Imaging genomics: Mapping the influence of genetics on brain structure and function

Reviewed by: Heredity under the Microscope: Chromosomes and the Study of the Human Genome by Soraya de Chadarevian Miguel García-Sancho Soraya de Chadarevian. Heredity under the Microscope: Chromosomes and the Study of the Human Genome. Chicago: University of Chicago Press, 2020. 272 pp. Ill. $37.50 (978-0-226-68511-3). In Heredity under the Microscope, Soraya de Chadarevian complements the picture of post-World War II biomedicine that she uncovered in her previous book, Designs for Life: Molecular Biology after World War II.1 Unlike in her earlier monograph, here she focuses on chromosomes as spaces of convergence of several lines of inquiry. This focus on research objects rather than disciplinary developments leads her to investigate a variety of practices that life scientists deployed to visualize and [End Page 466] interpret human chromosomes. The diversity of disciplinary backgrounds of these scientists and the multiplicity of uses to which their chromosome practices were put enable the author to expand the historiographical boundaries of both molecular biology and genetics research. Firstly, de Chadarevian disentangles “the study of postwar human heredity from the predominant concern about continuities with eugenic practices” (p. 5). The book does not limit itself to documenting the invention of karyotyping techniques to represent and detect anomalies in human chromosomes; it follows their standardization and spread, including their use as evidence of safe levels of radiation in the workplace (chapter 1) or sex assignment in the Olympic games (chapter 3). The emphasis on these uses, departed as they were from scientific theories about population improvement, displaces eugenics as the dominant interpretative framework of the history of human genetics. Secondly, the book presents chromosomes as showing “historical commonalities” (p. 177) between two approaches that have been traditionally considered as separate: molecular genetics and microscope-assisted chromosome observations. De Chadarevian stresses how these two approaches emerged as a consequence of the key role that nuclear research had played during World War II and the search of peacetime applications. Radioactive isotopes decisively fostered molecular biology, while the investigation of the effects of radiation was a crucial concern of human and medical geneticists using chromosome observations (chapter 1). Both molecular biologists and chromosome researchers also attempted to apply computers to their investigations, the former as an aid to the structural study of proteins and DNA, and the latter to automate the interpretation of karyotype images (chapter 4). However, whereas molecular biologists focused on simpler organisms, chromosome researchers engaged with both human populations and patients in the clinic. Radiation-induced leukemia was their first focus for then rapidly shifting to other conditions (especially those affecting mental abilities and sex identity) and larger-scale epidemiological studies (chapters 2 and 4). The 1960s, a decade that historians have dubbed the golden age of molecular biology,2 was also a time of expansion of chromosome observations. From the mid-1970s onward, molecular biologists turned to human subjects in order to realize the medical promise of the new recombinant DNA techniques. It is at this point when the intersection with chromosome research becomes more visible and de Chadarevian wonders “whose turn” this represents in history, a molecularization of human genetics or a humanization of molecular biology (pp. 171–76). Although subsequent success stories have put the emphasis on molecular biology, chapter 5 shows the importance of chromosome research as a key tool for gene mapping and the emergence of the human genome as an object of study. Even in the so-called post-genomic era, chromosome observations are [End Page 467] essential to clinically interpret the molecular sequence data derived from the Human Genome Project. Overall, the book offers a most welcomed framework to address the coexistence of chromosome observations and molecular biology, and their importance in genomics research. Understanding this is a pressing historiographical problem, given the dominance of molecular biologists in existing narratives and the apparent revival of chromosome research. There is yet still work to do in exploring specific overlaps between the visual and molecular approaches to the genome. A potential candidate is Victor McKusick, a main actor in de Chadarevian’s account and a co-author of the article in which Celera Genomics presented one of the draft sequences of the human...

