The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.

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Initial sequencing and analysis of the human genome.

Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.

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Evolution of genes and genomes on the Drosophila phylogeny.

The effective size of a population, N e , determines the rate of change in the composition of a population caused by genetic drift, which is the random sampling of genetic variants in a finite population. N e is crucial in determining the level of variability in a population, and the effectiveness of selection relative to drift. This article reviews the properties of N e in a variety of different situations of biological interest, and the factors that influence it. In particular, the action of selection means that N e varies across the genome, and advances in genomic techniques are giving new insights into how selection shapes N e .

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Effective population size and patterns of molecular evolution and variation

Since the completion of the genome sequence of Saccharomyces cerevisiae in 1996 (refs 1, 2), there has been a large increase in complete genome sequences, accompanied by great advances in our understanding of genome evolution. Although little is known about the natural and life histories of yeasts in the wild, there are an increasing number of studies looking at ecological and geographic distributions, population structure and sexual versus asexual reproduction. Less well understood at the whole genome level are the evolutionary processes acting within populations and species that lead to adaptation to different environments, phenotypic differences and reproductive isolation. Here we present one- to fourfold or more coverage of the genome sequences of over seventy isolates of the baker's yeast S. cerevisiae and its closest relative, Saccharomyces paradoxus. We examine variation in gene content, single nucleotide polymorphisms, nucleotide insertions and deletions, copy numbers and transposable elements. We find that phenotypic variation broadly correlates with global genome-wide phylogenetic relationships. S. paradoxus populations are well delineated along geographic boundaries, whereas the variation among worldwide S. cerevisiae isolates shows less differentiation and is comparable to a single S. paradoxus population. Rather than one or two domestication events leading to the extant baker's yeasts, the population structure of S. cerevisiae consists of a few well-defined, geographically isolated lineages and many different mosaics of these lineages, supporting the idea that human influence provided the opportunity for cross-breeding and production of new combinations of pre-existing variations.

/pdf/population-genomics-of-domestic-and-wild-yeasts-1incyifh0w.pdf

Population genomics of domestic and wild yeasts

A simple method for estimating and testing phylogenetic trees under the principle of minimum evolution (ME) is presented. The basic procedure of this method is first to obtain the neighbor-joining (NJ) tree by Saitou and Nei’s method and then to search for a tree with the minimum value of the sum (S) of branch lengths by examining all trees that are closely related to the NJ tree. Once the ME tree is identified, a statistical test is conducted for the difference in S between this tree and other closely related trees. The mathematical method required for conducting this test is developed by using the least-squares approach. Computer simulation has shown that this method identifies the correct tree with a high probability, as long as the number of nucleotides examined is sufficiently large. It has also been shown that the topology of the NJ tree is almost always identical with that of the ME tree. A method for obtaining least-squares estimates (and their standard errors) of branch lengths for a given topology is also presented. This method can be used for testing the reliability of the branching pattern of the ME tree. However, the statistical test of S values is more powerful in rejecting incorrect trees than is the branch-length test or bootstrapping. Furthermore, both a mathematical method for computing the number of trees with a given value of topological difference from the NJ tree and a computer algorithm for identifying all the topologies are developed.

/pdf/a-simple-method-for-estimating-and-testing-minimum-evolution-252hkh8gyo.pdf

A Simple Method for Estimating and Testing Minimum-Evolution Trees

It is argued that the bias in synonymous codon usage observed in unicellular organisms is due to a balance between the forces of selection and mutation in a finite population, with greater bias in highly expressed genes reflecting stronger selection for efficiency of translation. A population genetic model is developed taking into account population size and selective differences between synonymous codons. A biochemical model is then developed to predict the magnitude of selective differences between synonymous codons in unicellular organisms in which growth rate (or possibly growth yield) can be equated with fitness. Selection can arise from differences in either the speed or the accuracy of translation. A model for the effect of speed of translation on fitness is considered in detail, a similar model for accuracy more briefly. The model is successful in predicting a difference in the degree of bias at the beginning than in the rest of the gene under some circumstances, as observed in Escherichia coli, but grossly overestimates the amount of bias expected. Possible reasons for this discrepancy are discussed.

https://www.genetics.org/content/genetics/129/3/897.full.pdf

The selection-mutation-drift theory of synonymous codon usage.

The use of synonymous codons is strongly biased in the bacterium Escherichia coli and yeast, comprising both bias between codons recognized by the same transfer RNA and bias between groups of codons recognized by different synonymous tRNAs. A major determinant of the second sort of bias is tRNA content, codons recognized by abundant tRNAs being used more often than those recognised by rare tRNAs, particularly in highly expressed genes, probably owing to selection at the level of translation against codons recognized by rare tRNAs. Conversely, codon usage is likely to exert selection pressure on tRNA abundance. Here I develop a model for the coevolution of codon usage and tRNA abundance which explains why there are unequal abundances of synonymous tRNAs leading to biased usage between groups of codons recognized by them in unicellular organisms.

Coevolution of codon usage and transfer RNA abundance

It has been shown previously that the synonymous substitution rate between Escherichia coli and Salmonella typhimurium is lower in highly than in weakly expressed genes, and it has been suggested that this is due to stronger selection for translational efficiency in highly expressed genes as reflected in their greater codon usage bias. This hypothesis is tested here by comparing the substitution rate in codon families with different patterns of synonymous codon use. It is shown that the decline in the substitution rate across expression levels is as great for codon families that do not appear to be subject to selection for translational efficiency as for those that are. This implies that selection on translational efficiency is not responsible for the decline in the substitution rate across genes. It is argued that the most likely explanation for this decline is a decrease in the mutation rate. It is also shown that a simple evolutionary model in which synonymous codon use is determined by a balance between mutation, selection for an optimal codon, and genetic drift predicts that selection should have little effect on the substitution rate in the present case.

Reduced synonymous substitution rate at the start of enterobacterial genes.

Codon usage and intragenic position.

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Michael Bulmer

Papers

The selection-mutation-drift theory of synonymous codon usage.

Coevolution of codon usage and transfer RNA abundance

Reduced synonymous substitution rate at the start of enterobacterial genes.

Codon usage and intragenic position.

Synonymous substitution rates in enterobacteria.