Associate Professor Eric Yap Peng Huat
Associate Professor of Human and Microbial Genetics
Principal Investigator, Medical Genomics Laboratory
• Su’Aidah Binte Mustaffa, Research Assistant
• Audrey Chua Ming Hui, Research Assistant
Assoc Prof Eric Yap Peng Huat, a medical geneticist and a former Rhodes Scholar, spent his earlier career as a defence scientist. He was one of the pioneers in the Defence Medical & Environmental Research Institute, now part of DSO National Labs. As one of the few local researchers with dual backgrounds in medicine and science, his professional interest is in molecular genetics and genomics and its application to medicine, biotechnology and security.
Assoc Prof Yap’s laboratory seeks to explore the patterns and effects of variation in human, bacterial and viral genomes, and to exploit these differences for more accurate and rapid disease diagnosis. There is a particular focus on diseases and microbes prevalent in or threating East Asian populations and environments, such as melioidosis, myopia and other complex genetic diseases. The philosophy of the lab is to strive for clinical impact by translating research into diagnostic services, devices and processes. As such, the lab has collaboration across a wide range of disciplines including genomics, molecular biology, bioinformatics, epidemiology and bioengineering. It also works actively with start-up companies and clinical end-users.
The laboratory will focus on three areas of medical genomics that could significantly change medical practice in the coming decades.
Structural variation in the human genome
The completion of the Human Genome and the 1000 Genomes Projects has yielded comprehensive catalogues of single nucleotide and small variants, but larger genetic differences (Structural Variants) are not well understood because Next Gen Sequencing (NGS) tools are not efficient in identifying them. For instance, we observed and mapped large megabase-sized deletions in a gene poor region of human Chromosome Y that result in phenotypically normal males scoring as false negatives in conventional sexing assays using the AMELY1 locus. We are now investigating another type of SV, Copy Number Variants, which varies in dosage across human populations with particular emphasis on Asian population genetics, disease associations and quantitation tools. For instance, we are studying how the number of copies of the salivary amylase gene (AMY1), which interestingly can vary 10-fold between individuals, could be higher in Asian populations with starchy diets and whether they are associated with obesity.
Genomic analysis of complex diseases
The study of Mendelian (single gene) diseases has largely been successful to the extent that whole exome and whole genome sequencing has found clinical utility for these conditions. The same cannot be said for the more common diseases of complex genetic aetiology, like myopia, hypertension, obesity, and inherited cardiac arrhythmias. Despite large scale Genome Wide Association Studies (GWAS), common alleles are found to predispose to these phenotypes, collectively account for a small part of the total heritable predisposition. This missing heritability is now thought to be due to rare variants or SV that are not amenable to older hybridisation technologies. Our lab is participating in consortia to map these susceptibility alleles by NGS of exomes and whole genomes.
Rapid Diagnostic Technologies
The lab has a long interest in innovating tools for faster and more efficient DNA analysis. We have developed rapid biochemical methods for PCR, mutation screening and genotyping. Some of these assays are used in routine molecular diagnosis of pathogens. Riding on trends in rapid prototyping, mobile computing and digital media, we are interested in designing and testing new bio-analytical lab instruments that could allow 10-100 fold improvements in throughput, speed and cost-effectiveness. Miniaturiszation of vessels, channels and pumps allow automation and integration of otherwise wasteful biochemical assays, and also speed up and increase throughput and usability significantly. The lab has been working on integrating the many laboratory steps for DNA/RNA extraction and PCR amplification for point of care diagnostics. Such microfluidic devices can be coupled with novel technologies such as micro-optics, and we are exploiting such optofluidic platforms to characterise and manipulate single cells and bacteria, enabling single cell studies and diagnosis.
A polymorphic structural variant on the short arm of human Chromosome Y results from a large deletion spanning 3Mb (red box), equivalent to 5% of the entire chromosome (other large deletions in shaded bars have also been identified.) This deletion includes the Amelogenin (AMELY) locus, commonly used in genetic sexing assays. Males carrying this allele (which is more prevalent in ethnic Indian populations) will appear as genetic females on this assay. Hence, newer assays use other invariant or multiple ChrY loci.
