Grandomics (China)

Recent advances in long-read sequencing technologies have empowered the detection of structural variations (SVs) associated with genetic diseases. Despite the availability of numerous SV callers and efforts to merge SVs from multiple tools, there remains limited research on quantifying the confidence levels for the reported results. In this work, we propose a Bayesian integration model that combines SV calls from different tools. Notably, we introduce an approach for false discovery rate (FDR) control and provide a quantitative measure for the merged SVs. Our model can handle cases where certain tools lack quality scores, showcasing its flexibility in incorporating additional tools. Through extensive simulation studies, we evaluate the performance of our method under various conditions, demonstrating the FDR estimation accuracy and improved F1 score. Furthermore, we validate our model using simulated human genome sequencing data and the HG002dataset.

Abstract NADK is the sole cytosolic enzyme responsible for synthesizing NADP+from NAD+within cells. The homeostasis of NAD+/NADP+is controlled by NADK, usually dysregulated in various cancers, yet the precise underlying regulatory mechanisms remain largely unknown. In this study, we discover that PRMT6 methylates NADK at R39, R41, and R45, resulting in the suppression of NADK kinase activity and NADP+synthesis. Mutations of these sites promote cancer cell proliferation and tumor growth. PRMT6-mediated methylation of NADK coordinates with Akt-mediated phosphorylation to regulate NADK, which stimulates its activity to increase NADP+production through relief of an autoinhibitory function inherent to its amino terminus. PRMT6 also inhibits NADK activity in a phosphorylation-independent manner. Furthermore, NADK methylation is upregulated by RB1/E2F pathway in high-fat diet mice. Downregulation of NADK methylation in HCC enhances NADP+production to promote cancer development. Our findings illuminate the molecular regulatory mechanisms governing NAD+/NADP+homeostasis, suggesting that the PRMT6-NADK axis emerges as a direct player in high energy state. Furthermore, our research suggests potential therapeutic targets through chemical and genetic interventions.SignificancePrevious studies revealed that phosphorylation of NADK activates its activity in response to nutrient or other signaling pathways. Here, we discovered that PRMT6 methylates NADK at residues R39, R41, and R45, leading to the suppression of NADK kinase activity and NADP+synthesis. This PRMT6-mediated methylation works in conjunction with Akt-mediated phosphorylation to regulate NADK. Additionally, we found that NADK methylation is upregulated by the RB1/E2F pathway in mice on a high-fat diet. In hepatocellular carcinoma (HCC), the downregulation of NADK methylation enhances NADP+production, thereby promoting cancer development. Our findings provide a significant breakthrough in understanding the regulation of NADK and its response to environmental factors.

Wild barley, from “Evolution Canyon (EC)” in Mount Carmel, Israel, are ideal models for cereal chromosome evolution studies. Here, the wild barley EC_S1 is from the south slope with higher daily temperatures and drought, while EC_N1 is from the north slope with a cooler climate and higher relative humidity, which results in a differentiated selection due to contrasting environments. We assembled a 5.03 Gb genome with contig N50 of 3.53 Mb for wild barley EC_S1 and a 5.05 Gb genome with contig N50 of 3.45 Mb for EC_N1 using 145 Gb and 160.0 Gb Illumina sequencing data, 295.6 Gb and 285.35 Gb Nanopore sequencing data and 555.1 Gb and 514.5 Gb Hi-C sequencing data, respectively. BUSCOs and CEGMA evaluation suggested highly complete assemblies. Using full-length transcriptome data, we predicted 39,179 and 38,373 high-confidence genes in EC_S1 and EC_N1, in which 93.6% and 95.2% were functionally annotated, respectively. We annotated repetitive elements and non-coding RNAs. These two wild barley genome assemblies will provide a rich gene pool for domesticated barley.

