Determining De Novo Mutation Rates Knowing the Human De Novo Mutation Rate Is Important for Understanding Our Evolution and the Origins of Genetic Diseases

RESEARCH HIGHLIGHTS IN BRIEF GENE THERAPY Single-stranded RNAs for potent RNAi In the development of gene-based therapies, delivery of ssRNAs is simpler than it is for dsRNAs (as this requires lipid formulation, for example). However, ssRNAs have previously been found to be far less potent for gene silencing. Lima et al. have now overcome this limitation by chemical modifications of ssRNAs that increase their stability. They show that these modified ssRNAs act through the RNAi pathway as guide strands for Argonaute 2 to induce specific gene silencing. Yu et al. demonstrate the therapeutic potential of these RNAs in a mouse model of Huntington’s disease using ssRNAs that target the mutant HTT allele. The gene-silencing efficiency for the ssRNAs seems to be similar to equivalent dsRNAs. ORIGINAL RESEARCH PAPERS Lima, W. F. et al. Single-stranded siRNAs activate RNAi in animals. Cell 150, 883–894 (2012) | Yu, D. et al. Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression. Cell 150, 895–908 (2012) CLINICAL GENOMICS Sequencing to track bacterial infection outbreaks The use of genome sequencing to research disease outbreaks retrospectively has been demonstrated by high-profile cases, such as the recent cholera outbreak in Haiti. But can whole-genome sequencing be used to provide information that can be used in clinical decision making during an outbreak? Two recent studies suggest that it can. Köser et al. investigated a methicillin-resistant Staphylococcus aureus (MRSA) outbreak in a neonatal unit and identified transmission events, using data from the Illumina MiSeq platform. The authors note that the timescale (1.5 days from DNA extraction to sequence) and cost of their study demonstrates that such information can be obtained on a clinically relevant time frame. Snitkin et al. applied whole-genome sequencing to an outbreak of carbapenem-resistant Klebsiella pneumoniae. They combined the genetic data with epidemiological data to reveal the likely transmission route. Their work also provided information that should inform clinical responses, such as the verification of decontamination, in the case of such outbreaks. ORIGINAL RESEARCH PAPERS Köser, C. U. et al. Rapid whole-genome sequencing for investigation of a neonatal MRSA outbreak. N. Engl. J. Med. 366, 2267–2275 (2012) | Snitkin, E. S. et al. Tracking a hospital outbreak of carbapenem-resistant Klebsiella pneumoniae with whole-genome sequencing. Sci. Transl. Med. 4, 148ra116 (2012) HUMAN GENETICS Determining de novo mutation rates Knowing the human de novo mutation rate is important for understanding our evolution and the origins of genetic diseases. These two papers characterize the de novo mutation rate, both using Icelandic families. Kong et al. sequenced the whole genomes of 78 parent–offspring trios at high coverage to study the mutation rate directly, whereas Sun et al. analysed more than 85,000 individuals at 2,477 microsatellite repeats to get an indirect measurement. Both studies found that the paternal contribution to the de novo mutation rate is higher than that of the mother and that maternal age is not an important determinant. However, the rates estimated in the two studies are different (1.2 × 10−8 and 1.4 to 2.3 × 10−8 mutations per nucleotide per generation for Kong et al. and Sun et al., respectively), and Kong et al. identified a much stronger effect of paternal age; these discrepancies require further study. ORIGINAL RESEARCH PAPERS Kong, A. et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature 488, 471–475 (2012) | Sun, J. X. et al. A direct characterization of human mutation based on microsatellites. Nature Genet. 23 Aug 2012 (doi:10.1038/ng.2398) NATURE REVIEWS | GENETICS VOLUME 13 | OCTOBER 2012 © 2012 Macmillan Publishers Limited. All rights reserved.

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