Biology subjects

Ho, K.-L.

Publications and source records attributed to Ho, K.-L..

4 recordsLinked to original sources

bioRxiv2024

Initial Characterization of Canine T-cell Receptor Repertoires Using RNA-seq Data from Different Diseases and Tissues

The dog serves as a key translational model in cancer immunotherapy. Understanding the T cell receptor (TCR) repertoire is needed for various cancer immunotherapies. Compared to humans where >300 million TCRs have been identified, <100 canine TCRs are reported. To address this deficiency, we assembled >200,000 complete TCR complementarity-determining region 3 (CDR3) sequences from RNA-seq data published for [~]2,000 canine samples of blood, lymph node, and other tissues, of which 613 are tumors. We collected 1,324 human RNA-seq samples to compare the similarities and differences in T-cell repertoires between humans and dogs. Notably, our analysis revealed distinct variable gene usage patterns between blood samples and solid tissues in both canine and human samples for TRA and TRB loci. Moreover, our investigation led to the discovery of novel V gene and allele candidates in the canine genome. Our findings also revealed that the canine CDR3 resembled human CDR3 in terms of length and motifs. Additionally, our study unveiled shared traits in cancer TCRs between dogs and humans, including longer lengths and higher hydrophobicity of private CDR3s. Our results indicated the diversity of canine to be more comparable to that of humans than mice. Our study provides an initial landscape of the canine TCR repertoire, highlighting both its similarities and differences with the human counterpart, thus laying the groundwork for future research in comparative immunology and vaccine development.

immunology↗

bioRxiv2024

Canine major histocompatibility complex class I (MHC-I) diversity landscape

The genes of the Major Histocompatibility Complex class I (MHC-I) are among the most diverse in the mammalian genome, playing a crucial role in immunology. Understanding the diversity landscape of MHC-I is therefore of paramount importance. The dog is a key translational model in various biomedical fields. However, our understanding of the canine MHC-I diversity landscape lags significantly behind that of humans. To address this deficiency, we used our newly developed software, KPR de novo assembler and genotyper, to genotype 1,325 samples from 1,025 dogs with paired-end RNA-seq data from 43 BioProjects, after extensive quality control. Among 926 dogs that pass the QC, 591 dogs (64%) have at least one allele genotyped, and a total of 97 known alleles and 52 putative new alleles were identified. Further analysis reveals that DLA-I gene expression levels vary among the tissues, with lowest for testis and brain tissues and highest for blood, corpus luteum, and spleen. We identified dominant alleles in each of the 17 canine breeds, as well as among the entire canine population. Furthermore, our analysis also identifies breed-specific alleles and mutually co-occurred/exclusive alleles. Our study indicates that canine DLA-88 is as diversified as human HLA-A/B/C genes within the entire population, but less diversified within a breed than with HLA-A/B/C within an ethnic group. Lastly, we examined the hypervariable regions (HVR) within or across human/canine MHC-I alleles and found that 80% of the HVRs overlap between the two species. We further noted that 80% of the HVRs are within 4A contact with the peptides, and that the dog-human difference overlaps with only 20% HVRs. Our research offers valuable insights for immunological studies involving dogs.

bioinformatics↗

bioRxiv2023

Human basal-like breast cancer is represented by one of the two mammary tumor subtypes in dogs

BackgroundAbout 20% of breast cancers in humans are basal-like, a subtype that is often triple negative and difficult to treat. An effective translational model for basal-like breast cancer (BLBC) is currently lacking and urgently needed. To determine if spontaneous mammary tumors in pet dogs could meet this need, we subtyped canine mammary tumors and evaluated the dog-human molecular homology at the subtype level. MethodsWe subtyped 236 canine mammary tumors from 3 studies by applying various subtyping strategies on their RNA-seq data. We then performed PAM50 classification with canine tumors alone, as well as with canine tumors combined with human breast tumors. We investigated differential gene expression, signature gene set enrichment, expression association, mutational landscape, and other features for dog-human subtype comparison. ResultsOur independent genome-wide subtyping consistently identified two molecularly distinct subtypes among the canine tumors. One subtype is mostly basal-like and clusters with human BLBC in cross-species PAM50 classification, while the other subtype does not cluster with any human breast cancer subtype. Furthermore, the canine basal-like subtype recaptures key molecular features (e.g., cell cycle gene upregulation, TP53 mutation) and gene expression patterns that characterize human BLBC. It is enriched histological subtypes that match human breast cancer, unlike the other canine subtype. However, about 33% of canine basal-like tumors are estrogen receptor negative (ER-) and progesterone receptor positive (PR+), which is rare in human breast cancer. Further analysis reveals that these ER-PR+ canine tumors harbor additional basal-like features, including upregulation of genes of interferon-{gamma} response and of the Wnt-pluripotency pathway. Interestingly, we observed an association of PGR expression with gene silencing in all canine tumors, and with the expression of T cell exhaustion markers (e.g., PDCD1) in ER-PR+ canine tumors. ConclusionsWe identify a canine mammary tumor subtype that molecularly resembles human BLBC overall, and thus could serve as a vital spontaneous animal model of this devastating breast cancer subtype. Our study also sheds light on the dog-human difference in the mammary tumor histology and the hormonal cycle.

cancer biology↗

bioRxiv2020

Canine tumor mutation rate is positively correlated with TP53 mutation across cancer types and breeds

Spontaneous canine cancers are a valuable but relatively understudied and underutilized model in cancer research. To enhance their usage, we reanalyzed whole exome sequencing data published for 601 dogs with mammary cancer, osteosarcoma, oral melanoma, lymphoma, glioma or hemangiosarcoma from over 35 breeds, after rigorous quality control, including breed validation. Each cancer type harbors distinct molecular features, with major pathway alterations matching its human counterpart (e.g., PI3K for mammary cancer and p53 for osteosarcoma). On average, mammary cancer and glioma have lower mutation rates (median <0.5 mutation per Mb), whereas oral melanoma, osteosarcoma and hemangiosarcoma have higher mutation rates (median [≥]1 mutation per Mb). Across cancer types and across breeds, the mutation rate is strongly associated with TP53 mutation, but not with PIK3CA mutation. The mutation rate is also associated with a mutation signature enriched in osteosarcoma of Golden Retrievers, independent of TP53 mutation. Finally, compared to other breeds examined, DNA repair genes appear to be less conserved in Golden Retriever which is predisposed to numerous cancers.

cancer biology↗