Genetics/Genomics/Endocrinology/Physician scientist. Dr. Pei-Lung Chen has been in the fields of genetic mapping, human leukocyte antigen (HLA) genes, and personalized medicine for almost 20 years. He works on both Mendelian diseases and complex traits, including Graves’ disease (GD), antithyroid drug (ATD) induced agranulocytosis (TiA), thyroid cancer, multiple endocrine neoplasia (MEN), pheochromocytoma/paraganglioma (PPGL), pancreatic cancer, lung cancer, thoracic aortic aneurysm and dissection (TAAD), Kawasaki disease, type 1 diabetes (T1D), tuberous sclerosis complex (TSC), drug adverse effects (such as TiA and malignant hyperthermia (MH)), deafness, retinitis pigmentosum, jaundice associated diseases, Parkinsonism, pseudohypoparathyroidism, polycystic kidney disease (PKD), etc. Please refer to Dr. Chen’s personal website (https://www.mc.ntu.edu.tw/medgenpro/Fpage.action?muid=3060&fid=2193) for related publications. 

Precision Medicine. Dr. Chen and colleagues identified the pharmacogenomics risk genes for potentially lethal TiA, published in Nature Communications. This was a big breakthrough, and heralded the opening of a new field for precision medicine in ATDs use based on personal genomic data. The team got the patent (藥物不良反應風險評估方法及其裝置, 專利證書號碼 105104441), and then completed Technology Transfer to the industry. Another excellent clinical precision medicine application of Dr. Chen’s genetic study can be illustrated using the cochlear implantation outcome study. Dr. Chen and colleagues identified the genetic factors causing poor cochlear implantation outcomes, and can potentially save averaging ~NTD 1,000,000 cost per useless cochlear implantation operation. 

Immuno-genetics/-genomics. Dr. Chen has been working on HLA-related topics since 2000. Using various genetic mapping technologies, Dr. Chen identified HLA genes as the disease-susceptibility or disease protecting genes of many human diseases, including GD, TiA, T1D, etc. Dr. Chen has the ability to identify novel HLA alleles. Dr. Chen can also predict HLA genotypes using SNP genotypes. Dr. Chen and colleagues, as early as in 2014, invented a novel fault-tolerant bioinformatics method to call HLA genotypes using the NGS data from the Pacific Biosciences platform. In 2018, Dr. Chen got a 2-year Industry-Academia Cooperation Grant for a novel HLA genotyping method, with the product successfully completing a Technology Transfer to the industry partner. In 2020, Dr. Chen got a 1-year Industry-Academia Cooperation Grant for killer cell immunoglobulin-like receptor (KIR) genotyping. Dr. Chen recently made breakthroughs in targeted NGS for germline adaptive immune receptor repertoire (gAIRR, including T-cell receptor (TR) and immunoglobulin (IG) genes, Front. Immunol., doi:DOI: 10.3389/fimmu.2022.922513 (2022).).

Next-generation sequencing (NGS)/Bioinformatics/Artificial Intelligence (AI). Since 2014, Dr. Chen established and started to run an NGS-based clinical genetic testing laboratory at NTU Hospital (https://www.ntuh.gov.tw/gene-lab-mollab/Fpage.action?muid=4&fid=3848). The laboratory now covers a broad range of Mendelian diseases, and recently launched the whole exome sequencing (WES) and whole genome sequencing (WGS) service. Dr. Chen is also analyzing the WGS data from 1,496 Taiwan Biobank samples. Dr. Chen is collaborating with Taiwan AI Labs (https://ailabs.tw) for NGS and genomics analyses using AI approaches. In 2021, Dr. Chen got another 2-year Industry-Academia Cooperation Grant for development of novel genomic methods for third-generation sequencing platforms (especially focusing on the Oxford Nanopore Technologies platform).

Mouse model for human diseases. When Dr. Chen studied at Johns Hopkins University for his Ph.D. degree, he made two knock-out mouse lines to study the effect of Grid1 on schizophrenia. Dr. Chen continued to participate in research projects using mouse models for human diseases, and have several related publications (https://www.mc.ntu.edu.tw/medgenpro/Fpage.action?muid=3060&fid=2193).

Introduction:

        As a geneticist and an endocrine doctor, I have been focusing on identification of the genes responsible for various human diseases, a process being described as “genetic mapping”, which is crucial for precision medicine. Next-generation sequencing (NGS), immunogenomics, pharmacogenomics, other genotyping technologies, model organisms, and bioinformatics are the fields that I have been working on extensively.
 

