Comparative phylogeography of Mississippi embayment fishes.

The Mississippi Embayment is a prominent physiographic feature of eastern North America consisting of primarily lowland aquatic habitats and a fish fauna that is largely distinct from nearby highland regions. Numerous studies have demonstrated that both pre-Pleistocene and Pleistocene events have had a strong influence on the distributions and relationships of highland fishes in eastern North America. However, the extent to which these same events affected Embayment distributed taxa remains largely unexplored. The purpose of this study was to investigate the relative roles of pre-Pleistocene and Pleistocene events in shaping phylogeographic relationships of four stream dwelling fishes in the Mississippi Embayment. Molecular genetic analyses of the mitochondrial gene cytochrome b were performed for three ictalurid catfish species (Noturus miurus, n = 67; Noturus hildebrandi, n = 93, and Noturus phaeus, n = 44) and one minnow species (Cyprinella camura, n = 78), all distributed in tributary streams of the Mississippi Embayment. Phylogenetic relationships and divergence times among haplotypes for each species were estimated using maximum likelihood and Bayesian methods. Phylogenetic analyses recovered 6 major haplotype clades within N. miurus, 5 within N. hildbrandi, 8 within N. phaeus, and 8 within C. camura. All three Noturus species show a high degree of isolation by drainage, which is less evident in C. camura. A clade of haplotypes from tributaries in the southern portion of the Mississippi Embayment was consistently recovered in all four species. Divergence times among clades spanned the Pleistocene, Pliocene, and Miocene. Novel relationships presented here for C. camura and N. phaeus suggest the potential for cryptic species. Pre-Pleistocene and Pleistocene era sea level fluctuations coincide with some divergence events, but no single event explains any common divergence across all taxa. Like their highland relatives, a combination of both pre-Pleistocene and Pleistocene era events have driven divergences among Embayment lineages

Maps of the Mississippi Embayment region.

<p>A. Map of the eastern U.S. illustrating the location of the Mississippi Embayment relative to the Appalachian, Ozark, and Ouachita Highlands. Dashed line represents approximate extent of the Coastal Plain. Black rectangle inset indicates outline of area highlighted in section B. Data available from the U.S. Geological Survey. B. Map of major river drainages in the Mississippi Embayment region. Abbreviations as follows: AM, Amite River; AR, Arkansas River; BB, Big Black River; BP, Bayou Pierre; BR, Buffalo River, BS, Big Sandy River; CC, Coles Creek; CR, Coldwater River; CU, Cumberland River; FD, Forked Deer River; HR, Homochitto River; HT, Hatchie River; LI, Little River; LR, Loosahatchie River; MO, Missouri River; MR, Mississippi River; OB, Obion River; OR, Ohio River; OU, Ouachita River; PR, Pearl River; LT, Little Tallahatchie; RR, Red River; TR, Tennessee River; WR, Wolf River; WT, West Fork Thompson Creek; YA, Yalobusha River; YZ, Yazoo River; YO, Yocona River. Colored regions correspond with color coding used to designate clades in Figs <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0116719#pone.0116719.g003" target="_blank">3</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0116719#pone.0116719.g005" target="_blank">5</a>.</p

Average between-clade sequence divergence between major clades recovered in the phylogenetic analyses for each species.

<p>Clade names correspond with those presented in Figs <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0116719#pone.0116719.g003" target="_blank">3</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0116719#pone.0116719.g005" target="_blank">5</a>.</p><p>Average between-clade sequence divergence between major clades recovered in the phylogenetic analyses for each species.</p

Sample size (<i>n</i>), number of haplotypes, number of polymorphic sites, and average within-clade sequence divergence for all major clades recovered in the phylogenetic analyses.

<p>Clade names correspond with those presented in Figs <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0116719#pone.0116719.g003" target="_blank">3</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0116719#pone.0116719.g005" target="_blank">5</a>.</p><p>Sample size (<i>n</i>), number of haplotypes, number of polymorphic sites, and average within-clade sequence divergence for all major clades recovered in the phylogenetic analyses.</p

Distribution maps showing sampling localities for each species.

<p>A. <i>Noturus miurus</i>. B. <i>Noturus hildebrandi</i>. C. <i>Noturus phaeus</i>. D. <i>Cyprinella camura</i>. Gray shading indicates the natural range of each species. Circles indicate approximate sampling localities for specimens acquired for this study (•) and those used in previous studies with sequences acquired from GenBank (◯).</p

Haplotype networks (at left for each species) and Bayesian consensus topologies (at right for each species) based on cytochrome <i>b</i> sequence data.

<p>A. <i>Noturus miurus</i>. B. <i>Noturus hildebrandi</i>. C. <i>Noturus phaeus</i>. D. <i>Cyprinella camura</i>. Parenthetical numbers indicated haplotypes separated by ≥10 mutational steps. Nodes on trees with posterior probabilities ≥0.95 are indicated with an *. Numbers above nodes indicate likelihood bootstrap support. Locality abbreviations and colors correspond with <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0116719#pone.0116719.g001" target="_blank">Fig 1B</a>. Outgroups have been removed from phylogenies for clarity.</p

Genomic analyses identify molecular subtypes of pancreatic cancer

© 2016 Macmillan Publishers Limited. All rights reserved.Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63ΔN transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development