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The genetic code provides the translation table necessary to transform the information contained in DNA into the language of proteins. In this table, a correspondence between each codon and each amino acid is established: tRNA is the main adaptor that links the two. Although the genetic code is nearly universal, several variants of this code have been described in a wide range of nuclear and organellar systems, especially in metazoan mitochondria. These variants are generally found by searching for conserved positions that consistently code for a specific alternative amino acid in a new species. We have devised an accurate computational method to automate these comparisons, and have tested it with 626 metazoan mitochondrial genomes. Our results indicate that several arthropods have a new genetic code and translate the codon AGG as lysine instead of serine (as in the invertebrate mitochondrial genetic code) or arginine (as in the standard genetic code). We have investigated the evolution of the genetic code in the arthropods and found several events of parallel evolution in which the AGG codon was reassigned between serine and lysine. Our analyses also revealed correlated evolution between the arthropod genetic codes and the tRNA-Lys/-Ser, which show specific point mutations at the anticodons. These rather simple mutations, together with a low usage of the AGG codon, might explain the recurrence of the AGG reassignments. ; This work was supported by a research grant from the Fundación BBVA (Spain). DP is also supported by the Ramón y Cajal programme of the Spanish Government. ; Peer reviewed

Copyright © by National Academy of Sciences.-- La versión original está disponible en http://www.pnas.org/.-- Supplementary material available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=141039#supplementary-material-sec ; We have sequenced the genome of the intracellular symbiont Buchnera aphidicola from the aphid Baizongia pistacea. This strain diverged 80–150 million years ago from the common ancestor of two previously sequenced Buchnera strains. Here, a field-collected, nonclonal sample of insects was used as source material for laboratory procedures. As a consequence, the genome assembly unveiled intrapopulational variation, consisting of ≈1,200 polymorphic sites. Comparison of the 618-kb (kbp) genome with the two other Buchnera genomes revealed a nearly perfect gene-order conservation, indicating that the onset of genomic stasis coincided closely with establishment of the symbiosis with aphids, ≈200 million years ago. Extensive genome reduction also predates the synchronous diversification of Buchnera and its host; but, at a slower rate, gene loss continues among the extant lineages. A computational study of protein folding predicts that proteins in Buchnera, as well as proteins of other intracellular bacteria, are generally characterized by smaller folding efficiency compared with proteins of free living bacteria. These and other degenerative genomic features are discussed in light of compensatory processes and theoretical predictions on the long-term evolutionary fate of symbionts like Buchnera. ; This work was supported by Fondo Social Europeo, European Union; Fondo Social Europeo para el Desarrollo Regional, European Union; Comunidad Autónoma de Madrid, Spain; Comunidad Autónoma de València, Spain; Instituto Nacional de Técnica Aeroespacial, Spain; and Ministerio de Ciencia y Tecnología, Spain (Grants 2FD1997-1006 and BFM2000- 1383). ; Peer reviewed

Multiple myeloma (MM) is consistently preceded by precursor conditions recognized clinically as monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM). We interrogate the whole genome sequence (WGS) profile of 18 MGUS and compare them with those from 14 SMMs and 80 MMs. We show that cases with a non-progressing, clinically stable myeloma precursor condition (n=15) are characterized by later initiation in the patient's life and by the absence of myeloma defining genomic events including: chromothripsis, templated insertions, mutations in driver genes, aneuploidy, and canonical APOBEC mutational activity. This data provides evidence that WGS can be used to recognize two biologically and clinically distinct myeloma precursor entities that are either progressive or stable. The factors that are associated with myeloma precursor condition progression are not well understood. Here the authors find that monoclonal gammopathies of undetermined significance and smoldering myelomas that did not progress to multiple myelomas have a distinct genomic profile and emerge later in the patient's life. ; We want to thank Dr. Vincent S Rajkumar for important and useful scientific feedback on the final draft. This work was supported by the Society of Memorial Sloan Kettering, by the Sylvester Comprehensive Cancer Center NCI Core Grant (P30 CA 240139), by the Memorial Sloan Kettering Cancer Center NCI Core Grant (P30 CA 008748), by the Multiple Myeloma Research Foundation (MMRF), by the Perelman Family Foundation, and by the Riney Family Multiple Myeloma Research Program Fund. F.M. is supported by the American Society of Hematology, the International Myeloma Foundation and The Society of Memorial Sloan Kettering Cancer Center. N.B. is funded by the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement no. 817997). K.H.M. is supported by the Royal Australasian College of Physicians Dr. Helen Rarity McCreanor Traveling Fellowship. This study is part of the Limburg Clinical Research Center (LCRC) UHasselt-ZOL-Jessa, supported by the foundation Limburg Sterk Merk (LSM), Hasselt University, Ziekenhuis Oost-Limburg and Jessa Hospital. Additionally, this research is supported by Limburgs Kankerfonds, and LiveALife. ; Maura, F (corresponding author), Mem Sloan Kettering Canc Ctr, Dept Med, Myeloma Serv, 1275 York Ave, New York, NY 10021 USA. Landgren, O; Maura, F (corresponding author), Univ Miami, Sylvester Comprehens Canc Ctr, Myeloma Program, Miami, FL 33124 USA. col15@miami.edu; fxm557@med.miami.edu

The multiple myeloma (MM) genome is heterogeneous and evolves through preclinical and post-diagnosis phases. Here we report a catalog and hierarchy of driver lesions using sequences from 67 MM genomes serially collected from 30 patients together with public exome datasets. Bayesian clustering defines at least 7 genomic subgroups with distinct sets of co-operating events. Focusing on whole genome sequencing data, complex structural events emerge as major drivers, including chromothripsis and a novel replication-based mechanism of templated insertions, which typically occur early. Hyperdiploidy also occurs early, with individual trisomies often acquired in different chronological windows during evolution, and with a preferred order of acquisition. Conversely, positively selected point mutations, whole genome duplication and chromoplexy events occur in later disease phases. Thus, initiating driver events, drawn from a limited repertoire of structural and numerical chromosomal changes, shape preferred trajectories of evolution that are biologically relevant but heterogeneous across patients. ; F.M. is supported by AIL (Associazione Italiana Contro le Leucemie-Linfomi e Mieloma ONLUS), by SIES (Società Italiana di Ematologia Sperimentale), and by the Memorial Sloan Kettering Cancer Center NCI Core Grant (P30 CA 008748). N.B. is funded by AIRC (Associazione Italiana per la Ricerca sul Cancro) through a MFAG (no. 17658) and by the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement no. 817997). This work was supported by Department of Veterans Affairs Merit Review Award I01BX001584-01 (N.C.M.), NIH grants P01-155258 (N.C.M., H.A.L., M.F., P.J.C. and K.C.A.) and 5P50CA100707-13 (N.C.M., H.A.L. and K.C.A) ; SI