Informatic approaches to evolutionary systems biology

The sheer complexity of evolutionary systems biology requires us to develop more sophisticated tools for analysis, as well as more probing and biologically relevant representations of the data. My research has focused on three aspects of evolutionary systems biology. I ask whether a gene's position in the human metabolic network affects the degree to which natural selection prunes variation in that gene. I estimated the selective constraint (the ratio of non-synonymous to synonymous nucleotide substitutions) on 80.2% of the genes in the metabolic network using a maximum likelihood model of codon evolution and compared this value to the betweenness centrality of each enzyme. Second, I have focused on the evolution of metabolic systems in the presence of gene and genome duplication. I show that increases in a particular gene's copy number are correlated with limiting metabolic flux in the reaction associated with that gene. Finally, I have investigated the proliferative cell programs present in 6 different cancers (breast, colorectal, gastrointestinal, lung, oral squamous and prostate cancers). I found an overabundance of genes that share expression between cancer and embryonic tissue and that these genes form modular units within regulatory, proteininteraction, and metabolic networks. This despite the fact that these genes, as well as the proteins they encode and reactions they catalyze show little overlap among cancers, suggesting parallel independent reversion to an embryonic pattern of gene expression.Includes bibliographical references (pages 84-99)

Mitochondrial ancient DNA analysis of Lawson cave black bears (Ursus americanus)

Title from PDF of title page (University of Missouri--Columbia, viewed on Feb 17, 2010).The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file.Thesis advisor: Dr. R. Lee Lyman.Includes bibliographical references.M.A. University of Missouri--Columbia 2009.Dissertations, Academic -- University of Missouri--Columbia -- Anthropology.The distribution of black bear (Ursus americanus) in southern and central Missouri has been controversial. This controversy centers on two questions: 1) Where does the historical species fit into the continental phylogeography; 2) Are the contemporary black bears native to the region, or the result of an in-migration of black bears translocated into Arkansas? To answer these questions I extracted DNA from 10 black bears, collected from Lawson Cave, an Historical Era (0-550 year old) site in central Missouri. These bears are the most recent samples that can be unambiguously identified as native to Missouri. I successfully amplified the control region of the mitochondria of four of the 10 samples. Two of the four samples are exact matches to a known haplotype, extending from Minnesota to Mexico. Using modern samples and sequences from central North America I created a phylogeny that grouped into two clades. All of the samples from Lawson Cave grouped into clade 1. This suggests that this clade is recently native to Missouri. I also compared samples collected from a study of modern Missouri black bears. These bears fell into both clade 1 and clade 2. This study was unable to determine whether certain modern bears belong to clade 1 as a result of in situ mitochondrial continuity, or because of the widespread distribution of this clade throughout central North America. These results suggest that although certain bears belong to a clade native to Missouri, many also belong to a group not known from Missouri's historic past

A Conserved Mammalian Protein Interaction Network

Physical interactions between proteins mediate a variety of biological functions, including signal transduction, physical structuring of the cell and regulation. While extensive catalogs of such interactions are known from model organisms, their evolutionary histories are difficult to study given the lack of interaction data from phylogenetic outgroups. Using phylogenomic approaches, we infer a upper bound on the time of origin for a large set of human protein-protein interactions, showing that most such interactions appear relatively ancient, dating no later than the radiation of placental mammals. By analyzing paired alignments of orthologous and putatively interacting protein-coding genes from eight mammals, we find evidence for weak but significant co-evolution, as measured by relative selective constraint, between pairs of genes with interacting proteins. However, we find no strong evidence for shared instances of directional selection within an interacting pair. Finally, we use a network approach to show that the distribution of selective constraint across the protein interaction network is non-random, with a clear tendency for interacting proteins to share similar selective constraints. Collectively, the results suggest that, on the whole, protein interactions in mammals are under selective constraint, presumably due to their functional roles.A˚.P.B. is supported by Ga˚lo¨stiftelsen Stipendium fo¨r ho¨gre utlandsstudier. C.M.H. is supported by a National Library of Medicine Biomedical and Health Informatics Training Fellowship [LM007089-19]. G.C.C. is supported by the Reproductive Biology Group of the Food for the 21st Century program at the University of Missouri. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

The Clustering Dipole of the Local Universe from the Two Micron All Sky Survey

The unprecedented sky coverage and photometric uniformity of the Two Micron All Sky Survey (2MASS) provides a rich resource for investigating the galaxies populating the local Universe. A full characterization of the large-scale clustering distribution is important for theoretical studies of structure formation. 2MASS offers an all-sky view of the local galaxy population at 2.15 micron, unbiased by young stellar light and minimally affected by dust. We use 2MASS to map the local distribution of galaxies, identifying the largest structures in the nearby universe. The inhomogeneity of these structures causes an acceleration on the Local Group of galaxies, which can be seen in the dipole of the Cosmic Microwave Background (CMB). We find that the direction of the 2MASS clustering dipole is 11 degrees from the CMB dipole, confirming that the local galaxy distribution accelerates the Local Group. From the magnitude of the dipole we find a value of the linear bias parameter b=1.37 +/- 0.3 in the K_s-band. The 2MASS clustering dipole is 19 degrees from the latest measurement of the dipole using galaxies detected by the Infrared Astronomical Satellite (IRAS) suggesting that bias may be non-linear in some wavebands.Comment: 7 pages, 4 figures, submitted to ApJ Letters, a version of the paper with full resolution figures can be found here http://daisy.astro.umass.edu/~ari

