Comparative developmental genomics of sex-biased gene expression in early embryogenesis across mammals.

BACKGROUND: Mammalian gonadal sex is determined by the presence or absence of a Y chromosome and the subsequent production of sex hormones contributes to secondary sexual differentiation. However, sex chromosome-linked genes encoding dosage-sensitive transcription and epigenetic factors are expressed well before gonad formation and have the potential to establish sex-biased expression that persists beyond the appearance of gonadal hormones. Here, we apply a comparative bioinformatics analysis on a pair of published single-cell datasets from mouse and human during very early embryogenesis-from two-cell to pre-implantation stages-to characterize sex-specific signals and to assess the degree of conservation among early acting sex-specific genes and pathways. RESULTS: Clustering and regression analyses of gene expression across samples reveal that sex initially plays a significant role in overall gene expression patterns at the earliest stages of embryogenesis which potentially may be the byproduct of signals from male and female gametes during fertilization. Although these transcriptional sex effects rapidly diminish, sex-biased genes appear to form sex-specific protein-protein interaction networks across pre-implantation stages in both mammals providing evidence that sex-biased expression of epigenetic enzymes may establish sex-specific patterns that persist beyond pre-implantation. Non-negative matrix factorization (NMF) on male and female transcriptomes generated clusters of genes with similar expression patterns across sex and developmental stages, including post-fertilization, epigenetic, and pre-implantation ontologies conserved between mouse and human. While the fraction of sex-differentially expressed genes (sexDEGs) in early embryonic stages is similar and functional ontologies are conserved, the genes involved are generally different in mouse and human. CONCLUSIONS: This comparative study uncovers much earlier than expected sex-specific signals in mouse and human embryos that pre-date hormonal signaling from the gonads. These early signals are diverged with respect to orthologs yet conserved in terms of function with important implications in the use of genetic models for sex-specific disease.

Sex differences are traditionally assumed to arise after the reproductive systems are set up in male and female embryos, and especially after these organs begin producing sex hormones. However, very early in embryo development, the sex chromosomes distinguish males (XY) and females (XX) and genes on these chromosomes are expressed differentially. In this study, we have analyzed gene expression data from mouse and human early embryos to determine whether there is sex-biased expression before implantation. Our results confirm that there is abundant sex-biased expression from the earliest stages of development, soon after fertilization. The comparison between human and mouse embryos shows comparable function of the sex-biased genes, although the specific genes involved differ between the two species.

Extensive set of African ancestry-informative markers (AIMs) to study ancestry and population health.

Introduction: Human populations are often highly structured due to differences in genetic ancestry among groups, posing difficulties in associating genes with diseases. Ancestry-informative markers (AIMs) aid in the detection of population stratification and provide an alternative approach to map population-specific alleles to disease. Here, we identify and characterize a novel set of African AIMs that separate populations of African ancestry from other global populations including those of European ancestry. Methods: Using data from the 1000 Genomes Project, highly informative SNP markers from five African subpopulations were selected based on estimates of informativeness (In) and compared against the European population to generate a final set of 46,737 African ancestry-informative markers (AIMs). The AIMs identified were validated using an independent set and functionally annotated using tools like SIFT, PolyPhen. They were also investigated for representation of commonly used SNP arrays. Results: This set of African AIMs effectively separates populations of African ancestry from other global populations and further identifies substructure between populations of African ancestry. When a subset of these AIMs was studied in an independent dataset, they differentiated people who self-identify as African American or Black from those who identify their ancestry as primarily European. Most of the AIMs were found to be in their intergenic and intronic regions with only 0.6% in the coding regions of the genome. Most of the commonly used SNP array investigated contained less than 10% of the AIMs. Discussion: While several functional annotations of both coding and non-coding African AIMs are supported by the literature and linked these high-frequency African alleles to diseases in African populations, more effort is needed to map genes to diseases in these genetically diverse subpopulations. The relative dearth of these African AIMs on current genotyping platforms (the array with the highest fraction, llumina's Omni 5, harbors less than a quarter of AIMs), further demonstrates a greater need to better represent historically understudied populations.

Glue Genes Are Subjected to Diverse Selective Forces during Drosophila Development.

Molecular evolutionary studies usually focus on genes with clear roles in adult fitness or on developmental genes expressed at multiple time points during the life of the organism. Here, we examine the evolutionary dynamics of Drosophila glue genes, a set of eight genes tasked with a singular primary function during a specific developmental stage: the production of glue that allows animal pupa to attach to a substrate for several days during metamorphosis. Using phenotypic assays and available data from transcriptomics, PacBio genomes, and sequence variation from global populations, we explore the selective forces acting on glue genes within the cosmopolitan Drosophila melanogaster species and its five closely related species, D. simulans, D. sechellia, D. mauritiana, D. yakuba, and D. teissieri. We observe a three-fold difference in glue adhesion between the least and the most adhesive D. melanogaster strain, indicating a strong genetic component to phenotypic variation. These eight glue genes are among the most highly expressed genes in salivary glands yet they display no notable codon bias. New copies of Sgs3 and Sgs7 are found in D. yakuba and D. teissieri with the Sgs3 coding sequence evolving rapidly after duplication in the D. yakuba branch. Multiple sites along the various glue genes appear to be constrained. Our population genetics analysis in D. melanogaster suggests signals of local adaptive evolution for Sgs3, Sgs5, and Sgs5bis and traces of selective sweeps for Sgs1, Sgs3, Sgs7, and Sgs8. Our work shows that stage-specific genes can be subjected to various dynamic evolutionary forces.

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

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.

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

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.

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

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.

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

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.

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

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.

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

Gene expression patterns assayed across development can offer key clues about a gene's function and regulatory role. Drosophila melanogaster 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 in situ 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 in situ 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.

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

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 ß (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.

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

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.

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

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.

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

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.

Genomic signatures of domestication on neurogenetic genes in Drosophila melanogaster.

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.

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

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.

Sustained proliferation in cancer: Mechanisms and novel therapeutic targets.

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.

Genetic Architecture of Sexual Dimorphism in Humans.

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.

Hybridization reveals the evolving genomic architecture of speciation.

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.

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

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.

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

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.