Advanced genetics (Hoboken, N.J.)最新文献

In this article, a caveat for advancing the genetics of Lewy body disorders is raised, given the nosological controversy about whether to consider dementia with Lewy bodies (DLB) and Parkinson's disease (PD) as one entity or two separate entities. Using the framework of the sufficient and component causes model of causation, as further developed into an evolution-based model of causation, it is proposed that a disease of complex etiology is defined as having a relatively high degree of sharing of the component causes (a genetic or environmental factor), that is, a low degree of heterogeneity of the sufficient causes. Based on this definition, only if the sharing of component causes within each of two diseases is similar to their combined sharing can lumping be warranted. However, it is not known whether the separate and combined sharing are similar before conducting the etiologic studies. This means that lumping DLB and PD can be counterproductive as it can decrease the ability to detect component causes despite the potential benefit of conducting studies with larger sample sizes. In turn, this is relevant to the development of disease-modifying treatments, because non-overlapping causal genetic factors may result in distinct pathogenetic pathways providing promising targets for interventions.

The fundamental cause of transcription dysregulation in hepatocellular carcinoma (HCC) remains elusive. To investigate the underlying mechanisms, comprehensive 3D-epigenomic analyses are performed in cellular models of THLE2 (a normal hepatocytes cell line) and HepG2 (a hepatocellular carcinoma cell line) using integrative approaches for chromatin topology, genomic and epigenomic variation, and transcriptional output. Comparing the 3D-epigenomes in THLE2 and HepG2 reveal that most HCC-associated genes are organized in complex chromatin interactions mediated by RNA polymerase II (RNAPII). Incorporation of genome-wide association studies (GWAS) data enables the identification of non-coding genetic variants that are enriched in distal enhancers connecting to the promoters of HCC-associated genes via long-range chromatin interactions, highlighting their functional roles. Interestingly, CTCF binding and looping proximal to HCC-associated genes appear to form chromatin architectures that overarch RNAPII-mediated chromatin interactions. It is further demonstrated that epigenetic variants by DNA hypomethylation at a subset of CTCF motifs proximal to HCC-associated genes can modify chromatin topological configuration, which in turn alter RNAPII-mediated chromatin interactions and lead to dysregulation of transcription. Together, the 3D-epigenomic analyses provide novel insights of multifaceted interplays involving genetics, epigenetics, and chromatin topology in HCC cells.

Single-Cell RNA Sequencing

This cover illustrates the work of Xujun Wang, Xianmin Zhu, Peng Zhang, and co-workers in article number 2100060 which reveals the drug-resistance signature and immunosuppressive microenvironment in small cell lung cancer (SCLC) by single-cell RNA-sequencing. “Wu Song Fought the Tiger” comes from the famous Chinese novel: Outlaws of the Marsh. In the cover, the warrior Wu Song stands for the doctors and researchers. The tiger bearing “SCLC” on its face is dangerous for its sharp teeth and claws (early metastasis and drug resistance) and the surrounding water bubbles (immune infiltration). In addition, 2022 is the Year of the Tiger.

Metagenomic datasets of host-associated microbial communities often contain host DNA that is usually discarded because the amount of data is too low for accurate host genetic analyses. However, genotype imputation can be employed to reconstruct host genotypes if a reference panel is available. Here, the performance of a two-step strategy is tested to impute genotypes from four types of reference panels built using different strategies to low-depth host genome data (≈2× coverage) recovered from intestinal samples of two chicken genetic lines. First, imputation accuracy is evaluated in 12 samples for which both low- and high-depth sequencing data are available, obtaining high imputation accuracies for all tested panels (>0.90). Second, the impact of reference panel choice in population genetics statistics on 100 chickens is assessed, all four panels yielding comparable results. In light of the observations, the feasibility and application of the applied imputation strategy are discussed for different species with regard to the host DNA proportion, genomic diversity, and availability of a reference panel. This method enables leveraging insofar discarded host DNA to get insights into the genetic structure of host populations, and in doing so, facilitates the implementation of hologenomic approaches that jointly analyze host and microbial genomic data.

Recent advances in sequencing technologies enable genome-wide analyses for thousands of individuals. The sequential kernel association test (SKAT) is a widely used method to test for associations between a phenotype and a set of rare variants. As the sample size of human genetics studies increases, the computational time required to calculate a kernel is becoming more and more problematic. In this study, a new method to obtain kernel statistics without calculating a kernel matrix is proposed. A simple method for the computation of two kernel statistics, namely, a kernel statistic based on a genetic relationship matrix (GRM) and one based on an identity by state (IBS) matrix, are proposed. By using this method, calculation of the kernel statistics can be conducted using vector calculation without matrix calculation. The proposed method enables one to conduct SKAT for large samples of human genetics.

Parental RNA interference (pRNAi) is a powerful and widely used method for gene-specific knockdown. Yet in insects its efficacy varies between species, and how the systemic response is transmitted from mother to offspring remains elusive. Using the beetle Tribolium castaneum, an RT-qPCR strategy to distinguish the presence of double-stranded RNA (dsRNA) from endogenous mRNA is reported. It is found that injected dsRNA is directly transmitted into the egg and persists throughout embryogenesis. Despite this depletion of dsRNA from the mother, it is shown that strong pRNAi can persist for months before waning at strain-specific rates. In seeking the receptor proteins for cellular uptake of long dsRNA into the egg, a phylogenomics profiling approach of candidate proteins is also presented. A visualization strategy based on taxonomically hierarchical assessment of orthology clustering data to rapidly assess gene age and copy number changes, refined by sequence-based evidence, is demonstrated. Repeated losses of SID-1-like channel proteins in the arthropods, including wholesale loss in the Heteroptera (true bugs), which are nonetheless highly sensitive to pRNAi, are thereby documented. Overall, practical considerations for insect pRNAi against a backdrop of outstanding questions on the molecular mechanism of dsRNA transmission for long-term, systemic knockdown are elucidated.

Extracellular Vesicle Imaging

Cancer cell-derived extracellular vesicles (EVs) promote tumor growth and spread. Studying the distribution of EVs in the body is key to understanding cancer progression and developing therapies. In article number 2100055, Masamitsu Kanada and co-workers develop a highly sensitive EV reporter for tracking heterogeneous EV populations released from cancer cells in live mice.

Cerebellar ataxias (CAs) represent a group of autosomal dominant and recessive neurodegenerative disorders affecting cerebellum with or without spinal cord. Overall, CAs have preponderance for tandem nucleotide repeat expansions as an etiological factor (10 TREs explain nearly 30–40% of ataxia cohort globally). The experience of 10 years of common genetic ataxia subtypes for ≈5600 patients’ referrals (Pan-India) received at a single center is shared herein. Frequencies (in %, n) of SCA types and FRDA in the sample cohort are observed as follows: SCA12 (8.6%, 490); SCA2 (8.5%, 482); SCA1 (4.8%, 272); SCA3 (2%, 113); SCA7 (0.5%, 28); SCA6 (0.1%, 05); SCA17 (0.1%, 05), and FRDA (2.2%, 127). A significant amount of variability in TRE lengths at each locus is observed, we noted presence of biallelic expansion, co-occurrence of SCA-subtypes, and the presence of premutable normal alleles. The frequency of mutated GAA-FRDA allele in healthy controls is 1/158 (0.63%), thus an expected FRDA prevalence of 1:100 000 persons. The data of this study are relevant not only for clinical decision making but also for guidance in direction of genetic investigations, transancestral comparison of genotypes, and lastly provide insight for policy decision for the consideration of SCAs under rare disease category.