Biology subjects

Lin, H.-F.

Publications and source records attributed to Lin, H.-F..

6 recordsLinked to original sources

bioRxiv2025

deCYPher: Star Allele-Resolution Computational Framework of Pharmacogenes for Haplotype-Resolved Long-Read Assemblies

Although existing next-generation sequencing (NGS) tools, such as Aldy and Cyrius, have been applied for allele typing, they cannot achieve complete accuracy due to various genomic challenges including pseudogenes, structural variations, hybrid genes, copy number variations, and gene deletions. These complexities make accurate pharmacogene interpretation more challenging, despite the crucial role pharmacogenomics plays in precision medicine. We developed deCYPher, a tool that generates personalized pharmacogenomic reports from haplotype-resolved assemblies. The tool enables analysis of all PharmVar 1A level genes, such as CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A5, CYP4F2, DPYD, NUDT15, and SLCO1B1. Applied to all HPRC haplotypes (including both release 1 and release 2 data), deCYPher demonstrated high accuracy in resolving complex gene structures. In the case of CYP2D6, release 1 identified 6% gene multiplications, 6% full gene deletions, and 4% CYP2D6/CYP2D7 hybrids. By contrast, release 2 demonstrated an increased prevalence of multiplications (14%) and hybrids (11%), while the frequency of full gene deletions remained comparable at 5%. Comparison with pb-StarPhase revealed discrepancies in 12 of 94 assemblies in the release 1 dataset. For instance, in sample HG02257, Aldy, Cyrius, and deCYPher consistently identified the genotype as *2/*35, whereas pb-StarPhase reported *2/*2. Notably, the *35-defining variants were present in the BAM and VCF files in the pb-StarPhase pipeline, but the local read depth over the *35-specific region was only 5x in HG02257-p, suggesting that the misclassification likely resulted from insufficient coverage - a known limitation of pb-StarPhase under low-depth conditions.

bioinformatics↗

bioRxiv2025

TypeAssembly: Copy number estimation and allele typing for haplotype assemblies

Accurately annotating complex genes in the human genome, particularly from haplotype assemblies, remains a significant challenge. To overcome this, we developed TypeAssembly, a local alignment-based framework for copy number estimation and allele typing. Operating in two modes, mode-FASTA and mode-VCF, TypeAssembly can define alleles by either sequence or variant information. We successfully applied it to annotate 41 genes in the MHC locus, 17 KIR genes, and, for the first time, 15 pharmacogenes across 466 haplotype assemblies. This study establishes TypeAssembly as a robust method for accurately annotating complex genomic regions and provides an evaluation of existing gene annotations and callers.

bioinformatics↗

bioRxiv2024

Genomes of Wiebesia fig wasps reveal the adaptation and codiversification in fig-fig wasp mutualism

Figs and fig wasps represent one of the most intimate examples of plant-pollinator coevolution. As figs diversified into geographically isolated populations, both figs and fig wasps underwent selective pressures driven by local adaptation and coevolution. Ficus pumila comprises two ecologically distinct varieties: the creeping fig (F. pumila var. pumila), which is widely distributed across the lowlands of East Asia, and the jelly fig (F. pumila var. awkeotsang), endemic to Taiwan and found at mid-elevations. To elucidate how codiversification with fig hosts influences the evolutionary trajectories of fig wasps, we analyzed the genomes of Wiebesia sp. 2 and sp. 3, the respective pollinators of creeping fig and jelly fig. Our demographic analysis indicates that vicariance during the Last Glacial Period facilitated ecological differentiation between these two fig-fig wasp pairs. Through comparative and population genomic analyses, we identified selection signals linked to habitat adaptation, with evolutionary rates corresponding to the life history traits of their host figs. Variations in host preference behavior, chemosensory gene expression, and adaptive duplications in olfactory receptors highlight potential mechanisms for adaptation to host floral scents. These findings collectively underscore how the obligate mutualism between figs and their pollinating wasps allows the ecological traits and habitat preferences of fig hosts to shape the evolutionary pathways of their pollinators, leaving distinct molecular imprints in the fig wasp genomes. This study demonstrates the capacity of tightly intertwined life cycles between plants and pollinators to drive adaptation and diversification.

evolutionary biology↗

bioRxiv2023

Antagonistic pleiotropy plays an important role in governing the evolution and genetic diversity of SARS-CoV-2

