Complex Reorganization and Predominant Non-Homologous Repair Following Chromosomal Breakage in Karyotypically Balanced Germline Rearrangements and Transgenic Integration

We defined the genetic landscape of balanced chromosomal rearrangements at nucleotide resolution by sequencing 141 breakpoints from cytogenetically-interpreted translocations and inversions. We confirm that the recently described phenomenon of “chromothripsis” (massive chromosomal shattering and reorganization) is not unique to cancer cells but also occurs in the germline where it can resolve to a karyotypically balanced state with frequent inversions. We detected a high incidence of complex rearrangements (19.2%) and substantially less reliance on microhomology (31%) than previously observed in benign CNVs. We compared these results to experimentally-generated DNA breakage-repair by sequencing seven transgenic animals, and revealed extensive rearrangement of the transgene and host genome with similar complexity to human germline alterations. Inversion is the most common rearrangement, suggesting that a combined mechanism involving template switching and non-homologous repair mediates the formation of balanced complex rearrangements that are viable, stably replicated and transmitted unaltered to subsequent generations

Do Psychological Features Distinguish Those Who Sexually Offend Against Different Age Groups From Those Who Are Stable in Victim Age?

[Aim/Background] Victim age polymorphism occurs when someone offends against victims that span multiple age groups (e.g., child and adult victims). There is a need to better understand the correlates of age polymorphism, as clinicians are often asked about risk of offending against victims who may differ from the index offence victim as part of their risk formulation. The present study examines several potential correlates of age polymorphism: psychopathy, sexual preoccupation, multiple paraphilias, psychosis, and substance use disorders. [Materials/Method] Analyses were conducted using secondary clinical assessment data from a provincial forensic sexual behaviour program. The sample included 387 men with two or more contact sexual offence victims. The assessment data in the archival database included comprehensive information about victim age, as well as standardized assessment measures and diagnostic/clinical impressions. [Results] There were no significant associations between age polymorphism and psychopathy, multiple paraphilias, sexual preoccupation, psychosis, and substance use disorders. The only significant difference that emerged was that men who offended against victims 16 or older had a higher mean score on a measure of drug misuse than those who offended against victims 6 to 11. Most of the analyses produced small effects. [Conclusion] Our findings did not identify significant correlates of age polymorphism when restricting analyses to those men who offended against two or more victims. We consider key methodological differences that may have impacted our findings, as well as the need for rigorously designed research to develop a comprehensive model of age polymorphism

Whole-genome landscape of pancreatic neuroendocrine tumours

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling