Publications by authors named "Rob J Kulathinal"

37 Publications

The developmental origins of sex-biased expression in cardiac development.

Biol Sex Differ 2019 09 5;10(1):46. Epub 2019 Sep 5.

Fels Institute for Cancer Research, Lewis Katz School of Medicine, Temple University, 3400 N. Broad St, Philadelphia, PA, 19140, USA.

Background: Expression patterns between males and females vary in every adult tissue, even in organs with no conspicuous dimorphisms such as the heart. While studies of male and female differences have traditionally focused on the influence of sex hormones, these do not account for all the differences at the molecular and epigenetic levels. We previously reported that a substantial number of genes were differentially expressed in male and female mouse embryonic stem (ES) cells and revealed dose-dependent enhancer activity in response to Prdm14, a key pluripotency factor expressed more highly in female ES cells. In this work, we investigated the role of Prdm14 in establishing sex-specific gene expression networks. We surveyed the sex-specific landscape in early embryogenesis with special reference to cardiac development. We generated sex-specific co-expression networks from mouse ES cells, examined the presence of sex-specific chromatin domains, and analyzed previously published datasets from different developmental time points to characterize how sex-biased gene expression waxes and wanes to evaluate whether sex-biased networks are detectable throughout heart development.

Results: We performed ChIP-seq on male and female mouse ES cells to determine differences in chromatin status. Our study reveals sex-biased histone modifications, underscoring the potential for the sex chromosome complement to prime the genome differently in early development with consequences for later expression biases. Upon differentiation of ES cells to cardiac precursors, we found sex-biased expression of key transcription and epigenetic factors, some of which persisted from the undifferentiated state. Using network analyses, we also found that Prdm14 plays a prominent role in regulating a subset of dimorphic expression patterns. To determine whether sex-biased expression is present throughout cardiogenesis, we re-analyzed data from two published studies that sampled the transcriptomes of mouse hearts from 8.5 days post-coitum embryos to neonates and adults. We found sex-biased expression at every stage in heart development, and interestingly, identified a subset of genes that exhibit the same bias across multiple cardiogenic stages.

Conclusions: Overall, our results support the existence of sexually dimorphic gene expression profiles and regulatory networks at every stage of cardiac development, some of which may be established in early embryogenesis and epigenetically perpetuated.
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http://dx.doi.org/10.1186/s13293-019-0259-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727560PMC
September 2019

Gene expression profiling reveals deep-sea coral response to the Deepwater Horizon oil spill.

Mol Ecol 2018 10 22;27(20):4066-4077. Epub 2018 Sep 22.

Department of Biology, Temple University, Philadelphia, Pennsylvania.

Deep-sea coral communities are key components of the Gulf of Mexico ecosystem and were adversely affected by the Deepwater Horizon (DWH) oil spill. Coral colonies exposed to oil and dispersant exhibited mortality, damage and physiological signatures of stress. Understanding how corals respond to oil and dispersant exposure at the molecular level is important to elucidate the sublethal effects of the DWH disaster and reveal broader patterns of coral stress responses. Gene expression profiles from RNAseq data were compared between corals at an impacted site and from a reference site. A total of 1,439 differentially expressed genes (≥twofold) were shared among impacted Paramuricea biscaya colonies. Genes involved in oxidative stress, immunity, wound repair, tissue regeneration and metabolism of xenobiotics were significantly differentially expressed in impacted corals. Enrichment among the overexpressed genes indicates the corals were enduring high metabolic demands associated with cellular stress responses and repair mechanisms. Underexpression of genes vital to toxin processing also suggests a diminished capacity to cope with environmental stressors. Our results provide evidence that deep-sea corals exhibited genome-wide cellular stress responses to oil and dispersant exposure and demonstrate the utility of next-generation sequencing for monitoring anthropogenic impacts in deep waters. These analyses will facilitate the development of diagnostic markers for oil and dispersant exposure in deep-sea invertebrates and inform future oil spill response efforts.
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http://dx.doi.org/10.1111/mec.14847DOI Listing
October 2018

The whole lupus: Articulating biosocial interplay in systemic lupus erythematosus epidemiology and population disparities.

Health Place 2018 05 12;51:182-188. Epub 2018 Apr 12.

Department of Geography and Urban Studies, Temple University, Philadelphia, PA 19122, United States.

Systemic lupus erythematosus (SLE), commonly known simply as lupus, is an autoimmune disease in which the body's immune system attacks healthy tissue and organs. Characteristic of the disease is a disproportionate effect on women and communities of color, both in terms of prevalence and severity of symptoms. Lupus is also both genetically driven and subject to external environmental conditions, many with place based corollaries. Thus, lupus presents a series of complex and intersecting biosocial questions regarding its origin and treatment, questions which transdisciplinary approaches are uniquely suited to address. In this paper, we propose a framework, incorporating critical approaches to the production of embodied formations of race and gender as well as new understandings of the impact of environmental conditions and lived experience at the genetic level, that can direct future research into lupus that is both more inclusive of a range of influences and more precise in its ability to treat and diagnose the disease.
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http://dx.doi.org/10.1016/j.healthplace.2018.03.007DOI Listing
May 2018

Comparative Genomics Reveals Accelerated Evolution in Conserved Pathways during the Diversification of Anole Lizards.

Genome Biol Evol 2018 02;10(2):489-506

School of Life Sciences, Arizona State University.

Squamates include all lizards and snakes, and display some of the most diverse and extreme morphological adaptations among vertebrates. However, compared with birds and mammals, relatively few resources exist for comparative genomic analyses of squamates, hampering efforts to understand the molecular bases of phenotypic diversification in such a speciose clade. In particular, the ∼400 species of anole lizard represent an extensive squamate radiation. Here, we sequence and assemble the draft genomes of three anole species-Anolis frenatus, Anolis auratus, and Anolis apletophallus-for comparison with the available reference genome of Anolis carolinensis. Comparative analyses reveal a rapid background rate of molecular evolution consistent with a model of punctuated equilibrium, and strong purifying selection on functional genomic elements in anoles. We find evidence for accelerated evolution in genes involved in behavior, sensory perception, and reproduction, as well as in genes regulating limb bud development and hindlimb specification. Morphometric analyses of anole fore and hindlimbs corroborated these findings. We detect signatures of positive selection across several genes related to the development and regulation of the forebrain, hormones, and the iguanian lizard dewlap, suggesting molecular changes underlying behavioral adaptations known to reinforce species boundaries were a key component in the diversification of anole lizards.
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http://dx.doi.org/10.1093/gbe/evy013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798147PMC
February 2018

The fluidity of biosocial identity and the effects of place, space, and time.

Soc Sci Med 2018 02 18;198:46-52. Epub 2017 Dec 18.

Geography and Urban Studies, Temple University, Gladfelter Hall, 1801 N Broad St, Philadelphia, PA 19122, USA. Electronic address:

Public and scientific conceptions of identity are changing alongside advances in biotechnology, with important relevance to health and medicine. In particular, biological identity, once predominantly conceived as static (e.g., related to DNA, dental records, fingerprints) is now being recognized as dynamic or fluid, mirroring contemporary understandings of psychological and social identity. The dynamism of biological identity comes from the individual body's unique relationship with the world surrounding it, and therefore may best be described as biosocial. This paper reviews advances in scientific understandings of identity and presents a model that contrasts prior static approaches to biological identity from more recent dynamically-relational ones. This emerging viewpoint is of broad significance to health and medicine, particularly as medicine recognizes the significance of biography - i.e. the multiple, dense interactions imparted on a body across spatio-temporal dimensions - to phenotypic prediction, especially disease risk.
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http://dx.doi.org/10.1016/j.socscimed.2017.12.023DOI Listing
February 2018

FlyExpress 7: An Integrated Discovery Platform To Study Coexpressed Genes Using Hybridization Images in .

G3 (Bethesda) 2017 08 7;7(8):2791-2797. Epub 2017 Aug 7.

Institute for Genomic and Evolutionary Medicine and

Gene expression patterns assayed across development can offer key clues about a gene's function and regulatory role. is ideal for such investigations as multiple individual and high-throughput efforts have captured the spatiotemporal patterns of thousands of embryonic expressed genes in the form of images. FlyExpress (www.flyexpress.net), a knowledgebase based on a massive and unique digital library of standardized images and a simple search engine to find coexpressed genes, was created to facilitate the analytical and visual mining of these patterns. Here, we introduce the next generation of FlyExpress resources to facilitate the integrative analysis of sequence data and spatiotemporal patterns of expression from images. FlyExpress 7 now includes over 100,000 standardized images and implements a more efficient, user-defined search algorithm to identify coexpressed genes via Genomewide Expression Maps (GEMs). Shared motifs found in the upstream 5' regions of any pair of coexpressed genes can be visualized in an interactive dotplot. Additional webtools and link-outs to assist in the downstream validation of candidate motifs are also provided. Together, FlyExpress 7 represents our largest effort yet to accelerate discovery via the development and dispersal of new webtools that allow researchers to perform data-driven analyses of coexpression (image) and genomic (sequence) data.
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http://dx.doi.org/10.1534/g3.117.040345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555482PMC
August 2017

Integrative genomic analysis identifies ancestry-related expression quantitative trait loci on DNA polymerase β and supports the association of genetic ancestry with survival disparities in head and neck squamous cell carcinoma.

Cancer 2017 03 1;123(5):849-860. Epub 2016 Dec 1.

Cancer Prevention and Control Program, Fox Chase Cancer Center-Temple Health, Philadelphia, Pennsylvania.

Background: African Americans with head and neck squamous cell carcinoma (HNSCC) have a lower survival rate than whites. This study investigated the functional importance of ancestry-informative single-nucleotide polymorphisms (SNPs) in HNSCC and also examined the effect of functionally important genetic elements on racial disparities in HNSCC survival.

Methods: Ancestry-informative SNPs, RNA sequencing, methylation, and copy number variation data for 316 oral cavity and laryngeal cancer patients were analyzed across 178 DNA repair genes. The results of expression quantitative trait locus (eQTL) analyses were also replicated with a Gene Expression Omnibus (GEO) data set. The effects of eQTLs on overall survival (OS) and disease-free survival (DFS) were evaluated.

Results: Five ancestry-related SNPs were identified as cis-eQTLs in the DNA polymerase β (POLB) gene (false discovery rate [FDR] < 0.01). The homozygous/heterozygous genotypes containing the African allele showed higher POLB expression than the homozygous white allele genotype (P < .001). A replication study using a GEO data set validated all 5 eQTLs and also showed a statistically significant difference in POLB expression based on genetic ancestry (P = .002). An association was observed between these eQTLs and OS (P < .037; FDR < 0.0363) as well as DFS (P = .018 to .0629; FDR < 0.079) for oral cavity and laryngeal cancer patients treated with platinum-based chemotherapy and/or radiotherapy. Genotypes containing the African allele were associated with poor OS/DFS in comparison with homozygous genotypes harboring the white allele.

Conclusions: Analyses show that ancestry-related alleles could act as eQTLs in HNSCC and support the association of ancestry-related genetic factors with survival disparities in patients diagnosed with oral cavity and laryngeal cancer. Cancer 2017;123:849-60. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319896PMC
March 2017

Neurogenomics and the role of a large mutational target on rapid behavioral change.

Biol Direct 2016 11 8;11(1):60. Epub 2016 Nov 8.

Department of Biology, Temple University, Philadelphia, PA, 19122, USA.

Background: Behavior, while complex and dynamic, is among the most diverse, derived, and rapidly evolving traits in animals. The highly labile nature of heritable behavioral change is observed in such evolutionary phenomena as the emergence of converged behaviors in domesticated animals, the rapid evolution of preferences, and the routine development of ethological isolation between diverging populations and species. In fact, it is believed that nervous system development and its potential to evolve a seemingly infinite array of behavioral innovations played a major role in the successful diversification of metazoans, including our own human lineage. However, unlike other rapidly evolving functional systems such as sperm-egg interactions and immune defense, the genetic basis of rapid behavioral change remains elusive.

Presentation Of The Hypothesis: Here we propose that the rapid divergence and widespread novelty of innate and adaptive behavior is primarily a function of its genomic architecture. Specifically, we hypothesize that the broad diversity of behavioral phenotypes present at micro- and macroevolutionary scales is promoted by a disproportionately large mutational target of neurogenic genes. We present evidence that these large neuro-behavioral targets are significant and ubiquitous in animal genomes and suggest that behavior's novelty and rapid emergence are driven by a number of factors including more selection on a larger pool of variants, a greater role of phenotypic plasticity, and/or unique molecular features present in large genes. We briefly discuss the origins of these large neurogenic genes, as they relate to the remarkable diversity of metazoan behaviors, and highlight key consequences on both behavioral traits and neurogenic disease across, respectively, evolutionary and ontogenetic time scales.

Testing The Hypothesis: Current approaches to studying the genetic mechanisms underlying rapid phenotypic change primarily focus on identifying signatures of Darwinian selection in protein-coding regions. In contrast, the large mutational target hypothesis places genomic architecture and a larger allelic pool at the forefront of rapid evolutionary change, particularly in genetic systems that are polygenic and regulatory in nature. Genomic data from brain and neural tissues in mammals as well as a preliminary survey of neurogenic genes from comparative genomic data support this hypothesis while rejecting both positive and relaxed selection on proteins or higher mutation rates. In mammals and invertebrates, neurogenic genes harbor larger protein-coding regions and possess a richer regulatory repertoire of miRNA targets and transcription factor binding sites. Overall, neurogenic genes cover a disproportionately large genomic fraction, providing a sizeable substrate for evolutionary, genetic, and molecular mechanisms to act upon. Readily available comparative and functional genomic data provide unexplored opportunities to test whether a distinct neurogenomic architecture can promote rapid behavioral change via several mechanisms unique to large genes, and which components of this large footprint are uniquely metazoan.

