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Abstract Background Among six extant tiger subspecies, the South China tiger (Panthera tigris amoyensis) once was widely distributed but is now the rarest one and extinct in the wild. All living South China tigers are descendants of only two male and four female wild-caught tigers and they survive solely in zoos after 60 years of effective conservation efforts. Inbreeding depression and hybridization with other tiger subspecies were believed to have occurred within the small, captive South China tiger population. It is therefore urgently needed to examine the genomic landscape of existing genetic variation among the South China tigers. Results In this study, we assembled a high-quality chromosome-level genome using long-read sequences and re-sequenced 29 high-depth genomes of the South China tigers. By combining and comparing our data with the other 40 genomes of six tiger subspecies, we identified two significantly differentiated genomic lineages among the South China tigers, which harbored some rare genetic variants introgressed from other tiger subspecies and thus maintained a moderate genetic diversity. We noticed that the South China tiger had higher F ROH values for longer runs of homozygosity (ROH > 1 Mb), an indication of recent inbreeding/founder events. We also observed that the South China tiger had the least frequent homozygous genotypes of both high- and moderate-impact deleterious mutations, and lower mutation loads than both Amur and Sumatran tigers. Altogether, our analyses indicated an effective genetic purging of deleterious mutations in homozygous states from the South China tiger, following its population contraction with a controlled increase in inbreeding based on its pedigree records. Conclusions The identification of two unique founder/genomic lineages coupled with active genetic purging of deleterious mutations in homozygous states and the genomic resources generated in our study pave the way for a genomics-informed conservation, following the real-time monitoring and rational exchange of reproductive South China tigers among zoos.

BackgroundStroke is a leading cause of long‐term disability worldwide. However, current therapies that promote functional recovery from stroke are limited to physical rehabilitation. No pharmacological therapy is available. Thus, understanding the role of histone deacetylase 2 (HDAC2) in the pathophysiological process of stroke‐induced functional loss may provide a novel strategy for stroke recovery. Methods and ResultsFocal stroke was induced by photothrombosis. LV‐HDAC2‐shRNA‐GFP, LV‐GFP, Ad‐HDAC2‐Flag, or Ad‐inactive‐HDAC2‐Flag was microinjected into the peri‐infarct area immediately after stroke. HDAC inhibitors were microinjected into the peri‐infarct area 4 to 10 days after stroke. Grid‐walking task and cylinder task were conducted to assess motor function. Golgi‐Cox staining, chromatin immunoprecipitation, and electrophysiology were used to reveal the mechanisms underlying stroke recovery. Knockdown or knockout of HDAC2 promoted stroke recovery, whereas overexpression of HDAC2 worsened stroke‐induced functional impairment. More importantly, trichostatin A, a pan‐HDAC inhibitor, promoted functional recovery from stroke in WT mice when used in the delayed phase, but it was ineffective in Hdac2 conditional knockout (Hdac2 CKO) mice. Treatment with suberoylanilide hydroxamic acid, a selective HDAC1 and HDAC2 inhibitor, in the delayed phase of stroke produced sustained functional recovery in mice via epigenetically enhancing neuroplasticity of surviving neurons in the peri‐infarct zone. ConclusionsOur novel findings provide evidence that HDAC2 is a crucial target for functional recovery from stroke. As there are clinically available HDAC inhibitors, our findings could be directly translated into clinical research of stroke.

Narrow therapeutic window limits treatments with thrombolysis and neuroprotection for most stroke patients. Widening therapeutic window remains a critical challenge. Understanding the key mechanisms underlying the pathophysiological events in the peri-infarct area where secondary injury coexists with neuroplasticity over days to weeks may offer an opportunity for expanding the therapeutic window. Here we show that ischemia-induced histone deacetylase 2 (HDAC2) upregulation from 5 to 7 d after stroke plays a crucial role. In this window phase, suppressing HDAC2 in the peri-infarct cortex of rodents by HDAC inhibitors, knockdown or knock-out of Hdac2 promoted recovery of motor function from stroke via epigenetically enhancing cells survival and neuroplasticity of surviving neurons as well as reducing neuroinflammation, whereas overexpressing HDAC2 worsened stroke-induced functional impairment of both WT and Hdac2 conditional knock-out mice. More importantly, inhibiting other isoforms of HDACs had no effect. Thus, the intervention by precisely targeting HDAC2 in this window phase is a novel strategy for the functional recovery of stroke survivors. [ABSTRACT FROM AUTHOR]