The study of the inherited dystrophies represents one of the greatest success stories of modern molecular genetics. This is a story that began with the description of linkage to part of the short arm of the X chromosome (described as early as 1985 for one of the loci for X-linked retinitis pigmentosa) and the identification of the first gene known to be mutated in adRP (encoding the polypeptide rhodopsin) in 1990. The successful international effort to sequence the entire human genome – the Human Genome Project – represented a landmark collaborative project and its completion, which has enabled the entire human genome to be mapped, further accelerated the ability of scientists to understand the underlying molecular basis of human genetic disease. Consequently, at the time of writing over 200 gene loci and 150 genes have been described underlying human monogenic retinal disorders implying a level of complexity that was unsuspected 20 years ago. This has allowed an entirely new understanding of the genetic basis of this group of conditions. The ‘genetic’ conditions referred to in this text, and within this section, will be monogenic, or Mendelian, conditions. However, it is now recognised that many common conditions have a substantial genetic contribution; the recent delineation of polymorphisms in the complement pathway as key genetic contributors to age-related macular degeneration demonstrates that molecular genetic discoveries have by no means been limited to the Mendelian retinal dystrophies.

The past half century has seen a tremendous progress in technology. The first hand held mobile phones began production in 1973[1] and today about 45% of the world's population owns a smart phone.[2] In 1983, the publicly available and practical version of the internet was invented allowing standard computer networks to communicate with one another.[3] Today, it is rare to find a stand-alone computer not connected to the world wide web. Science took a historical leap forward approximately a quarter of a century ago with the development of the human genome project (HGP).[4] While the HGP was the complete mapping of all the genes in the human genome, ultimately it changed how science was approached. The ushering in of genomics via the HGP quickly led to en masse measurement of gene transcripts (transcriptomics), proteins (proteomics), and finally metabolites (metabolomics). While the knowledge gained from these branches of omics will continue to increase as time passes, one thing we have learned for certain is that the human cell is an amazing feat of engineering. Its genome is made up of approximately 20 000 protein coding genes and produces an estimated 200 000 transcripts. Within the genomic code are blueprints for potentially producing upwards of a billion protein species when various splice variants and post-translational modifications are considered. The human metabolite database currently lists over 114 000 metabolites that have either been detected or are predicted to be present within human cells.[5] Compare these numbers to an automobile, which contains on the order of tens of thousands of moving parts. Just like an automobile engine, the components of the cell work together to create a functional entity. Also like an engine, the source of a dysfunctional component within a cell may not be directly connected to the component itself. For example, rapid cell proliferation in human epidermal growth factor receptor 2 (HER-2) breast cancer is caused by an excess of HER-2 receptors on the surface of the cells.[6] The source of this receptor expansion, however, can be traced to gene duplication events. Historically, studies would be designed to identify this connection molecule by molecule, specifically targeting the protein receptor and HER-2 gene. In today's omics-era it is possible to collect data on thousands of genes, transcripts, and proteins so that not only the source of the biological problem can be detected but also the peripheral damage it creates. The systems biology era has given rise to a plethora of different omics fields that aim to characterize various aspects of cells and organisms. The foundation of systems biology, however, remains the "big-four" omics: genomics, transcriptomics, proteomics, and metabolomics. The initial article in this edition provides a reflection on the progress that has been made in omics research beginning with the HGP, which arguably changed the strategy in how scientists design biological studies.[7] The article highlights the incredible progress that has been made in the big-four omic fields. Description of an article detailing a multi-omics study of plasma samples obtained from individuals infected with COVID-19 demonstrates how mainstream systems biology studies have become in just the past few years. While the article also highlights challenges in systems biology, it provides a glimpse into the many different databases and consortiums that have arisen to address the ambitious nature of attempting to characterize all the components within cells and organisms. While much effort has been spent in the past couple of decades identifying the entire complement of cellular biomolecules, the need to identify how these biomolecules interact to carry out the many functions that occur within these cells has become paramount. In their article, Basu et al., describe the use of functional proteomics and systems biology to generate protein-protein interaction networks in neurons, glia, and other cell types.