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A common assumption in comparative genomics is that orthologous genes share greater functional similarity than do paralogous genes (the "ortholog conjecture"). Many methods used to computationally predict protein function are based on this assumption, even though it is largely untested. Here we present the first large-scale test of the ortholog conjecture using comparative functional genomic data from human and mouse. We use the experimentally derived functions of more than 8,900 genes, as well as an independent microarray dataset, to directly assess our ability to predict function using both orthologs and paralogs. Both datasets show that paralogs are often a much better predictor of function than are orthologs, even at lower sequence identities. Among paralogs, those found within the same species are consistently more functionally similar than those found in a different species. We also find that paralogous pairs residing on the same chromosome are more functionally similar than those on different chromosomes, perhaps due to higher levels of interlocus gene conversion between these pairs. In addition to offering implications for the computational prediction of protein function, our results shed light on the relationship between sequence divergence and functional divergence. We conclude that the most important factor in the evolution of function is not amino acid sequence, but rather the cellular context in which proteins act., (© 2011 Nehrt et al.)

The two "rules of speciation"--the Large X-effect and Haldane's rule--hold throughout the animal kingdom, but the underlying genetic mechanisms that cause them are still unclear. Two predominant explanations--the "dominance theory" and faster male evolution--both have some empirical support, suggesting that the genetic basis of these rules is likely multifarious. We revisit one historical explanation for these rules, based on dysfunctional genetic interactions involving genes recently moved between chromosomes. We suggest that gene movement specifically off or onto the X chromosome is another mechanism that could contribute to the two rules, especially as X chromosome movements can be subject to unique sex-specific and sex chromosome specific consequences in hybrids. Our hypothesis is supported by patterns emerging from comparative genomic data, including a strong bias in interchromosomal gene movements involving the X and an overrepresentation of male reproductive functions among chromosomally relocated genes. In addition, our model indicates that the contribution of gene movement to the two rules in any specific group will depend upon key developmental and reproductive parameters that are taxon specific. We provide several testable predictions that can be used to assess the importance of gene movement as a contributor to these rules in the future.

Phylogenetic comparative methods have long been a mainstay of evolutionary biology, allowing for the study of trait evolution across species while accounting for their common ancestry. These analyses typically assume a single, bifurcating phylogenetic tree describing the shared history among species. However, modern phylogenomic analyses have shown that genomes are often composed of mosaic histories that can disagree both with the species tree and with each other--so-called discordant gene trees. These gene trees describe shared histories that are not captured by the species tree, and therefore that are unaccounted for in classic comparative approaches. The application of standard comparative methods to species histories containing discordance leads to incorrect inferences about the timing, direction, and rate of evolution. Here, we develop two approaches for incorporating gene tree histories into comparative methods: one that constructs an updated phylogenetic variance-covariance matrix from gene trees, and another that applies Felsenstein's pruning algorithm over a set of gene trees to calculate trait histories and likelihoods. Using simulation, we demonstrate that our approaches generate much more accurate estimates of tree-wide rates of trait evolution than standard methods. We apply our methods to two clades of the wild tomato genus Solanum with varying rates of discordance, demonstrating the contribution of gene tree discordance to variation in a set of floral traits. Our approaches have the potential to be applied to a broad range of classic inference problems in phylogenetics, including ancestral state reconstruction and the inference of lineage-specific rate shifts. [ABSTRACT FROM AUTHOR]

Introgression is a pervasive biological process, and many statistical methods have been developed to infer its presence from genomic data. However, many of the consequences and genomic signatures of introgression remain unexplored from a methodological standpoint. Here, we develop a model for the timing and direction of introgression based on the multispecies network coalescent, and from it suggest new approaches for testing introgression hypotheses. We suggest two new statistics, D1 and D2, which can be used in conjunction with other information to test hypotheses relating to the timing and direction of introgression, respectively. D1 may find use in evaluating cases of homoploid hybrid speciation (HHS), while D2 provides a four-taxon test for polarizing introgression. Although analytical expectations for our statistics require a number of assumptions to be met, we show how simulations can be used to test hypotheses about introgression when these assumptions are violated. We apply the D1 statistic to genomic data from the wild yeast Saccharomyces paradoxus--a proposed example of HHS--demonstrating its use as a test of this model. These methods provide new and powerful ways to address questions relating to the timing and direction of introgression. [ABSTRACT FROM AUTHOR]

