Selection Has Countered High Mutability to Preserve the Ancestral Copy Number of Y Chromosome Amplicons in Diverse Human Lineages.

Amplicons-large, highly identical segmental duplications-are a prominent feature of mammalian Y chromosomes. Although they encode genes essential for fertility, these amplicons differ vastly between species, and little is known about the selective constraints acting on them. Here, we develop computational tools to detect amplicon copy number with unprecedented accuracy from high-throughput sequencing data. We find that one-sixth (16.9%) of 1,216 males from the 1000 Genomes Project have at least one deleted or duplicated amplicon. However, each amplicon's reference copy number is scrupulously maintained among divergent branches of the Y chromosome phylogeny, including the ancient branch A00, indicating that the reference copy number is ancestral to all modern human Y chromosomes. Using phylogenetic analyses and simulations, we demonstrate that this pattern of variation is incompatible with neutral evolution and instead displays hallmarks of mutation-selection balance. We also observe cases of amplicon rescue, in which deleted amplicons are restored through subsequent duplications. These results indicate that, contrary to the lack of constraint suggested by the differences between species, natural selection has suppressed amplicon copy number variation in diverse human lineages.

The validity and reliability of the OneStep smartphone application under various gait conditions in healthy adults with feasibility in clinical practice.

OBJECTIVE: Primary purpose of this study was to determine the validity and reliability of the OneStep smartphone application in healthy adults. Secondary purpose was to determine the feasibility of measuring gait dysfunction, limitation in spatiotemporal characteristics, longitudinally in patients following total hip or knee arthroplasty. METHODS: First objective, 20 healthy adults (mean age, 42.3 ± 19.7 years; 60% males; mean body mass index, 29.0 ± 5.2 kg/m2) underwent gait analysis under four gait conditions (self-selected gait speed, fixed gait speed at 0.8 m/s, fixed gait speed at 2.0 m/s and self-selected gait speed with dual task) for the validity and reliability of the smartphone to the motion laboratory. Reliability was determined by intraclass correlation coefficients. Validity was determined by Pearson correlations. Agreement was assessed by the Bland-Altman method. Second objective, 12 additional patients with total hip or knee arthroplasty (mean age, 58.7 ± 6.5 years; 58% males; mean body mass index, 28.9 ± 5.8 kg/m2) were measured at 2- and 10 weeks postoperatively. The smartphone application was used to evaluate change in gait dysfunction over time within the patients' own environment using paired t test. RESULTS: The smartphone application demonstrated moderate-to-excellent intraclass correlation coefficients for reliability between-system (ICC range, 0.56-0.99), -limb (ICC range, 0.62-0.99) and -device (ICC range, 0.61-0.96) for gait analysis of healthy adults. Pearson correlations were low-to-very high between methods (r range, 0.45-0.99). Bland-Altman analysis revealed relative underestimation of spatiotemporal variables by the smartphone application compared to the motion system. For patients following total hip or knee arthroplasty, gait analysis using the OneStep application demonstrated significant improvement (p < 0.001, Cohen's d > 0.95) in gait dysfunction between 2- and 10 weeks postoperatively. CONCLUSION: The smartphone application can be a valid, reliable and feasible alternative to motion laboratories in evaluating deficits in gait dysfunction in various environments and clinical settings.

Selective Y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining.

Chromosome missegregation into a micronucleus can cause complex and localized genomic rearrangements known as chromothripsis, but the underlying mechanisms remain unresolved. Here we developed an inducible Y centromere-selective inactivation strategy by exploiting a CENP-A/histone H3 chimaera to directly examine the fate of missegregated chromosomes in otherwise diploid human cells. Using this approach, we identified a temporal cascade of events that are initiated following centromere inactivation involving chromosome missegregation, fragmentation, and re-ligation that span three consecutive cell cycles. Following centromere inactivation, a micronucleus harbouring the Y chromosome is formed in the first cell cycle. Chromosome shattering, producing up to 53 dispersed fragments from a single chromosome, is triggered by premature micronuclear condensation prior to or during mitotic entry of the second cycle. Lastly, canonical non-homologous end joining (NHEJ), but not homology-dependent repair, is shown to facilitate re-ligation of chromosomal fragments in the third cycle. Thus, initial errors in cell division can provoke further genomic instability through fragmentation of micronuclear DNAs coupled to NHEJ-mediated reassembly in the subsequent interphase.