The Masatoshi Nei Lecture

SMBE members attending the 1999 Business Meeting in Brisbane, Australia, voted to establish the Masatoshi Nei Lecture to be delivered by the President at annual Society meetings.

Masatoshi Nei (根井正利 Nei Masatoshi) is Evan Pugh Professor of Biology at Pennsylvania State University and Director of the Institute of Molecular Evolutionary Genetics since 1990. He was born in 1931 in Miyazaki Prefecture, on Kyūshū Island, Japan. He was associate professor and professor of biology at Brown University from 1969 to 1972 and professor of population genetics at the Center for Demographic and Population Genetics, University of Texas at Houston, from 1972 to 1990. He is a theoretical population geneticist and evolutionary biologist. Acting alone or working with his students, he has continuously developed new statistical theories of molecular evolution taking into account frontier knowledge of molecular biology. He has also made several conceptual developments of evolutionary theory.

Theoretical Studies

He was 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 finding of linkage modification by natural selection. Recent molecular data indicate that many sets of interacting genes such as Hox genes, immunoglobulin genes, and histone genes often exist as gene clusters for a long evolutionary time. This observation can also be explained by his principle of maintenance of linkage of interacting genes. 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 ignored for many years but later vindicated when many multigene families and pseudogenes were discovered in the 1980s. 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. Later, he developed another distance measure called DA, which is appropriate for finding the topology of a phylogenetic tree. He also developed statistics of measuring the extent of population differentiation for any types of mating system using GST 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 developed a mathematical theory for studying genetic variation in terms of restriction enzymes.[10] In collaboration with Takeo Maruyama and Chung-I Wu, he also developed a theory of evolution of reproductive isolation using various models of incompatibility of genes between two isolated populations.

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 students 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., could not reject the null hypothesis of neutral evolution though a large amount of data for various genes from diverse groups of species were examined. The only exception was the major histocompatibility complex (MHC) loci, which show an extraordinarily high degree of polymorphism. He also showed that pseudogenes may represent a paradigm of neutral evolution without any selection.

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, which was in agreement with the results published by R. C. Lewontin in the same year. Nei and Roychoudhury 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 are still widely used. This study was a forerunner of the out of Africa theory of human origin by Allan Wilson.

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. 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 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.[19] Although various statistical methods for this test have been later developed, their original methods are still widely used. He maintains that the Bayesian method of inferring positively selected amino acid sites tends to give false-positives and experimental tests are necessary for confirmation of these sites.

Birth-and-death evolution and neomutationism

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 and 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 genetic changes and natural selection is merely a force eliminating less fit genotypes (neomutationism). He conducted statistical analyses of the evolution of genes controlling phenotypic characters such as olfactory reception and obtained evidence supporting his neomutationism.

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 have become leading figures in molecular evolution including Margaret Kidwell, Wen-Hsiung Li, Ranajit Chakraborty, Shozo Yokoyama, Aravinda Chakravarti, Dan Graur, Fumio Tajima, Chung-I Wu, Naoyuki Takahata, Takashi Gojobori, Pekka Pamilo, Austin Hughes, Andrey Rzhetsky, Jianzhi (George) Zhang, and Sudhir Kumar.

Recognition

Year Title
1977 Japan Society of Human Genetics Award
1990 Fellow, American Academy of Arts and Sciences
1990 Kihara Prize, Genetics Society of Japan
1997 Member, National Academy of Sciences, USA
2002 International Prize for Biology, Japan Society of the Promotion of Sciences
2003 Barbara Bowman Award, Texas Geneticist Society
2006 Thomas Hunt Morgan Medal, Genetics Society of America

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swarming in the bacterium Pseudomonas aeruginosa. Using genetic engineering, we excised a locus encoding a key metabolic regulator and disrupted P. aeruginosa’s metabolic prudence, the regulatory mechanism that controls expression of swarming public goods and protects this social behavior from exploitation by cheaters. Then, using experimental evolution, we followed the joint evolution of the genome, the metabolome and the social behavior as swarming re-evolved. New variants emerged spontaneously with mutations that reorganized the metabolome and compensated in distinct ways for the disrupted metabolic prudence. These experiments with a unicellular organism provide a detailed view of how metabolism—currency of all physiological processes—can determine the costs and benefits of a social behavior and ultimately influence how an organism behaves towards other organisms of the same species.