Motivation Genome sequencing projects have revealed frequent gains and losses of genes between species. Previous versions of our software, Computational Analysis of gene Family Evolution (CAFE), have allowed researchers to estimate parameters of gene gain and loss across a phylogenetic tree. However, the underlying model assumed that all gene families had the same rate of evolution, despite evidence suggesting a large amount of variation in rates among families. Results Here, we present CAFE 5, a completely re-written software package with numerous performance and user-interface enhancements over previous versions. These include improved support for multithreading, the explicit modeling of rate variation among families using gamma-distributed rate categories, and command-line arguments that preclude the use of accessory scripts. Availability and implementation CAFE 5 source code, documentation, test data and a detailed manual with examples are freely available at https://github.com/hahnlab/CAFE5/releases. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Convergent evolution--the appearance of the same character state in apparently unrelated organisms--is often inferred when a trait is incongruent with the species tree. However, trait incongruence can also arise from changes that occur on discordant gene trees, a process referred to as hemiplasy. Hemiplasy is rarely taken into account in studies of convergent evolution, despite the fact that phylogenomic studies have revealed rampant discordance. Here, we study the relative probabilities of homoplasy (including convergence and reversal) and hemiplasy for an incongruent trait. We derive expressions for the probabilities of the two events, showing that they depend on many of the same parameters. We find that hemiplasy is as likely--or more likely--than homoplasy for a wide range of conditions, even when levels of discordance are low. We also present a method to calculate the ratio of these two probabilities (the "hemiplasy risk factor") along the branches of a phylogeny of arbitrary length. Such calculations can be applied to any tree to identify when and where incongruent traits may be due to hemiplasy. [ABSTRACT FROM AUTHOR]

The article focuses on the gene family evolution.Gene family evolution is pervasive and is important in its own evolution. It examines the rate and distribution of changes in the gene family size and the evolutionary forces that govern the changes. It discusses operational and computational methods for gene gains and losses through comparative genomics. The mechanisms which result in the new origin of new families and the circumstances that result in gene family death are also tackled.

Variation in gene expression may underlie many important evolutionary traits. However, it is not known at what stage in organismal development changes in gene expression are most likely to result in changes in phenotype. One widely held belief is that changes in early development are more likely to result in changes in downstream phenotypes. In order to discover how much genetic variation for transcript level is present in natural populations, we studied zygotic gene expression in nine inbred lines of Drosophila melanogaster at two time points in their development. We find abundant variation for transcript level both between lines and over time; close to half of all expressed genes show a significant line effect at either time point. We examine the contribution of maternally loaded genes to this variation, as well as the contribution of variation in upstream genes to variation in their downstream targets in two well-studied gene regulatory networks. Finally, we estimate the dimensionality of gene expression in these two networks and find that—despite large numbers of varying genes—there appear to be only two factors controlling this variation. [ABSTRACT FROM AUTHOR]

Chromosomal inversion polymorphisms are thought to play a role in adaptive divergence, but the genes conferring adaptive benefits remain elusive. Here we study 2La, a common polymorphic inversion in the African malaria vector Anopheles gambiae. The frequency of 2La varies clinally and seasonally in a pattern suggesting response to selection for aridity tolerance. By hybridizing genomic DNA from individual mosquitoes to oligonucleotide microarrays, we obtained a complete map of differentiation across the A. gambiae genome. Comparing mosquitoes homozygous for the 2La gene arrangement or its alternative (2L+a), divergence was highest at loci within the rearranged region. In the 22 Mb included within alternative arrangements, two ~1.5 Mb regions near but not adjacent to the breakpoints were identified as being significantly diverged, a conclusion validated by targeted sequencing. The persistent association of both regions with the 2La arrangement is highly unlikely given known recombination rates across the inversion in 2La heterozygotes, thus implicating selection on genes underlying these regions as factors responsible for the maintenance of 2La. Polymorphism and divergence data are consistent with a model in which the inversion is maintained by migration-selection balance between multiple alleles inside these regions, but further experiments will be needed to fully distinguish between the epistasis (coadaptation) and local adaptation models for the maintenance of 2La. [ABSTRACT FROM AUTHOR]