Source: Molecular characterization of a polymorphic 3-Mb deletion at chromosome Yp11.2 containing the AMELY locus in Singapore and Malaysia populations. Human Genetics. 2007, 122(3-4): 237-249. Rita Y. Y. Yong, Linda S. H. Gan, Yuet Meng Chang, Eric P. H. Yap
Improvements in biochemistry and thermofluidics allow extremely short cycling times for DNA amplification. In this example, 40 cycles of PCR are performed in under 3 minutes for a 115bp amplicon, detected by direct fluorescent visualisation (left inset) and by gel electrophoresis (right inset). This assay is for the Type III Secretion System of Burkolderia pseudomallei, a Gram negative bacterium which causes potentially fatal pneumonia, Meliodosis. This slow growing bacterium typically takes 3-5 days for culture-based diagnosis, so rapid diagnostic methods could lead to quantum improvement in patient management.
Source: Eric Yap (unpublished)
Schematic illustration of an optofluidic method for detecting bacteriophages by quantitating their inhibition of E coli bacterial growth. Microdroplets of sample and host bacteria are merged in a microchannel and allowed to co-culture (not shown). The microdroplets flow past a laser beam and the degree of diffractive scattering is indicative of their bacterial content, analogous to its optical density.
Source: Droplet optofluidic imaging for λ-bacteriophage detection via co-culture with host cell Escherichia coli. J. Q. Yu, W. Huang, L. K. Chin, et al. Lab Chip, 2014, 14, 3519
1. PY Liu, LK Chin, W Ser, TC Ayi, PH Yap, T Bourouina and Y Leprince-Wang. (2014). An optofluidic imaging system to measure the biophysical signature of single waterborne bacteria. Lab on a Chip. (In press).
2. JQ Yu, W Huang, LK Chin, L Lei, ZP Lin, W Ser, H Chen, TC Ayi, PH Yap, CH Chen and AQ Liu. (2014). Droplet optofluidic imaging for λ-bacteriophage detection via co-culture with host cell Escherichia coli. Lab on a Chip. 14:3519-3524.
3. Wong LP, Ong RT, Poh WT, Liu X, Chen P, Li R, Lam KK, Pillai NE, Sim KS, Xu H, Sim NL, Teo SM, Foo JN, Tan LW, Lim Y, Koo SH, Gan LS, Cheng CY, Wee S, Yap EP, Ng PC, Lim WY, Soong R, Wenk MR, Aung T, Wong TY, Khor CC, Little P, Chia KS and Teo YY. (2013). Deep whole-genome sequencing of 100 southeast Asian Malays. Am J Hum Genet. 92(1):52-66.
4. Wasan PS, Uttamchandani U, Moochhala SM, Yap VM, Yap PH. (2013). Application of Statistics and Machine Learning for Risk Stratification of Heritable Cardiac Arrhythmias. Expert Systems With Applications. 40(7):2476-2486.
5. Oh VM, Chua BM, Heng CK, Yeo SB, Yim OS, Yap EP. (2012). Association of intronic single-nucleotide polymorphisms in the EMILIN1 gene with essential hypertension in a Chinese population. J Hum Hypertens. 26(9):553-61.
6. Li YJ, Goh L, Khor CC, Fan Q, Yu M, Han S, Sim X, Ong RT, Wong TY, Vithana EN, Yap E, Nakanishi H, Matsuda F, Ohno-Matsui K, Yoshimura N, Seielstad M, Tai ES, Young TL, Saw SM. (2011). Genome-wide association studies reveal genetic variants in CTNND2 for high myopia in Singapore Chinese. Ophthalmology.118(2):368-75.
7. Yong RY, Gan LS, Chang YM, Yap EP. (2007). Molecular characterization of a polymorphic 3-Mb deletion at chromosome Yp11.2 containing the AMELY locus in Singapore and Malaysia populations. Hum Genet. 122(3-4):237-49.
8. Yap EPH, Koh WHV, Loh JP, Ng YY, Ooi EE. (2005). South-Asian tsunami. The Lancet. 365:933-938
9. Yap E. (2005). Ethical, legal, social and policy issues in medical genetic testing of relevance to Singapore: Personal perspectives. Singapore: Genetic Testing And Genetic Research – A Report By The Bioethics Advisory Committee. [November 2005].
10. Wu HM, Seet B, Yap EPH, Saw SM, Lim TH, Chia KS, Lee L. (2001) Does education explain ethnic differences in myopia prevalence? A population-based study of young adult males in Singapore. Optometry & Vision Science. 78(4):234-239.