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Sequences homologous to human herpesvirus 6 (HHV-6) are integrated within the nuclear genome of about 1% of humans, but it is not clear how this came about. It is also uncertain whether integrated HHV-6 can reactive into an infectious virus. HHV-6 integrates into telomeres, and this has recently been associated with polymorphisms affecting MOV10L1. MOV10L1 is located on the subtelomere of chromosome 22q (chr22q) and is required to make PIWI-interacting RNAs (piRNAs). As piRNAs block germline integration of transposons, piRNA-mediated repression of HHV-6 integration has been proposed to explain this association. In vitro, recombination of the HHV-6 genome along its terminal direct repeats (DRs) leads to excision from the telomere and viral reactivation, but the expected "solo-DR scar" has not been described in vivo. Here we screened for integrated HHV-6 in 7,485 Japanese subjects using whole-genome sequencing (WGS). Integrated HHV-6 was associated with polymorphisms on chr22q. However, in contrast to prior work, we find that the reported MOV10L1 polymorphism is physically linked to an ancient endogenous HHV-6A variant integrated into the telomere of chr22q in East Asians. Unexpectedly, an HHV-6B variant has also endogenized in chr22q; two endogenous HHV-6 variants at this locus thus account for 72% of all integrated HHV-6 in Japan. We also report human genomes carrying only one portion of the HHV-6B genome, a solo-DR, supporting in vivo excision and possible viral reactivation. Together these results explain the recently-reported association between integrated HHV-6 and MOV10L1/piRNAs, suggest potential exaptation of HHV-6 in its coevolution with human chr22q, and clarify the evolution and risk of reactivation of the only intact (non-retro)viral genome known to be present in human germlines. Author summary: Human herpesvirus 6 (HHV-6) infects most people during childhood and can reactivate later in life to contribute to diseases. The HHV-6 genome is also inherited by about 1% of people, included in the end "cap" of one of their 46 chromosomes. Little is known about how HHV-6 genomes entered human genomes, whether or not they still do, and the risk this poses for virus reactivation. We looked for HHV-6 in genome sequences from ~7,500 Japanese people. Most integrated HHV-6 variants have been co-evolving with human chromosomes for many generations. Surprisingly, in almost three-fourths of Japanese people with HHV-6 in their genome, HHV-6 is integrated in the same end of the same chromosome– 22q. Persistence of the HHV-6 genome within the short "cap" that preserves the end of chromosome 22q raises the question of whether the integrated viral sequence has taken on a useful function for this chromosome. Some human genomes harbor only one part of the HHV-6 genome–the same part that remains after experimental HHV-6 reactivation, during which most of the virus is cut out of the genome. This suggests that integration of HHV-6 into inherited human genomes is not irreversible, and possibly leads to production of infectious virus. [ABSTRACT FROM AUTHOR]

Background: Genetic testing has been conducted in patients with prostate cancer (PCa) using multigene panels, but no centralized guidelines for genetic testing exist. To overcome this limitation, we investigated the demographic and clinical characteristics of patients with pathogenic variants.Methods: We sequenced eight genes associated with hereditary PCa in 7636 unselected Japanese patients with PCa and 12 366 male, cancer-free control individuals. We assigned clinical significance for all 1456 variants using the American College of Medical Genetics and Genomics guidelines and ClinVar. We compared the frequency of carriers bearing pathogenic variants between cases and control participants with calculated PCa risk in each gene and documented the demographic and clinical characteristics of patients bearing pathogenic variants. All statistical tests were two-sided.Results: We identified 136 pathogenic variants, and 2.9% of patients and 0.8% of control individuals had a pathogenic variant. Association with PCa risk was statistically significant for variants in BRCA2 (P < .001, odds ratio [OR] = 5.65, 95% confidence interval [CI] = 3.55 to 9.32), HOXB13 (P < .001, OR = 4.73, 95% CI = 2.84 to 8.19), and ATM (P < .001, OR = 2.86, 95% CI = 1.63 to 5.15). We detected recurrent new pathogenic variants such as p.Gly132Glu of HOXB13. Patients with pathogenic variants were 2.0 years younger at diagnosis and more often had smoking and alcohol drinking histories as well as family histories of breast, pancreatic, lung, and liver cancers.Conclusions: This largest sequencing study of PCa heredity provides additional evidence supporting the latest consensus among clinicians for developing genetic testing guidelines for PCa. [ABSTRACT FROM AUTHOR]

Family and twin studies have indicated that genetic factors have an important role in panic disorder (PD), whereas its pathogenesis has remained elusive. We conducted a genome-wide copy number variation (CNV) association study to elucidate the involvement of structural variants in the etiology of PD. The participants were 2055 genetically unrelated Japanese people (535 PD cases and 1520 controls). CNVs were detected using Genome-Wide Human SNP array 6.0, determined by Birdsuite and confirmed by PennCNV. They were classified as rare CNVs (found in <1% of the total sample) or common CNVs (found in 5%). PLINK was used to perform global burden analysis for rare CNVs and association analysis for common CNVs. The sample yielded 2039 rare CNVs and 79 common CNVs. Significant increases in the rare CNV burden in PD cases were not found. Common duplications in 16p11.2 showed Bonferroni-corrected P-values <0.05. Individuals with PD did not exhibit an increased genome-wide rare CNV burden. Common duplications were associated with PD and found in the pericentromeric region of 16p11.2, which had been reported to be rich in low copy repeats and to harbor developmental disorders, neuropsychiatric disorders and dysmorphic features. [ABSTRACT FROM AUTHOR]