Analysis of sex-biased gene expression in a Eurasian admixed population.

Sex-biased gene expression differs across human populations; however, the underlying genetic basis and molecular mechanisms remain largely unknown. Here, we explore the influence of ancestry on sex differences in the human transcriptome and its genetic effects on a Eurasian admixed population: Uyghurs living in Xinjiang (XJU), by analyzing whole-genome sequencing data and transcriptome data of 90 XJU and 40 unrelated Han Chinese individuals. We identified 302 sex-biased expressed genes and 174 sex-biased cis-expression quantitative loci (sb-cis-eQTLs) in XJU, which were enriched in innate immune-related functions, indicating sex differences in immunity. Notably, approximately one-quarter of the sb-cis-eQTLs showed a strong correlation with ancestry composition; i.e. populations of similar ancestry tended to show similar patterns of sex-biased gene expression. Our analysis further suggested that genetic admixture induced a moderate degree of sex-biased gene expression. Interestingly, analysis of chromosome interactions revealed that the X chromosome acted on autosomal immunity-associated genes, partially explaining the sex-biased phenotypic differences. Our work extends the knowledge of sex-biased gene expression from the perspective of genetic admixture and bridges the gap in the exploration of sex-biased phenotypes shaped by autosome and X-chromosome interactions. Notably, we demonstrated that sex chromosomes cannot fully explain sex differentiation in immune-related phenotypes.

Ultra-short cell-free DNA fragments enhance cancer early detection in a multi-analyte blood test combining mutation, protein and fragmentomics.

OBJECTIVES: Cancer morbidity and mortality can be reduced if the cancer is detected early. Cell-free DNA (cfDNA) fragmentomics emerged as a novel epigenetic biomarker for early cancer detection, however, it is still at its infancy and requires technical improvement. We sought to apply a single-strand DNA sequencing technology, for measuring genetic and fragmentomic features of cfDNA and evaluate the performance in detecting multiple cancers. METHODS: Blood samples of 364 patients from six cancer types (colorectal, esophageal, gastric, liver, lung, and ovarian cancers) and 675 healthy individuals were included in this study. Circulating tumor DNA mutations, cfDNA fragmentomic features and a set of protein biomarkers were assayed. Sensitivity and specificity were reported by cancer types and stages. RESULTS: Circular Ligation Amplification and sequencing (CLAmp-seq), a single-strand DNA sequencing technology, yielded a population of ultra-short fragments (<100 bp) than double-strand DNA preparation protocols and reveals a more significant size difference between cancer and healthy cfDNA fragments (25.84 bp vs. 16.05 bp). Analysis of the subnucleosomal peaks in ultra-short cfDNA fragments indicates that these peaks are regulatory element "footprints" and correlates with gene expression and cancer stages. At 98 % specificity, a prediction model using ctDNA mutations alone showed an overall sensitivity of 46 %; sensitivity reaches 60 % when protein is added, sensitivity further increases to 66 % when fragmentomics is also integrated. More improvements observed for samples representing earlier cancer stages than later ones. CONCLUSIONS: These results suggest synergistic properties of protein, genetic and fragmentomics features in the identification of early-stage cancers.

Genetic Connections and Convergent Evolution of Tropical Indigenous Peoples in Asia.

Tropical indigenous peoples in Asia (TIA) attract much attention for their unique appearance, whereas their genetic history and adaptive evolution remain mysteries. We conducted a comprehensive study to characterize the genetic distinction and connection of broad geographical TIAs. Despite the diverse genetic makeup and large interarea genetic differentiation between the TIA groups, we identified a basal Asian ancestry (bASN) specifically shared by these populations. The bASN ancestry was relatively enriched in ancient Asian human genomes dated as early as ∼50,000 years before the present and diminished in more recent history. Notably, the bASN ancestry is unlikely to be derived from archaic hominins. Instead, we suggest it may be better modeled as a survived lineage of the initial peopling of Asia. Shared adaptations inherited from the ancient Asian ancestry were detected among the TIA groups (e.g., LIMS1 for hair morphology, and COL24A1 for bone formation), and they are enriched in neurological functions either at an identical locus (e.g., NKAIN3), or different loci in an identical gene (e.g., TENM4). The bASN ancestry could also have formed the substrate of the genetic architecture of the dark pigmentation observed in the TIA peoples. We hypothesize that phenotypic convergence of the dark pigmentation in TIAs could have resulted from parallel (e.g., DDB1/DAK) or genetic convergence driven by admixture (e.g., MTHFD1 and RAD18), new mutations (e.g., STK11), or notably purifying selection (e.g., MC1R). Our results provide new insights into the initial peopling of Asia and an advanced understanding of the phenotypic convergence of the TIA peoples.

