A reversible mouse model of myotonic dystrophy, the most common form of muscular dystrophy in adults, is reported in a study to be published in the September issue of Nature Genetics. The mouse model shows for the first time that at least some aspects of the disease might be fully reversible, and suggests that a potential therapy might be devised by targeting a particular kind of toxic molecule present in the diseased muscle.

Myotonic dystrophy occurs because of a large expansion in the number of 'CTG' repeats in a region flanking a gene called DMPK, and is associated with skeletal muscle loss, cardiac abnormalities, cataracts and insulin resistance. While there has been good evidence in favor of the idea that the expanded DMPK messenger RNA is toxic to cells in which it is expressed, and is the underlying cause of the disease, a definitive demonstration has been lacking. Mani Mahadevan and colleagues at the University of Virginia generated a mouse carrying an extra normal copy of the DMPK gene that could be turned on and off by adding (or removing) an antibiotic to the drinking water. Mice that expressed very high levels of this extra DMPK—and thus had more copies of the CTG repeat—showed all of the cardinal features of myotonic dystrophy. When expression of DMPK was turned off, normal skeletal and cardiac muscle function was restored in many of the mice. These results suggest that muscle damage in individuals with the disease might not be permanent, and that eliminating messenger RNAs carrying the extra CTG repeats might have therapeutic benefit.

Three papers to be published in the September issue of Nature Genetics describe a recurrent cause of mental retardation, which results from the deletion of a large segment of DNA from chromosome 17. The deletion, encompassing several genes, is associated with a region of DNA that is commonly carried in an inverted orientation by a large portion of the human population.

The deletion arises recurrently, and is reported to account for roughly 1% of cases of mental retardation among the populations screened in the three studies. It seems to be found preferentially among children of individuals who carry one particular form of the inversion, which is common among Europeans. Individuals carrying the deletion also show characteristic facial, behavioral and other clinical features, which should aid clinicians in diagnosing similar cases.

One of the deleted genes, MAPT, has been previously implicated as having a causal role in neurodegenerative disorders such as Alzheimer’s and Parkinson's diseases. Loss of this gene is therefore a prime candidate for explaining some of the characteristic features associated with mental retardation.

The first comprehensive molecular analysis of aggressive behavior in any laboratory species is reported in a study to be published in the September issue of Nature Genetics. Herman Dierick and Ralph Greenspan developed an original set of assays to record and quantify aggression in the fruit fly Drosophila melanogaster.

Most laboratory strains of D. melanogaster rapidly lose the aggressiveness that is common to strains in the wild, suggesting that aggressive behavior might be recoverable in laboratory strains by deliberately selecting for it. Dierick and Greenspan devised a new ‘two-male arena assay’, in which twenty pairs of males were placed in a chamber containing separate arenas, and assessed for several parameters related to aggression, including the frequency, intensity, and total amount of time spent fighting (see video and still image). More aggressive males were then selected and mated to random females, a procedure which was repeated for more than twenty generations. Flies in the final generation were thirty times as aggressive as those in the first generation.

The authors report that approximately eighty genes were significantly differentially expressed between the more aggressive and less aggressive flies. One of the genes, Cyp6a20, when mutated, alone had a significant effect on aggressive behavior. Although it is not yet possible to generalize from these preliminary data, the assay and approach used should set a new standard for the genetic analysis of aggressive behavior.

The genetic factors influencing susceptibility to a degenerative eye disorder are explored in two papers in the September issue of Nature Genetics. The scientists report that multiple genetic variants together explain a high proportion of inherited individual disease risk.

Age-related macular degeneration—AMD—is a degenerative disorder of the eye, affecting the central retina, which gradually reduces vision and is one of the most common causes of vision loss in the elderly. The risk of developing AMD increases with age, and is influenced by environmental as well as genetic components. Previous studies showed that a common, variant form of a protein called complement factor H (CFH) is associated with increased susceptibility to AMD. These new studies show that additional variants within the CFH gene, which do not affect the function of the protein, also make an important contribution to increase disease risk.

In one study, Gonçalo Abecasis and colleagues examined variants within and surrounding the CFH gene, in AMD patients and healthy individuals from a single study population. They find that variants in the gene encoding CFH, which do not change the protein itself, strongly contribute to the risk of AMD. They also show that multiple variants together define a high proportion of risk. In an accompanying paper, Mark Daly and colleagues examine an independent set of AMD cases and similarly find that a common non-protein-coding variant in CFH influences disease risk. The authors also confirm previous associations between disease susceptibility and variation in two additional genes, and show that, together, the genetic variation at these three genes defines a broad spectrum of individual disease risk. It has been noted that siblings of individuals with AMD show a 3-6 higher incidence of disease compared to the general population. Daly and colleagues estimate that variation in the three genes they study explains roughly half of this increased risk seen among siblings.