QTL analysis for growth and wood properties across multiple pedigrees and sites in Eucalyptus globulus

Eucalyptus globulus is the most widely planted species for pulpwood production in temperate regions of the world and there are breeding programs in numerous countries. There is interest in molecular approaches to breeding, particularly marker assisted selection of wood properties. QTL analysis has an important role in identifying positional candidate genes responsible for variation in wood properties. This is one approach to targeting genes which may harbour functional allelic variants (SNPs). The objective of this study was to detect and validate QTL across multiple sites and pedigrees, in order to identify genomic regions and genes affecting growth and wood properties with wide applicability in the species. We also aimed to determine the proportion of QTL which were stable in their expression across sites of contrasting productivity. Such information will be important to exploit the full potential of the impending Eucalyptus genome sequences. [Oral Presentation

Genomic patterns of species diversity and divergence in Eucalyptus

We examined genome-wide patterns of DNA sequence diversity and divergence among six species of the important tree genus Eucalyptus and investigated their relationship with genomic architecture. Using c. 90 range-wide individuals of each Eucalyptus species (E. grandis, E. urophylla, E. globulus, E. nitens, E. dunnii and E. camaldulensis), genetic diversity and divergence were estimated from 2840 polymorphic diversity arrays technology markers covering the 11 chromosomes. Species differentiating markers (SDMs) identified in each of 15 pairwise species comparisons, along with species diversity (HHW) and divergence (FST), were projected onto the E. grandis reference genome. Across all species comparisons, SDMs totalled 1.1–5.3% of markers and were widely distributed throughout the genome. Marker divergence (FST and SDMs) and diversity differed among and within chromosomes. Patterns of diversity and divergence were broadly conserved across species and significantly associated with genomic features, including the proximity of markers to genes, the relative number of clusters of tandem duplications, and gene density within or among chromosomes. These results suggest that genomic architecture influences patterns of species diversity and divergence in the genus. This influence is evident across the six species, encompassing diverse phylogenetic lineages, geography and ecology.Australian Research Council (DP110101621, DP0986491, DP130104220 and DP140102552), Sappi and Mondi, the Technology and Human Resources for Industry Programme (THRIP, UID 80118), the National Research Foundation (NRF, UID 71255 and 86936) and the Department of Science and Technology (DST) of South Africa.http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1469-81372016-06-30hb201

Defending Our Public Biological Databases as a Global Critical Infrastructure

Progress in modern biology is being driven, in part, by the large amounts of freely available data in public resources such as the International Nucleotide Sequence Database Collaboration (INSDC), the world's primary database of biological sequence (and related) information. INSDC and similar databases have dramatically increased the pace of fundamental biological discovery and enabled a host of innovative therapeutic, diagnostic, and forensic applications. However, as high-value, openly shared resources with a high degree of assumed trust, these repositories share compelling similarities to the early days of the Internet. Consequently, as public biological databases continue to increase in size and importance, we expect that they will face the same threats as undefended cyberspace. There is a unique opportunity, before a significant breach and loss of trust occurs, to ensure they evolve with quality and security as a design philosophy rather than costly “retrofitted” mitigations. This Perspective surveys some potential quality assurance and security weaknesses in existing open genomic and proteomic repositories, describes methods to mitigate the likelihood of both intentional and unintentional errors, and offers recommendations for risk mitigation based on lessons learned from cybersecurity

A reference linkage map for Eucalyptus

Background: Genetic linkage maps are invaluable resources in plant research. They provide a key tool for many genetic applications including: mapping quantitative trait loci (QTL); comparative mapping; identifying unlinked (i.e. independent) DNA markers for fingerprinting, population genetics and phylogenetics; assisting genome sequence assembly; relating physical and recombination distances along the genome and map-based cloning of genes. Eucalypts are the dominant tree species in most Australian ecosystems and of economic importance globally as plantation trees. The genome sequence of E. grandis has recently been released providing unprecedented opportunities for genetic and genomic research in the genus. A robust reference linkage map containing sequence-based molecular markers is needed to capitalise on this resource. Several high density linkage maps have recently been constructed for the main commercial forestry species in the genus (E. grandis, E. urophylla and E. globulus) using sequenced Diversity Arrays Technology (DArT) and microsatellite markers. To provide a single reference linkage map for eucalypts a composite map was produced through the integration of data from seven independent mapping experiments (1950 individuals) using a marker-merging method. Results: The composite map totalled 1107 cM and contained 4101 markers; comprising 3880 DArT, 213 microsatellite and eight candidate genes. Eighty-one DArT markers were mapped to two or more linkage groups, resulting in the 4101 markers being mapped to 4191 map positions. Approximately 13% of DArT markers mapped to identical map positions, thus the composite map contained 3634 unique loci at an average interval of 0.31 cM. Conclusion: The composite map represents the most saturated linkage map yet produced in Eucalyptus. As the majority of DArT markers contained on the map have been sequenced, the map provides a direct link to the E. grandis genome sequence and will serve as an important reference for progressing eucalypt research