Genetic Origins and Sex-Biased Admixture of the Huis.

The Hui people are unique among Chinese ethnic minorities in that they speak the same language as Han Chinese (HAN) but practice Islam. However, as the second-largest minority group in China numbering well over 10 million, the Huis are under-represented in both global and regional genomic studies. Here, we present the first whole-genome sequencing effort of 234 Hui individuals (NXH) aged over 60 who have been living in Ningxia, where the Huis are mostly concentrated. NXH are genetically more similar to East Asian than to any other global populations. In particular, the genetic differentiation between NXH and HAN (FST = 0.0015) is only slightly larger than that between northern and southern HAN (FST = 0.0010), largely attributed to the western ancestry in NXH (∼10%). Highly differentiated functional variants between NXH and HAN were identified in genes associated with skin pigmentation (e.g., SLC24A5), facial morphology (e.g., EDAR), and lipid metabolism (e.g., ABCG8). The Huis are also distinct from other Muslim groups such as the Uyghurs (FST = 0.0187), especially, NXH derived much less western ancestry (∼10%) compared with the Uyghurs (∼50%). Modeling admixture history indicated that NXH experienced an episode of two-wave admixture. An ancient admixture occurred ∼1,025 years ago, reflecting the intensive west-east contacts during the late Tang Dynasty, and the Five Dynasties and Ten Kingdoms period. A recent admixture occurred ∼500 years ago, corresponding to the Ming Dynasty. Notably, we identified considerable sex-biased admixture, that is, excess of western males and eastern females contributing to the NXH gene pool. The origins and the genomic diversity of the Hui people imply the complex history of contacts between western and eastern Eurasians.

Y-LineageTracker: a high-throughput analysis framework for Y-chromosomal next-generation sequencing data.

BACKGROUND: Y-chromosome DNA (Y-DNA) has been used for tracing paternal lineages and offers a clear path from an individual to a known, or likely, direct paternal ancestor. The advance of next-generation sequencing (NGS) technologies increasingly improves the resolution of the non-recombining region of the Y-chromosome (NRY). However, a lack of suitable computer tools prevents the use of NGS data from the Y-DNA studies. RESULTS: We developed Y-LineageTracker, a high-throughput analysis framework that not only utilizes state-of-the-art methodologies to automatically determine NRY haplogroups and identify microsatellite variants of Y-chromosome on a fine scale, but also optimizes comprehensive Y-DNA analysis methods for NGS data. Notably, Y-LineageTracker integrates the NRY haplogroup and Y-STR analysis modules with recognized strategies to robustly suggest an interpretation for paternal genetics and evolution. NRY haplogroup module mainly covers haplogroup classification, clustering analysis, phylogeny construction, and divergence time estimation of NRY haplogroups, and Y-STR module mainly includes Y-STR genotyping, statistical calculation, network analysis, and estimation of time to the most recent common ancestor (TMRCA) based on Y-STR haplotypes. Performance comparison indicated that Y-LineageTracker outperformed existing Y-DNA analysis tools for the high performance and satisfactory visualization effect. CONCLUSIONS: Y-LineageTracker is an open-source and user-friendly command-line tool that provide multiple functions to efficiently analyze Y-DNA from NGS data at both Y-SNP and Y-STR level. Additionally, Y-LineageTracker supports various formats of input data and produces high-quality figures suitable for publication. Y-LineageTracker is coded with Python3 and supports Windows, Linux, and macOS platforms, and can be installed manually or via the Python Package Index (PyPI). The source code, examples, and manual of Y-LineageTracker are freely available at https://www.picb.ac.cn/PGG/resource.php or CodeOcean ( https://codeocean.com/capsule/7424381/tree ).

Analysis of five deep-sequenced trio-genomes of the Peninsular Malaysia Orang Asli and North Borneo populations.