Identification of disease-causing genes/variants:
        Genetic mapping is a critical step for individualized medicine and translational medicine. Linkage analysis and association study are the two classical methods; NGS is a new powerful technology for it. Identification of disease-causing/susceptibility genes can facilitate genetic diagnosis, genetic counseling, treatment choice and pathophysiology understanding. Our laboratory can do both complex traits and mendelian disease. The diseases that I am currently working on (or used to study) include Graves’ disease, schizophrenia, hearing impairment, tuberous sclerosis complex, type 1 diabetes, multiple endocrine neoplasia type 1 and 2, familial medullary thyroid cancer, pheochromocytoma/paraganglioma, hereditary retinal dystrophy, polycystic kidney disease, familial hyperlipidemia, thoracic aortic aneurysm and dissection syndrome, epilepsy, antithyroid drug-induced agranulocytosis, malignant hyperthermia, etc. 

        In addition to academic interest in genetic mapping, I personally conduct clinical genetic testing of many Mendelian diseases at the NGS laboratory of Department of Medical Genetics, NTU Hospital. Details are available at the Laboratory website (https://www.ntuh.gov.tw/gene-lab-mollab/Fpage.action?muid=4&fid=3848).

Fig 1. Examples of identification of disease-causing genes/variants. (A). The genome-wide association study (GWAS) of antithyroid drug-induced agranulocytosis. (Chen et al. Nature Communications (2015) 6(1), 1-8); (B). NGS study of familial hypercholesterolemia. (Hsiung et al. Atherosclerosis (2018) 277, 440-447); (C). Pedigree information (including clinical disease status and genotypes) of a family with malignant hyperthermia. (Yeh et al. Journal of the Formosan Medical Association (2021) 120(2), 883-892)

Application and development of NGS and NGS-related technologies:

        NGS is probably the most exciting technology breakthrough in the genetic/genomics field during the past 5-10 years. By massively paralleling the amplification and/or sequencing steps, NGS provides unimaginable high throughput and low cost. There are several NGS platforms available. Our laboratory can handle NGS experiment and data analysis; we mainly use the platforms from Illumina and Oxford Nanopore Technologies. We have applied NGS to genetic mapping and several other genetic fields, including those described in the later sections such as the STAR-capture project, single-cell sequencing, DNA methylation analysis and certain innovative NGS technologies.

        The expertise and experience in “targeted” sequencing really make our team quite unique. Furthermore, bioinformatics analysis of NGS data is also our superiority. 

Fig 2. Developments in NGS. (Data and platforms updated up to 2016.) (Figure from Lex Nederbragt: https://figshare.com/articles/dataset/developments_in_NGS/100940）

The STAR-capture project (immunogenomics and pharmacogenomics):

        Human leucocyte antigen (HLA), killer cell immunoglobulin-like receptor (KIR), and B-/T-cell receptor (BCR/TCR) genes are important but difficult-to-sequence immunogenomic genes. Additionally, pharmacogenes also include many polymorphic cytochrome P450 (CYP) genes and other pharmacokinetics- or pharmacodynamics-related genes. Because there are numerous polymorphic genes belonging to the immunogenomics or pharmacogenomics fields, it is necessary to introduce the “*” (STAR) symbol and special rules to denote various “alleles”. Representative examples include HLA-B*38:02, KIR2DL1*00301, TRAV38-2/DV8*01, IGHV4-61*02, CYP2D6*36+*10, etc.  

        During the past several decades, the genotyping methods for the immunogenomics or pharmacogenomics genes have been quite expensive, time-consuming and special technique-dependent (such as the methods for HLA and certain CYP genes), or even been too challenging (or unattainable) (such as the methods for KIR, BCR/TCR and certain CYP genes). I am particularly interested in these challenging but important genes, and have devoted to the development of NGS-based genotyping methods for them. My core technology and design are probe capture-based targeted sequencing and analysis. I name this project “STAR-capture”.

Fig 3. The STAR-capture project. Important immunogenomics and pharmacogenomics genes include HLA, KIR, BCR/TCR and CYP genes.

        As a successful example of the STAR-capture project, we have made a breakthrough in profiling genes encoding the adaptive immune receptor repertoire (gAIRR, comprising BCR/TCR) with gAIRR Suite (Lin et al. Frontiers in Immunology (2022) 922513). This could be really powerful and useful for the investigation of various immune-related phenotypes in the future.

Fig 4. The gAIRR Suite pipelines. The three modules are gAIRR-seq, gAIRR-call and gAIRR-annotate. The gray arrows show the verification methods between the two pipelines when both gAIRR-seq reads and personal assembly are available. (Lin et al. Frontiers in Immunology (2022) 922513)

Mouse model:

        We are in the process of developing humanized major histocompatibility complex mouse models. We hope this series of mouse models can have breakthrough contribution to the study of autoimmune diseases (such as Graves’ disease), human immune response (such as antithyroid drug-induced agranulocytosis), pathogen defense and other immune-related phenotypes. 

Fig 5. Model organism. The C57BL/6 mouse. (Figure from https://commons.wikimedia.org/wiki/File:Lab_mouse_mg_3213.jpg)

One more thing:

        Additionally, our lab members also work on several other fascinating fields, including development of novel genotyping method, DNA methylation analysis, bioinformatics, long-range haplotype phasing, analysis of data from Taiwan Biobank, and clinical decision support system (CDSS).