Analyses of the genomic diversity of SARS-CoV-2 found that some sites across the genome appear to have mutated independently multiple times with frequency significantly higher than four-fold sites, which can be either due to mutational bias, i.e., elevated mutation rate in some sites of the genome, or selection of the variants due to antagonistic pleiotropy, a condition where mutations increase some components of fitness at a cost to others. To examine how different forces shaped evolution of SARS-CoV-2 in 2020-2021, we analyzed a large set of genome sequences (~ 2 million). Here we show that while evolution of SARS-CoV-2 during the pandemic was largely mutation-driven, a group of nonsynonymous changes is probably maintained by antagonistic pleiotropy. To test this hypothesis, we studied the function of one such mutation, spike M1237I. Spike I1237 increases viral assembly and secretion, but decreases efficiency of transmission in vitro. Therefore, while the frequency of spike M1237I may increase within hosts, viruses carrying this mutation would be outcompeted at the population level. We also discuss how the antagonistic pleiotropy might facilitate positive epistasis to promote virus adaptation and reconcile discordant estimates of SARS-CoV-2 transmission bottleneck sizes in previous studies.

evolutionary biology↗

bioRxiv2022

Spatial and temporal origin of the third SARS-CoV-2 Outbreak in Taiwan

Since the first report of SARS-CoV-2 in December 2019, Taiwan has gone through three local outbreaks. Unlike the first two outbreaks, the spatial and temporal origin of the third outbreak (April 20 to November 5, 2021) is still unclear. We assembled and analyzed a data set of more than 6,000 SARS-CoV-2 genomes, including 300 from Taiwan and 5812 related sequences downloaded from GISAID as of 2021/12/08. We found that the third outbreak in Taiwan was caused by a single virus lineage belonging to Alpha (B.1.1.7) strain. This lineage, T-III (the third outbreak in Taiwan), carries a distinct genetic fingerprint, consisting of spike M1237I (S-M1237I) and three silent mutations, C5812T, C15895T, and T27869C. The T-III is closest to the sequences derived from Turkey on February 8, 2021. The estimated age of the most recent common ancestor (TMRCA) of T-III is March 23, 2021 (95% highest posterior density [HPD] February 24 - April 13, 2021), almost one month before the first three confirmed cases on April 20, 2021. The effective population size of the T-III showed approximately 20-fold increase after the onset of the outbreak and reached a plateau in early June 2021. Our results reconcile several unresolved observations, including the occurrence of two infection clusters at the same time without traceable connection and several airline pilots who were PCR negative but serum IgM-/IgG+ for SARS-CoV-2 in late April. Therefore, in contrast to the general notion that the third SARS-CoV-2 outbreak in Taiwan was sparked by two imported cases from USA on April 20, 2021, which, in turn, was caused by the partial relaxation of entry quarantine measures in early April 2021, our comprehensive analyses demonstrated that the outbreak was most likely originated from Europe in February 2021.

evolutionary biology↗

bioRxiv2021

Identification of a novel lineage bat SARS-related coronaviruses that use bat ACE2 receptor

Severe respiratory disease coronavirus-2 (SARS-CoV-2) causes the most devastating disease, COVID-19, of the recent century. One of the unsolved scientific questions around SARS-CoV-2 is the animal origin of this virus. Bats and pangolins are recognized as the most probable reservoir hosts that harbor the highly similar SARS-CoV-2 related viruses (SARSr-CoV-2). Here, we report the identification of a novel lineage of SARSr-CoVs, including RaTG15 and seven other viruses, from bats at the same location where we found RaTG13 in 2015. Although RaTG15 and the related viruses share 97.2% amino acid sequence identities to SARS-CoV-2 in the conserved ORF1b region, but only show less than 77.6% to all known SARSr-CoVs in genome level, thus forms a distinct lineage in the Sarbecovirus phylogenetic tree. We then found that RaTG15 receptor binding domain (RBD) can bind to and use Rhinolophus affinis bat ACE2 (RaACE2) but not human ACE2 as entry receptor, although which contains a short deletion and has different key residues responsible for ACE2 binding. In addition, we show that none of the known viruses in bat SARSr-CoV-2 lineage or the novel lineage discovered so far use human ACE2 efficiently compared to SARSr-CoV-2 from pangolin or some of the SARSr-CoV-1 lineage viruses. Collectively, we suggest more systematic and longitudinal work in bats to prevent future spillover events caused by SARSr-CoVs or to better understand the origin of SARS-CoV-2.

microbiology↗