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Chen Award for Distinguished Academic Achievement in Human Genetic and Genomic Research (2008)

Li Wen-Hsiung, Taiwan
Academia Sinica

Wen-Hsiung Li is currently the James Watson Professor, University of Chicago (2004-) and the Director of Biodiversity Research Center, Academia Sinica, Taiwan (2008-). Before that, he was the George Beadle Professor, University of Chicago (1999-2004), and the Betty Wheless Trotter Professor in Medical Sciences, The University of Texas Health Science Center-Houston (1996-1998).

Prof. Li obtained a BE in Engineering (1965), a MS in geophysics (1968), and a Ph.D. in applied mathematics (1972).

His early work was on population genetics theory with applications to human genetics. He studied the burden of disease-causing mutations on human society and the maintenance of genetic variability in populations. He was the first to show that the nucleotide (DNA) diversity in humans is low, only ~0.1%. A major focus of his research has been on molecular evolution, especially evolution of DNA sequences. He has made highly significant contributions to the mechanisms of molecular evolution, molecular clock, sex differences in mutation rate, the origin and evolution of color vision, and other issues. For example, he estimated that the molecular clock runs about five times faster in rodents than in humans and that in humans the male mutation rate is 5 to 6 times higher than that in females. In the late 1980s he started to work on genomic evolution and has since made germinal contributions to the genomic differences between human and apes, annotation of human genes, the origin of human genes, and other topics. For example, he showed that the genomes of human and chimpanzee differ by only 1.2% in nucleotide sequences. Also, his lab has produced large amounts of DNA polymorphism data in humans and apes, leading to a good understanding of the genetic variability in humans and apes. In addition to his experimental work, he has developed many computational methods that have been widely used in the study of molecular and genomic evolution. His work has been cited more than 25,000 times.

Prof. Li received Balzan Prize 2003 for Genetics, which is the most prestigious prize in his field of research. Also, he received the Outstanding Achievement in Science Award of the Taiwan-US Foundation in 2005. He was elected an Academician, Academia Sinica, Taiwan in 1998; Fellow, American Academy of Arts and Sciences in 1999; and Member, National Academy of Sciences 2003. He was the President of the Society for Molecular Biology and Evolution, 2000. He has served or is serving as editor or associate editor of many international journals.

Acceptance Speech

Dr. Edison Liu, the President of HUGO, and my fellow scientists 

I feel greatly honored and encouraged to have been chosen for the inaugural Chen Award for Distinguished Academic Achievement in Human Genetics and Genomics. I started as a mathematician and could not imagine then that one day I would be receiving this highly prestigious award in biomedicine. On this special occasion, I would like to thank Dr. Masatoshi Nei for introducing me to genetics, and my Ph.D. advisor Dr. Wendell Fleming for supporting my pursuit of applying mathematics to biology during my graduate student days at Brown University.

I like adventure and exploration of new fields. I tried engineering in college and geophysics in a master degree program. After I went to Brown I pursued applied mathematics for my Ph.D. In the second summer (1970) I met Dr. Nei, who introduced me to population genetics. I immediately found genetics fascinating, because it is intimately related to the mysteries of life. 

My Ph.D. thesis and immediate subsequent work were on human population genetics, especially on the population dynamics of mutant genes such as the acheiropodia mutant, which is a recessive mutation that causes the handless/footless syndrome. However, a few years later I became more interested in the theory of population genetics and in molecular evolution. In 1980 I saw that a substantial amount of DNA sequence data had accumulated and I decided to devote most of my time to the study of DNA sequence evolution. I was able to develop methods for using DNA sequence data to reconstruct phylogenetic trees and for estimating the statistical confidence of an inferred tree. I also developed methods for comparative analyses of DNA and protein sequence data, which are needed for inferring the processes and mechanisms of molecular evolution. I am delighted that many of my methods have been widely used and some became standard methods in the field. 