Implications Of The Hypothesis: The large mutational target hypothesis highlights the eminent roles of mutation and functional genomic architecture in generating rapid developmental and evolutionary change. It has broad implications on our understanding of the genetics of complex adaptive traits such as behavior by focusing on the importance of mutational input, from SNPs to alternative transcripts to transposable elements, on driving evolutionary rates of functional systems. Such functional divergence has important implications in promoting behavioral isolation across short- and long-term timescales. Due to genome-scaled polygenic adaptation, the large target effect also contributes to our inability to identify adapted behavioral candidate genes. The presence of large neurogenic genes, particularly in the mammalian brain and other neural tissues, further offers emerging insight into the etiology of neurodevelopmental and neurodegenerative diseases. The well-known correlation between neurological spectrum disorders in children and paternal age may simply be a direct result of aging fathers accumulating mutations across these large neurodevelopmental genes. The large mutational target hypothesis can also explain the rapid evolution of other functional systems covering a large genomic fraction such as male fertility and its preferential association with hybrid male sterility among closely related taxa. Overall, a focus on mutational potential may increase our power in understanding the genetic basis of complex phenotypes such as behavior while filling a general gap in understanding their evolution.
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http://dx.doi.org/10.1186/s13062-016-0162-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5101817PMC
November 2016

Large-Scale Discovery of Disease-Disease and Disease-Gene Associations.

Sci Rep 2016 08 31;6:32404. Epub 2016 Aug 31.

Center for Data Analytics and Biomedical Informatics, Temple University, Philadelphia, PA 19122 USA.

Data-driven phenotype analyses on Electronic Health Record (EHR) data have recently drawn benefits across many areas of clinical practice, uncovering new links in the medical sciences that can potentially affect the well-being of millions of patients. In this paper, EHR data is used to discover novel relationships between diseases by studying their comorbidities (co-occurrences in patients). A novel embedding model is designed to extract knowledge from disease comorbidities by learning from a large-scale EHR database comprising more than 35 million inpatient cases spanning nearly a decade, revealing significant improvements on disease phenotyping over current computational approaches. In addition, the use of the proposed methodology is extended to discover novel disease-gene associations by including valuable domain knowledge from genome-wide association studies. To evaluate our approach, its effectiveness is compared against a held-out set where, again, it revealed very compelling results. For selected diseases, we further identify candidate gene lists for which disease-gene associations were not studied previously. Thus, our approach provides biomedical researchers with new tools to filter genes of interest, thus, reducing costly lab studies.
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http://dx.doi.org/10.1038/srep32404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006166PMC
August 2016

flyDIVaS: A Comparative Genomics Resource for Drosophila Divergence and Selection.

G3 (Bethesda) 2016 08 9;6(8):2355-63. Epub 2016 Aug 9.

Department of Biology, Temple University, Philadelphia, Pennsylvania 19122

With arguably the best finished and expertly annotated genome assembly, Drosophila melanogaster is a formidable genetics model to study all aspects of biology. Nearly a decade ago, the 12 Drosophila genomes project expanded D. melanogaster's breadth as a comparative model through the community-development of an unprecedented genus- and genome-wide comparative resource. However, since its inception, these datasets for evolutionary inference and biological discovery have become increasingly outdated, outmoded, and inaccessible. Here, we provide an updated and upgradable comparative genomics resource of Drosophila divergence and selection, flyDIVaS, based on the latest genomic assemblies, curated FlyBase annotations, and recent OrthoDB orthology calls. flyDIVaS is an online database containing D. melanogaster-centric orthologous gene sets, CDS and protein alignments, divergence statistics (% gaps, dN, dS, dN/dS), and codon-based tests of positive Darwinian selection. Out of 13,920 protein-coding D. melanogaster genes, ∼80% have one aligned ortholog in the closely related species, D. simulans, and ∼50% have 1-1 12-way alignments in the original 12 sequenced species that span over 80 million yr of divergence. Genes and their orthologs can be chosen from four different taxonomic datasets differing in phylogenetic depth and coverage density, and visualized via interactive alignments and phylogenetic trees. Users can also batch download entire comparative datasets. A functional survey finds conserved mitotic and neural genes, highly diverged immune and reproduction-related genes, more conspicuous signals of divergence across tissue-specific genes, and an enrichment of positive selection among highly diverged genes. flyDIVaS will be regularly updated and can be freely accessed at www.flydivas.info We encourage researchers to regularly use this resource as a tool for biological inference and discovery, and in their classrooms to help train the next generation of biologists to creatively use such genomic big data resources in an integrative manner.
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http://dx.doi.org/10.1534/g3.116.031138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4978890PMC
August 2016

Genomic signatures of domestication on neurogenetic genes in Drosophila melanogaster.

BMC Evol Biol 2016 Jan 5;16. Epub 2016 Jan 5.

Department of Biology, Temple University, Philadelphia, PA, USA.

Background: Domesticated animals quickly evolve docile and submissive behaviors after isolation from their wild conspecifics. Model organisms reared for prolonged periods in the laboratory also exhibit similar shifts towards these domesticated behaviors. Yet whether this divergence is due to inadvertent selection in the lab or the fixation of deleterious mutations remains unknown.

Results: Here, we compare the genomes of lab-reared and wild-caught Drosophila melanogaster to understand the genetic basis of these recently endowed behaviors common to laboratory models. From reassembled genomes of common lab strains, we identify unique, derived variants not present in global populations (lab-specific SNPs). Decreased selective constraints across low frequency SNPs (unique to one or two lab strains) are different from patterns found in the wild and more similar to neutral expectations, suggesting an overall accumulation of deleterious mutations. However, high-frequency lab SNPs found in most or all lab strains reveal an enrichment of X-linked loci and neuro-sensory genes across large extended haplotypes. Among shared polymorphisms, we also find highly differentiated SNPs, in which the derived allele is higher in frequency in the wild (Fst*wild>lab), enriched for similar neurogenetic ontologies, indicative of relaxed selection on more active wild alleles in the lab.

Conclusions: Among random mutations that continuously accumulate in the laboratory, we detect common adaptive signatures in domesticated lab strains of fruit flies. Our results demonstrate that lab animals can quickly evolve domesticated behaviors via unconscious selection by humans early on a broad pool of disproportionately large neurogenetic targets followed by the fixation of accumulated deleterious mutations on functionally similar targets.
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http://dx.doi.org/10.1186/s12862-015-0580-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4700609PMC
January 2016

Ancestral-derived effects on the mutational landscape of laryngeal cancer.

Genomics 2016 Mar 22;107(2-3):76-82. Epub 2015 Dec 22.