[8] They summarize findings from recent studies that compare these interaction networks in normally functioning neurons, in developing neurons, and neurodegenerative diseases. The article goes on to demonstrate how these interaction networks can be used to decipher cellular functions that regulate neuronal activity and brain function. While the era of systems biology has increased the amount of data per study, most laboratories are not historically designed to accommodate this requirement. A complete systems biology view of a cell requires data from a variety of classes of biomolecules (e.g., DNA, RNA, proteins, etc.), however, most labs are designed to analyze only one (or possibly two) of these classes. Another barrier to limited lab resources is the ability to integrate data from multiple similar investigations to test the veracity of hypotheses that may be generated from omic studies. In their review, Mantini et al. describe various methods for integrating phosphoproteomic data particularly in the context of cancer research.[9] They proceed to present various methods that enable phosphoproteomic data to be integrated with data from other omic fields to provide a broader systems biology perspective. As briefly mentioned in the initial article of this special edition, a number of researchers are working towards generating omics data on single cell as a means of avoiding the inherent heterogeneity of cell populations. In an application of this area, Zhiyuan et al. developed a novel integrated microfluidic chip capable of isolating and characterizing the RNA expression profile of a single circulating cancer cells (CTCs).[10] While CTCs are effective for monitoring tumor metastasis, they are also heterogeneous. To validate their device, Zhiyuan et al. performed transcriptome profiling of single MCF-7 and white blood cells. When the transcriptomic profiles of the two cell types were compared significant genetic differences were observed based on three different measures. While proteomic diversity is mostly a result of cell-mediated post-translational modifications and the post-transcriptional occurrence of splice variants, there are many exogenous compounds that can modify proteins within the proteome.[11] In an article illustrating how dynamic the proteome can be, Tocmo et al. review how plant-derived natural products can covalently modify proteins.[13] In their article they describe how various proteomic techniques are used to identify various modifications derived from plant-based natural products can alter protein conformation, resulting in an alteration of their function and the biological activity that they modulate. One of the major benefits of the omics-era has been the discovery of the vast diversity of the biomolecules that make up cells. As scientists develop more creative uses of technologies, the number of known variations of biomolecules continues to increase. In their article, Muroski et al. build upon the observation that cyclized immonium ions that are observed in the tandem mass spectrometry (MS) spectra of acylated lysine residues could be used to identify acyl-lysine modifications.[14] They developed a stepped collision energy method that provides unique features in the tandem MS spectra of acyl-lysine containing peptides by optimizing the abundance of the immonium ion without sacrificing the information available to identify the modified peptide's sequence. Testing this novel MS method on a proteome extracted from Synotrophus aciditrophicus that had been spiked with three peptides that differed in their type and location of acetylation. This novel stepped collision energy method was able to successfully identify each of the three peptides within a complex background of peptides. In a further application, the researchers were able to identify, for the first time, a hydroxypimelyl-lysine residues within the Synotrophus aciditrophicus proteome. There is a basic paradigm in protein science that structure dictates function. But what about proteins that do not have a unique stable structure? So-called intrinsically disordered proteins (IDPs) are known to affect many cellular processes and have even been associated with diseases. The challenge, however, has been identifying and deciphering the mechanisms of this atypical class of proteins. Conventional techniques such as X-ray crystallography and nuclear magnetic resonance spectroscopy are designed to characterize stable structures within proteins but generally fail when dealing with unstructured domains. The article not only highlights the impact that MS has had on characterizing IDPs but discusses the future potential of this technique in uncovering further facets of this underexplored group of proteins.[15] Oxylipins are a family of oxygenated natural products derived from polyunsaturated fatty acids by the action of cyclooxygenase (COX) and lipoxygenase enzymes.[15] These highly potent molecules stimulate a variety of biological responses including inflammation, vasoconstriction, vasodilation, blood-clotting, etc. in response to tissue injury. In a combined targeted proteomics/metabolomics approach Scheb et al. developed a selected reaction monitoring-MS assay to measure the absolute abundance of the COX-2 enzyme and compared changes in its level to changes in the abundance of a panel of oxylipins.[16] They applied this method to study the association between COX-2 and oxylipin levels in the human colon carcinoma cell lines and lipopolysaccharide-stimulated macrophages. This combined, targeted omics approach has the potential to be expanded to include additional enzymes involved in oxylipin synthesis and can be used to further elucidate the biological mechanisms that modulate the response to tissue injury from exogenous and endogenous sources. I would like to express my deepest gratitude to all of the contributors who made this special issue possible. This past year is unlike any other that we have lived through. Even with all of the changes each of the contributors had to make to their labs and day-to-day duties because of the COVID-19 pandemic, they were generous enough to share their time to prepare an article for this issue. My hope as editor is that the reader will be impressed by the progress made in omics research in the recent past and be excited about what the next few years of continuing developments will reveal about the human organism. The author declares no conflict of interest.