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Distribution, Diversity, and Long-Term Retention of Grass Short Interspersed Nuclear Elements (SINEs)

2017-08-17

Abstract
Instances of highly conserved plant short interspersed nuclear element (SINE) families and their enrichment near genes have been well documented, but little is known about the general patterns of such conservation and enrichment and underlying mechanisms. Here, we perform a comprehensive investigation of the structure, distribution, and evolution of SINEs in the grass family by analyzing 14 grass and 5 other flowering plant genomes using comparative genomics methods. We identify 61 SINE families composed of 29,572 copies, in which 46 families are first described. We find that comparing with other grass TEs, grass SINEs show much higher level of conservation in terms of genomic retention: The origin of at least 26% families can be traced to early grass diversification and these families are among most abundant SINE families in 86% species. We find that these families show much higher level of enrichment near protein coding genes than families of relatively recent origin (51%:28%), and that 40% of all grass SINEs are near gene and the percentage is higher than other types of grass TEs. The pattern of enrichment suggests that differential removal of SINE copies in gene-poor regions plays an important role in shaping the genomic distribution of these elements. We also identify a sequence motif located at 3′ SINE end which is shared in 17 families. In short, this study provides insights into structure and evolution of SINEs in the grass family.

Whole-Genome Sequence of the Anaerobic Isosaccharinic Acid Degrading Isolate, Macellibacteroides fermentans Strain HH-ZS

2017-08-16

Abstract
The ability of micro-organisms to degrade isosaccharinic acids (ISAs) while tolerating hyperalkaline conditions is pivotal to our understanding of the biogeochemistry associated within these environs, but also in scenarios pertaining to the cementitious disposal of radioactive wastes. An alkalitolerant, ISA degrading micro-organism was isolated from the hyperalkaline soils resulting from lime depositions. Here, we report the first whole-genome sequence, ISA degradation profile and carbohydrate preoteome of a Macellibacteroides fermentans strain HH-ZS, 4.08 Mb in size, coding 3,241 proteins, 64 tRNA, and 1 rRNA.

Ultraconserved Sequences Associated with HoxD Cluster Have Strong Repression Activity

2017-08-14

Abstract
Increase in the complexity of organisms during evolution strongly correlates with the increase in the noncoding DNA content of their genomes. Although a gradual increase in the proportion of repetitive DNA elements along with increasing complexity is known, most of the noncoding components of the genome remain uncharacterized. A nonrepetitive but highly conserved noncoding component of the genome in vertebrates, called ultraconserved DNA sequences, constitutes up to 5% of the human genome. The function of most of the ultraconserved DNA elements is not well known. One such ultraconserved stretch of DNA has been identified upstream of the HoxD cluster in vertebrates. We analyzed the function of these elements in different cell lines and zebrafish. Our results suggest that these ultraconserved sequences work as repressor elements. This is the first report which reveals the repressor function of ultraconserved sequences and implicates their role in the regulation of developmental genes.

Comparative Genomics Reveals Two Major Bouts of Gene Retroposition Coinciding with Crucial Periods of Symbiodinium Evolution

