Developmental constraints on vertebrate genome evolution

Constraints in embryonic development are thought to bias the direction of evolution by making some changes less likely, and others more likely, depending on their consequences on ontogeny. Here, we characterize the constraints acting on genome evolution in vertebrates. We used gene expression data from two vertebrates: zebrafish, using a microarray experiment spanning 14 stages of development, and mouse, using EST counts for 26 stages of development. We show that, in both species, genes expressed early in development (1) have a more dramatic effect of knock-out or mutation and (2) are more likely to revert to single copy after whole genome duplication, relative to genes expressed late. This supports high constraints on early stages of vertebrate development, making them less open to innovations (gene gain or gene loss). Results are robust to different sources of data-gene expression from microarrays, ESTs, or in situ hybridizations; and mutants from directed KO, transgenic insertions, point mutations, or morpholinos. We determine the pattern of these constraints, which differs from the model used to describe vertebrate morphological conservation ("hourglass" model). While morphological constraints reach a maximum at mid-development (the "phylotypic" stage), genomic constraints appear to decrease in a monotonous manner over developmental time

Detecting patterns of species diversification in the presence of both rate shifts and mass extinctions

Recent methodological advances are enabling better examination of speciation and extinction processes and patterns. A major open question is the origin of large discrepancies in species number between groups of the same age. Existing frameworks to model this diversity either focus on changes between lineages, neglecting global effects such as mass extinctions, or focus on changes over time which would affect all lineages. Yet it seems probable that both lineages differences and mass extinctions affect the same groups. Here we used simulations to test the performance of two widely used methods, under complex scenarios. We report good performances, although with a tendency to over-predict events when increasing the complexity of the scenario. Overall, we find that lineage shifts are better detected than mass extinctions. This work has significance for assessing the methods currently used for estimating changes in diversification using phylogenies and developing new tests.Comment: 34 pages, 11 figure

Harvard College OSO-IV pointed experiment - An analysis of the malfunction during orbit 637

Telemetered malfunction data analysis from orbiting OSO- 4 implicating transforme

Generating Homology Relationships by Alignment of Anatomical Ontologies

The anatomy of model species is described in ontologies, which are used to standardize the annotations of experimental data, such as gene expression patterns. To compare such data between species, we aim to establish homology relations between ontologies describing different species. We present a new algorithm, and its implementation in the software Homolonto, to create new relationships between anatomical ontologies, based on the homology concept. These relationships and the Homolonto software are available at "http://bgee.unil.ch/.":http://bgee.unil.ch

Molecular Evolution and Gene Function

One of the basic questions of phylogenomics is how gene function evolves, whether among species or inside gene families. In this chapter, we provide a brief overview of the problems associated with defining gene function in a manner which allows comparisons which are both large scale and evolutionarily relevant. The main source of functional data, despite its limitations, is transcrip-tomics. Functional data provides information on evolutionary mechanisms primarily by showing which functional classes of genes evolve under stronger or weaker purifying or adaptive selection, and on which classes of mutations (e.g., substitutions or duplications). However, the example of the "ortholog conjecture" shows that we are still not at a point where we can confidently study phylogenomically the evolution of gene function at a precise scale

Age-dependent gain of alternative splice forms and biased duplication explain the relation between splicing and duplication.

We analyze here the relation between alternative splicing and gene duplication in light of recent genomic data, with a focus on the human genome. We show that the previously reported negative correlation between level of alternative splicing and family size no longer holds true. We clarify this pattern and show that it is sufficiently explained by two factors. First, genes progressively gain new splice variants with time. The gain is consistent with a selectively relaxed regime, until purifying selection slows it down as aging genes accumulate a large number of variants. Second, we show that duplication does not lead to a loss of splice forms, but rather that genes with low levels of alternative splicing tend to duplicate more frequently. This leads us to reconsider the role of alternative splicing in duplicate retention

IQRray, a new method for Affymetrix microarray quality control, and the homologous organ conservation score, a new benchmark method for quality control metrics

Motivation: Microarray results accumulated in public repositories are widely reused in meta-analytical studies and secondary databases. The quality of the data obtained with this technology varies from experiment to experiment, and an efficient method for quality assessment is necessary to ensure their reliability. Results: The lack of a good benchmark has hampered evaluation of existing methods for quality control. In this study, we propose a new independent quality metric that is based on evolutionary conservation of expression profiles. We show, using 11 large organ-specific datasets, that IQRray, a new quality metrics developed by us, exhibits the highest correlation with this reference metric, among 14 metrics tested. IQRray outperforms other methods in identification of poor quality arrays in datasets composed of arrays from many independent experiments. In contrast, the performance of methods designed for detecting outliers in a single experiment like Normalized Unscaled Standard Error and Relative Log Expression was low because of the inability of these methods to detect datasets containing only low-quality arrays and because the scores cannot be directly compared between experiments. Availability and implementation: The R implementation of IQRray is available at: ftp://lausanne.isb-sib.ch/pub/databases/Bgee/general/IQRray.R. Contact: [email protected] Supplementary information: Supplementary data are available at Bioinformatics onlin

The branch-site test of positive selection is surprisingly robust but lacks power under synonymous substitution saturation and variation in GC.

Positive selection is widely estimated from protein coding sequence alignments by the nonsynonymous-to-synonymous ratio ω. Increasingly elaborate codon models are used in a likelihood framework for this estimation. Although there is widespread concern about the robustness of the estimation of the ω ratio, more efforts are needed to estimate this robustness, especially in the context of complex models. Here, we focused on the branch-site codon model. We investigated its robustness on a large set of simulated data. First, we investigated the impact of sequence divergence. We found evidence of underestimation of the synonymous substitution rate for values as small as 0.5, with a slight increase in false positives for the branch-site test. When dS increases further, underestimation of dS is worse, but false positives decrease. Interestingly, the detection of true positives follows a similar distribution, with a maximum for intermediary values of dS. Thus, high dS is more of a concern for a loss of power (false negatives) than for false positives of the test. Second, we investigated the impact of GC content. We showed that there is no significant difference of false positives between high GC (up to ∼80%) and low GC (∼30%) genes. Moreover, neither shifts of GC content on a specific branch nor major shifts in GC along the gene sequence generate many false positives. Our results confirm that the branch-site is a very conservative test

Developmental Constraints on Genome Evolution in Four Bilaterian Model Species.

Developmental constraints on genome evolution have been suggested to follow either an early conservation model or an "hourglass" model. Both models agree that late development strongly diverges between species, but debate on which developmental period is the most conserved. Here, based on a modified "Transcriptome Age Index" approach, that is, weighting trait measures by expression level, we analyzed the constraints acting on three evolutionary traits of protein coding genes (strength of purifying selection on protein sequences, phyletic age, and duplicability) in four species: Nematode worm Caenorhabditis elegans, fly Drosophila melanogaster, zebrafish Danio rerio, and mouse Mus musculus. In general, we found that both models can be supported by different genomic properties. Sequence evolution follows an hourglass model, but the evolution of phyletic age and of duplicability follow an early conservation model. Further analyses indicate that stronger purifying selection on sequences in the middle development are driven by temporal pleiotropy of these genes. In addition, we report evidence that expression in late development is enriched with retrogenes, which usually lack efficient regulatory elements. This implies that expression in late development could facilitate transcription of new genes, and provide opportunities for acquisition of function. Finally, in C. elegans, we suggest that dosage imbalance could be one of the main factors that cause depleted expression of high duplicability genes in early development