Impacts of the Cretaceous Terrestrial Revolution and KPg extinction on mammal diversification.

Previous analyses of relations, divergence times, and diversification patterns among extant mammalian families have relied on supertree methods and local molecular clocks. We constructed a molecular supermatrix for mammalian families and analyzed these data with likelihood-based methods and relaxed molecular clocks. Phylogenetic analyses resulted in a robust phylogeny with better resolution than phylogenies from supertree methods. Relaxed clock analyses support the long-fuse model of diversification and highlight the importance of including multiple fossil calibrations that are spread across the tree. Molecular time trees and diversification analyses suggest important roles for the Cretaceous Terrestrial Revolution and Cretaceous-Paleogene (KPg) mass extinction in opening up ecospace that promoted interordinal and intraordinal diversification, respectively. By contrast, diversification analyses provide no support for the hypothesis concerning the delayed rise of present-day mammals during the Eocene Period.

Natural selection and mammalian BRCA1 sequences: elucidating functionally important sites relevant to breast cancer susceptibility in humans.

Comparison of orthologous gene sequences is emerging as a powerful approach to elucidating functionally important positions in human disease genes. Using a diverse array of 132 mammalian BRCA1 (exon 11) sequences, we evaluated the functional significance of specific sites in the context of selection information (purifying, neutral, or diversifying) as well as the ability to extract such information from alignments that index varying degrees of mammalian diversity. Small data sets of either closely related taxa (Primates) or divergent placental taxa were unable to distinguish sites conserved due to purifying selection from sites conserved due to chance (false-positive rate = 65%-99%). Increasing the number of placental taxa to 57 greatly reduced the potential false-positive rate (0%-1.5%). Using the larger data set, we ranked the oncogenic risk of human missense mutations using a novel method that incorporates site-specific selection level and severity of the amino acid change evaluated against the amino acids present in other mammalian taxa. In addition to sites undergoing positive selection in Marsupialia, Laurasiatheria, Euarchontoglires, and Primates, we identified sites most likely to be undergoing divergent selection pressure in different lineages and six pairs of potentially interacting sites. Our results demonstrate the necessity of including large numbers of sequences to elucidate functionally important sites of a protein when using a comparative evolutionary approach.