BACKGROUND: Recent advances in genomic technologies have facilitated genome-wide investigation of human genetic variations. However, most efforts have focused on the major populations, yet trio genomes of indigenous populations from Southeast Asia have been under-investigated. RESULTS: We analyzed the whole-genome deep sequencing data (~ 30×) of five native trios from Peninsular Malaysia and North Borneo, and characterized the genomic variants, including single nucleotide variants (SNVs), small insertions and deletions (indels) and copy number variants (CNVs). We discovered approximately 6.9 million SNVs, 1.2 million indels, and 9000 CNVs in the 15 samples, of which 2.7% SNVs, 2.3% indels and 22% CNVs were novel, implying the insufficient coverage of population diversity in existing databases. We identified a higher proportion of novel variants in the Orang Asli (OA) samples, i.e., the indigenous people from Peninsular Malaysia, than that of the North Bornean (NB) samples, likely due to more complex demographic history and long-time isolation of the OA groups. We used the pedigree information to identify de novo variants and estimated the autosomal mutation rates to be 0.81 × 10- 8 - 1.33 × 10- 8, 1.0 × 10- 9 - 2.9 × 10- 9, and ~ 0.001 per site per generation for SNVs, indels, and CNVs, respectively. The trio-genomes also allowed for haplotype phasing with high accuracy, which serves as references to the future genomic studies of OA and NB populations. In addition, high-frequency inherited CNVs specific to OA or NB were identified. One example is a 50-kb duplication in DEFA1B detected only in the Negrito trios, implying plausible effects on host defense against the exposure of diverse microbial in tropical rainforest environment of these hunter-gatherers. The CNVs shared between OA and NB groups were much fewer than those specific to each group. Nevertheless, we identified a 142-kb duplication in AMY1A in all the 15 samples, and this gene is associated with the high-starch diet. Moreover, novel insertions shared with archaic hominids were identified in our samples. CONCLUSION: Our study presents a full catalogue of the genome variants of the native Malaysian populations, which is a complement of the genome diversity in Southeast Asians. It implies specific population history of the native inhabitants, and demonstrated the necessity of more genome sequencing efforts on the multi-ethnic native groups of Malaysia and Southeast Asia.

Ancestral Origins and Genetic History of Tibetan Highlanders.

The origin of Tibetans remains one of the most contentious puzzles in history, anthropology, and genetics. Analyses of deeply sequenced (30×-60×) genomes of 38 Tibetan highlanders and 39 Han Chinese lowlanders, together with available data on archaic and modern humans, allow us to comprehensively characterize the ancestral makeup of Tibetans and uncover their origins. Non-modern human sequences compose ∼6% of the Tibetan gene pool and form unique haplotypes in some genomic regions, where Denisovan-like, Neanderthal-like, ancient-Siberian-like, and unknown ancestries are entangled and elevated. The shared ancestry of Tibetan-enriched sequences dates back to ∼62,000-38,000 years ago, predating the Last Glacial Maximum (LGM) and representing early colonization of the plateau. Nonetheless, most of the Tibetan gene pool is of modern human origin and diverged from that of Han Chinese ∼15,000 to ∼9,000 years ago, which can be largely attributed to post-LGM arrivals. Analysis of ∼200 contemporary populations showed that Tibetans share ancestry with populations from East Asia (∼82%), Central Asia and Siberia (∼11%), South Asia (∼6%), and western Eurasia and Oceania (∼1%). Our results support that Tibetans arose from a mixture of multiple ancestral gene pools but that their origins are much more complicated and ancient than previously suspected. We provide compelling evidence of the co-existence of Paleolithic and Neolithic ancestries in the Tibetan gene pool, indicating a genetic continuity between pre-historical highland-foragers and present-day Tibetans. In particular, highly differentiated sequences harbored in highlanders' genomes were most likely inherited from pre-LGM settlers of multiple ancestral origins (SUNDer) and maintained in high frequency by natural selection.

A Simple and Scalable Route to Synthesize Cox Cu1- x Co2 O4 @Coy Cu1- y Co2 O4 Yolk-Shell Microspheres, A High-Performance Catalyst to Hydrolyze Ammonia Borane for Hydrogen Production.

