Briefings in Bioinformatics Advance Access originally published online on August 11, 2006
Briefings in Bioinformatics 2006 7(3):309-312; doi:10.1093/bib/bbl024
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Abstracts
Briefings in Bioinformatics aims to provide working biologists with an awareness and understanding of the computational approaches available for research and discovery. The Abstracts section of the journal consists of summaries of bioinformatics manuscripts published in the previous quarter. Inclusion of an article in this section indicates that the editors consider it to be among the most interesting and/or useful contributions to the field for the quarter covered. The contents of these reports are briefly distilled for the readers with an emphasis placed on their biological context and potential utility. Publications from the second quarter of 2006 (April–June), with an emphasis on the evolutionary divergence of the human and chimpanzee genomes, are reviewed here. |
Functional partitioning of yeast co-expression networks after genome duplication |
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 TOP Functional partitioning of yeast... Evolution of hormone-receptor...Positive selection, relaxation,...The fate of laterally...Identification, characterization...Genetic evidence for complex... |
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Gavin C. Conant and Kenneth H. Wolfe
PLoS Biology (2006) Vol. 4, no. 4, p. e109
Gene duplication is an important evolutionary force that often leads to the emergence of novel function. Many studies of this phenomenon have been conducted, and for the most part they have focused on the evolutionary rates and functions of individual paralogous gene pairs. Conant and Wolfe have added a new dimension to the evolutionary study of gene duplication by considering the effects of this process from a systems level perspective. They achieved this feat through the analysis of networks of interacting paralogous genes of the yeast Saccharomyces cerevisiae. A few years back, Wolfe and co-workers demonstrated that a whole genome duplication occurred along the evolutionary lineage leading to S. cerevisiae. Many of the paralogous gene copies generated by this duplication event have since been lost from the streamlined yeast genome, but many others, 551 duplicated pairs to be exact, remain and presumably contribute to functional diversification in the yeast genome. In order to better understand functional partitioning among yeast gene duplicates, the authors started with networks where the nodes were members of duplicated gene pairs and the edges consisted of coexpression relationships between genes. Given n pairs of paralogous genes, the authors devised and implemented a heuristic algorithm that partitions the two sets of n duplicated genes such that the number of interactions between the two sets (so-called crossing edges) is minimized. This approach has the effect of delineating maximally distinct subnetworks of paralogous gene sets. 19 paralogous sets were identified in this way, and their paralgous subnets were evaluated for asymmetry of interactions between subnets as well as functional coherence within subnets. Substantial asymmetry was found for paralogous subnetworks whereby one subnetwork contained far more interactions than its paralogous partner. However, there was also substantial redundancy between subnetworks, as indicated by the same within subnet interactions between paralogous genes. Taken together, these two observations suggest substantial, but incomplete, functional divergence between paralogous genes since the whole genome duplication event. In addition, individual subnets showed evidence of functional coherence in terms of tight clustering of interactions as well as similar subcellular localization and upstream regulatory sequence motifs. This work demonstrates the potential and utility of a systems level approach to evolutionary genomics.
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Evolution of hormone-receptor complexity by molecular exploitation |
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Jamie T. Bridgham, Sean M. Carroll and Joseph W. Thornton
Science (2006) Vol. 312, no. 5770, pp. 97–101
Tightly integrated functional complexes, composed of multiple interacting parts, pose a conceptual challenge to Darwinian theory. This is because it is difficult to imagine how any single molecule's function can be selected unless its interacting partners are already present. Thus, the gradual stepwise emergence of such complexes via Darwinian selection would seem to be precluded. Darwin himself recognized this and even proposed a solution, namely the evaluation of ancient forms of the system, in order to better understand the transitions that have led to the emergence of the extant complex. Bridgham et al. analyze a specific kind of molecular complex, steroid hormones and their receptors, and their study exemplifies and illuminates how the evolutionary processes leading to an integrated functional complex actually occur. Using phylogenetic comparison of extant steroid hormone receptor sequences, they reconstructed an ancestral corticoid receptor (ACR). The ACR gave rise to two extant receptors through a gene duplication event – glucocorticoid (GC) and mineralocorticoid (MC) – each of which has a specific binding partner; GC binds cortisol and MC binds aldosterone. Paradoxically, aldosterone evolved much later than the MC receptor to which it binds, so it is unclear how MC could have evolved to bind the non-existent (i.e. as yet unevolved) aldosterone via Darwinian selection. The authors were able to demonstrate that the ACR already possessed a binding affinity for aldosterone, presumably as a by-product of its affinity to other substrates, thus resolving this conundrum. They went on to show the specific mutational steps that led to the retention of aldosterone binding by MC and its loss by GC. The authors refer to this process as ‘molecular exploitation’—meaning the capture of an ancient molecular function, encoded by a protein that evolved to perform a different function, and its recruitment into a novel functional complex. This study has important implications for the politically charged intelligent design debate. Although the authors do not explicitly raise this issue in their manuscript, Chris Adami frames their work in these terms in his commentary that can be found in the same issue of Science. Adami points out how a seemingly irreducibly complex system, i.e. one not capable of evolving in a stepwise fashion, actually evolved through a series of mutational intermediates.