Cancer Prevention and Control Program, Fox Chase Cancer Center-Temple Health, Philadelphia, PA 19111, USA; African-Caribbean Cancer Consortium; Department of Otolaryngology - Head and Neck Surgery, Temple University School of Medicine, Philadelphia, PA 19140, USA; College of Public Health, Temple University, Philadelphia, PA 19122, USA. Electronic address:

Laryngeal cancer disproportionately affects more African-Americans than European-Americans. Here, we analyze the genome-wide somatic point mutations from the tumors of 13 African-Americans and 57 European-Americans from TCGA to differentiate between environmental and ancestrally-inherited factors. The mean number of mutations was different between African-Americans (151.31) and European-Americans (277.63). Other differences in the overall mutational landscape between African-American and European-American were also found. The frequency of C>A, and C>G were significantly different between the two populations (p-value<0.05). Context nucleotide signatures for some mutation types significantly differ between these two populations. Thus, the context nucleotide signatures along with other factors could be related to the observed mutational landscape differences between two races. Finally, we show that mutated genes associated with these mutational differences differ between the two populations. Thus, at the molecular level, race appears to be a factor in the progression of laryngeal cancer with ancestral genomic signatures best explaining these differences.
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http://dx.doi.org/10.1016/j.ygeno.2015.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761303PMC
March 2016

Designing a broad-spectrum integrative approach for cancer prevention and treatment.

Authors:
Keith I Block Charlotte Gyllenhaal Leroy Lowe Amedeo Amedei A R M Ruhul Amin Amr Amin Katia Aquilano Jack Arbiser Alexandra Arreola Alla Arzumanyan S Salman Ashraf Asfar S Azmi Fabian Benencia Dipita Bhakta Alan Bilsland Anupam Bishayee Stacy W Blain Penny B Block Chandra S Boosani Thomas E Carey Amancio Carnero Marianeve Carotenuto Stephanie C Casey Mrinmay Chakrabarti Rupesh Chaturvedi Georgia Zhuo Chen Helen Chen Sophie Chen Yi Charlie Chen Beom K Choi Maria Rosa Ciriolo Helen M Coley Andrew R Collins Marisa Connell Sarah Crawford Colleen S Curran Charlotta Dabrosin Giovanna Damia Santanu Dasgupta Ralph J DeBerardinis William K Decker Punita Dhawan Anna Mae E Diehl Jin-Tang Dong Q Ping Dou Janice E Drew Eyad Elkord Bassel El-Rayes Mark A Feitelson Dean W Felsher Lynnette R Ferguson Carmela Fimognari Gary L Firestone Christian Frezza Hiromasa Fujii Mark M Fuster Daniele Generali Alexandros G Georgakilas Frank Gieseler Michael Gilbertson Michelle F Green Brendan Grue Gunjan Guha Dorota Halicka William G Helferich Petr Heneberg Patricia Hentosh Matthew D Hirschey Lorne J Hofseth Randall F Holcombe Kanya Honoki Hsue-Yin Hsu Gloria S Huang Lasse D Jensen Wen G Jiang Lee W Jones Phillip A Karpowicz W Nicol Keith Sid P Kerkar Gazala N Khan Mahin Khatami Young H Ko Omer Kucuk Rob J Kulathinal Nagi B Kumar Byoung S Kwon Anne Le Michael A Lea Ho-Young Lee Terry Lichtor Liang-Tzung Lin Jason W Locasale Bal L Lokeshwar Valter D Longo Costas A Lyssiotis Karen L MacKenzie Meenakshi Malhotra Maria Marino Maria L Martinez-Chantar Ander Matheu Christopher Maxwell Eoin McDonnell Alan K Meeker Mahya Mehrmohamadi Kapil Mehta Gregory A Michelotti Ramzi M Mohammad Sulma I Mohammed D James Morre Vinayak Muralidhar Irfana Muqbil Michael P Murphy Ganji Purnachandra Nagaraju Rita Nahta Elena Niccolai Somaira Nowsheen Carolina Panis Francesco Pantano Virginia R Parslow Graham Pawelec Peter L Pedersen Brad Poore Deepak Poudyal Satya Prakash Mark Prince Lizzia Raffaghello Jeffrey C Rathmell W Kimryn Rathmell Swapan K Ray Jörg Reichrath Sarallah Rezazadeh Domenico Ribatti Luigi Ricciardiello R Brooks Robey Francis Rodier H P Vasantha Rupasinghe Gian Luigi Russo Elizabeth P Ryan Abbas K Samadi Isidro Sanchez-Garcia Andrew J Sanders Daniele Santini Malancha Sarkar Tetsuro Sasada Neeraj K Saxena Rodney E Shackelford H M C Shantha Kumara Dipali Sharma Dong M Shin David Sidransky Markus David Siegelin Emanuela Signori Neetu Singh Sharanya Sivanand Daniel Sliva Carl Smythe Carmela Spagnuolo Diana M Stafforini John Stagg Pochi R Subbarayan Tabetha Sundin Wamidh H Talib Sarah K Thompson Phuoc T Tran Hendrik Ungefroren Matthew G Vander Heiden Vasundara Venkateswaran Dass S Vinay Panagiotis J Vlachostergios Zongwei Wang Kathryn E Wellen Richard L Whelan Eddy S Yang Huanjie Yang Xujuan Yang Paul Yaswen Clement Yedjou Xin Yin Jiyue Zhu Massimo Zollo

Semin Cancer Biol 2015 Dec;35 Suppl:S276-S304

Centro di Ingegneria Genetica e Biotecnologia Avanzate, Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, Federico II, Via Pansini 5, 80131 Naples, Italy.

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered.
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http://dx.doi.org/10.1016/j.semcancer.2015.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819002PMC
December 2015

Sustained proliferation in cancer: Mechanisms and novel therapeutic targets.

Semin Cancer Biol 2015 Dec 17;35 Suppl:S25-S54. Epub 2015 Apr 17.

Mayo Graduate School, Mayo Medical School, Mayo Clinic Medical Scientist Training Program, Rochester, MN, United States.

Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression.
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http://dx.doi.org/10.1016/j.semcancer.2015.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4898971PMC
December 2015

Genetic Architecture of Sexual Dimorphism in Humans.

J Cell Physiol 2015 Oct;230(10):2304-10

Department of Biology, Temple University, Philadelphia, 19122, PA.

Males and females differ across a broad spectrum of morphological, physiological, and behavioral characters. In fact, sexually dimorphic traits typically contribute the largest component of phenotypic variance in most taxa that use sex to reproduce. However, we know very little about the mechanisms that maintain these dimorphic states and how these sexually dimorphic traits evolve. Here, we review our current knowledge of the underlying genetic basis of sexual dimorphism in humans. First, we briefly review the etiology of sex differences starting from sex determination's initial switch early in embryogenesis. We then survey recent sex-biased transcriptomic expression literature in order to provide additional insight into the landscape of sex-biased gene expression in both gonadal and non-gonadal tissues: from overall prevalence to tissue specificity to conservation across species. Finally, we discuss implications of sex-biased genetic architecture to human health and disease in light of the National Institute of Health's recently proposed initiative to promote study samples from both sexes.
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http://dx.doi.org/10.1002/jcp.24979DOI Listing
October 2015

Hybridization reveals the evolving genomic architecture of speciation.

Cell Rep 2013 Nov 31;5(3):666-77. Epub 2013 Oct 31.