Cortical Inhibition in Alcohol Dependence

Preface

No field of medicine is better able to translate the revolutionary advances in molecular biology and genetics into the care of patients than the field of molecular nuclear medicine. The human genome project has been a stimulus to the development of what might be called “genetic sciences,” i.e., molecular genetics, human genetics, molecular nuclear medicine, and pharmacology.

In 1996, when the time since the advent of ‘‘systems of care’’ (Stroul and Friedman 1996) for youths with serious emotional and behavioral problems was still measured in terms of years and not decades, this journal provided the children’s services field with a landmark Special Issue focused on research on the wraparound process and individualized services for children with complex needs (Clark and Clarke 1996). The Special Issue aimed to provide the first comprehensive academic perspective on wraparound, which was at the time one of a variety of ‘‘innovative alternatives to highly restrictive, categorical services and costly institutional care’’ (p. 2), on which outcomes studies were only beginning to be published. The goals for the 1996 special issue were to: (a) provide a definition of the wraparound process and a rationale for its use, (b) illustrate potential applications of the approach, and (c) present results from studies that shed light on the potential for wraparound’s positive impact. As described by the Special Issue’s discussant (Rosenblatt 1996), the Special Issue also aimed to put this new strategy on a developmental pathway that would lead its specification and refinement to be guided by theory and research, rather than by ‘‘fad and fashion,’’ lest wraparound become yet another ‘‘program of great promise that fell by the wayside once [its] moment in the sun passed’’ (p. 114). Fifteen years later, we can report that far from falling by the wayside the wraparound process has become an organizing framework and prominent practice model through which community-based services for a broad range of populations with complex needs are delivered. As described by Bruns, Sather, Pullmann, and Stambaugh in this Special Section, it is estimated that the wraparound process is available via nearly 1,000 initiatives in nearly every one of the United States with the number of states taking implementation statewide increasing every year (Bruns et al. 2010). We also have observed that the field has continued to make progress in the areas discussed in the 1996 Special Issue. Wraparound’s principles, practice model, and organizational and system support conditions have undergone systematic examination over the past 10 years, in a way that intends to provide adequate specificity to permit replicability and quality assurance while maintaining the strategy’s ability to be adapted to local conditions and populations (Bruns et al. 2010; Walker and Bruns 2006; Walker et al. 2011). Nine controlled studies of wraparound are now in the peer reviewed literature (Bruns and Suter 2010), with a recently completed meta-analysis demonstrating significant positive effects and mean effect sizes ranging from 0.31 for mental health symptomotology to 0.44 for residential placement (Suter and Bruns 2009). Finally, examples of applications of wraparound continue to proliferate and gain national attention. The initiatives studied in the above reviews and meta-analysis span mental health, juvenile justice, and child welfare (Suter and Bruns 2009), and the wraparound process is now frequently referenced as a practice model that can facilitate integration of care for complex populations of all ages. Achieving E. J. Bruns (&) Division of Public Behavioral Health and Justice Policy, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA e-mail: ebruns@u.washington.edu

