The dead shall be raised : Multidisciplinary analysis of human skeletons reveals complexity in 19th century immigrant socioeconomic history and identity in New Haven, Connecticut

In July 2011, renovations to Yale-New Haven Hospital inadvertently exposed the cemetery of Christ Church, New Haven, Connecticut’s first Catholic cemetery. While this cemetery was active between 1833 and 1851, both the church and its cemetery disappeared from public records, making the discovery serendipitous. Four relatively well-preserved adult skeletons were recovered with few artifacts. All four individuals show indicators of manual labor, health and disease stressors, and dental health issues. Two show indicators of trauma, with the possibility of judicial hanging in one individual. Musculoskeletal markings are consistent with physical stress, and two individuals have arthritic indicators of repetitive movement/specialized activities. Radiographic analyses show osteopenia, healed trauma, and other pathologies in several individuals. Dental calculus analysis did not identify any tuberculosis indicators, despite osteological markers. Isotopic analyses of teeth indicate that all four were likely recent immigrants to the Northeastern United States. Nuclear and mitochondrial DNA were recovered from three individuals, and these analyses identified ancestry, hair/eye color, and relatedness. Genetic and isotopic results upended our initial ancestry assessment based on burial context alone. These individuals provide biocultural evidence of New Haven’s Industrial Revolution and the plasticity of ethnic and religious identity in the immigrant experience. Their recovery and the multifaceted analyses described here illuminate a previously undescribed part of the city’s rich history. The collective expertise of biological, geochemical, archaeological, and historical researchers interprets socioeconomic and cultural identity better than any one could alone. Our combined efforts changed our initial assumptions of a poor urban Catholic cemetery’s membership, and provide a template for future discoveries and analyses

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

CX3CR1 is dysregulated in blood and brain from schizophrenia patients

International audienceThe molecular mechanisms underlying schizophrenia remain largely unknown. Although schizophrenia is a mental disorder, there is increasing evidence to indicate that inflammatory processes driven by diverse environmental factors play a significant role in its development. With gene expression studies having been conducted across a variety of sample types, e.g., blood and postmortem brain, it is possible to investigate convergent signatures that may reveal interactions between the immune and nervous systems in schizophrenia pathophysiology. We conducted two meta-analyses of schizophrenia microarray gene expression data (N = 474) and non-psychiatric control (N = 485) data from postmortem brain and blood. Then, we assessed whether significantly dysregulated genes in schizophrenia could be shared between blood and brain. To validate our findings, we selected a top gene candidate and analyzed its expression by RT-qPCR in a cohort of schizophrenia subjects stabilized by atypical antipsychotic monotherapy (N = 29) and matched controls (N = 31). Meta-analyses highlighted inflammation as the major biological process associated with schizophrenia and that the chemokine receptor CX3CR1 was significantly down-regulated in schizophrenia. This differential expression was also confirmed in our validation cohort. Given both the recent data demonstrating selective CX3CR1 expression in subsets of neuroimmune cells, as well as behavioral and neuropathological observations of CX3CR1 deficiency in mouse models, our results of reduced CX3CR1 expression adds further support for a role played by monocyte/microglia in the neurodevelopment of schizophrenia

An ordered pattern of Ana2 phosphorylation by Plk4 is required for centriole assembly

Polo-like kinase 4 (Plk4) initiates an early step in centriole assembly by phosphorylating Ana2/STIL, a structural component of the procentriole. Here, we show that Plk4 binding to the central coiled-coil (CC) of Ana2 is a conserved event involving Polo-box 3 and a previously unidentified putative CC located adjacent to the kinase domain. Ana2 is then phosphorylated along its length. Previous studies showed that Plk4 phosphorylates the C-terminal STil/ANa2 (STAN) domain of Ana2/STIL, triggering binding and recruitment of the cartwheel protein Sas6 to the procentriole assembly site. However, the physiological relevance of N-terminal phosphorylation was unknown. We found that Plk4 first phosphorylates the extreme N terminus of Ana2, which is critical for subsequent STAN domain modification. Phosphorylation of the central region then breaks the Plk4-Ana2 interaction. This phosphorylation pattern is important for centriole assembly and integrity because replacement of endogenous Ana2 with phospho-Ana2 mutants disrupts distinct steps in Ana2 function and inhibits centriole duplication.Division of Intramural Research at the National Heart, Lung, and Blood Institute [1ZIA HL006104]; National Cancer Institute [P30 CA23074]; National Institute of General Medical Sciences [R01GFM110166]; National Science Foundation [MCB1158151]; Phoenix Friends6 month embargo; published online: 1 March 2018This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Variation and Genetic Control of Gene Expression in Primary Immunocytes across Inbred Mouse Strains.