Department of Ecology and Evolution, University of Chicago, Chicago, IL 60637, USA. Electronic address:

The rate at which genomes diverge during speciation is unknown, as are the physical dynamics of the process. Here, we compare full genome sequences of 32 butterflies, representing five species from a hybridizing Heliconius butterfly community, to examine genome-wide patterns of introgression and infer how divergence evolves during the speciation process. Our analyses reveal that initial divergence is restricted to a small fraction of the genome, largely clustered around known wing-patterning genes. Over time, divergence evolves rapidly, due primarily to the origin of new divergent regions. Furthermore, divergent genomic regions display signatures of both selection and adaptive introgression, demonstrating the link between microevolutionary processes acting within species and the origin of species across macroevolutionary timescales. Our results provide a uniquely comprehensive portrait of the evolving species boundary due to the role that hybridization plays in reducing the background accumulation of divergence at neutral sites.
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http://dx.doi.org/10.1016/j.celrep.2013.09.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388300PMC
November 2013

Functional genetics in the post-genomics era: building a better roadmap in Drosophila.

Authors:
Rob J Kulathinal

G3 (Bethesda) 2013 Sep 4;3(9):1451-2. Epub 2013 Sep 4.

Department of Biology, Temple University, Philadelphia, Pennsylvania 19122.

In this commentary, Rob Kulathinal describes two papers from the Perrimon laboratory, each describing a new online resource that can assist geneticists with the design of their RNAi experiments. Hu et al.'s "UP-TORR: online tool for accurate and up-to-date annotation of RNAi reagents" and "FlyPrimerBank: An online database for Drosophila melanogaster gene expression analysis and knockdown evaluation of RNAi reagents" are published, respectively, in this month's issue of GENETICS and G3: Genes|Genomes|Genetics.
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http://dx.doi.org/10.1534/g3.113.007351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3755906PMC
September 2013

Functional genetics in the post-genomics era: building a better roadmap in Drosophila.

Authors:
Rob J Kulathinal

Genetics 2013 Sep;195(1):7-8

Department of Biology, Temple University, Philadelphia, Pennsylvania 19122.

In this commentary, Rob Kulathinal describes two articles from the Perrimon lab, each describing a new online resource that can assist geneticists with the design of their RNA interference (RNAi) experiments. Hu et al.'s "UP-TORR: online tool for accurate and up-to-date annotation of RNAi reagents" and "FlyPrimerBank: An online database for Drosophila melanogaster gene expression analysis and knockdown evaluation of RNAi reagents" are published, respectively, in this month's issues of GENETICS and G3.
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http://dx.doi.org/10.1534/genetics.113.156497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3761314PMC
September 2013

Sex-biased networks and nodes of sexually antagonistic conflict in Drosophila.

Int J Evol Biol 2013 22;2013:545392. Epub 2013 Jan 22.

Department of Biology, Temple University, 1900 N 12th Street, Philadelphia, PA 19122, USA.

Sexual antagonism, or conflict, can occur when males and females harbor opposing reproductive strategies. The large fraction of sex-biased genes in genomes present considerable opportunities for conflict to occur, suggesting that sexual antagonism may potentially be a general phenomenon at the molecular level. Here, we employ a novel strategy to identify potential nodes of sexual conflict in Drosophila melanogaster by coupling male, female, and sex-unbiased networks derived from genome-wide expression data with available genetic and protein interaction data. We find that sex-biased networks comprise a large fraction (~1/3) of the total interaction network with the male network possessing nearly twice the number of nodes (genes) relative to the female network. However, there are far less edges or interaction partners among male relative to female subnetworks as seen in their power law distributions. We further identified 598 sex-unbiased genes that can act as indirect nodes of interlocus sexual conflict as well as 271 direct nodal pairs of potential conflict between male- and female-biased genes. The pervasiveness of such potentially conflicting nodes may explain the rapid evolution of sex-biased as well as non-sex-biased genes via this molecular mechanism of sexual selection even among taxa such as Drosophila that are nominally sexually dimorphic.
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http://dx.doi.org/10.1155/2013/545392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566611PMC
February 2013

Developing a community-based genetic nomenclature for anole lizards.

BMC Genomics 2011 Nov 11;12:554. Epub 2011 Nov 11.

School of Life Sciences, Arizona State University, PO Box 874501, Tempe, AZ 85287-4501, USA.

Background: Comparative studies of amniotes have been hindered by a dearth of reptilian molecular sequences. With the genomic assembly of the green anole, Anolis carolinensis available, non-avian reptilian genes can now be compared to mammalian, avian, and amphibian homologs. Furthermore, with more than 350 extant species in the genus Anolis, anoles are an unparalleled example of tetrapod genetic diversity and divergence. As an important ecological, genetic and now genomic reference, it is imperative to develop a standardized Anolis gene nomenclature alongside associated vocabularies and other useful metrics.

Results: Here we report the formation of the Anolis Gene Nomenclature Committee (AGNC) and propose a standardized evolutionary characterization code that will help researchers to define gene orthology and paralogy with tetrapod homologs, provide a system for naming novel genes in Anolis and other reptiles, furnish abbreviations to facilitate comparative studies among the Anolis species and related iguanid squamates, and classify the geographical origins of Anolis subpopulations.

Conclusions: This report has been generated in close consultation with members of the Anolis and genomic research communities, and using public database resources including NCBI and Ensembl. Updates will continue to be regularly posted to new research community websites such as lizardbase. We anticipate that this standardized gene nomenclature will facilitate the accessibility of reptilian sequences for comparative studies among tetrapods and will further serve as a template for other communities in their sequencing and annotation initiatives.
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http://dx.doi.org/10.1186/1471-2164-12-554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248570PMC
November 2011

Elevated Evolutionary Rates among Functionally Diverged Reproductive Genes across Deep Vertebrate Lineages.

Int J Evol Biol 2011 28;2011:274975. Epub 2011 Jul 28.

Department of Botany, University of British Columbia, 6270 University Boulevard, Vancouver, BC, Canada V6T 1Z4.

Among closely related taxa, proteins involved in reproduction generally evolve more rapidly than other proteins. Here, we apply a functional and comparative genomics approach to compare functional divergence across a deep phylogenetic array of egg-laying and live-bearing vertebrate taxa. We aligned and annotated a set of 4,986 1 : 1 : 1 : 1 : 1 orthologs in Anolis carolinensis (green lizard), Danio rerio (zebrafish), Xenopus tropicalis (frog), Gallus gallus (chicken), and Mus musculus (mouse) according to function using ESTs from available reproductive (including testis and ovary) and non-reproductive tissues as well as Gene Ontology. For each species lineage, genes were further classified as tissue-specific (found in a single tissue) or tissue-expressed (found in multiple tissues). Within independent vertebrate lineages, we generally find that gonadal-specific genes evolve at a faster rate than gonadal-expressed genes and significantly faster than non-reproductive genes. Among the gonadal set, testis genes are generally more diverged than ovary genes. Surprisingly, an opposite but nonsignificant pattern is found among the subset of orthologs that remained functionally conserved across all five lineages. These contrasting evolutionary patterns found between functionally diverged and functionally conserved reproductive orthologs provide evidence for pervasive and potentially cryptic lineage-specific selective processes on ancestral reproductive systems in vertebrates.
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http://dx.doi.org/10.4061/2011/274975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3147129PMC
November 2011

Using comparative genomic hybridization to survey genomic sequence divergence across species: a proof-of-concept from Drosophila.

