Acceptance Speech – Bern, 07.11.2003


Wen-Hsiung Li

2003 Balzan Prize for Genetics and Evolution

Wen-Hsiung Li has made seminal contributions to the field of evolutionary molecular genetics. He has developed widely used methods for inferring phylogenetic relationships and has made important discoveries about the rate of genetic change in different groups of animals.

The Vice President of the Swiss Federal Council
Officers of the Balzan Foundation
Members of the General Prize Committee
Ladies and Gentlemen

I feel greatly honored and encouraged to have been chosen for the 2003 Balzan Prize for Genetics and Evolution. I started as an engineer and a mathematician and could not imagine then that one day I would be given this highly prestigious award in biology. On this special occasion, I would like to thank Dr. Masatoshi Nei, who introduced me to the field of evolutionary biology, and my Ph.D. advisor Dr. Wendell Fleming, who supported my pursuit of applications in biology during my graduate student days at Brown University.
I am an adventurer. I tried engineering in college and geophysics in graduate school. After I went to Brown I pursued applied mathematics for my Ph.D. and in the second summer (1970) I met Dr. Nei, who introduced me to population genetics. I immediately realized that genetics is a fascinating subject, being intimately related to the mysteries of life. There were indeed numerous challenging problems for a mathematician and I was happy to have chosen that subject for my research. I made a lucky choice because genetics and molecular biology were expanding rapidly in the 1970s, producing great amounts of data for pursuing research in population genetics and molecular evolution. Then, 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. Appreciating the power of DNA sequence data for the inference of evolutionary history, I developed many methods to utilize DNA sequences for phylogenetic tree reconstruction and for estimating the statistical confidence of inferred trees. Moreover, I developed methods for comparative analyses of DNA and protein sequence data, which are needed for inferring the processes and mechanisms of molecular evolution. These methods have been widely used by scientists in my field; indeed, some of them became standard methods in the field.
To my satisfaction, my work on molecular clocks has received even more attention. A molecular clock refers to the rate of amino acid substitution in the evolution of a protein sequence or 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 among evolutionary lineages. When it was proposed in 1965 by Zuckerkandl and Pauling, 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 materials for reexamining the hypothesis and in 1985 my postdoc Chung-I Wu and I used a substantial amount of DNA sequence data to show that the rate of nucleotide substitution in the rodent lineage is at least two times higher than that in the primate lineage, rejecting the hypothesis of a global clock in mammals. In my 1987 Nature paper and in many subsequent papers my colleagues and I estimated that the rate of nucleotide substitution is about five times higher in rodents than in higher primates. We also showed that the rate became slower during 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. These findings largely resolved the controversy over the molecular clock hypothesis and have stimulated the development of better methods for estimating species divergence times.
In the late 1980s I decided to establish a molecular biology lab, so that I could obtain molecular data for pursuing some intriguing issues. One of them was the so-called male-driven evolution hypothesis, which stipulates that the rate of mutation is higher in male mammals than in females. This was a hot topic not only because of its relevance to the mechanism of mutation, but also for the generation time effect hypothesis that I just discussed. 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. Our results not only support male-driven evolution but also fit well the expectation of the generation time effect hypothesis, that is, the male-to-female ratio of mutation rate should be higher in long-lived organisms such as humans, because of many more rounds of germ cell divisions, than in short-lived ones such as rodents. 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 vertebrates.
With the advent of the genomic era my interests have turned to evolutionary genomics and bioinformatics. Genomic data provide an unprecedented opportunity to examine molecular evolution on a much larger scale than traditional data. For example, I have been interested in the evolution of duplicate genes since the 1970s because gene duplication has long been recognized as the primary source of genetic novelties. Now the availability of genomic data enables one to address questions like, “How often and how fast have duplicate genes diverged in function?” I have also been interested in the prediction of human genes because it remains unclear how many genes there are in the human genome. In general, we develop methods for analyzing genomic data and carry out systematic analyses of data.
It has been and continues to be a highly exciting, rewarding career. For this, I thank my students and postdoctoral fellows, past and present, for their support and their contributions to the lab and my mentors for their guidance. 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 Balzan Prize gives me great encouragement and financial support for pursuing my interests further.
It is a long way from a farm boy in a small village in Taiwan to a recipient of the Balzan Prize, and I sincerely thank the Balzan Foundation for the appreciation of my endeavors.

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