To determine the breadth and underpinning of changes in immunocyte gene expression due to genetic variation in mice, we performed, as part of the Immunological Genome Project, gene expression profiling for CD4(+) T cells and neutrophils purified from 39 inbred strains of the Mouse Phenome Database. Considering both cell types, a large number of transcripts showed significant variation across the inbred strains, with 22% of the transcriptome varying by 2-fold or more. These included 119 loci with apparent complete loss of function, where the corresponding transcript was not expressed in some of the strains, representing a useful resource of natural knockouts. We identified 1222 cis-expression quantitative trait loci (cis-eQTL) that control some of this variation. Most (60%) cis-eQTLs were shared between T cells and neutrophils, but a significant portion uniquely impacted one of the cell types, suggesting cell type-specific regulatory mechanisms. Using a conditional regression algorithm, we predicted regulatory interactions between transcription factors and potential targets, and we demonstrated that these predictions overlap with regulatory interactions inferred from transcriptional changes during immunocyte differentiation. Finally, comparison of these and parallel data from CD4(+) T cells of healthy humans demonstrated intriguing similarities in variability of a gene\u27s expression: the most variable genes tended to be the same in both species, and there was an overlap in genes subject to strong cis-acting genetic variants. We speculate that this conservation of variation reflects a differential constraint on intraspecies variation in expression levels of different genes, either through lower pressure for some genes, or by favoring variability for others. J Immunol 2014 Nov 1; 193(9):4485-96

Variation and genetic control of gene expression in primary immunocytes across inbred mouse strains.

To determine the breadth and underpinning of changes in immunocyte gene expression due to genetic variation in mice, we performed, as part of the Immunological Genome Project, gene expression profiling for CD4(+) T cells and neutrophils purified from 39 inbred strains of the Mouse Phenome Database. Considering both cell types, a large number of transcripts showed significant variation across the inbred strains, with 22% of the transcriptome varying by 2-fold or more. These included 119 loci with apparent complete loss of function, where the corresponding transcript was not expressed in some of the strains, representing a useful resource of "natural knockouts." We identified 1222 cis-expression quantitative trait loci (cis-eQTL) that control some of this variation. Most (60%) cis-eQTLs were shared between T cells and neutrophils, but a significant portion uniquely impacted one of the cell types, suggesting cell type-specific regulatory mechanisms. Using a conditional regression algorithm, we predicted regulatory interactions between transcription factors and potential targets, and we demonstrated that these predictions overlap with regulatory interactions inferred from transcriptional changes during immunocyte differentiation. Finally, comparison of these and parallel data from CD4(+) T cells of healthy humans demonstrated intriguing similarities in variability of a gene's expression: the most variable genes tended to be the same in both species, and there was an overlap in genes subject to strong cis-acting genetic variants. We speculate that this "conservation of variation" reflects a differential constraint on intraspecies variation in expression levels of different genes, either through lower pressure for some genes, or by favoring variability for others

Identification of transcriptional regulators in the mouse immune system

The differentiation of hematopoietic stem cells into cells of the immune system has been studied extensively in mammals, but the transcriptional circuitry that controls it is still only partially understood. Here, the Immunological Genome Project gene-expression profiles across mouse immune lineages allowed us to systematically analyze these circuits. To analyze this data set we developed Ontogenet, an algorithm for reconstructing lineage-specific regulation from gene-expression profiles across lineages. Using Ontogenet, we found differentiation stage–specific regulators of mouse hematopoiesis and identified many known hematopoietic regulators and 175 previously unknown candidate regulators, as well as their target genes and the cell types in which they act. Among the previously unknown regulators, we emphasize the role of ETV5 in the differentiation of γδ T cells. As the transcriptional programs of human and mouse cells are highly conserved, it is likely that many lessons learned from the mouse model apply to humans.National Institute of Allergy and Infectious Diseases (U.S.) (R24 AI072073)National Institutes of Health (U.S.)Burroughs Wellcome FundKlarman Cell ObservatoryHoward Hughes Medical InstituteMerkin Family Foundation for Stem Cell Researc

Identification of transcriptional regulators in the mouse immune system.

The differentiation of hematopoietic stem cells into cells of the immune system has been studied extensively in mammals, but the transcriptional circuitry that controls it is still only partially understood. Here, the Immunological Genome Project gene-expression profiles across mouse immune lineages allowed us to systematically analyze these circuits. To analyze this data set we developed Ontogenet, an algorithm for reconstructing lineage-specific regulation from gene-expression profiles across lineages. Using Ontogenet, we found differentiation stage-specific regulators of mouse hematopoiesis and identified many known hematopoietic regulators and 175 previously unknown candidate regulators, as well as their target genes and the cell types in which they act. Among the previously unknown regulators, we emphasize the role of ETV5 in the differentiation of γδ T cells. As the transcriptional programs of human and mouse cells are highly conserved, it is likely that many lessons learned from the mouse model apply to humans