Evolutionary Inference in Transposable Elements

Transposable elements (TEs) are a large component of many eukaryotic genomes, and the evolution of TEs is closely connected to that of their hosts. Accurate inference of TE evolutionary relationships is essential to understanding the biology and evolution of TE families and the role they play in genome evolution. Additionally, the great quantity of TEs makes them a useful model system for understanding genomic processes such as mutation and recombination, and their utility as a research system also depends on accurate evolutionary inference. In this dissertation, I describe novel computational methods for evolutionary inference in TEs, applying them primarily to the Alu family of primate retroelements. A major task in TE evolutionary study is the classification of elements of a family into subfamilies. I developed the AnTE algorithm, a Bayesian approach to subfamily classification that, in contrast to previous deterministic methods, allows for probabilistic subfamily classification, an important advance due to the high uncertainty involved. I use AnTE to provide a more complete picture of the evolutionary history of Alu elements than provided by previous analyses, especially regarding the role of gene conversion. This work suggests that current Alu subfamily classification found in widely-used databases such as RepeatMasker and RepBase provides a misleading account of Alu evolutionary relationships. Building on the AnTE research, I developed a Bayesian phylogenetics approach to the detection and characterization of gene conversion events among TEs in a genome. I use this approach to identify a burst of interlocus gene conversion among Alu elements in the gorilla genome, occurring at much higher rates than on any other branch of the Great Ape phylogeny. Abnormally high Alu gene conversion rates in gorilla appear to be driven by binding to Alu by PRDM9, a rapidly-evolving protein that targets DNA sequence motifs for double-strand breaks in meiosis. These findings indicate one evolutionary pathway for rapid gene conversion in a TE family, and the conversion events identified provide a rich dataset for understanding the dynamics of gene conversion in primates

Prediagnostic Serum Organochlorine Concentrations and Metastatic Prostate Cancer: A Nested Case–Control Study in the Norwegian Janus Serum Bank Cohort

BackgroundOrganochlorine (OC) insecticides and polychlorinated biphenyls (PCBs) have been shown to have estrogenic, antiestrogenic, or antiandrogenic properties; as a result, the impact of exposure to these compounds and risk of hormonal cancers, such as prostate cancer, is a concern.ObjectivesWe conducted a nested case–control study, using prospectively collected serum, to estimate associations between OC exposures and metastatic prostate cancer in a population-based cohort from Norway.MethodsSera from 150 cases and 314 controls matched on date of blood draw, age at blood draw, and region was used to determine concentrations of 11 OC pesticide metabolites and 34 PCB congeners. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for quartiles of lipid-corrected metabolite levels were calculated using conditional logistic regression.ResultsMetastatic prostate cancer was two times as likely among men with serum concentrations of oxychlordane in the highest quartile compared with those in the lowest quartile (OR = 2.03; 95% CI: 1.03, 4.03; p-trend 0.05). Elevated but nonsignificant ORs were estimated for the highest versus lowest quartile of heptachlor epoxide, HCB, and mirex, although these exposures were correlated with oxychlordane. Findings for specific PCB congeners showed a significant inverse association between natural log–transformed lipid-adjusted PCB 44 and metastatic prostate cancer (OR = 0.74; 95% CI: 0.56, 0.97; p-trend = 0.02).ConclusionsOur study highlights the importance of estimating associations with specific OC chemicals and suggests a possible role of OC insecticides and PCBs in the etiology of metastatic prostate cancer.CitationKoutros S, Langseth H, Grimsrud TK, Barr DB, Vermeulen R, Portengen L, Wacholder S, Beane Freeman LE, Blair A, Hayes RB, Rothman N, Engel LS. 2015. Prediagnostic serum organochlorine concentrations and metastatic prostate cancer: a nested case–control study in the Norwegian Janus Serum Bank cohort. Environ Health Perspect 123:867–872; http://dx.doi.org/10.1289/ehp.140824

Applying new biotechnologies to the study of occupational cancer--a workshop summary.

As high-throughput technologies in genomics, transcriptomics, and proteomics evolve, questions arise about their use in the assessment of occupational cancers. To address these questions, the National Institute for Occupational Safety and Health, the National Cancer Institute, the National Institute of Environmental Health Sciences, and the American Chemistry Council sponsored a workshop 8-9 May 2002 in Washington, DC. The workshop brought together 80 international specialists whose objective was to identify the means for best exploiting new technologies to enhance methods for laboratory investigation, epidemiologic evaluation, risk assessment, and prevention of occupational cancer. The workshop focused on identifying and interpreting markers for early biologic effect and inherited modifiers of risk

A vast evolutionarily transient translatome contributes to phenotype and fitness: ribosome profiling tracks

Tracks for ribosome profiling reads assembled over hundreds of experiments and the ORFs inferred to be translated from this data.</p

Biological factors and statistical limitations prevent detection of most noncanonical proteins by mass spectrometry.

