Copy number variation and lupus

3 February 2016

Professor Yu Chack-Yung (Croucher Scholarship 1981, Croucher Fellowship 1986) was one of the first of Croucher scholars to stay in Hong Kong for his masters degree. At the time (the early 1980s) molecular biologists were fascinated by genetic engineering, with breakthroughs in DNA sequencing and molecular cloning, but that was just the start of a new era of research in life sciences.

Yu’s research team did the original work that contributed to the establishment of copy number variations (CNVs) among healthy subjects, and determined the differences in immune effector gene copy number variations on susceptibilities of systemic lupus erythematosus (SLE), dermatomyositis, rheumatoid arthritis, and type-1 diabetes.

From Hong Kong to Oxbridge

Following his Masters degree, Yu moved to Oxford to work on human immunology and biochemistry. One of Yu’s research focuses was component C4 polymorphism, which is strongly associated with systemic lupus erythematosus (SLE or lupus) - though he was not working on lupus at that point. Yu’s mentor and role model at Oxford, the esteemed Noble laureate Rodney Porter, sadly died in a road accident at the end of Yu’s second year. Many of Porter’s colleagues were based at Cambridge University, where he had trained. For this very reason, Yu moved to the MRC Laboratory of Molecular Biology at Cambridge for his post-doctorate studies as a Croucher fellow (1986). There, Yu was mentored by Nobel Prize winning biochemist, Dr César Milstein. He acquired the skills and knowledge to dissect the genetic diversity of complex phenotypes in the immune system.

To the United States and Lupus Research

Following Yu’s post-doctorate studies, it would have been difficult for him to continue his scientific career in the UK. In 1990, Yu arrived in Ohio. Research in the U.S. was very disease oriented - research proposed not in relation to a disease would be difficult to compete for funding.

This is how Yu came to work on lupus. Complement C4 deficiency is linked to systemic lupus erythematosus - particularly in Caucasian subjects. We have two copies of most genes - one from our father and one from our mother. C4 is different: on each Chromosome 6 the number of C4 genes varies from one to five, so we can have from two up to ten copies of C4 genes in a diploid genome. In the past, this was not known, but the simple “one-gene one-protein” concept just could not explain the complex phenomenon of complement C4 diversity. Yu’s team came up with a new hypothesis about copy number variations among different individuals and they have proven it. Copy number variations have now been linked to many diseases, but they also have an advantage: genetic variation. This variation means that as a species, we are stronger. However, it can also result in some of us being too strong, leading to immune-mediated or inflammatory disease; or in being too weak, increasing the vulnerability to recurrent infections and the risk of autoimmune diseases.

Yu’s team did a study to show the effect of copy number variation in C4 genes in Caucasian lupus patients. The study started initially with about 250 patients and 500 healthy subjects. Yu points out that the choice to start with Caucasian subjects was due to sample size availability in Ohio; for statistical significance, the study needed a large sample size. The study currently has engaged more than 3000 patients and as many healthy subjects. Now, the team has expanded to research on African American and Chinese patients. The phenomenon of complement C4A deficiency as a risk factor of lupus is similar, but patterns of gene copy number variation are markedly different between different races. Yu currently collaborates with research teams at the University of Hong Kong, Chang Gang Hospital in Taiwan, and Tuen Mun Hospital in Kowloon to examine how complement C4 genetic diversity contributes to disease risk and complications of Chinese SLE. Their first research paper on gene copy number variation of C4 in Chinese SLE is now in press.

Yu believes that getting to grips with the understanding of complement C4 will change the way in which physicians are able to diagnose patients; allowing more precise, tailored forms of treatment. For example, lupus can be caused by a number of defects, but 30-40% of patients have a C4A deficiency. To treat the 40 or so percent of lupus patients with that defect, it is appropriate to supplement the complement that is in deficient state; for the other 60 percent who do not, it is not. The idea is to move to the direction of incorporating genetic factors into therapy. It is currently possible to determine the DNA sequence of an entire genome within a couple of days. The problem is to know what to do with the data. Because we have more than 20,000 genes and many more variants, it is difficult to know which variants cause a disease - and it won’t be possible to make use of this data without very strong computer power and skilful bioinformaticians, not to mention the expert laboratory scientists needed to do experiments to verify or validate phenotypes. This is the future of precision medicine. 


Professor Yu Chack-Yung is a Principal Investigator at the Centre for Molecular and Human Genetics at the Nationwide Children’s Hospital, Columbus, Ohio. He received his BSc (1981), majoring in Biology and minoring in Biochemistry at The Chinese University of Hong Kong, where he also completed his MPhil (1983) in Molecular Biology. He completed his DPhil in Biochemistry at Trinity College, Oxford University.