Non-invasive measurements of brain function and structure as neuroimaging in patients with mental illnesses are useful and powerful tools for studying discriminatory biomarkers. To date, functional MRI (fMRI), structural MRI (sMRI) represent the most used techniques to provide multiple perspectives on brain function, structure, and their connectivity. Recently, there has been rising attention in using machine‐learning (ML) techniques, pattern recognition methods, applied to neuroimaging data to characterize disease-related alterations in brain structure and function and to identify phenotypes, for example, for translation into clinical and early diagnosis. Our aim was to provide a systematic review according to the PRISMA statement of Support Vector Machine (SVM) techniques in making diagnostic discrimination between SCZ patients from healthy controls using neuroimaging data from functional MRI as input. We included studies using SVM as ML techniques with patients diagnosed with Schizophrenia. From an initial sample of 660 papers, at the end of the screening process, 22 articles were selected, and included in our review. This technique can be a valid, inexpensive, and non-invasive support to recognize and detect patients at an early stage, compared to any currently available assessment or clinical diagnostic methods in order to save crucial time. The higher accuracy of SVM models and the new integrated methods of ML techniques could play a decisive role to detect patients with SCZ or other major psychiatric disorders in the early stages of the disease or to potentially determine their neuroimaging risk factors in the near future.

Technical advances in molecular genetics that were being developed in the 1970s led to the initiation of the Human Genome Project (HGP), a long-term international research effort to completely map and sequence the human genome. In 1988, U.S. Congress appropriated funds to the Department of Energy (DOE) and the National Institutes of Health (NIH) to begin the planning stages of this vast endeavor (Collins, 1999). The HGP objectives included construction of a detailed genetic and physical map of the human genome, determination of the complete nucleotide sequence of human DNA, and localization of the currently estimated 30,000 genes within the human genome. The completed HGP therefore comprises a resource of detailed information about the structure, organization, and function of human DNA. Similar analyses of the genomes of other model organisms used extensively in research laboratories are also being performed. This information will change the way medical services are provided in the future, including the treatment of individuals with oral-facial clefting disorders. In addition to promoting the development of improved technologies for biomedical research and genomic analysis, project goals included training scientists to utilize tools and resources developed through the HGP to pursue biological studies that would ultimately improve human health. Specific additional benefits include an enhanced understanding of the genetic contributions to human disease and the development of rational strategies for minimizing or preventing disease phenotypes. Sequencing the human genome greatly improves our understanding of the genetic and molecular basis of disease mechanisms and suggests new therapeutic regimens for disease prevention or, at the very least, the targeting of specific treatment modalities to the individual patient on the basis of their genotype.

Cancer genetics has become a burgeoning area of both cytogenetic and molecular genetic research and practical clinical application of the findings of such research in human cancer and leukemia. This review summarizes the specific types of chromosomal and associated molecular genetic alterations in leukemia and cancer. The primary objective is to acquaint physicians of various disciplines with the application of cytogenetics and molecular genetics as diagnostic, prognostic and therapeutic indices, as approaches to the evaluation of minimal residual disease and as guides for differentiation therapy and the molecular localization of oncogenes and tumor suppressor genes related to gene therapy in leukemias and cancers.

Historically, safety in the biomedical research laboratory during the past 50 years or so was limited to the areas of chemical, fire, radiation, and industrial safety. Only recently has biological safety become an issue for many academic and industrial organizations. Extensive media coverage of public concerns about research involving “genetic engineering” has resulted in much public attention being given to these new research techniques. The need to address these concerns led many academic and industrial organizations to adopt biological safety programs that included not only genetic engineering research but also the whole range of biomedical research. Some of these special programs have survived, albeit in somewhat altered form, despite well-defined government guidelines for research in molecular genetics. A heightened awareness of biosafety matters in general has been the major result of all this public scrutiny, and as a result of this, biological safety programs have become firmly established in most major organizations. In this chapter we will discuss some of the major biosafety concerns, such as hazard identification, risk assessment, containment practices, and hazard management.