2017-08-07

Abstract
Gene retroposition is an important mechanism of genome evolution but the role it plays in dinoflagellates, a critical player in marine ecosystems, is not known. Until recently, when the genomes of two coral-symbiotic dinoflagellate genomes, Symbiodinium kawagutii and S. minutum, were released, it has not been possible to systematically study these retrogenes. Here we examine the abundant retrogenes (∼23% of the total genes) in these species. The hallmark of retrogenes in the genome is the presence of DCCGTAGCCATTTTGGCTCAAG, a spliced leader (DinoSL) constitutively trans-spliced to the 5′-end of all nucleus-encoded mRNAs. Although the retrogenes have often lost part of the 22-nt DinoSL, the putative promoter motif from the DinoSL, TTT(T/G), is consistently retained in the upstream region of these genes, providing an explanation for the high survival rate of retrogenes in dinoflagellates. Our analysis of DinoSL sequence divergence revealed two major bursts of retroposition in the evolutionary history of Symbiodinium, occurring at ∼60 and ∼6 Ma. Reconstruction of the evolutionary trajectory of the Symbiodinium genomes mapped these 2 times to the origin and rapid radiation of this dinoflagellate lineage, respectively. GO analysis revealed differential functional enrichment of the retrogenes between the two episodes, with a broad impact on transport in the first bout and more localized influence on symbiosis-related processes such as cell adhesion in the second bout. This study provides the first evidence of large-scale retroposition as a major mechanism of genome evolution for any organism and sheds light on evolution of coral symbiosis.

Phylogenomic Resolution of the Phylogeny of Laurasiatherian Mammals: Exploring Phylogenetic Signals within Coding and Noncoding Sequences

2017-08-02

Abstract
The interordinal relationships of Laurasiatherian mammals are currently one of the most controversial questions in mammalian phylogenetics. Previous studies mainly relied on coding sequences (CDS) and seldom used noncoding sequences. Here, by data mining public genome data, we compiled an intron data set of 3,638 genes (all introns from a protein-coding gene are considered as a gene) (19,055,073 bp) and a CDS data set of 10,259 genes (20,994,285 bp), covering all major lineages of Laurasiatheria (except Pholidota). We found that the intron data contained stronger and more congruent phylogenetic signals than the CDS data. In agreement with this observation, concatenation and species-tree analyses of the intron data set yielded well-resolved and identical phylogenies, whereas the CDS data set produced weakly supported and incongruent results. Further analyses showed that the phylogeny inferred from the intron data is highly robust to data subsampling and change in outgroup, but the CDS data produced unstable results under the same conditions. Interestingly, gene tree statistical results showed that the most frequently observed gene tree topologies for the CDS and intron data are identical, suggesting that the major phylogenetic signal within the CDS data is actually congruent with that within the intron data. Our final result of Laurasiatheria phylogeny is (Eulipotyphla,((Chiroptera, Perissodactyla),(Carnivora, Cetartiodactyla))), favoring a close relationship between Chiroptera and Perissodactyla. Our study 1) provides a well-supported phylogenetic framework for Laurasiatheria, representing a step towards ending the long-standing “hard” polytomy and 2) argues that intron within genome data is a promising data resource for resolving rapid radiation events across the tree of life.

The Evolutionary Dynamics of the Odorant Receptor Gene Family in Corbiculate Bees

2017-08-02

Abstract
Insects rely on chemical information to locate food, choose mates, and detect potential predators. It has been hypothesized that adaptive changes in the olfactory system facilitated the diversification of numerous insect lineages. For instance, evolutionary changes of Odorant Receptor (OR) genes often occur in parallel with modifications in life history strategies. Corbiculate bees display a diverse array of behaviors that are controlled through olfaction, including varying degrees of social organization, and manifold associations with floral resources. Here we investigated the molecular mechanisms driving the evolution of the OR gene family in corbiculate bees in comparison to other chemosensory gene families. Our results indicate that the genomic organization of the OR gene family has remained highly conserved for ∼80 Myr, despite exhibiting major changes in repertoire size among bee lineages. Moreover, the evolution of OR genes appears to be driven mostly by lineage-specific gene duplications in few genomic regions that harbor large numbers of OR genes. A selection analysis revealed that OR genes evolve under positive selection, with the strongest signals detected in recently duplicated copies. Our results indicate that chromosomal translocations had a minimal impact on OR evolution, and instead local molecular mechanisms appear to be main drivers of OR repertoire size. Our results provide empirical support to the longstanding hypothesis that positive selection shaped the diversification of the OR gene family. Together, our results shed new light on the molecular mechanisms underlying the evolution of olfaction in insects.

