Biology subjects

Liao, W.-W.

Publications and source records attributed to Liao, W.-W..

6 recordsLinked to original sources

bioRxiv2026

HPRC2: A human pangenome reference with near-complete coverage of common genetic variation

A pangenome reference overcomes the inherent limitation of any individual reference genome by integrating the variation present in a population. We present the Human Pangenome Reference Consortiums (HPRC) Release 2 (HPRC2), an openly available, second phase pangenome that is an approximately fivefold expansion in genome number over HPRC Release 1 (HPRC1) and measurable improvement in genome completeness, contiguity, and accuracy. Selecting samples with a principled algorithm prioritising common variant coverage, HPRC2 contributes 460 haplotypes that together capture over 99% of common variation observed in the All of Us Research Program v8 cohort. Combining high-coverage long and ultra-long reads with modern assemblers and polishers, we produce thousands of telomere-to-telomere (T2T) chromosomes, and relative to HPRC1 halve the number of structurally unreliable regions as well as individual base errors per haplotype. We complement the assemblies with whole genome multiple alignments and gene annotations, and derive formal pangenome coordinate systems for addressing off-reference variation, demonstrating that individual human genomes contain more than one hundred thousand variants not succinctly described with respect to existing reference genomes. We also present the first matched long-read backed pantranscriptome and panepigenome at this scale, provide continuous local-ancestry estimates spanning every genome, and outline a host of new tools and applications that leverage the pangenome resource for improved genomics analysis.

genomics↗

bioRxiv2026

Pangenome-based human genome analysis improves trait association and genomic prediction

The Human Pangenome Reference Consortium has generated 462 open-access reference genomes and a variation graph that represents differences among them, providing a substrate for pangenome-based analysis methods that overcome the longstanding limitation of comparing all genomic data to a single linear reference. A key unresolved question is the extent to which these approaches can improve trait mapping. We investigate this using the genetics of gene expression variation as a model. We developed a graph-based method (EdgeDepth) for associating sequence variation with traits using short-read genome sequencing data, and show that it captures complex forms of genetic variation missed by other methods. We evaluated trait mapping performance using 430 samples with deep RNA-seq data, and found that pangenomic methods enable the detection of expression quantitative trait loci involving multiallelic indels and structural variants, leading to increased power at a subset of genes. These include 812 genes (7.9% of total) with [≥]20% improvement in statistical significance relative to the 1000 Genomes Project callset, and 185 (1.8%) with a 50% improvement, 10 of which are candidates to explain prior GWAS results. Notably, these analyses implicate GBAP1 pseudogene copy number as a causal factor in Crohns disease, likely via miRNA-mediated regulation of GBA1, which explains prior GWAS results based on flanking SNPs. The inclusion of pangenome-specific variation also improved the performance of gene expression prediction models, with median variance explained increasing from 10.1% to 12.5%, and 14.6% of genes showing significant improvement ({Delta}r2>0.05). Taken together, these results suggest that integration of pangenomic methods into human genetic studies will improve trait association and genomic prediction at a meaningful subset of genes.

genetics↗

bioRxiv2026

LongcallD: joint calling and phasing of small, structural and mosaic variants from long reads

Long-read sequencing is a powerful technique capturing multiple variants within single continuous reads. This length allows individual reads to bridge small and structural variants while carrying crucial phasing information. However, current computational tools treat small variant calling, structural variant (SV) detection and phasing as largely disconnected problems, failing to unleash the full potential of long reads. Here, we present longcallD, a unified framework utilizing local multiple-sequence alignment to simultaneously call and phase small and structural variants. By integrating germline phasing and retrotransposition hallmarks, longcallD also identifies low-fraction mosaic variants and detects mobile element insertions supported by a single read. Compared to existing methods, our unified approach substantially improves SV discovery and mosaic variants accuracy while maintaining competitive small variant calling. We anticipate that longcallD will provide a robust foundation for resolving complex genetic architectures in clinical and evolutionary applications.

genomics↗

bioRxiv2022

A Draft Human Pangenome Reference

The Human Pangenome Reference Consortium (HPRC) presents a first draft human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individuals. These assemblies cover more than 99% of the expected sequence and are more than 99% accurate at the structural and base-pair levels. Based on alignments of the assemblies, we generated a draft pangenome that captures known variants and haplotypes, reveals novel alleles at structurally complex loci, and adds 119 million base pairs of euchromatic polymorphic sequence and 1,529 gene duplications relative to the existing reference, GRCh38. Roughly 90 million of the additional base pairs derive from structural variation. Using our draft pangenome to analyze short-read data reduces errors when discovering small variants by 34% and boosts the detected structural variants per haplotype by 104% compared to GRCh38-based workflows, and by 34% compared to using previous diversity sets of genome assemblies.

