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Dive into the research topics where Laurence D. Hurst is active.

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Featured researches published by Laurence D. Hurst.


Nature | 2003

Dosage sensitivity and the evolution of gene families in yeast

Balázs Papp; Csaba Pál; Laurence D. Hurst

According to what we term the balance hypothesis, an imbalance in the concentration of the subcomponents of a protein–protein complex can be deleterious. If so, there are two consequences: first, both underexpression and overexpression of protein complex subunits should lower fitness, and second, the accuracy of transcriptional co-regulation of subunits should reflect the deleterious consequences of imbalance. Here we show that all these predictions are upheld in yeast (Saccharomyces cerevisiae). This supports the hypothesis that dominance is a by-product of physiology and metabolism rather than the result of selection to mask the deleterious effects of mutations. Beyond this, single-gene duplication of protein subunits is expected to be harmful, as this, too, leads to imbalance. As then expected, we find that members of large gene families are rarely involved in complexes. The balance hypothesis therefore provides a single theoretical framework for understanding components both of dominance and of gene family size.


Nature Reviews Genetics | 2006

Hearing silence: non-neutral evolution at synonymous sites in mammals

J. V. Chamary; Joanna L. Parmley; Laurence D. Hurst

Although the assumption of the neutral theory of molecular evolution — that some classes of mutation have too small an effect on fitness to be affected by natural selection — seems intuitively reasonable, over the past few decades the theory has been in retreat. At least in species with large populations, even synonymous mutations in exons are not neutral. By contrast, in mammals, neutrality of these mutations is still commonly assumed. However, new evidence indicates that even some synonymous mutations are subject to constraint, often because they affect splicing and/or mRNA stability. This has implications for understanding disease, optimizing transgene design, detecting positive selection and estimating the mutation rate.


Nature Reviews Genetics | 2004

The evolutionary dynamics of eukaryotic gene order

Laurence D. Hurst; Csaba Pál; Martin J. Lercher

In eukaryotes, unlike in bacteria, gene order has typically been assumed to be random. However, the first statistically rigorous analyses of complete genomes, together with the availability of abundant gene-expression data, have forced a paradigm shift: in every complete eukaryotic genome that has been analysed so far, gene order is not random. It seems that genes that have similar and/or coordinated expression are often clustered. Here, we review this evidence and ask how such clusters evolve and how this relates to mechanisms that control gene expression.


Nature Genetics | 2002

Clustering of housekeeping genes provides a unified model of gene order in the human genome.

Martin J. Lercher; Araxi O. Urrutia; Laurence D. Hurst

It is often supposed that, except for tandem duplicates, genes are randomly distributed throughout the human genome. However, recent analyses suggest that when all the genes expressed in a given tissue (notably placenta and skeletal muscle) are examined, these genes do not map to random locations but instead resolve to clusters. We have asked three questions: (i) is this clustering true for most tissues, or are these the exceptions; (ii) is any clustering simply the result of the expression of tandem duplicates and (iii) how, if at all, does this relate to the observed clustering of genes with high expression rates? We provide a unified model of gene clustering that explains the previous observations. We examined Serial Analysis of Gene Expression (SAGE) data for 14 tissues and found significant clustering, in each tissue, that persists even after the removal of tandem duplicates. We confirmed clustering by analysis of independent expressed-sequence tag (EST) data. We then tested the possibility that the human genome is organized into subregions, each specializing in genes needed in a given tissue. By comparing genes expressed in different tissues, we show that this is not the case: those genes that seem to be tissue-specific in their expression do not, as a rule, cluster. We report that genes that are expressed in most tissues (housekeeping genes) show strong clustering. In addition, we show that the apparent clustering of genes with high expression rates is a consequence of the clustering of housekeeping genes.


Journal of Molecular Evolution | 1998

The genetic code is one in a million.

Stephen J. Freeland; Laurence D. Hurst

Abstract. Statistical and biochemical studies of the genetic code have found evidence of nonrandom patterns in the distribution of codon assignments. It has, for example, been shown that the code minimizes the effects of point mutation or mistranslation: erroneous codons are either synonymous or code for an amino acid with chemical properties very similar to those of the one that would have been present had the error not occurred. This work has suggested that the second base of codons is less efficient in this respect, by about three orders of magnitude, than the first and third bases. These results are based on the assumption that all forms of error at all bases are equally likely. We extend this work to investigate (1) the effect of weighting transition errors differently from transversion errors and (2) the effect of weighting each base differently, depending on reported mistranslation biases. We find that if the bias affects all codon positions equally, as might be expected were the code adapted to a mutational environment with transition/transversion bias, then any reasonable transition/transversion bias increases the relative efficiency of the second base by an order of magnitude. In addition, if we employ weightings to allow for biases in translation, then only 1 in every million random alternative codes generated is more efficient than the natural code. We thus conclude not only that the natural genetic code is extremely efficient at minimizing the effects of errors, but also that its structure reflects biases in these errors, as might be expected were the code the product of selection.