BMC Genomics 2010 Apr 29;11:271. Epub 2010 Apr 29.

Department of Biology, Reed College, Portland, OR 97202, USA.

Background: Genome-wide analysis of sequence divergence among species offers profound insights into the evolutionary processes that shape lineages. When full-genome sequencing is not feasible for a broad comparative study, we propose the use of array-based comparative genomic hybridization (aCGH) in order to identify orthologous genes with high sequence divergence. Here we discuss experimental design, statistical power, success rate, sources of variation and potential confounding factors. We used a spotted PCR product microarray platform from Drosophila melanogaster to assess sequence divergence on a gene-by-gene basis in three fully sequenced heterologous species (D. sechellia, D. simulans, and D. yakuba). Because complete genome assemblies are available for these species this study presents a powerful test for the use of aCGH as a tool to measure sequence divergence.

Results: We found a consistent and linear relationship between hybridization ratio and sequence divergence of the sample to the platform species. At higher levels of sequence divergence (< 92% sequence identity to D. melanogaster) approximately 84% of features had significantly less hybridization to the array in the heterologous species than the platform species, and thus could be identified as "diverged". At lower levels of divergence (>or= 97% identity), only 13% of genes were identified as diverged. While approximately 40% of the variation in hybridization ratio can be accounted for by variation in sequence identity of the heterologous sample relative to D. melanogaster, other individual characteristics of the DNA sequences, such as GC content, also contribute to variation in hybridization ratio, as does technical variation.

Conclusions: Here we demonstrate that aCGH can accurately be used as a proxy to estimate genome-wide divergence, thus providing an efficient way to evaluate how evolutionary processes and genomic architecture can shape species diversity in non-model systems. Given the increased number of species for which microarray platforms are available, comparative studies can be conducted for many interesting lineages in order to identify highly diverged genes that may be the target of natural selection.
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http://dx.doi.org/10.1186/1471-2164-11-271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2873954PMC
April 2010

The genomics of speciation in Drosophila: diversity, divergence, and introgression estimated using low-coverage genome sequencing.

PLoS Genet 2009 Jul 3;5(7):e1000550. Epub 2009 Jul 3.

Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.

In nature, closely related species may hybridize while still retaining their distinctive identities. Chromosomal regions that experience reduced recombination in hybrids, such as within inversions, have been hypothesized to contribute to the maintenance of species integrity. Here, we examine genomic sequences from closely related fruit fly taxa of the Drosophila pseudoobscura subgroup to reconstruct their evolutionary histories and past patterns of genic exchange. Partial genomic assemblies were generated from two subspecies of Drosophila pseudoobscura (D. ps.) and an outgroup species, D. miranda. These new assemblies were compared to available assemblies of D. ps. pseudoobscura and D. persimilis, two species with overlapping ranges in western North America. Within inverted regions, nucleotide divergence among each pair of the three species is comparable, whereas divergence between D. ps. pseudoobscura and D. persimilis in non-inverted regions is much lower and closer to levels of intraspecific variation. Using molecular markers flanking each of the major chromosomal inversions, we identify strong crossover suppression in F(1) hybrids extending over 2 megabase pairs (Mbp) beyond the inversion breakpoints. These regions of crossover suppression also exhibit the high nucleotide divergence associated with inverted regions. Finally, by comparison to a geographically isolated subspecies, D. ps. bogotana, our results suggest that autosomal gene exchange between the North American species, D. ps. pseudoobscura and D. persimilis, occurred since the split of the subspecies, likely within the last 200,000 years. We conclude that chromosomal rearrangements have been vital to the ongoing persistence of these species despite recent hybridization. Our study serves as a proof-of-principle on how whole genome sequencing can be applied to formulate and test hypotheses about species formation in lesser-known non-model systems.
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http://dx.doi.org/10.1371/journal.pgen.1000550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2696600PMC
July 2009

The molecular basis of speciation: from patterns to processes, rules to mechanisms.

J Genet 2008 Dec;87(4):327-38

Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA.

The empirical study of speciation has brought us closer to unlocking the origins of life's vast diversity. By examining recently formed species, a number of general patterns, or rules, become apparent. Among fixed differences between species, sexual genes and traits are one of the most rapidly evolving and novel functional classes, and premating isolation often develops earlier than postmating isolation. Among interspecific hybrids, sterility evolves faster than inviability, the X-chromosome has a greater effect on incompatibilities than autosomes, and hybrid dysfunction affects the heterogametic sex more frequently than the homogametic sex (Haldane's rule). Haldane's rule, in particular, has played a major role in reviving interest in the genetics of speciation. However, the large genetic and reproductive differences between taxa and the multi-factorial nature of each rule have made it difficult to ascribe general mechanisms. Here, we review the extensive progress made since Darwin on understanding the origin of species. We revisit the rules of speciation, regarding them as landmarks as species evolve through time. We contrast these 'rules' of speciation to 'mechanisms' of speciation representing primary causal factors ranging across various levels of organization-from genic to chromosomal to organismal. To explain the rules, we propose a new 'hierarchical faster-sex' theory: the rapid evolution of sex and reproduction-related (SRR) genes (faster-SRR evolution), in combination with the preferential involvement of the X-chromosome (hemizygous X-effects) and sexually selected male traits (faster-male evolution). This unified theory explains a comprehensive set of speciation rules at both the prezyotic and postzygotic levels and also serves as a cohesive alternative to dominance, composite, and recent genomic conflict interpretations of Haldane's rule.
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http://dx.doi.org/10.1007/s12041-008-0055-xDOI Listing
December 2008

Population genomic inferences from sparse high-throughput sequencing of two populations of Drosophila melanogaster.

Genome Biol Evol 2009 Nov 18;1:449-65. Epub 2009 Nov 18.

Department of Organismic and Evolutionary Biology, Harvard University, Boston, MA, USA.

Short-read sequencing techniques provide the opportunity to capture genome-wide sequence data in a single experiment. A current challenge is to identify questions that shallow-depth genomic data can address successfully and to develop corresponding analytical methods that are statistically sound. Here, we apply the Roche/454 platform to survey natural variation in strains of Drosophila melanogaster from an African (n = 3) and a North American (n = 6) population. Reads were aligned to the reference D. melanogaster genomic assembly, single nucleotide polymorphisms were identified, and nucleotide variation was quantified genome wide. Simulations and empirical results suggest that nucleotide diversity can be accurately estimated from sparse data with as little as 0.2x coverage per line. The unbiased genomic sampling provided by random short-read sequencing also allows insight into distributions of transposable elements and copy number polymorphisms found within populations and demonstrates that short-read sequencing methods provide an efficient means to quantify variation in genome organization and content. Continued development of methods for statistical inference of shallow-depth genome-wide sequencing data will allow such sparse, partial data sets to become the norm in the emerging field of population genomics.
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http://dx.doi.org/10.1093/gbe/evp048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2839279PMC
November 2009

Fine-scale mapping of recombination rate in Drosophila refines its correlation to diversity and divergence.