Yolk-shell structured micro/nano-sized materials have broad and important applications in different areas due to their unique spatial configurations. In this study, yolk-shell structured Co3 O4 @Co3 O4 is prepared using a simple and scalable hydrothermal reaction, followed by a calcination process. Then, Cox Cu1- x Co2 O4 @Coy Cu1- y Co2 O4 microspheres are synthesized via adsorption and calcination processes using the as-prepared Co3 O4 @Co3 O4 as the precursor. A possible formation mechanism of the yolk-shell structures is proposed based on the characterization results, which is different from those of yolk-shell structures in previous study. For the first time, the catalytic activity of yolk-shell structured catalysts in ammonia borane (AB) hydrolysis is studied. It is discovered that the yolk-shell structured Cox Cu1- x Co2 O4 @Coy Cu1- y Co2 O4 microspheres exhibit high performance with a turnover frequency (TOF) of 81.8 molhydrogen min-1 molcat -1 . This is one of the highest TOF values reported for a noble-metal-free catalyst in the literature. Additionally, the yolk-shell structured Cox Cu1- x Co2 O4 @Coy Cu1- y Co2 O4 microspheres are highly stable and reusable. These yolk-shell structured Cox Cu1- x Co2 O4 @Coy Cu1- y Co2 O4 microsphere is a promising catalyst candidate in AB hydrolysis considering the excellent catalytic behavior and low cost.

Genetic History of Xinjiang's Uyghurs Suggests Bronze Age Multiple-Way Contacts in Eurasia.

The Uyghur people residing in Xinjiang, a territory located in the far west of China and crossed by the Silk Road, are a key ethnic group for understanding the history of human dispersion in Eurasia. Here we assessed the genetic structure and ancestry of 951 Xinjiang's Uyghurs (XJU) representing 14 geographical subpopulations. We observed a southwest and northeast differentiation within XJU, which was likely shaped jointly by the Tianshan Mountains, which traverses from east to west as a natural barrier, and gene flow from both east and west directions. In XJU, we identified four major ancestral components that were potentially derived from two earlier admixed groups: one from the West, harboring European (25-37%) and South Asian ancestries (12-20%), and the other from the East, with Siberian (15-17%) and East Asian (29-47%) ancestries. By using a newly developed method, MultiWaver, the complex admixture history of XJU was modeled as a two-wave admixture. An ancient wave was dated back to ∼3,750 years ago (ya), which is much earlier than that estimated by previous studies, but fits within the range of dating of mummies that exhibited European features that were discovered in the Tarim basin, which is situated in southern Xinjiang (4,000-2,000 ya); a more recent wave occurred around 750 ya, which is in agreement with the estimate from a recent study using other methods. We unveiled a more complex scenario of ancestral origins and admixture history in XJU than previously reported, which further suggests Bronze Age massive migrations in Eurasia and East-West contacts across the Silk Road.

Genomic structure of the native inhabitants of Peninsular Malaysia and North Borneo suggests complex human population history in Southeast Asia.

Southeast Asia (SEA) is enriched with a complex history of peopling. Malaysia, which is located at the crossroads of SEA, has been recognized as one of the hubs for early human migration. To unravel the genomic complexity of the native inhabitants of Malaysia, we sequenced 12 samples from 3 indigenous populations from Peninsular Malaysia and 4 native populations from North Borneo to a high coverage of 28-37×. We showed that the Negritos from Peninsular Malaysia shared a common ancestor with the East Asians, but exhibited some level of gene flow from South Asia, while the North Borneo populations exhibited closer genetic affinity towards East Asians than the Malays. The analysis of time of divergence suggested that ancestors of Negrito were the earliest settlers in the Malay Peninsula, whom first separated from the Papuans ~ 50-33 thousand years ago (kya), followed by East Asian (~ 40-15 kya), while the divergence time frame between North Borneo and East Asia populations predates the Austronesian expansion period implies a possible pre-Neolithic colonization. Substantial Neanderthal ancestry was confirmed in our genomes, as was observed in other East Asians. However, no significant difference was observed, in terms of the proportion of Denisovan gene flow into these native inhabitants from Malaysia. Judging from the similar amount of introgression in the Southeast Asians and East Asians, our findings suggest that the Denisovan gene flow may have occurred before the divergence of these populations and that the shared similarities are likely an ancestral component.