It is pleasing to see that my work on molecular clocks has also received much attention. A molecular clock refers to the rate of nucleotide substitution in the evolution of a DNA sequence. The molecular clock hypothesis postulates that the rate of molecular evolution is constant over time. When it was proposed in 1965, it stimulated a great controversy but also great excitement because if protein sequences evolved at constant rates, they would be extremely useful for dating species divergence times and other evolutionary events. In the 1970s there were many strong advocates of the hypothesis, so it became widely accepted and used in the field. I thought that DNA sequence data would be excellent material for reexamining the hypothesis and in the 1980s and 1990s my lab conducted extensive data analyses to examine this issue. For example, we estimated that the rate of nucleotide substitution is about five times higher in rodents than in higher primates and we showed that the rate has become slower in the evolution from monkeys to humans. These observations supported the generation time effect hypothesis, which postulates that the rate of molecular evolution is slower in animals with long generations than in animals with short generations. Our studies showed that no global clock exists in mammals and that methods without the assumption of a linear clock are needed for dating evolutionary events. 

In the late 1980s I decided to establish a molecular biology lab, so that I could obtain molecular data for resolving some outstanding issues. One of them was male-driven evolution, which stipulates that the rate of mutation is higher in male mammals than in females. This was a hot topic not only for its relevance to the mechanism of mutation, but also for the generation time effect hypothesis I just mentioned. Through a series of papers my colleagues and I showed that the mutation rate of male humans is about 6 times higher than that of females. In rodents the ratio is, however, only about 2. This makes sense because humans live much longer than rodents, so the human male germline goes through many more rounds of cell division per generation than does the rodent male germline. Thus, our results not only support male-driven evolution but also fit the expectation of the generation time effect hypothesis. Moreover, our results suggest that errors during DNA replication in the germline are the primary source of mutation and support the view that there is no global molecular clock in mammals. We have also studied other topics such as the origin of trichromatic color vision in primates. 

For my work in molecular evolution, I received the 2003 Balzan Prize for Genetics and Evolution and was elected to the National Academy of Sciences, USA. 

I of course have continued to work on human genetics. In the 1980s I wrote many papers on the structure-function relationships and the evolution of human apolipoprotein genes. Moreover, I worked extensively on single nucleotide polymorphism (SNP) or nucleotide diversity in humans. In 1991, I estimated an upper bound of 0.1% for the nucleotide diversity in humans, which was surprisingly low but was found to be accurate when large amounts of data became available ten years later. In addition, using PCR and an ABI sequencer, my lab obtained large amounts of DNA polymorphism data in humans and apes. 

With the advent of genomics my interests turned to evolutionary genomics and bioinformatics. My lab was the first to give estimates of sequence divergence between human and ape genomes. For example, in 2001 we estimated that the sequence divergence between the human and chimpanzee genomes is only 1.2%, which was found to be highly accurate when the chimp genome draft became available in 2005. Genomic data provided the opportunity to examine molecular evolution on a much larger scale than traditional data. For example, we have used such data to study the extent of gene duplication and the composition of repetitive sequences in the human genome, and the evolutionary history of human genes. Also, I was interested in predicting human genes because it was unclear how many genes there are in the human genome. An application of our prediction method to the genome sequences of human, mouse and rat led to the discovery of more than 10,000 coding exons that had not then been annotated in any database. In general, we develop methods for analyzing genomic data and carry out systematic analyses of data. 

My career has been highly exciting and rewarding. For this, I thank my students and postdoctoral fellows, past and present, for their contributions to the lab. Especially, I thank my wife Sue-Jean and children Vivian, Herman, and Joyce for their support and for bearing with me over so many years, hiding in my office or behind piles of papers. I tremendously enjoy doing science and find it a fulfilling life. The Chen Award gives me great encouragement. 

It is a long way from a farm boy in a small village in Taiwan to a recipient of the Chen Award, and I sincerely thank HUGO for the appreciation of my endeavors. 

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