Trends in Ecology and Evolution | 1996

Recent advances in understanding of the evolution and maintenance of sex

Laurence D. Hurst; Joel R. Peck

The evolution of sex has been the focus of considerable attention during recent years. There is some consensus that the solution to the mystery is that sex either enables the creation and spread of advantageous traits (possibly parasite resistance) or helps to purge the genome of deleterious mutations. Recent experimental work has allowed testing of some of the assumptions underlying the theoretical models, most particularly whether interactions between genes are synergistic and whether the mutation rate is adequately high. However, although a variety of theories point out advantages to sex, most of them predict that a little sex and recombination can go a long way towards improving the fitness of a population, and it remains unclear why obligate sex is so common.


Nature | 2004

Metabolic network analysis of the causes and evolution of enzyme dispensability in yeast

Balázs Papp; Csaba Pál; Laurence D. Hurst

Under laboratory conditions 80% of yeast genes seem not to be essential for viability. This raises the question of what the mechanistic basis for dispensability is, and whether it is the result of selection for buffering or an incidental side product. Here we analyse these issues using an in silico flux model of the yeast metabolic network. The model correctly predicts the knockout fitness effects in 88% of the genes studied and in vivo fluxes. Dispensable genes might be important, but under conditions not yet examined in the laboratory. Our model indicates that this is the dominant explanation for apparent dispensability, accounting for 37–68% of dispensable genes, whereas 15–28% of them are compensated by a duplicate, and only 4–17% are buffered by metabolic network flux reorganization. For over one-half of those not important under nutrient-rich conditions, we can predict conditions when they will be important. As expected, such condition-specific genes have a more restricted phylogenetic distribution. Gene duplicates catalysing the same reaction are not more common for indispensable reactions, suggesting that the reason for their retention is not to provide compensation. Instead their presence is better explained by selection for high enzymatic flux.


Trends in Genetics | 2002

Human SNP variability and mutation rate are higher in regions of high recombination.

Martin J. Lercher; Laurence D. Hurst

Understanding the co-variation of nucleotide diversity and local recombination rates is important both for the mapping of disease-associated loci and in understanding the causes of sequence evolution. It is known that single nucleotide polymorphisms (SNPs) around protein coding genes show higher diversity in regions of high recombination. Here, we find that this correlation holds for SNPs across the entire human genome, the great majority of which are not near exons or control elements. Contrasting with results from coding regions, we provide evidence that the higher nucleotide diversity in regions of high recombination is most likely due, at least in part, to a higher mutation rate. One possible explanation for this is that recombination is mutagenic.


Journal of Molecular Evolution | 1991

A quantitative measure of error minimization in the genetic code

David Haig; Laurence D. Hurst

SummaryWe have calculated the average effect of changing a codon by a single base for all possible single-base changes in the genetic code and for changes in the first, second, and third codon positions separately. Such values were calculated for an amino acids polar requirement, hydropathy, molecular volume, and isoelectric point. For each attribute the average effect of single-base changes was also calculated for a large number of randomly generated codes that retained the same level of redundancy as the natural code. Amino acids whose codons differed by a single base in the first and third codon positions were very similar with respect to polar requirement and hydropathy. The major differences between amino acids were specified by the second codon position. Codons with U in the second position are hydrophobic, whereas most codons with A in the second position are hydrophilic. This accounts for the observation of complementary hydropathy. Single-base changes in the natural code had a smaller average effect on polar requirement than all but 0.02% of random codes. This result is most easily explained by selection to minimize deleterious effects of translation errors during the early evolution of the code.


Genome Biology | 2005

Evidence for selection on synonymous mutations affecting stability of mRNA secondary structure in mammals

Jean-Vincent Chamary; Laurence D. Hurst

BackgroundIn mammals, contrary to what is usually assumed, recent evidence suggests that synonymous mutations may not be selectively neutral. This position has proven contentious, not least because of the absence of a viable mechanism. Here we test whether synonymous mutations might be under selection owing to their effects on the thermodynamic stability of mRNA, mediated by changes in secondary structure.ResultsWe provide numerous lines of evidence that are all consistent with the above hypothesis. Most notably, by simulating evolution and reallocating the substitutions observed in the mouse lineage, we show that the location of synonymous mutations is non-random with respect to stability. Importantly, the preference for cytosine at 4-fold degenerate sites, diagnostic of selection, can be explained by its effect on mRNA stability. Likewise, by interchanging synonymous codons, we find naturally occurring mRNAs to be more stable than simulant transcripts. Housekeeping genes, whose proteins are under strong purifying selection, are also under the greatest pressure to maintain stability.ConclusionTaken together, our results provide evidence that, in mammals, synonymous sites do not evolve neutrally, at least in part owing to selection on mRNA stability. This has implications for the application of synonymous divergence in estimating the mutation rate.

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