genomics↗

bioRxiv2018

TEsmall identifies small RNAs associated with targeted inhibitor resistance in melanoma

MicroRNAs (miRNAs) are small 21-22nt RNAs that act to regulate the expression of mRNA target genes through direct binding to mRNA targets. While miRNAs typically dominate small RNA transcriptomes, many other classes are present including tRNAs, snoRNAs, snRNAs, Y-RNAs, piRNAs, and siRNAs. Interactions between processing machinery and targeting networks of these various small RNA classes remains unclear, largely because these small RNAs are typically analyzed separately. Here we present TEsmall, a tool that allows for the simultaneous processing and analysis of small RNAs from each annotated class in a single integrated workflow. The pipeline begins with raw fastq reads and proceeds all the way to producing count tables formatted for differential expression. Several interactive charts are also produced to look at overall distributions in length and annotation classes. We next applied the TEsmall pipeline to small RNA libraries generated from melanoma cells responding to targeted inhibitors of the MAPK pathway. Targeted oncogene inhibitors have emerged as way to tailor cancer therapies to the particular mutations present in a given tumor. While these targeted strategies are typically effective for short intervals, the emergence of resistance is extremely common, limiting the effectiveness of single-agent therapeutics and driving the need for a better understanding of resistance mechanisms. Using TEsmall, we identified several microRNAs and other small RNA classes that are enriched in inhibitor resistant melanoma cells in multiple melanoma cell lines and may be able to serve as markers of resistant populations more generally.

genomics↗

bioRxiv2016

Retrotransposon Activation Contributes to Neurodegeneration in a DrosophilaTDP-43 Model of ALS.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two incurable neurodegenerative disorders that exist on a symptomological spectrum and share both genetic underpinnings and pathophysiological hallmarks. Functional abnormality of TAR DNA-binding protein 43 (TDP-43), an aggregation-prone RNA and DNA binding protein, is observed in the vast majority of both familial and sporadic ALS cases and in [~]40% of FTLD cases, but the cascade of events leading to cell death are not understood. We have expressed human TDP-43 (hTDP-43) in Drosophila neurons and glia, a model that recapitulates many of the characteristics of TDP-43-linked human disease including protein aggregation pathology, locomotor impairment, and premature death. We report that such expression of hTDP-43 impairs small interfering RNA (siRNA) silencing, which is the major post-transcriptional mechanism of retrotransposable element (RTE) control in somatic tissue. This is accompanied by de-repression of a panel of both LINE and LTR families of RTEs, with somewhat different elements being active in response to hTDP-43 expression in glia versus neurons. hTDP-43 expression in glia causes an early and severe loss of control of a specific RTE, the endogenous retrovirus (ERV) gypsy. We demonstrate that gypsy causes the degenerative phenotypes in these flies because we are able to rescue the toxicity of glial hTDP-43 either by genetically blocking expression of this RTE or by pharmacologically inhibiting RTE reverse transcriptase activity. Moreover, we provide evidence that activation of DNA damage-mediated programmed cell death underlies both neuronal and glial hTDP-43 toxicity, consistent with RTE-mediated effects in both cell types. Our findings suggest a novel mechanism in which RTE activity contributes to neurodegeneration in TDP-43-mediated diseases such as ALS and FTLD.\n\nAUTHOR SUMMARYFunctional abnormality of TAR DNA-binding protein 43 (TDP-43), an aggregation-prone RNA and DNA binding protein, is observed in the vast majority of both familial and sporadic ALS cases and in [~]40% of FTLD cases, and mutations in TDP-43 are causal in a subset of familial ALS cases. Although cytoplasmic inclusions of this mostly nuclear protein are a hallmark of the disease, the cascade of events leading to cell death are not understood. We demonstrate that expression of human TDP-43 (hTDP-43) in Drosophila neurons or glial cells, which results in toxic cytoplasmic accumulation of TDP-43, causes broad expression of retrotransposons. In the case of glial hTDP-43 expression, the endogenous retrovirus (ERV) gypsy causally contributes to degeneration because inhibiting gypsy genetically or pharmacologically is sufficient to rescue the phenotypic effects. Moreover, we demonstrate that activation of DNA damage-mediated programmed cell death underlies hTDP-43 and gypsy mediated toxicity. Finally, we find that hTDP-43 pathology impairs small interfering RNA silencing, which is an essential system that normally protects the genome from RTEs. These findings suggest a novel mechanism in which a storm of retrotransposon activation drives neurodegeneration in TDP-43 mediated diseases such as ALS and FTLD.

neuroscience↗