Masatoshi Nei

Theoretical studies

He is the first to show mathematically that in the presence of gene interaction natural selection always tends to enhance the linkage intensity between genetic loci or maintain the same linkage relationship. He then observed that the average recombination value per genome is generally lower in higher organisms than in lower organisms and attributed this observation to his theory of linkage modification. Recent molecular data indicate that many sets of interacting genes such as Hox genes, immunoglobulin genes, and histone genes have often existed as gene clusters for a long evolutionary time. This observation can also be explained by his theory of linkage modification. He also showed that, unlike R. A. Fisher’s argument, deleterious mutations can accumulate rather quickly on the Y chromosome or duplicate genes in finite populations. In 1969, considering the rates of amino acid substitution, gene duplication, and gene inactivation, he predicted that higher organisms contain a large number of duplicate genes and nonfunctional genes (now called pseudogenes). This prediction was shown to be correct when many multigene families and pseudogenes were discovered in the 1980s and 1990s. His notable contribution in the early 1970s is the proposal of a new measure of genetic distance (Nei’s distance) between populations and its use for studying evolutionary relationships of populations or closely related species. He later developed another distance measure called D_A, which is appropriate for finding the topology of a phylogenetic tree of populations. He also developed statistics of measuring the extent of population differentiation for any types of mating system using G_ST measure. In 1975, he and collaborators presented a mathematical formulation of population bottleneck effects and clarified the genetic meaning of bottleneck effects. In 1979, he proposed a statistical measure called nucleotide diversity, which is now widely used for measuring the extent of nucleotide polymorphism. He also developed several different models of speciation and concluded that the reproductive isolation between species occurs as a passive process of accumulation of interspecific incompatibility mutations

Protein polymorphism and neutral theory

In the early 1960s and 1970s, there was a great controversy over the mechanism of protein evolution and the maintenance of protein polymorphism. Nei and his collaborators developed various statistical methods for testing the neutral theory of evolution by using polymorphism data. Their analysis of the allele frequency distribution, the relationship between average heterozygosity and protein divergence between species, etc., showed that a large portion of protein polymorphism can be explained by neutral theory. The only exception was the major histocompatibility complex (MHC) loci, which show an extraordinarily high degree of polymorphism. For these reasons, he accepted the neutral theory of evolution.

Human evolution

Using his genetic distance theory, he and A. K. Roychoudhury showed that the genetic variation between Europeans, Asians, and Africans is only about 11 percent of the total genetic variation of the human population. They then estimated that Europeans and Asians diverged about 55,000 years ago and these two populations diverged from Africans about 115,000 years ago. This conclusion was supported by many later studies using larger numbers of genes and populations, and the estimates appear to be still roughly correct. This finding represents the first indication of the out-of-Africa theory of human origins.

Molecular phylogenetics

Around 1980, Nei and his students initiated a study of inference of phylogenetic trees based on distance data. In 1985 they developed a statistical method for testing the accuracy of a phylogenetic tree by examining the statistical significance of interior branch lengths. They then developed the neighbor-joining and minimum-evolution methods of tree inference. At present, the neighbor-joining method is most widely used in molecular phylogenetics, though some theoreticians advocate the likelihood and the Bayesian methods. They also developed statistical methods for estimating evolutionary times from molecular phylogenies. In collaboration with Sudhir Kumar and Koichiro Tamura, he developed a widely used computer program package for phylogenetic analysis called MEGA.

MHC loci and positive Darwinian selection

Nei’s group invented a simple statistical method for detecting positive Darwinian selection by comparing the numbers of synonymous nucleotide substitutions and nonsynonymous nucleotide substitutions. . Applying this method, they showed that the exceptionally high degree of sequence polymorphism at MHC loci is caused by overdominant selection. Although various statistical methods for this test have been developed later, their original methods are still widely used.

New evolutionary concepts

Nei and his students studied the evolutionary patterns of a large number of multigene families and showed that they generally evolve following the model of a birth-and-death process. In some gene families this process is very fast, caused by random events of gene duplication and gene deletion and generates genomic drift of gene copy number. Nei has long maintained the view that the driving force of evolution is mutation including any types of DNA changes (nucleotide changes, chromosomal changes, and genome duplication) and natural selection is merely a force eliminating less fit genotypes (theory of mutation-driven evolution). He conducted statistical analyses of evolution of genes controlling phenotypic characters such as immunity and olfactory reception and obtained evidence supporting this theory.

New journal, new society, and students

He founded the journal Molecular Biology and Evolution in 1983 and the Society for Molecular Biology and Evolution in 1993, together with Walter M. Fitch. He also trained many graduate students and postdoctorals who later became leading figures in molecular evolutionary biology including Wen-Hsiung Li, Margaret Kidwell, Ranajit Chakraborty, Shozo Yokoyama, Aravinda Chakravarti, Dan Graur, Fumio Tajima, Naruya Saitou, Chung-I Wu, Naoyuki Takahata, Takashi Gojobori, Pekka Pamilo, Austin Hughes, Andrey Rzhetsky, Jianzhi (George) Zhang, and Sudhir Kumar

Awards and honors

Appointments

Books