Proc Natl Acad Sci U S A 2008 Jul 11;105(29):10051-6. Epub 2008 Jul 11.

Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.

Regional rates of recombination often correlate with levels of nucleotide diversity, and either selective or neutral hypotheses can explain this relationship. Regional recombination rates also correlate with nucleotide differences between human and chimpanzee, consistent with models where recombination is mutagenic; however, a lack of correlation is observed in the Drosophila melanogaster group, consistent with models invoking natural selection. Here, we revisit the relationship among recombination, diversity, and interspecies difference by generating empirical estimates of these parameters in Drosophila pseudoobscura. To measure recombination rate, we genotyped 1,294 backcross hybrids at 50 markers across the largest assembled linkage group in this species. Genome-wide diversity was estimated by sequencing a second isolate of D. pseudoobscura at shallow coverage. Alignment to the sequenced genome of the closely related species, Drosophila persimilis, provided nucleotide site orthology. Our findings demonstrate that scale is critical in determining correlates to recombination rate: fine-scale cross-over rate estimates are far stronger predictors of both diversity and interspecies difference than broad-scale estimates. The correlation of fine-scale recombination rate to diversity and interspecies difference appears to be genome-wide, evidenced by examination of an X-linked region in greater detail. Because we observe a strong correlation of cross-over rate with interspecies difference, even after correcting for segregating ancestral variation, we suggest that both mutagenic and selective forces generate these correlations, the latter in regions of low crossing over. We propose that it is not cross-overs per se that are mutagenic, but rather repair of DNA double-strand break precursors via crossing over and gene conversion.
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http://dx.doi.org/10.1073/pnas.0801848105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2481358PMC
July 2008

Evolution in the fast lane: rapidly evolving sex-related genes in Drosophila.

Genetics 2007 Nov;177(3):1321-35

Department of Biology, McMaster University, Hamilton, Ontario L8S 4K1, Canada.

A large portion of the annotated genes in Drosophila melanogaster show sex-biased expression, indicating that sex and reproduction-related genes (SRR genes) represent an appreciable component of the genome. Previous studies, in which subsets of genes were compared among few Drosophila species, have found that SRR genes exhibit unusual evolutionary patterns. Here, we have used the newly released genome sequences from 12 Drosophila species, coupled to a larger set of SRR genes, to comprehensively test the generality of these patterns. Among 2505 SRR genes examined, including ESTs with biased expression in reproductive tissues and genes characterized as involved in gametogenesis, we find that a relatively high proportion of SRR genes have experienced accelerated divergence throughout the genus Drosophila. Several testis-specific genes, male seminal fluid proteins (SFPs), and spermatogenesis genes show lineage-specific bursts of accelerated evolution and positive selection. SFP genes also show evidence of lineage-specific gene loss and/or gain. These results bring us closer to understanding the details of the evolutionary dynamics of SRR genes with respect to species divergence.
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http://dx.doi.org/10.1534/genetics.107.078865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2147986PMC
November 2007

Evolution of genes and genomes on the Drosophila phylogeny.

