culprits.
Published online: 5 March 2006; doi:10.1038/ng1750