Sex determination mechanisms differ among animal species, but it is not clear how these differences evolve. New sex determiners may arise in response to sexual conflicts, which occur when traits benefit one sex but hinder the other. Here we identified the genetic basis for the orange-blotch (OB) color pattern, a trait under sexually antagonistic selection in the cichlid fish of Lake Malawi, East Africa. The OB phenotype is due to a cis-regulatory mutation in the Pax7 gene. OB provides benefits of camouflage to females, but disrupts the species-specific male color patterns used for mate recognition. We suggest that the resulting sexual conflict at OB has been resolved by selection for a novel female sex determination locus, promoting its invasion into populations with an ancestral male sex determination system.

Background: The expression of carcino-embryonic antigen by colorectal cancer is an example of oncogenic activation of embryonic gene expression. Hypothesizing that oncogenesis-recapitulatingontogenesis may represent a broad programmatic commitment, we compared gene expression patterns of human colorectal cancers (CRCs) and mouse colon tumor models to those of mouse colon development embryonic days 13.5-18.5.

Several models have been proposed to suggest how the evolution of sex determining mechanisms might contribute to speciation. Here we describe the inheritance of sex in 19 fish species from the rapidly evolving flock of cichlids in Lake Malawi, Africa. We found that many of these species have a male heterogametic (XY) system on linkage group 7. Some species also segregate for a female heterogametic (ZW) system on linkage group 5 which is coincident with a dominant orange-blotch (OB) color pattern in females. The ZW system is epistatically dominant to the XY system when both are segregating within a family. Several lines of evidence suggest that additional sex-determining loci are segregating in some species. These results are consistent with the idea that genetic conflicts play an important role in the evolution of these species flocks and suggest that evolution of sex-determining mechanisms has contributed to the radiation of cichlid fishes in East Africa.

We used the hypomorphic Egfr wa2 allele to genetically examine the impact of impaired epidermal growth factor receptor (Egfr) signaling on the Apc Min mouse model of familial adenomatous polyposis. Transfer of the Apc Min allele onto a homozygous Egfr wa2 background results in a 90% reduction in intestinal polyp number relative to Apc Min mice carrying a wild-type Egfr allele. This Egfr effect is potentially synergistic with the actions of the modifierof-min (Mom1) locus. Surprisingly, the size, expansion, and pathological progression of the polyps appear Egfr-independent. Histological examination of the ilea of younger animals revealed no differences in the number of microadenomas, the presumptive precursor lesions to gross intestinal polyps. Pharmacological inhibition with EKI-785, an Egfr tyrosine kinase inhibitor, produced similar results in the Apc Min model. These data suggest that normal Egfr activity is required for establishment of intestinal tumors in the Apc Min model between initiation and subsequent expansion of initiated tumors. The role of Egfr signaling during later stages of tumorigenesis was examined by using nude mice xenografts of two human colorectal cancer cell lines. Treatment with EKI-785 produced a dose-dependent reduction in tumor growth, suggesting that Egfr inhibitors may be useful for advanced colorectal cancer treatment. E pidermal growth factor receptor (Egfr) is the prototypical member of the Erbb family of ligand-activated receptor tyrosine kinases (1). Mice homozygous for the targeted null Egfr tm1Mag allele show strain-dependent lethality (2). Genetic backgrounds supporting survival of Egfr tm1Mag homozygous mutants to term demonstrate the importance of Egfr for epithelial homeostasis (2-4); neonatal mice lacking Egfr maintain a robust proliferative compartment but develop disorganized cryptal architecture of the lower gastrointestinal (GI) tract (2) and hemorrhagic enteritis (4). The hypomorphic Egfr wa2 allele contains a single nucleotide mutation producing a valine to glycine amino acid substitution in the kinase domain, resulting in up to a 90% reduction in kinase activity (5,6 mice exhibit delayed intestinal adaptation and reestablishment of epithelial homeostasis after intestinal resection (7) as well as increased susceptibility to dextran sulfate-induced colitis (8). Furthermore, ectopic Egfr activation promotes increased intestinal epithelial cell proliferation and crypt size but a decrease in crypt fission rates (9).Overexpression of Egfr, the most commonly observed cancerassociated misregulation in Egfr signaling, correlates with poor prognosis in a number of cancers including breast, ovarian, and head and neck (10-12). Because Egfr activation can promote proliferation and maintain survival, amplification of receptor signaling by means of overexpression may promote tumor growth and resistance to apoptosis. Egfr signaling up-regulates its cognate ligands, creating autocrine loops that maintain and amplify levels of Egfr activity (13). For instance, although Egfr activi...

Adaptive variation in craniofacial structure contributes to resource specialization and speciation, but the genetic loci that underlie craniofacial adaptation remain unknown. Here we show that alleles of the hedgehog pathway receptor Patched1 (Ptch1) gene are responsible for adaptive variation in the shape of the lower jaw both within and among genera of Lake Malawi cichlid fish. The evolutionarily derived allele of Ptch1 reduces the length of the retroarticular (RA) process of the lower jaw, a change predicted to increase speed of jaw rotation for improved suction-feeding. The alternate allele is associated with a longer RA and a more robustly mineralized jaw, typical of species that use a biting mode of feeding. Genera with the most divergent feeding morphologies are nearly fixed for different Ptch1 alleles, whereas species with intermediate morphologies still segregate variation at Ptch1. Thus, the same alleles that help to define macroevolutionary divergence among genera also contribute to microevolutionary fine-tuning of adaptive traits within some species. Variability of craniofacial morphology mediated by Ptch1 polymorphism has likely contributed to niche partitioning and ecological speciation of these fishes.T he astounding diversity of vertebrate craniofacial morphology reflects adaptation to a wide variety of resources and environments. Evolution of craniofacial structure has been key to niche specialization and speciation in vertebrates (1), most famously exemplified by the varied beak morphology of Darwin's finches (2). The radiation of finches demonstrates both speciesdefining craniofacial divergence (2) and rapid adaptation of craniofacial morphology within species over the course of a few years in response to changes in resource availability (3). Although shifts in the expression of key craniofacial genes have been correlated with differences in trophic morphology among species of birds and cichlid fishes (4-8), the specific genetic loci producing these differences remain uncharacterized. As a result, it is not clear whether interspecific divergence and intraspecific adaptation share the same molecular genetic basis.