Monkeys serve as important model species for studying human diseases and developing therapeutic strategies, yet the application of monkeys in biomedical researches has been significantly hindered by the difficulties in producing animals genetically modified at the desired target sites. Here, we first applied the CRISPR/Cas9 system, a versatile tool for editing the genes of different organisms, to target monkey genomes. By coinjection of Cas9 mRNA and sgRNAs into one-cell-stage embryos, we successfully achieve precise gene targeting in cynomolgus monkeys. We also show that this system enables simultaneous disruption of two target genes (Ppar-γ and Rag1) in one step, and no off-target mutagenesis was detected by comprehensive analysis. Thus, coinjection of one-cell-stage embryos with Cas9 mRNA and sgRNAs is an efficient and reliable approach for gene-modified cynomolgus monkey generation.

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Summary Recent advances in gene editing technology have introduced the potential for application of mutagenesis approaches in non-human primates to model human development and disease. Here we report successful TALEN-mediated mutagenesis of an X-linked, Rett Syndrome (RTT) gene, the methyl-CpG binding protein 2 (MECP2), in both rhesus and cynomolgus monkeys. Microinjection of MECP2-targeting TALEN plasmids into rhesus and cynomolgus zygotes leads to effective gene editing of MECP2 with no detected off-target mutagenesis. Male rhesus (2) and cynomolgous (1) fetuses carrying MECP2 mutations in various tissues including testes were miscarried during mid-gestation, consistent with RTT-linked male embryonic lethality in humans. One live delivery of a female cynomolgus monkey occurred after 162 days of gestation, with abundant MECP2 mutations in peripheral tissues. We conclude that TALEN-mediated mutagenesis can be an effective tool for genetic modeling of human disease in non-human primates.

[1] Antigorite, the high-temperature (HT) form of serpentinite, is believed to play a critical role in various geological processes of subduction zones. We have measured P-and Swave velocities (V p and V s ), anisotropy and shear-wave splitting of 17 serpentinite samples containing >90% antigorite at pressures up to 650 MPa. The new results, combined with data for low-temperature (LT) lizardite and/or chrysolite, reveal distinct effects of LT and HT serpentinization on the seismic properties of mantle rocks. At 600 MPa, V p = 5.10 and 6.68 km/s, V s = 2.32 and 3.67 km/s, and V p /V s = 2.15 and 1.81 for pure LT and HT serpentinites, respectively. Above the crack-closure pressure (~150 MPa), the velocity ratio of antigorite serpentinites displays little dependence on pressure or temperature. Serpentine contents within subduction zones and forearc mantle wedges where temperature is >300 C should be at least twice that of previous estimates based on LT serpentinization. The presence of seismic anisotropy, high-pressure fluids, or partial melt is also needed to interpret HT serpentinized mantle with V p < 6.68 km/s, V s < 3.67 km/s, and V p /V s > 1.81. The intrinsic anisotropy of the serpentinites (3.8-16.9% with an average value of 10.5% for V p , and 3.6-18.3% with an average value of 10.4% for V s ) is caused by dislocation creepinduced lattice-preferred orientation of antigorite. Three distinct patterns of seismic anisotropy correspond to three types of antigorite fabrics (S-, L-, and LS-tectonites) formed by three categories of strain geometry (i.e., coaxial flattening, coaxial constriction, and simple shear), respectively. Our results are thought to provide a new explanation for various anisotropic patterns of subduction systems observed worldwide.Citation: Ji, S., A. Li, Q. Wang, C. Long, H. Wang, D. Marcotte, and M. Salisbury (2013), Seismic velocities, anisotropy, and shear-wave splitting of antigorite serpentinites and tectonic implications for subduction zones,

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[1] The Chinese Continental Drilling Project (CCSD) has drilled to a depth of 5100 m at Maobei (N34.40, E118.67), Donghai County, Jiangsu Province in the eastern segment of the Dabie-Sulu ultrahigh pressure (UHP) metamorphic terrane. The borehole, which penetrated through all of the high velocity layers and seismic reflectors observed within the uppermost crust on seismic refraction and reflection profiles, reveals the main lithologies to be coesite-bearing felsic gneisses, metabasic rocks (i.e., amphibolite, retrogressed, and non-retrogressed eclogites) and ultramafic rocks (i.e., garnet peridotite and serpentinite). P wave velocities, anisotropy, and hysteresis of 31 typical CCSD core samples and 35 representative surface samples collected from the Sulu UHP belt were measured at hydrostatic confining pressures up to 800 MPa. The velocity-pressure curves can be well described by a four-parameter exponential equation derived from theory: V(P) = V 0 + DP À B 0 exp(ÀkP), where V 0 is the projected velocity at zero pressure if pores/cracks were absent; D is the intrinsic pressure derivative of velocity in the linear elastic regime; B 0 is the initial velocity drop caused by the presence of pores/cracks at zero pressure; and k is the decay constant of the velocity drop in the nonlinear poro-elastic regime. The seismic hysteresis is caused by irreversible changes in grain contact, increases in microcrack aspect ratios and reduction of void space during the pressurizationdepressurization cycle. The statistical properties of P wave velocities in the UHP rocks provide an important set of basic information for the interpretation of field seismic data from the root zones of continental convergent orogenic belts and modern and ancient subduction zones.