A) integrative Personal Omics Profile Analysis (iPOP)
During my postdoctoral training with Dr. Michael Snyder, my main focus was to apply high-throughput technologies to disease-related research. To ascertain whether longitudinal omics profiling can be achieved on a reasonable scale, we developed the iPOP approach and performed it on a generally healthy individual during a course of 26 months in a proof-of-principal study (the first 14 months were published). Our research was highlighted as the only research paper in the March 16th, 2012 special issue of Cell, and was selected into Cell -- Best of 2012, as well as “Genome Advance of the Month” by the National Human Genome Research Institute. In our study, we determined the genome of this individual at high accuracy with 2 whole genome sequencing (Illumina and Complete Genomics) and 3 whole exome sequencing (Agilent, Roche Nimblegen and Illumina) platforms, and identified genetic predispositions for this individual (both for diseases, including Type 2 Diabetes, and for drug sensitivity). We then successfully monitored personalized physiological state changes (including the onset of Type 2 Diabetes and 2 viral infections) with integrative information of the transcriptome, proteome and metabolome from blood components (peripheral blood mononuclear cells and serum). In the integrative profile, we observed both trend changes, which may be associated with chronologic changes such as aging, and spike changes, in which particular genes and pathways were enriched especially at the beginning of each physiological state change event. The integrative analysis provided a much more comprehensive view of the biological pathways that change during disease onset. In addition, we also observed dynamic changes in allele-specific expression that may also be associated with the corresponding physiological states. Moreover, I am currently adding epigenomic information (DNA methylation with whole methylome sequencing) and more extensive autoantibody profiling to our iPOP analysis, which will be reported in follow-up studies. These profiles may have a great potential to serve as personalized biomarkers for disease onset and progression, and we believe our approach opened new venues for personalized medicine.
Selected Media Reports:
a) In Science.
b) In Nature.
c) In Genome Biology.
d) In GenomeWeb Daily News.
e) In The Wall Street Journal.
f) In The New York Times.
g) In ABC News.
h) In Diabetes Forecast.
In Different Languages:
i) In Chinese.
j) In French.
k) In German.
l) In Russian.
B) An Omics View of Asthma
My postdoctoral research also focused on the investigation of genetic basis of asthma with high-throughput sequencing technologies. Asthma is a common disease with evident genetic contribution, but the actual genetic mechanism is still unknown. In this project, we enrolled 12 pairs of monozygotic twins discordant in allergic asthma, and I sequenced their whole genome and transcriptome in search of high-risk variants and expression profiles. I also sequenced the genome of 2 healthy pairs and transcriptome of 8 additional discordant monozygotic twin pairs. Interestingly, despite their monozygosity, I observed genetic differences including single nucleotide variants, insertions/deletions, structural variants, copy number variants, and differential mobile element insertions within each twin pair, as well as differential expression profiles. Our study is the first to investigate asthma-related genomic and transcriptomic variations with next-generation sequencing technologies in discordant monozygotic twins.
C) Genetics of Rare Mendelian Diseases
I have also been involved in projects to identify causal genes of rare Mendelian diseases with whole exome sequencing. We enrolled a total of 21 families with various rare Mendelian diseases (e.g. Shone’s Disease, Combined Immune Deficiency with Multiple Intestinal Atresias, Craniodiaphyseal Dysplasia, and Moyamoya Disease). I tested 3 different exome-enrichment platforms (Agilent, Roche Nimblegen and Illumina) to be used for this study and the performance comparison of these platforms was published in 2011. We identified candidate variants for each family, and are following up with functional studies. Our study on CID-MIA (Combined Immune Deficiency with Multiple Intestinal Atresias) was published in 2013 in the Journal of Allergy and Clinical Immunology.
D) Plasma Autoantibody Signatures for Myelodysplastic Syndromes
My other project was to identify autoantibody biomarkers for the progression of Myelodysplastic Syndromes (MDS). Current diagnosis of MDS still relies on examination of bone marrow samples from the patients, which is invasive (requiring anesthesia) and stressful for the patients. Our goal was to develop a simple diagnosis method by looking for plasma autoantibody biomarkers with high-density protein microarrays. We identified a list of candidates in our initial set and confirmed 3 of them with focused protein microarrays in a broader validation set. Our findings were published in 2013 in Scientific Reports, the only open access journal from Nature Publishing Group.
E) Role of Toll-Like Receptor Signaling Pathways in Ovarian Cancer Chemoresistance
I received extensive cancer-oriented training during my Ph.D. research in a laboratory active in ovarian cancer early detection. My Ph.D. dissertation focused on the role of inflammation, especially Toll-Like Receptor pathways, in chemoresistance of epithelial ovarian cancer patients, and identified the contribution of IKKbeta, as well as its regulator miR-199a, to cancer chemoresistance.