Our understanding of phylogenetic relationships among bony fishes has been transformed by analysis of a small number of genes, but uncertainty remains around critical nodes. Genome-scale inferences so far have sampled a limited number of taxa and genes. Here we leveraged 144 genomes and 159 transcriptomes to investigate fish evolution with an unparalleled scale of data: >0.5 Mb from 1,105 orthologous exon sequences from 303 species, representing 66 out of 72 ray-finned fish orders. We apply phylogenetic tests designed to trace the effect of whole-genome duplication events on gene trees and find paralogy-free loci using a bioinformatics approach. Genome-wide data support the structure of the fish phylogeny, and hypothesis-testing procedures appropriate for phylogenomic datasets using explicit gene genealogy interrogation settle some long-standing uncertainties, such as the branching order at the base of the teleosts and among early euteleosts, and the sister lineage to the acanthomorph and percomorph radiations. Comprehensive fossil calibrations date the origin of all major fish lineages before the end of the Cretaceous.

Notch has been linked to ␤-catenin-dependent tumorigenesis; however, the mechanisms leading to Notch activation and the contribution of the Notch pathway to colorectal cancer is not yet understood. By microarray analysis, we have identified a group of genes downstream of Wnt/␤-catenin (down-regulated when blocking Wnt/␤-catenin) that are directly regulated by Notch (repressed by ␥-secretase inhibitors and up-regulated by active Notch1 in the absence of ␤-catenin signaling). We demonstrate that Notch is downstream of Wnt in colorectal cancer cells through ␤-catenin-mediated transcriptional activation of the Notch-ligand Jagged1. Consistently, expression of activated Notch1 partially reverts the effects of blocking Wnt/␤-catenin pathway in tumors implanted s.c. in nude mice. Crossing APC Min/؉ with Jagged1 ؉/⌬ mice is sufficient to significantly reduce the size of the polyps arising in the APC mutant background indicating that Notch is an essential modulator of tumorigenesis induced by nuclear ␤-catenin. We show that this mechanism is operating in human tumors from Familial Adenomatous Polyposis patients. We conclude that Notch activation, accomplished by ␤-catenin-mediated up-regulation of Jagged1, is required for tumorigenesis in the intestine. The Notch-specific genetic signature is sufficient to block differentiation and promote vasculogenesis in tumors whereas proliferation depends on both pathways. beta-catenin ͉ APC ͉ intestine ͉ crosstalk

Genomes contain a large number of genes that do not have recognizable homologues in other species and that are likely to be involved in important species-specific adaptive processes. The origin of many such "orphan" genes remains unknown. Here we present the first systematic study of the characteristics and mechanisms of formation of primate-specific orphan genes. We determine that codon usage values for most orphan genes fall within the bulk of the codon usage distribution of bona fide human proteins, supporting their current protein-coding annotation. We also show that primate orphan genes display distinctive features in relation to genes of wider phylogenetic distribution: higher tissue specificity, more rapid evolution, and shorter peptide size. We estimate that around 24% are highly divergent members of mammalian protein families. Interestingly, around 53% of the orphan genes contain sequences derived from transposable elements (TEs) and are mostly located in primate-specific genomic regions. This indicates frequent recruitment of TEs as part of novel genes. Finally, we also obtain evidence that a small fraction of primate orphan genes, around 5.5%, might have originated de novo from mammalian noncoding genomic regions.

The dramatic phenotypic changes that occur in organisms during domestication leave indelible imprints on their genomes. Although many domesticated plants and animals have been systematically compared with their wild genetic stocks, the molecular and genomic processes underlying fungal domestication have received less attention. Here, we present a nearly complete genome assembly for the recently described yeast species Saccharomyces eubayanus and compare it to the genomes of multiple domesticated alloploid hybrids of S. eubayanus × S. cerevisiae (S. pastorianus syn. S. carlsbergensis), which are used to brew lager-style beers. We find that the S. eubayanus subgenomes of lager-brewing yeasts have experienced increased rates of evolution since hybridization, and that certain genes involved in metabolism may have been particularly affected. Interestingly, the S. eubayanus subgenome underwent an especially strong shift in selection regimes, consistent with more extensive domestication of the S. cerevisiae parent prior to hybridization. In contrast to recent proposals that lager-brewing yeasts were domesticated following a single hybridization event, the radically different neutral site divergences between the subgenomes of the two major lager yeast lineages strongly favor at least two independent origins for the S. cerevisiae × S. eubayanus hybrids that brew lager beers. Our findings demonstrate how this industrially important hybrid has been domesticated along similar evolutionary trajectories on multiple occasions.