Ribosome profiling experiments indicate pervasive translation of short open reading frames (ORFs) outside of annotated protein-coding genes. However, shotgun mass spectrometry (MS) experiments typically detect only a small fraction of the predicted protein products of this noncanonical translation. The rarity of detection could indicate that most predicted noncanonical proteins are rapidly degraded and not present in the cell; alternatively, it could reflect technical limitations. Here, we leveraged recent advances in ribosome profiling and MS to investigate the factors limiting detection of noncanonical proteins in yeast. We show that the low detection rate of noncanonical ORF products can largely be explained by small size and low translation levels and does not indicate that they are unstable or biologically insignificant. In particular, proteins encoded by evolutionarily young genes, including those with well-characterized biological roles, are too short and too lowly expressed to be detected by shotgun MS at current detection sensitivities. Additionally, we find that decoy biases can give misleading estimates of noncanonical protein false discovery rates, potentially leading to false detections. After accounting for these issues, we found strong evidence for 4 noncanonical proteins in MS data, which were also supported by evolution and translation data. These results illustrate the power of MS to validate unannotated genes predicted by ribosome profiling, but also its substantial limitations in finding many biologically relevant lowly expressed proteins

Evolutionary Characterization of the Short Protein SPAAR

Microproteins (de novo emergence from a noncoding sequence. By integrating syntenic alignments and homology searches, we identify SPAAR orthologs in marsupials and monotremes, establishing that SPAAR has existed at least since the emergence of mammals. SPAAR shows substantial primary sequence divergence but retains a conserved protein structure. In primates, we infer two independent evolutionary events leading to the de novo origination of 5′ elongated isoforms of SPAAR from a noncoding sequence and find evidence of adaptive evolution in this extended region. Thus, SPAAR may be of ancient origin, but it appears to be experiencing continual evolutionary innovation in mammals

Datafile

This file is a .zip compressed archive containing subdirectories each having raw data and analysis scripts for producing the 7 figures in the paper

Inference of Transposable Element Ancestry

<div><p>Most common methods for inferring transposable element (TE) evolutionary relationships are based on dividing TEs into subfamilies using shared diagnostic nucleotides. Although originally justified based on the “master gene” model of TE evolution, computational and experimental work indicates that many of the subfamilies generated by these methods contain multiple source elements. This implies that subfamily-based methods give an incomplete picture of TE relationships. Studies on selection, functional exaptation, and predictions of horizontal transfer may all be affected. Here, we develop a Bayesian method for inferring TE ancestry that gives the probability that each sequence was replicative, its frequency of replication, and the probability that each extant TE sequence came from each possible ancestral sequence. Applying our method to 986 members of the newly-discovered LAVA family of TEs, we show that there were far more source elements in the history of LAVA expansion than subfamilies identified using the CoSeg subfamily-classification program. We also identify multiple replicative elements in the <i>Alu</i>Sc subfamily in humans. Our results strongly indicate that a reassessment of subfamily structures is necessary to obtain accurate estimates of mutation processes, phylogenetic relationships and historical times of activity.</p></div

Prediagnostic Serum Organochlorine Concentrations and Metastatic Prostate Cancer: A Nested Case-Control Study in the Norwegian Janus Serum Bank Cohort

BACKGROUND: Organochlorine (OC) insecticides and polychlorinated biphenyls (PCBs) have been shown to have estrogenic, antiestrogenic, or antiandrogenic properties; as a result, the impact of exposure to these compounds and risk of hormonal cancers, such as prostate cancer, is a concern. OBJECTIVES: We conducted a nested case-control study, using prospectively collected serum, to estimate associations between OC exposures and metastatic prostate cancer in a population-based cohort from Norway. METHODS: Sera from 150 cases and 314 controls matched on date of blood draw, age at blood draw, and region was used to determine concentrations of 11 OC pesticide metabolites and 34 PCB congeners. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for quartiles of lipid-corrected metabolite levels were calculated using conditional logistic regression. RESULTS: Metastatic prostate cancer was two times as likely among men with serum concentrations of oxychlordane in the highest quartile compared with those in the lowest quartile (OR = 2.03; 95% CI: 1.03, 4.03; p-trend 0.05). Elevated but nonsignificant ORs were estimated for the highest versus lowest quartile of heptachlor epoxide, HCB, and mirex, although these exposures were correlated with oxychlordane. Findings for specific PCB congeners showed a significant inverse association between natural log-transformed lipid-adjusted PCB 44 and metastatic prostate cancer (OR = 0.74; 95% CI: 0.56, 0.97; p-trend = 0.02). CONCLUSIONS: Our study highlights the importance of estimating associations with specific OC chemicals and suggests a possible role of OC insecticides and PCBs in the etiology of metastatic prostate cancer. CITATION: Koutros S, Langseth H, Grimsrud TK, Barr DB, Vermeulen R, Portengen L, Wacholder S, Beane Freeman LE, Blair A, Hayes RB, Rothman N, Engel LS. 2015. Prediagnostic serum organochlorine concentrations and metastatic prostate cancer: a nested case-control study in the Norwegian Janus Serum Bank cohort. Environ Health Perspect 123:867-872; http://dx.doi.org/10.1289/ehp.1408245

Ancestral relationships among LAVA elements.

<p>The predicted network of LAVA ancestral relationships is shown. A) All sequences that replicated with probability >30% are represented as nodes in the network. Arrows are drawn between sequences if there was at least 5% probability that an ancestral relationship existed between those sequences, with the direction of the ancestor-descendant relationships indicated by the arrows. Sequences are colored based on their CoSeg subfamily assignments (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004482#pgen.1004482.s005" target="_blank">Table S2</a>). Sequences colored white do not exist in the data, but are inferred to have existed ancestrally. B) The network in A is modified by the addition of all extant TEs in the data added to the network as nodes represented by small dots. Edges are drawn between an element and an ancestral sequence if there was at least 5% probability the element descended from the ancestral sequence. Nodes are colored based on CoSeg subfamily assignment.</p