Comparison of whole genomes has revealed large and frequent changes in the size of gene families. These changes occur because of high rates of both gene gain (via duplication) and loss (via deletion or pseudogenization), as well as the evolution of entirely new genes. Here we use the genomes of 12 fully sequenced Drosophila species to study the gain and loss of genes at unprecedented resolution. We find large numbers of both gains and losses, with over 40% of all gene families differing in size among the Drosophila. Approximately 17 genes are estimated to be duplicated and fixed in a genome every million years, a rate on par with that previously found in both yeast and mammals. We find many instances of extreme expansions or contractions in the size of gene families, including the expansion of several sex- and spermatogenesis-related families in D. melanogaster that also evolve under positive selection at the nucleotide level. Newly evolved gene families in our dataset are associated with a class of testes-expressed genes known to have evolved de novo in a number of cases. Gene family comparisons also allow us to identify a number of annotated D. melanogaster genes that are unlikely to encode functional proteins, as well as to identify dozens of previously unannotated D. melanogaster genes with conserved homologs in the other Drosophila. Taken together, our results demonstrate that the apparent stasis in total gene number among species has masked rapid turnover in individual gene gain and loss. It is likely that this genomic revolving door has played a large role in shaping the morphological, physiological, and metabolic differences among species. [ABSTRACT FROM AUTHOR]

Comparison of whole genomes has revealed that changes in the size of gene families among organisms is quite common. However, there are as yet no models of gene family evolution that make it possible to estimate ancestral states or to infer upon which lineages gene families have contracted or expanded. In addition, large differences in family size have generally been attributed to the effects of natural selection, without a strong statistical basis for these conclusions. Here we use a model of stochastic birth and death for gene family evolution and show that it can be efficiently applied to multispecies genome comparisons. This model takes into account the lengths of branches on phylogenetic trees, as well as duplication and deletion rates, and hence provides expectations for divergence in gene family size among lineages. The model offers both the opportunity to identify large-scale patterns in genome evolution and the ability to make stronger inferences regarding the role of natural selection in gene family expansion or contraction. We apply our method to data from the genomes of five yeast species to show its applicability. [ABSTRACT FROM AUTHOR]

To characterize the coding-sequence divergence of closely related genomes, we compared DNA sequence divergence between sequences from a Brassica rapa ssp. pekinensis EST library isolated from flower buds and genomic sequences from Arabidopsis thaliana. The specific objectives were (i) to determine the distribution of and relationship between Ka and Ks, (ii) to identify genes with the lowest and highest Ka:Ks values, and (iii) to evaluate how codon usage has diverged between two closely related species. We found that the distribution of Ka:Ks was unimodal, and that substitution rates were more variable at nonsynonymous than synonymous sites, and detected no evidence that Ka and Ks were positively correlated. Several genes had Ka:Ks values equal to or near zero, as expected for genes that have evolved under strong selective constraint. In contrast, there were no genes with Ka:Ks >1 and thus we found no strong evidence that any of the 218 sequences we analyzed have evolved in response to positive selection. We detected a stronger codon bias but a lower frequency of GC at synonymous sites in A. thaliana than B. rapa. Moreover, there has been a shift in the profile of most commonly used synonymous codons since these two species diverged from one another. This shift in codon usage may have been caused by stronger selection acting on codon usage or by a shift in the direction of mutational bias in the B. rapa phylogenetic lineage. [ABSTRACT FROM AUTHOR]

Focuses on the announcement of the draft human genome sequence. Disjunction between the number of genes and organismal complexity; Discovery of noncoding DNA; Increase of the number of genes on an organism.

Establishing the molecular basis of DNA mutations that cause inherited disease is of fundamental importance to understanding the origin, nature, and clinical sequelae of genetic disorders in humans. The majority of disease-associated mutations constitute singlebase substitutions and short deletions and/or insertions resulting from DNA replication errors and the repair of damaged bases. However, pathological mutations can also be introduced by nonreciprocal recombination events between paralogous sequences, a phenomenon known as interlocus gene conversion (IGC). IGC events have thus far been linked to pathology in more than 20 human genes. However, the large number of duplicated gene sequences in the human genome implies that many more disease-associated mutations could originate via IGC. Here, we have used a genome-wide computational approach to identify disease-associated mutations derived from IGC events. Our approach revealed hundreds of known pathological mutations that could have been caused by IGC. Further, we identified several dozen high-confidence cases of inherited disease mutations resulting from IGC in 1/41% of all genes analyzed. About half of the donor sequences associated with such mutations are functional paralogous genes, suggesting that epistatic interactions or differential expression patterns will determine the impact upon fitness of specific substitutions between duplicated genes. In addition, we identified thousands of hitherto undescribed and potentially deleterious mutations that could arise via IGC. Our findings reveal the extent of the impact of interlocus gene conversion upon the spectrum of human inherited disease. [ABSTRACT FROM AUTHOR]