SUMMARY Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer.

Although nucleotide resolution maps of genomic structural variants (SVs) have provided insights into the origin and impact of phenotypic diversity in humans, comparable maps in nonhuman primates have thus far been lacking. Using massively parallel DNA sequencing, we constructed fine-resolution genomic structural variation maps in five chimpanzees, five orang-utans, and five rhesus macaques. The SV maps, which are comprised of thousands of deletions, duplications, and mobile element insertions, revealed a high activity of retrotransposition in macaques compared with great apes. By comparison, nonallelic homologous recombination is specifically active in the great apes, which is correlated with architectural differences between the genomes of great apes and macaque. Transcriptome analyses across nonhuman primates and humans revealed effects of species-specific whole-gene duplication on gene expression. We identified 13 gene duplications coinciding with the species-specific gain of tissue-specific gene expression in keeping with a role of gene duplication in the promotion of diversification and the acquisition of unique functions. Differences in the present day activity of SV formation mechanisms that our study revealed may contribute to ongoing diversification and adaptation of great ape and Old World monkey lineages. genome evolution | retrotransposons | neofunctionalization | copy-number variation G enomic structural variants (SVs), including copy number variants and balanced SV forms (such as inversions), are a major source of human genetic variation (1, 2). The development of massively parallel sequencing (MPS) to characterize SVs (3-5) has enabled comprehensive analyses of origin and functional impact of SVs in humans (3, 6). Although SVs are presumed to play a major role in primate evolution and phenotypic variation (7) as well, empirical evidence showing such a role remains scarce (8). Comparative analyses of reference genome assemblies of the chimpanzee (9), orang-utan (10), and rhesus macaque (11) have provided some initial insights into large-scale structural changes in primate genome evolution (12). Microarray technology-based surveys have provided additional glimpses of the abundance of polymorphic unbalanced SVs (i.e., copy number variants) in different primate species, enabling the construction of SV maps at a resolution of tens to hundreds of kilobases (13-16).Thus far, despite ongoing progress in assessing SNP variation in primates (10,(17)(18)(19), no study has leveraged MPS technology for ascertaining inter-and intraspecies SVs in different primates. We, therefore, performed MPS-based genome analyses in five individuals from each of these primate species, Pan troglodytes (chimpanzee), Pongo abelii (orang-utan), and Macaca mulatta (rhesus macaque), to construct comprehensive SV maps in these species. Our analyses have revealed marked differences in SV formation mechanism activities and further yielded a complex relationship between genomic copy number and gene expression patterns, with several gen...

BackgroundWhile active LINE-1 (L1) elements possess the ability to mobilize flanking sequences to different genomic loci through a process termed transduction influencing genomic content and structure, an approach for detecting polymorphic germline non-reference transductions in massively-parallel sequencing data has been lacking.ResultsHere we present the computational approach TIGER (Transduction Inference in GERmline genomes), enabling the discovery of non-reference L1-mediated transductions by combining L1 discovery with detection of unique insertion sequences and detailed characterization of insertion sites. We employed TIGER to characterize polymorphic transductions in fifteen genomes from non-human primate species (chimpanzee, orangutan and rhesus macaque), as well as in a human genome. We achieved high accuracy as confirmed by PCR and two single molecule DNA sequencing techniques, and uncovered differences in relative rates of transduction between primate species.ConclusionsBy enabling detection of polymorphic transductions, TIGER makes this form of relevant structural variation amenable for population and personal genome analysis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2670-x) contains supplementary material, which is available to authorized users.

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