Eucommia ulmoides Oliver is a typical dioecious plant endemic to China that has great medicinal and economic value. Here, we report a high-quality chromosome-level female genome of E. ulmoides obtained by PacBio and Hi-C technologies. The size of the female genome assembly was 1.01 Gb with 17 pseudochromosomes and 31,665 protein coding genes. In addition, Hi-C technology was used to reassemble the male genome released in 2018. The reassembled male genome was 1.24 Gb with the superscaffold N50 (48.30 Mb), which was increased 25.69 times, and the number of predicted genes increased by 11,266. Genome evolution analysis indicated that E. ulmoides has undergone two whole-genome duplication events before the divergence of female and male, including core eudicot γ whole-genome triplication event (γ-WGT) and a recent whole genome duplication (WGD) at approximately 27.3 million years ago (Mya). Based on transcriptome analysis, EuAP3 and EuAG may be the key genes involved in regulating the sex differentiation of E. ulmoides. Pathway analysis showed that the high expression of ω-3 fatty acid desaturase coding gene EU0103017 was an important reason for the high α-linolenic acid content in E. ulmoides. The genome of female and male E. ulmoides presented here is a valuable resource for the molecular biological study of sex differentiation of E. ulmoides and also will provide assistance for the breeding of superior varieties.

Abstract Long read sequencing data, particularly those derived from the Oxford Nanopore (ONT) sequencing platform, tend to exhibit a high error rate. Here, we present NextDenovo, a highly efficient error correction and assembly tool for noisy long reads, which achieves a high level of accuracy in genome assembly. NextDenovo can rapidly correct reads; these corrected reads contain fewer errors than other comparable tools and are characterized by fewer chimeric alignments. We applied NextDenovo to the assembly of high quality reference genomes of 35 diverse humans from across the world using ONT Nanopore long read sequencing data. Based on these de novo genome assemblies, we were able to identify the landscape of segmental duplications and gene copy number variation in the modern human population. The use of the NextDenovo program should pave the way for population-scale long-read assembly, thereby facilitating the construction of human pan-genomes, using Nanopore long read sequencing data.

Sericinus montelus (Lepidoptera, Papilionidae, Parnassiinae) is a high-value ornamental swallowtail butterfly species widely distributed in Northern and Central China, Japan, Korea, and Russia. The larval stage of this species feeds exclusively on Aristolochia plants. The Aristolochia species is well known for its high levels of aristolochic acids (AAs), which have been found to be carcinogenic for numerous animals. The swallowtail butterfly is among the few that can feed on these toxic host plants. However, the genetic adaptation of S. montelus to confer new abilities for AA tolerance has not yet been well explored, largely due to the limited genomic resources of this species. This study aimed to present a chromosome-level reference genome for S. montelus using the Oxford Nanopore long-read sequencing, Illumina short-read sequencing, and Hi-C technology. The final assembly was composed of 581.44Mb with an expected genome size of 619.27Mb. Further, 99.98% of the bases could be anchored onto 30 chromosomes. The N50 of contigs and scaffolds was 5.74 and 19.12Mb, respectively. Approximately 48.86% of the assembled genome was suggested to be repeat elements, and 13,720 protein-coding genes were predicted in the current assembly. The phylogenetic analysis indicated that S. montelus diverged from the common ancestor of swallowtails about 58.57-80.46 million years ago. Compared with related species, S. montelus showed a significant expansion of P450 gene family members, and positive selections on eloa, heatr1, and aph1a resulted in the AA tolerance for S. montelus larva. The de novo assembly of a high-quality reference genome for S. montelus provided a fundamental genomic tool for future research on evolution, genome genetics, and toxicology of the swallowtail butterflies.

Divergent selection of populations in contrasting environments leads to functional genomic divergence. However, the genomic architecture underlying heterogeneous genomic differentiation remains poorly understood. Here, we de novo assembled two high-quality wild barley (Hordeum spontaneum K. Koch) genomes and examined genomic differentiation and gene expression patterns under abiotic stress in two populations. These two populations had a shared ancestry and originated in close geographic proximity but experienced different selective pressures due to their contrasting micro-environments. We identified structural variants that may have played significant roles in affecting genes potentially associated with well-differentiated phenotypes such as flowering time and drought response between two wild barley genomes. Among them, a 29-bp insertion into the promoter region formed a cis-regulatory element in the HvWRKY45 gene, which may contribute to enhanced tolerance to drought. A single SNP mutation in the promoter region may influence HvCO5 expression and be putatively linked to local flowering time adaptation. We also revealed significant genomic differentiation between the two populations with ongoing gene flow. Our results indicate that SNPs and small SVs link to genetic differentiation at the gene level through local adaptation and are maintained through divergent selection. In contrast, large chromosome inversions may have shaped the heterogeneous pattern of genomic differentiation along the chromosomes by suppressing chromosome recombination and gene flow. Our research offers novel insights into the genomic basis underlying local adaptation and provides valuable resources for the genetic improvement of cultivated barley.