In recent years, research in molecular genetics has been instrumental in deciphering the molecular heterogeneity of acute myeloid leukemia (AML), in particular the subset of patients with “intermediate-risk” cytogenetics. However, at present, only the markers NPM1, CEBPA, and FLT3 have entered clinical practice. Treatment of intermediate-risk AML patients eligible for intensive therapy has not changed substantially. The “3 + 7” induction therapy still represents the standard of care. The addition of the immunoconjugate gemtuzumab ozogamicin to therapy has been shown to improve outcome; however, the drug is not approved for this use. A common standard for postremission therapy is the administration of repeated cycles of intermediate- to high-dose cytarabine. Allogeneic stem cell transplantation may offer a survival benefit for many patients with intermediate-risk AML. Patients are best selected based on the genetic profile of the leukemia cells and the risk associated with the transplantation itself. A myriad of novel agents targeting mutant leukemia drivers or deregulated pathways are in clinical development. In the past, many novel compounds have not met expectations; nonetheless, with the rapid developments in comprehensive molecular profiling and new drug design, there is the prospect of personalizing therapy and improving patient outcome.

Research in molecular genetics in streptococci is rapidly expanding [1]. A major technical problem lies in the difficulties in lysing the streptococcal cell. Most methods used are adaptions of procedures developed for Gram-negative bacteria and involve the use of ionic or non-ionic detergents such as sarkosyl, sodium dodecyl sulfate (SDS) or Brij-deoxycholate. Furthermore, addition of D amino acids [2,3] and glycine [4] during culturing of the bacteria followed by prolonged periods of digestion by egg white muramidase (lysozyme) and other cell-wall degrading enzymes are required to improve lysis of the streptococci. Even under these conditions lysis is usually incomplete except for Streptococcus faecafis [1,5] and S. sanguis (Malke, personal communication) which are relatively sensitive to lysozyme. Most published studies of molecular genetics in streptococci therefore refer to plasmid (DNA) isolated after conjugal transfer to S. faecalis [5]. On the other hand, the chromosome or nontransferable plasmids of e.g. group A streptococci (S. pyogenes), the most important human pathogen of the genus, has eluded molecular study so far. Mutanolysin (M-1 muramidase) isolated from Streptomyces globisporus 1829 has been used for lysis of Bacillus subtilis, lactobacilli, Diplococcus pneumoniae and viridans streptococci such as S. sanguis, S. mutans and S. salivarius [6.7]. The enzyme was recently used also for successful digestion of cell-wall peptidoglycan of group B streptococci (S. agalactiae type III) isolated by mechanical disruption of the cells followed by SDS extraction of envelopes [8]. We have investigated a preparation of M-1 muramidase which recently became commercially available (see MATERIALS). In the presence of the non-ionic detergent Triton X-100 and high concentrations of NaC1 this enzyme was found to effect rapid lysis of S. pyogenes and members of a broad range of streptococci belonging to serogroups A, A (rough), B, C, D, E, G, H and L.

Physical maps showing the relative locations of cloned DNA fragments in the genome are important resources for research in molecular genetics, genome analysis, and evolutionary biology. In addition to affording a common frame of reference for organizing diverse types of genetic data, physical maps also provide ready access to clones containing DNA sequences from any defined region of the genome. In this paper, we present a physical map of the genome of Drosophila melanogaster based on in situ hybridization with 2461 DNA fragments, averaging approximately 80 kilobase pairs each, cloned in bacteriophage P1. The map is a framework map in the sense that most putative overlaps between clones have not yet been demonstrated at the molecular level. Nevertheless, the framework map includes approximately 85% of all genes in the euchromatic genome. A continuous physical map composed of sets of overlapping P1 clones (contigs), which together span most of the euchromatic genome, is currently being assembled by screening a library of 9216 P1 clones with single-copy genetic markers as well as with the ends of the P1 clones already assigned positions in the framework map. Because most P1 clones from D. melanogaster hybridize in situ with chromosomes from related species, the framework map also makes it possible to determine the genome maps of D. pseudoobscura and other species in the subgenus Sophophora. Likewise, a P1 framework map of D. virilis affords potential access to genome organization and evolution in the subgenus Drosophila.

Management of recurrent cutaneous melanoma