Authors:
Andrew G Clark Michael B Eisen Douglas R Smith Casey M Bergman Brian Oliver Therese A Markow Thomas C Kaufman Manolis Kellis William Gelbart Venky N Iyer Daniel A Pollard Timothy B Sackton Amanda M Larracuente Nadia D Singh Jose P Abad Dawn N Abt Boris Adryan Montserrat Aguade Hiroshi Akashi Wyatt W Anderson Charles F Aquadro David H Ardell Roman Arguello Carlo G Artieri Daniel A Barbash Daniel Barker Paolo Barsanti Phil Batterham Serafim Batzoglou Dave Begun Arjun Bhutkar Enrico Blanco Stephanie A Bosak Robert K Bradley Adrianne D Brand Michael R Brent Angela N Brooks Randall H Brown Roger K Butlin Corrado Caggese Brian R Calvi A Bernardo de Carvalho Anat Caspi Sergio Castrezana Susan E Celniker Jean L Chang Charles Chapple Sourav Chatterji Asif Chinwalla Alberto Civetta Sandra W Clifton Josep M Comeron James C Costello Jerry A Coyne Jennifer Daub Robert G David Arthur L Delcher Kim Delehaunty Chuong B Do Heather Ebling Kevin Edwards Thomas Eickbush Jay D Evans Alan Filipski Sven Findeiss Eva Freyhult Lucinda Fulton Robert Fulton Ana C L Garcia Anastasia Gardiner David A Garfield Barry E Garvin Greg Gibson Don Gilbert Sante Gnerre Jennifer Godfrey Robert Good Valer Gotea Brenton Gravely Anthony J Greenberg Sam Griffiths-Jones Samuel Gross Roderic Guigo Erik A Gustafson Wilfried Haerty Matthew W Hahn Daniel L Halligan Aaron L Halpern Gillian M Halter Mira V Han Andreas Heger LaDeana Hillier Angie S Hinrichs Ian Holmes Roger A Hoskins Melissa J Hubisz Dan Hultmark Melanie A Huntley David B Jaffe Santosh Jagadeeshan William R Jeck Justin Johnson Corbin D Jones William C Jordan Gary H Karpen Eiko Kataoka Peter D Keightley Pouya Kheradpour Ewen F Kirkness Leonardo B Koerich Karsten Kristiansen Dave Kudrna Rob J Kulathinal Sudhir Kumar Roberta Kwok Eric Lander Charles H Langley Richard Lapoint Brian P Lazzaro So-Jeong Lee Lisa Levesque Ruiqiang Li Chiao-Feng Lin Michael F Lin Kerstin Lindblad-Toh Ana Llopart Manyuan Long Lloyd Low Elena Lozovsky Jian Lu Meizhong Luo Carlos A Machado Wojciech Makalowski Mar Marzo Muneo Matsuda Luciano Matzkin Bryant McAllister Carolyn S McBride Brendan McKernan Kevin McKernan Maria Mendez-Lago Patrick Minx Michael U Mollenhauer Kristi Montooth Stephen M Mount Xu Mu Eugene Myers Barbara Negre Stuart Newfeld Rasmus Nielsen Mohamed A F Noor Patrick O'Grady Lior Pachter Montserrat Papaceit Matthew J Parisi Michael Parisi Leopold Parts Jakob S Pedersen Graziano Pesole Adam M Phillippy Chris P Ponting Mihai Pop Damiano Porcelli Jeffrey R Powell Sonja Prohaska Kim Pruitt Marta Puig Hadi Quesneville Kristipati Ravi Ram David Rand Matthew D Rasmussen Laura K Reed Robert Reenan Amy Reily Karin A Remington Tania T Rieger Michael G Ritchie Charles Robin Yu-Hui Rogers Claudia Rohde Julio Rozas Marc J Rubenfield Alfredo Ruiz Susan Russo Steven L Salzberg Alejandro Sanchez-Gracia David J Saranga Hajime Sato Stephen W Schaeffer Michael C Schatz Todd Schlenke Russell Schwartz Carmen Segarra Rama S Singh Laura Sirot Marina Sirota Nicholas B Sisneros Chris D Smith Temple F Smith John Spieth Deborah E Stage Alexander Stark Wolfgang Stephan Robert L Strausberg Sebastian Strempel David Sturgill Granger Sutton Granger G Sutton Wei Tao Sarah Teichmann Yoshiko N Tobari Yoshihiko Tomimura Jason M Tsolas Vera L S Valente Eli Venter J Craig Venter Saverio Vicario Filipe G Vieira Albert J Vilella Alfredo Villasante Brian Walenz Jun Wang Marvin Wasserman Thomas Watts Derek Wilson Richard K Wilson Rod A Wing Mariana F Wolfner Alex Wong Gane Ka-Shu Wong Chung-I Wu Gabriel Wu Daisuke Yamamoto Hsiao-Pei Yang Shiaw-Pyng Yang James A Yorke Kiyohito Yoshida Evgeny Zdobnov Peili Zhang Yu Zhang Aleksey V Zimin Jennifer Baldwin Amr Abdouelleil Jamal Abdulkadir Adal Abebe Brikti Abera Justin Abreu St Christophe Acer Lynne Aftuck Allen Alexander Peter An Erica Anderson Scott Anderson Harindra Arachi Marc Azer Pasang Bachantsang Andrew Barry Tashi Bayul Aaron Berlin Daniel Bessette Toby Bloom Jason Blye Leonid Boguslavskiy Claude Bonnet Boris Boukhgalter Imane Bourzgui Adam Brown Patrick Cahill Sheridon Channer Yama Cheshatsang Lisa Chuda Mieke Citroen Alville Collymore Patrick Cooke Maura Costello Katie D'Aco Riza Daza Georgius De Haan Stuart DeGray Christina DeMaso Norbu Dhargay Kimberly Dooley Erin Dooley Missole Doricent Passang Dorje Kunsang Dorjee Alan Dupes Richard Elong Jill Falk Abderrahim Farina Susan Faro Diallo Ferguson Sheila Fisher Chelsea D Foley Alicia Franke Dennis Friedrich Loryn Gadbois Gary Gearin Christina R Gearin Georgia Giannoukos Tina Goode Joseph Graham Edward Grandbois Sharleen Grewal Kunsang Gyaltsen Nabil Hafez Birhane Hagos Jennifer Hall Charlotte Henson Andrew Hollinger Tracey Honan Monika D Huard Leanne Hughes Brian Hurhula M Erii Husby Asha Kamat Ben Kanga Seva Kashin Dmitry Khazanovich Peter Kisner Krista Lance Marcia Lara William Lee Niall Lennon Frances Letendre Rosie LeVine Alex Lipovsky Xiaohong Liu Jinlei Liu Shangtao Liu Tashi Lokyitsang Yeshi Lokyitsang Rakela Lubonja Annie Lui Pen MacDonald Vasilia Magnisalis Kebede Maru Charles Matthews William McCusker Susan McDonough Teena Mehta James Meldrim Louis Meneus Oana Mihai Atanas Mihalev Tanya Mihova Rachel Mittelman Valentine Mlenga Anna Montmayeur Leonidas Mulrain Adam Navidi Jerome Naylor Tamrat Negash Thu Nguyen Nga Nguyen Robert Nicol Choe Norbu Nyima Norbu Nathaniel Novod Barry O'Neill Sahal Osman Eva Markiewicz Otero L Oyono Christopher Patti Pema Phunkhang Fritz Pierre Margaret Priest Sujaa Raghuraman Filip Rege Rebecca Reyes Cecil Rise Peter Rogov Keenan Ross Elizabeth Ryan Sampath Settipalli Terry Shea Ngawang Sherpa Lu Shi Diana Shih Todd Sparrow Jessica Spaulding John Stalker Nicole Stange-Thomann Sharon Stavropoulos Catherine Stone Christopher Strader Senait Tesfaye Talene Thomson Yama Thoulutsang Dawa Thoulutsang Kerri Topham Ira Topping Tsamla Tsamla Helen Vassiliev Andy Vo Tsering Wangchuk Tsering Wangdi Michael Weiand Jane Wilkinson Adam Wilson Shailendra Yadav Geneva Young Qing Yu Lisa Zembek Danni Zhong Andrew Zimmer Zac Zwirko David B Jaffe Pablo Alvarez Will Brockman Jonathan Butler CheeWhye Chin Sante Gnerre Manfred Grabherr Michael Kleber Evan Mauceli Iain MacCallum

Nature 2007 Nov;450(7167):203-18

Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA.

Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
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http://dx.doi.org/10.1038/nature06341DOI Listing
November 2007

Revisiting the protein-coding gene catalog of Drosophila melanogaster using 12 fly genomes.

Genome Res 2007 Dec 7;17(12):1823-36. Epub 2007 Nov 7.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02139, USA.

The availability of sequenced genomes from 12 Drosophila species has enabled the use of comparative genomics for the systematic discovery of functional elements conserved within this genus. We have developed quantitative metrics for the evolutionary signatures specific to protein-coding regions and applied them genome-wide, resulting in 1193 candidate new protein-coding exons in the D. melanogaster genome. We have reviewed these predictions by manual curation and validated a subset by directed cDNA screening and sequencing, revealing both new genes and new alternative splice forms of known genes. We also used these evolutionary signatures to evaluate existing gene annotations, resulting in the validation of 87% of genes lacking descriptive names and identifying 414 poorly conserved genes that are likely to be spurious predictions, noncoding, or species-specific genes. Furthermore, our methods suggest a variety of refinements to hundreds of existing gene models, such as modifications to translation start codons and exon splice boundaries. Finally, we performed directed genome-wide searches for unusual protein-coding structures, discovering 149 possible examples of stop codon readthrough, 125 new candidate ORFs of polycistronic mRNAs, and several candidate translational frameshifts. These results affect >10% of annotated fly genes and demonstrate the power of comparative genomics to enhance our understanding of genome organization, even in a model organism as intensively studied as Drosophila melanogaster.
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http://dx.doi.org/10.1101/gr.6679507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2099591PMC
December 2007

Male sex drive and the masculinization of the genome.

Bioessays 2005 May;27(5):518-25

Department of Biology, McMaster University, Hamilton, ON, Canada.

Charles Darwin remarked that "males, with their superior strength, pugnacity, armaments, unwieldly passion and love songs, are almost always the more active and most often, the initiators of sexual interactions". Here, we propose that such male sex drive directly impacts the genome by leading to its progressive masculinization--genes that possess sex-specific effects on male fitness accumulate to a much greater extent and are generally more diverged. The larger proportion of male versus female fitness modifiers in combination with stronger sexual selection may generate evolutionary signatures such as a greater sensitivity to male sterility and a paucity of X-linked male-specific genes. Male sex-drive theory complements the female-choice theory of sexual selection and allows for the genetic variation of costly sexual traits to be continuously replenished.
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http://dx.doi.org/10.1002/bies.20212DOI Listing
May 2005