Search

Introduction Down syndrome (DS), the most common form of intellectual disability, arises from total or partial triplication of chromosome 21. As one of the critical risk factors for early-onset Alzheimer's [...], Down syndrome (DS), or trisomy 21, is one of the critical risk factors for early-onset Alzheimer's disease (AD), implicating key roles for chromosome 21-encoded genes in the pathogenesis of AD. We previously identified a role for the deubiquitinase USP25, encoded on chromosome 21, in regulating microglial homeostasis in the AD brain; however, whether USP25 affects amyloid pathology remains unknown. Here, by crossing 5*FAD AD and Dp16 DS mice, we observed that trisomy 21 exacerbated amyloid pathology in the 5*FAD brain. Moreover, bacterial artificial chromosome (BAC) transgene-mediated USP25 overexpression increased amyloid deposition in the 5*FAD mouse brain, whereas genetic deletion of Usp25 reduced amyloid deposition. Furthermore, our results demonstrate that USP25 promoted p cleavage of APP and Ap generation by reducing the ubiquitination and lysosomal degradation of both APP and BACE1. Importantly, pharmacological inhibition of USP25 ameliorated amyloid pathology in the 5*FAD mouse brain. In summary, we identified the DS-related gene USP25 as a critical regulator of AD pathology, and our data suggest that USP25 serves as a potential pharmacological target for AD drug development.

Mongolians dwell at the Eastern Eurasian Steppe, where is the agriculture and pasture interlaced area, practice pastoral subsistence strategies for generations, and have their own complex genetic formation history. There is evidence that the eastward expansion of Western Steppe herders transformed the lifestyle of post-Bronze Age Mongolia Plateau populations and brought gene flow into the gene pool of Eastern Eurasians. Here, we reported genome-wide data for 42 individuals from the Inner Mongolia Autonomous Region of North China. We observed that our studied Mongolians were structured into three distinct genetic clusters possessing different genetic affinity with previous studied Inner Mongolians and Mongols and various Eastern and Western Eurasian ancestries: two subgroups harbored dominant Eastern Eurasian ancestry from Neolithic millet farmers of Yellow River Basin; another subgroup derived Eastern Eurasian ancestry primarily from Neolithic hunter-gatherers of North Asia. Besides, three-way/four-way qpAdm admixture models revealed that both north and southern Western Eurasian ancestry related to the Western Steppe herders and Iranian farmers contributed to the genetic materials into modern Mongolians. ALDER-based admixture coefficient and haplotype-based GLOBETROTTER demonstrated that the former western ancestry detected in modern Mongolian could be recently traced back to a historic period in accordance with the historical record about the westward expansion of the Mongol empire. Furthermore, the natural selection analysis of Mongolians showed that the Major Histocompatibility Complex (MHC) region underwent significantly positive selective sweeps. The functional genes, alcohol dehydrogenase (ADH) and lactase persistence (LCT), were not identified, while the higher/lower frequencies of derived mutations were strongly correlated with the genetic affinity to East Asian/Western Eurasian populations. Our attested complex population movement and admixture in the agriculture and pasture interlaced area played an important role in the formation of modern Mongolians. [ABSTRACT FROM AUTHOR]

Mongolian populations are widely distributed geographically, showing abundant ethnic diversity with geographic and tribal differences. To infer the genetic substructure, admixture and ancient genetic sources of Mongolians together with Kazakhs We genotyped more than 690,000 genome-wide SNPs from 33 Mongolian and Chinese Kazakh individuals and compared these with both ancient and present-day Eurasian populations using Principal Component Analysis (PCA), ADMIXTURE, Refine-IBD, f statistics, qpWave and qpAdm. We found genetic substructures within Mongolians corresponding to Ölöd, Chahar, and Inner Mongolian clusters, which was consistent with tribe classifications. Mongolian and Kazakh groups derived about 6–40% of West Eurasian related ancestry, most likely from Bronze Age Steppe populations. The East Asian related ancestry in Mongolian and Kazakh groups was well represented by the Neolithic DevilsCave related nomadic lineage, comprising 42–64% of studied groups. We also detected 10–51% of Han Chinese related ancestry in Mongolian and Kazakh groups, especially in Inner Mongolians. The average admixture times for Inner Mongolian, Mongolian_Chahar, Mongolian_Ölöd and Chinese Kazakh were about 1381, 626, 635 and 632 years ago, respectively, with Han and French as the sources. The DevilsCave related ancestry was once widespread westwards covering a wide geographical range from Far East Russia to the Mongolia Plateau. The formation of present-day Mongolic and Turkic-speaking populations has also received genetic influence from agricultural expansion. [ABSTRACT FROM AUTHOR]