Discerning the Origins of the Negritos, First Sundaland People: Deep Divergence and Archaic Admixture

2017-07-11

Abstract
Human presence in Southeast Asia dates back to at least 40,000 years ago, when the current islands formed a continental shelf called Sundaland. In the Philippine Islands, Peninsular Malaysia, and Andaman Islands, there exist indigenous groups collectively called Negritos whose ancestry can be traced to the “First Sundaland People.” To understand the relationship between these Negrito groups and their demographic histories, we generated genome-wide single nucleotide polymorphism data in the Philippine Negritos and compared them with existing data from other populations. Phylogenetic tree analyses show that Negritos are basal to other East and Southeast Asians, and that they diverged from West Eurasians at least 38,000 years ago. We also found relatively high traces of Denisovan admixture in the Philippine Negritos, but not in the Malaysian and Andamanese groups, suggesting independent introgression and/or parallel losses involving Denisovan introgressed regions. Shared genetic loci between all three Negrito groups could be related to skin pigmentation, height, facial morphology and malarial resistance. These results show the unique status of Negrito groups as descended from the First Sundaland People.

Silencing Effect of Hominoid Highly Conserved Noncoding Sequences on Embryonic Brain Development

2017-06-19

Abstract
Superfamily Hominoidea, which consists of Hominidae (humans and great apes) and Hylobatidae (gibbons), is well-known for sharing human-like characteristics, however, the genomic origins of these shared unique phenotypes have mainly remained elusive. To decipher the underlying genomic basis of Hominoidea-restricted phenotypes, we identified and characterized Hominoidea-restricted highly conserved noncoding sequences (HCNSs) that are a class of potential regulatory elements which may be involved in evolution of lineage-specific phenotypes. We discovered 679 such HCNSs from human, chimpanzee, gorilla, orangutan and gibbon genomes. These HCNSs were demonstrated to be under purifying selection but with lineage-restricted characteristics different from old CNSs. A significant proportion of their ancestral sequences had accelerated rates of nucleotide substitutions, insertions and deletions during the evolution of common ancestor of Hominoidea, suggesting the intervention of positive Darwinian selection for creating those HCNSs. In contrary to enhancer elements and similar to silencer sequences, these Hominoidea-restricted HCNSs are located in close proximity of transcription start sites. Their target genes are enriched in the nervous system, development and transcription, and they tend to be remotely located from the nearest coding gene. Chip-seq signals and gene expression patterns suggest that Hominoidea-restricted HCNSs are likely to be functional regulatory elements by imposing silencing effects on their target genes in a tissue-restricted manner during fetal brain development. These HCNSs, emerged through adaptive evolution and conserved through purifying selection, represent a set of promising targets for future functional studies of the evolution of Hominoidea-restricted phenotypes.

Genome-Wide SNP Analysis Reveals Distinct Origins of Trypanosoma evansi and Trypanosoma equiperdum

2017-05-25

Abstract
Trypanosomes cause a variety of diseases in man and domestic animals in Africa, Latin America, and Asia. In the Trypanozoon subgenus, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense cause human African trypanosomiasis, whereas Trypanosoma brucei brucei, Trypanosoma evansi, and Trypanosoma equiperdum are responsible for nagana, surra, and dourine in domestic animals, respectively. The genetic relationships between T. evansi and T. equiperdum and other Trypanozoon species remain unclear because the majority of phylogenetic analyses has been based on only a few genes. In this study, we have conducted a phylogenetic analysis based on genome-wide SNP analysis comprising 56 genomes from the Trypanozoon subgenus. Our data reveal that T. equiperdum has emerged at least once in Eastern Africa and T. evansi at two independent occasions in Western Africa. The genomes within the T. equiperdum and T. evansi monophyletic clusters show extremely little variation, probably due to the clonal spread linked to the independence from tsetse flies for their transmission.