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Positive selection, relaxation, and acceleration in the evolution of the human and chimp genome |
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TOPFunctional partitioning of yeast...Evolution of hormone-receptor...Positive selection, relaxation,...The fate of laterally...Identification, characterization...Genetic evidence for complex... |
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Leonardo Arbiza, Joaquín Dopazo and Hernán Dopazo
PLoS Computational Biology (2006) Vol. 2, no. 4, p. e38
The recent completion of the chimpanzee genome sequence has allowed for genomic-scale comparative studies of human and chimp gene sequences. It is hoped that ultimately these types of studies will lead to an understanding of how natural selection has facilitated the emergence of biological features that are uniquely human. Arbiza et al. have conducted one such large-scale comparison of human and chimp gene sequences to search for the effects of natural selection. The idea is to identify gene sequences that have evolved under the influence of the kind of adaptive selection, also known as positive or diversifying selection, described by Darwin. The study of Arbiza et al. follows closely on the heels of several other attempts to identify positively selected human genes, but it is distinguished from these earlier works in its differentiation between cases of positive selection versus relaxation of selective constraint. Although positive selection and relaxation of selective constraint can both lead to increases in evolutionary rates and deviations from a strict molecular clock, they have very different biological implications. Relaxation of selective constraint suggests some degree of loss of function, while positive selection implies an active process of diversification leading to a new function. Starting with 13,198 human–chimp gene pairs, the authors identified statistically significant deviations from the molecular clock in 651 chimp and 469 human genes. Their test for positive selection revealed 577 cases in chimp and only 108 cases along the human lineage. The authors take these relatively small fractions of affected genes to suggest that the processes of accelerated evolution and positive selection have not been frequent events in the evolution of human and chimp genomes. They also suggest that this difference in the numbers of positively selected genes between the two species may be due to smaller population sizes for chimpanzees. Importantly, many accelerate genes did not show evidence of positive selection and numerous positively selected genes did not show evidence of evolutionary rate acceleration. This finding underscores the ability of their approach to distinguish these different modes of evolution. Most of the accelerated and positively selected genes identified by the authors fall into the same functional categories suggesting that it is the specific individual functions of positively selected genes that are important in generating differences between species.
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The fate of laterally transferred genes: life in the fast lane to adaptation or death |
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Weilong Hao and G. Brian Golding
Genome Research (2006) Vol. 16, no. 5, pp. 636–643
With the complete genome sequences of literally hundreds of bacterial genomes now available, the prevalence of lateral gene transfer (LGT)—i.e. non-vertical transmission of genes across species boundaries—is becoming increasing apparent. Indeed, LGT is so widespread that it has been taken to threaten the very existence of any coherent bacterial species phylogeny. Hao and Golding have carefully examined both the pattern of LGT and the fate of laterally transferred genes by studying 13 closely related Bacillaceae genomes. An important aspect of this work is the methodology that the authors employ to measure whole gene insertion/deletion (indel) events among genomes. They combine (i) analysis of closely related species and (ii) whole genome comparison with (iii) a sensitive maximum likelihood method. Together these approaches allow for robust estimation of the extent and frequency of indels attributed to LGT events. Closely related genome sequences facilitate the reliable estimation of the number of transferred genes. Comparison of whole genomes is critical because it rules out the mis-inference of LGT based on either hidden paralogs or genome re-arrangements that obscure homologs. The maximum-likelihood method allows for a robust and sensitive phylogeny based approach to estimating LGT, with indel parameters free to vary across the tree. Given what was already known about bacterial genome evolution, it was not so surprising that they found abundant evidence for LGT. However, the extent and speed by which this process was found to occur is impressive. The rate of LGT among the Bacilliacea is even greater than the rate of nucleotide substitution. Furthermore, considering how relatively large-scale, i.e. the transfer of entire genes or even operons, LGT events are, their frequency really emphasizes the profound evolutionary impact that they must have had. This study shows how the power of the comparative genomics approach is enhanced by the ever-increasing genome sequence space and the continued refinement of the analytical methods brought to bear on these data.
