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ResearchResearch interestsThanks to rapid advances in resources and technology, biology has entered a dynamic, data-driven era in the 21st century. With the advent of new DNA sequencing technologies, it is a particularly exciting yet challenging time now for computational research, as more and more biological data are being generated at an ever-accelerating speed. My lab investigates the genetics of aging and human complex diseases at the interface of data science and clinical medicine through data integration, algorithm development, and software implementation of state-of-the-art methods in computational genetics and systems biology to analyze and integrate multifarious genetic and multiomic datasets. Method development and data analysis are essential to uncovering the underlying genetic mechanisms in biomedical research. My lab specializes in both advanced genetic data analysis and novel analytical method development. Over the years, we have contributed significantly to the field by developing computational frameworks and analytical methods, including integrated post-GWAS gene prioritization techniques, rare variant-based risk gene identification methods, and protocols for genomic gene expansion analysis. Currently, our lab is actively developing Bayesian statistical methods to quantify the loss of Y chromosome (LOY), structural equation modeling (SEM) to elucidate the complexities of human aging, and Bayesian hierarchical modeling to understand congenital heart defects (CHD). Our interdisciplinary approach continues to provide new insights into genetics and disease pathogenesis, emphasizing both rigorous data analysis and methodological innovation. Aging research is increasingly critical due to global demographic shifts, with aging populations facing heightened risks for chronic diseases such as Alzheimer's disease, cardiovascular conditions, and various forms of cancer. Understanding the genetic and molecular mechanisms underlying aging is essential for developing strategies to extend healthspan and improve quality of life. Our lab has significantly contributed to aging research through comprehensive comparative analyses of genome maintenance and DNA repair mechanisms in long-lived species like humans and naked mole rats, uncovering genetic features linked to enhanced longevity and disease resistance. We have also developed system-level approaches to identify aging-specific genetic networks and rare genetic variants that influence human longevity and episodic memory decline. By elucidating the genetic basis of extreme longevity and cognitive aging, our research aims to guide innovative therapeutic strategies and interventions to mitigate age-related decline and disease. Human disease genetics is critical for understanding the underlying mechanisms of complex disorders and developing targeted therapies. My lab has actively contributed to this research area through innovative computational analyses, identifying novel risk genes and variants in Alzheimer's disease, schizophrenia, and 22q11.2 deletion syndrome (22q11.2DS). Our integrated post-GWAS analyses of Alzheimer's disease uncovered new genetic pathways linked to immune responses and neuronal function. In schizophrenia research, we developed computational frameworks to prioritize disease-associated genes, pinpointing those crucial for brain development and synaptic plasticity. Additionally, our studies in 22q11.2DS have identified rare coding variants that modify schizophrenia risk, emphasizing their role in postnatal cortical development. Collectively, these efforts demonstrate the importance of genetic research in decoding the biological foundations of complex diseases and enhancing patient care. Research projects, active» DNA Repair, Mutations and Cellular Aging
This research program project is supported by a grant from NIH/NIA. » Comparative genomes of longevity
This research program project is supported by a grant from NIH/NIA. » Genetic variant-based drug discovery targeting conserved pathways of aging
This research project is supported by a grant from NIH/NIA. » Complex biology of resilience to Alzheimer’s disease risk
This research project is supported by a grant from NIH/NIA. » Systems biology of organismal aging
This research project is supported by a grant from the Irma T. Hirschl Trust. Research projects, completed» Human non-coding variants
This research project is supported by a grant from NIH/NHGRI. » Brain and behavior in 22q11.2 deletion syndrome
This research project is supported by a grant from NIH/NIMH. » Congenital heart defects of 22q11.2 deletion syndrome
This research project was supported by a grant from the American Heart Association. » Systems biology of human aging
This research project was supported by a New Scholar Award from the Ellison Medical Foundation. » Computational analyses of gene regulation: a next-gen sequencing approach
The biological system currently under investigation is breast cancer metastasis, a complex multi-step process during which tumor cells spread from the primary tumor mass to distant organs. To study the genetic and biochemical determinations of this deadly aspect of cancer progression, we analyze various microarray and sequencing profiles to discover its regulatory sub-networks, DNA binding of key regulators, and copy number variations during the progression. This research project was supported by a grant from NIH/NLM. |
Genome instability, driven by DNA damage, is now generally considered a hallmark of aging, which is underscored by increasing evidence for DNA damage as a driver of aging-related disease, most notably cancer and neurodegenerative disease. However, what remains lacking is specific insight into the genetic control and molecular mechanisms that link DNA damage and genome instability to aging and longevity in humans. This program project is organized around three major research questions that remain in this field: (1) the key genome maintenance genotypes that control human aging and longevity; (2) the genetic and molecular basis of DNA damage-driven aging; and (3) How DNA damage and its molecular sequelae affect cell fate diversity in aging.
Aging is a fundamental biological process accompanied by a general decline in tissue function and increased risk for many diseases. Instead of a passive, entropic process of deterioration, it is subject to active regulation by signaling pathways and transcription factors. In this project, using C. elegans as the model organism, we will develop innovative systems and computational biology approaches to construct regulatory networks of aging and identify emergent properties about the molecular mechanisms of aging.
People’s genomes differ at tens of millions of sites, and interpreting how this variation affects phenotypes and disease risk is extremely challenging. Most disease-associated variants lie outside of protein-coding regions. We are developing highly innovative computational approaches to determine which non-coding variants contribute to differences in organismal phenotypes and disease risk.
The International Consortium on Brain and Behavior in 22q11.2DS is a collaborative R01 of 22 institutions, with one genomic and four phenotyping leading sites. The collaboration combines genomic with neuropsychiatric and neurobehavioral paradigms to advance the understanding of the pathogenesis of schizophrenia and related phenotypes. The project as a whole will be an unprecedented international initiative to examine a common deletion associated with schizophrenia and elucidate its genomic and behavioral substrates. Beyond the potential for yielding a better understanding of a severe manifestation of 22q11.2DS, the results will help identify pathways leading to schizophrenia in the general population in a way that will inform novel treatments.
About 65% of 22q11.2DS patients have a heart defect such as tetralogy of Fallot – a form of conotruncal heart defects (CTDs) – and 35% have a normal heart. It is not clear why CTDs only occur in some, not all, of 22q11.2DS patients. Lack of such knowledge is an important problem, because, without it, acquiring the ability for prenatal diagnosis and intervention of CTDs among 22q11.2DS carriers is highly unlikely. Our project is to unravel the genetic basis for this phenotypic heterogeneity. By finding the genetic basis for CTDs in 22q11.2DS individuals, this study may pave the way for prenatal diagnosis and intervention of CTDs among 22q11.2DS carriers.
For reasons significant to individuals and the society as a whole, human aging is of great interest not only to the academic community but also to medicine and the public in general. However, despite much research progress made over the years, it still remains a poorly understood biological process. To gain novel insights, we use a systems-biology approach to analyze aging-related genes in the context of biological networks. 
Gene expression in living cells is under strict spatial and temporal control, and its dysregulation is the direct cause of many human diseases. The primary focus of research in my lab is gene expression and its regulation, for which we take an integrated approach to study the following aspects on the whole genome scale: