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Liu, H.-J.

Publications and source records attributed to Liu, H.-J..

4 recordsLinked to original sources

JanusX: an integrated and high-performance platform for scalable genome-wide association studies and genomic selection

As genomic datasets expand in both sample size and marker density, genome-wide association studies (GWAS) and genomic selection (GS) require workflows that remain statistically rigorous, computationally efficient, and reproducible across the full analysis path, from genotype matrix to decision-relevant outputs. Here we present JanusX, an integrated high-performance framework that provides a streamlined, user-oriented workflow for GWAS and GS by unifying data handling, model execution, and visualization. Across simulated and real datasets, JanusX maintained high concordance with established baselines while substantially reducing runtime and memory usage. In GWAS, JanusX achieved up to a 19-fold speedup over GEMMA in linear mixed model (LMM) inference, and implemented additional LMM inference based on a sparse genomic relationship matrix with GRAMMAR-Gamma calibration, alleviating computational and memory bottlenecks in large-scale cohorts. JanusX also provides a FarmCPU implementation within its GWAS module, achieving a median 11.4-fold runtime improvement and reducing peak memory usage by 84.9% relative to rMVP. In GS, JanusX integrates an optimized best linear unbiased prediction (BLUP) backend that adaptively selects sample- and SNP-space solvers and incorporates a Preconditioned Conjugate Gradient (PCG) solver. This implementation efficiently completes five-fold cross-validation of 500k individuals x 500k single-nucleotide polymorphisms (SNPs) in 35.1 minutes with only 14.3 gibibyte (GiB) of peak memory. Beyond BLUP, JanusX integrates Bayesian and machine-learning predictors under a single interface with compact automatic tuning to ensure robust cross-model performance. JanusX therefore enables efficient locus discovery and genomic prediction under consistent analytical assumptions, even in large-scale cohorts.

bioinformatics↗

Towards an unbiased characterization of genetic polymorphism

Our view of genetic polymorphism is shaped by methods that provide a limited and reference-biased picture. Long-read sequencing technologies, which are starting to provide nearly complete genome sequences for population samples, should solve the problem--except that characterizing and making sense of non-SNP variation is difficult even with perfect sequence data. Here we analyze 27 genomes of Arabidopsis thaliana in an attempt to address these issues, and illustrate what can be learned by analyzing whole-genome polymorphism data in an unbiased manner. Estimated genome sizes range from 135 to 155 Mb, with differences almost entirely due to centromeric and rDNA repeats that are difficult to assemble. The completely assembled chromosome arms comprise roughly 120 Mb in all accessions, but are full of structural variants, largely due to transposable elements. Even with only 27 accessions, a pan-genome coordinate system that includes the resulting variation ends up being [~] 70% larger than the size of any one genome. Our analysis reveals an incompletely annotated mobile-ome: we not only detect several novel TE families, but also find that existing TE annotation is a poor predictor of elements that have recently been active. In contrast to this, the genic portion, or "gene-ome", is highly conserved. By annotating each genome using accession-specific transcriptome data, we find that 13% of all (non-TE) genes are segregating in our 27 accessions, but most of these are transcriptionally silenced. Finally, we show that with short-read data we previously massively underestimated genetic variation of all kinds, including SNPs--mostly in regions where short reads could not be mapped reliably, but also where reads were mapped incorrectly. We demonstrate that SNP-calling errors can be biased by the choice of reference genome, and that RNA-seq and BS-seq results can be strongly affected by mapping reads only to a reference genome rather than to the genome of the assayed individual. In conclusion, while whole-genome polymorphism data pose tremendous analytical challenges, they also have the potential to revolutionize our understanding of genome evolution.

genomics↗

On the contribution of genetic heterogeneity to complex traits

Genetic heterogeneity, where different alleles or loci are responsible for similar phenotypes, reduces the power of genome-wide association studies and can cause misleading results. Although many striking examples have been identified, the general importance of genetic heterogeneity for complex traits is unclear. Here, we use a novel interpretative machine-learning approach to look for evidence of genetic heterogeneity in plants and humans. Our approach helps identify new loci/alleles influencing trait variation in several agriculturally important species, and we show that at least 6% of maize eQTL, half of them newly identified, exhibit evidence of allelic heterogeneity. Finally, we search for evidence of synthetic associations in human GWAS data, and find that as many as 3-5% may be affected. Our results highlight the need to take genetic heterogeneity seriously, and provide a simple approach for doing so.

genetics↗

Interleukin-6 mediates PSAT1 expression and serine metabolism in TSC2-deficient cells

Tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM) are caused by aberrant mechanistic Target of Rapamycin Complex 1 (mTORC1) activation due to loss of either TSC1 or TSC2. Cytokine profiling of TSC2-deficient LAM patient-derived cells revealed striking upregulation of Interleukin-6 (IL-6). LAM patient plasma contained increased circulating IL-6 compared with healthy controls, and TSC2-deficient cells showed upregulation of IL-6 transcription and secretion compared to wildtype cells. IL-6 blockade repressed the proliferation and migration of TSC2-deficient cells and reduced oxygen consumption and extracellular acidification. U-13C glucose tracing revealed that IL-6 knockout reduced 3-phosphoserine and serine production in TSC2-deficient cells, implicating IL-6 in de novo serine metabolism. IL-6 knockout reduced expression of phosphoserine aminotransferase 1 (PSAT1), an essential enzyme in serine biosynthesis. Importantly, recombinant IL-6 treatment rescued PSAT1 expression in the TSC2-deficient, IL-6 knockout clones selectively and had no effect on wildtype cells. Treatment with anti-IL-6 (aIL-6) antibody similarly reduced cell proliferation and migration and reduced renal tumors in Tsc2+/- mice, while reducing PSAT1 expression. These data reveal a novel mechanism through which IL-6 regulates serine biosynthesis, with potential relevance to the therapy of tumors with mTORC1 hyperactivity. ClassificationMajor category: Biological Sciences Minor category: Cell Biology

pathology↗