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Identification, characterization and comparative genomics of chimpanzee endogenous retroviruses |
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TOPFunctional partitioning of yeast...Evolution of hormone-receptor...Positive selection, relaxation,...The fate of laterally...Identification, characterization...Genetic evidence for complex... |
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Nalini Polavarapu, Nathan J. Bowen and John F. McDonald
Genome Biology (2006) Vol. 7, no. 6, p. R51
Transposable elements (TEs) are DNA sequences capable of moving around the genome, and mammalian genomes are made up primarily of the remnants of TE insertions. Retrotransposons—TEs that transpose via the reverse transcription of an RNA intermediate—are particularly abundant in the human genome, making up >40% of the genome sequence. Most studies of human–chimp genome divergence have focused on the evolution of typical protein encoding genes. However, the most divergent parts of these genomes correspond to TEs, retrotransposons in particular. In other words, if one wants to fully comprehend the genomic differences between humans and their closest living relatives, the differences among their TEs must be laid out in full. Nalini Polavarapu and colleagues have done just this for one particular class of retrotransposons—the endogenous retroviruses (ERVs). ERVs are genomic elements that are very similar to the more familiar infectious retroviruses, such as HIV, but they are unable to move from cell-to-cell. These elements are thought to be remnants of ancient germline infections, and they are capable of transposing within the genome. These transposition events lead to the accumulation of ERV sequences in the genome and, along with the elimination of element sequences, can lead to pronounced differences between evolutionary lineages. The authors report 42 families of ERVs in the chimp genome including the discovery of 9 previously unknown families. The vast majority of these families were found to have orthologs, i.e. elements in corresponding genomic positions, in the human genome. The presence of orthologous families indicates that these elements were around prior to the diversification of the two species. Nevertheless, nine families of chimp ERVs have been transpositionally active since the human–chimp divergence, while only one family has been active along the human lineage. It has previously been reported that the biggest differences between the human and chimp genomes result from insertion and deletion (indel) events rather than point substitutions. The authors of this study were able to demonstrate that 7% of the indel variation between the human and chimp genomes can be localized to ERV sequences. This underscores the role that ERVs have played in driving changes between the two species, and suggests the possibility that they may possess some as yet undiscovered particular evolutionary significance.
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Genetic evidence for complex speciation of humans and chimpanzees |
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Nick Patterson, Daniel J. Richter, Sante Gnerre, Eric S. Lander and David Reich
Nature (2006) Vol. 441, no. 7097, pp. 1103–1108
Patterson and colleagues have published a startling paper with results that have the potential to substantially alter prevailing notions about human evolution. The issue at hand is the timing of the divergence event that led to the two separate human and chimpanzee evolutionary lineages. For years, the only way to date this speciation event was through the comparison of fossil data. Paleontologists typically placed the human–chimp divergence event at 
10–20 million years ago. Starting in the late sixties, comparison of genetic data led to substantially more recent estimates for the time of the human–chimp divergence. The current consensus among molecular evolutionists is that the human and chimp lineages diverged 5–6 million years ago. Patterson et al. compared genome sequences from five primate genomes—human, chimp, gorilla, orangutan and macaque—and concurred with this date, estimating that the human–chimp divergence occurred just over 6 million years ago. This estimate is more recent than fossils suggest, and so the issue remains contentious, for paleontologists in particular. However, it should be noted that the estimate error levels associated with genetic dating could bring the two camps substantially closer together. The really provocative finding of this report is based on the demonstration that different regions of the genome show different levels of average divergence between human and chimpanzee. Regional human–chimp sequence divergence ranges from 87 to 147% of the average genome levels, which corresponds to a difference in age of 4 million years. The X-chromosome, in particular, shows exceedingly low levels of human–chimp sequence divergence along its entire length. From this difference, it can be estimated that the X-chromosome became species-specific 1.2 million years after the rest of the genome. This could have occurred if the human and chimpanzee genomic lineages continued to exchange genes before separating completely. In other words, our early hominid ancestors appear to have been interbreeding with chimpanzees and the resulting hybrids were, to some extent, fertile. X-chromosome compatibility would have been important in order to maintain hybrid fertility, and this could have been the source of strong purifying selection that kept the X-sequences more similar between lineages. This issue is, not surprisingly, highly controversial and more data will be needed to resolve it. In any case, this work highlights the power of genomic comparisons to reveal unexpected aspects of our evolutionary history and tell us things that fossil gazing cannot.
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