Personal genomics and individual identities: motivations and moral imperatives of early users

Since 2007, consumer genomics companies have marketed personal genome scanning services to assess users' genetic predispositions to a variety of complex diseases and traits. This study investigates early users' reasons for utilizing personal genome services, their evaluation of the technology, how they interpret the results, and how they incorporate the results into health-related decision-making. The analysis contextualizes early users' relationships to the technology, the knowledge generated by it, and how it mediates their relationship to their own health and to biomedicine more broadly. The results reveal that early users approach personal genome scanning with both optimism for genomic research and scepticism about the technology's current capabilities, which runs contrary to concerns that consumers may be ill equipped to interpret and understand genome scan results. These findings provide important qualitative insight into early users' conceptualizations of personal genomic risk assessment and illuminate their involvement in configuring this technology in the making.     

Gatekeepers or Intermediaries? The Role of Clinicians in Commercial Genomic Testing

Background

Many commentators on “direct-to-consumer” genetic risk information have raised concerns that giving results to individuals with insufficient knowledge and training in genomics may harm consumers, the health care system, and society. In response, several commercial laboratories offering genomic risk profiling have shifted to more traditional “direct-to-provider” (DTP) marketing strategies, repositioning clinicians as the intended recipients of advertising of laboratory services and as gatekeepers to personal genomic information. Increasing popularity of next generation sequencing puts a premium on ensuring that those who are charged with interpreting, translating, communicating and managing commercial genomic risk information are appropriately equipped for the job. To shed light on their gatekeeping role, we conducted a study to assess how and why early clinical users of genomic risk assessment incorporate these tools in their clinical practices and how they interpret genomic information for their patients.

Methods and Findings

We conducted qualitative in-depth interviews with 18 clinicians providing genomic risk assessment services to their patients in partnership with DNA Direct and Navigenics. Our findings suggest that clinicians learned most of what they knew about genomics directly from the commercial laboratories. Clinicians rely on the expertise of the commercial laboratories without the ability to critically evaluate the knowledge or assess risks.

Conclusions

DTP service delivery model cannot guarantee that providers will have adequate expertise or sound clinical judgment. Even if clinicians want greater genomic knowledge, the current market structure is unlikely to build the independent substantive expertise of clinicians, but rather promote its continued outsourcing. Because commercial laboratories have the most “skin in the game” financially, genetics professionals and policymakers should scrutinize the scientific validity and clinical soundness of the process by which these laboratories interpret their findings to assess whether self-interested commercial sources are the most appropriate entities for gate-keeping genomic interpretation.     

Affective loop experiences: designing for interactional embodiment

Involving our corporeal bodies in interaction can create strong affective experiences. Systems that both can be influenced by and influence users corporeally exhibit a use quality we name an affective loop experience. In an affective loop experience, (i) emotions are seen as processes, constructed in the interaction, starting from everyday bodily, cognitive or social experiences; (ii) the system responds in ways that pull the user into the interaction, touching upon end users'' physical experiences; and (iii) throughout the interaction the user is an active, meaning-making individual choosing how to express themselves—the interpretation responsibility does not lie with the system. We have built several systems that attempt to create affective loop experiences with more or less successful results. For example, eMoto lets users send text messages between mobile phones, but in addition to text, the messages also have colourful and animated shapes in the background chosen through emotion-gestures with a sensor-enabled stylus pen. Affective Diary is a digital diary with which users can scribble their notes, but it also allows for bodily memorabilia to be recorded from body sensors mapping to users'' movement and arousal and placed along a timeline. Users can see patterns in their bodily reactions and relate them to various events going on in their lives.The experiences of building and deploying these systems gave us insights into design requirements for addressing affective loop experiences, such as how to design for turn-taking between user and system, how to create for ‘open’ surfaces in the design that can carry users'' own meaning-making processes, how to combine modalities to create for a ‘unity’ of expression, and the importance of mirroring user experience in familiar ways that touch upon their everyday social and corporeal experiences.But a more important lesson gained from deploying the systems is how emotion processes are co-constructed and experienced inseparable from all other aspects of everyday life. Emotion processes are part of our social ways of being in the world; they dye our dreams, hopes and bodily experiences of the world. If we aim to design for affective interaction experiences, we need to place them into this larger picture.     

The promise and reality of personal genomics

The publication of the highest-quality and best-annotated personal genome yet tells us much about sequencing technology, something about genetic ancestry, but still little of medical relevance.Which country has published the largest per-capita number of personal genomes? The United States, the United Kingdom? Actually, it is Korea. A recent article in Nature by Kim et al. [1] presents the genome sequence of a Korean male, AK1 - the seventh published sequence of an individual human genome and the second from Korea. The rapid progress in personal genome sequencing is possible because so-called ''next-generation'' sequencing technology has decreased costs by orders of magnitude and increased throughput. But those advantages come at a price: short, error-prone reads derived from single molecules that have to be stitched back together to make a best-guess at the starting sequence. We are still at the stage of working out how to apply the available technologies to coax out biological information: the goal of a US$1,000 genome providing life-changing personal medical insights is still some way off.     

Genomic determinants of protein folding thermodynamics in prokaryotic organisms

Here we investigate how thermodynamic properties of orthologous proteins are influenced by the genomic environment in which they evolve. We performed a comparative computational study of 21 protein families in 73 prokaryotic species and obtained the following main results. (i) Protein stability with respect to the unfolded state and with respect to misfolding are anticorrelated. There appears to be a trade-off between these two properties, which cannot be optimized simultaneously. (ii) Folding thermodynamic parameters are strongly correlated with two genomic features, genome size and G+C composition. In particular, the normalized energy gap, an indicator of folding efficiency in statistical mechanical models of protein folding, is smaller in proteins of organisms with a small genome size and a compositional bias towards A+T. Such genomic features are characteristic for bacteria with an intracellular lifestyle. We interpret these correlations in light of mutation pressure and natural selection. A mutational bias toward A+T at the DNA level translates into a mutational bias toward more hydrophobic (and in general more interactive) proteins, a consequence of the structure of the genetic code. Increased hydrophobicity renders proteins more stable against unfolding but less stable against misfolding. Proteins with high hydrophobicity and low stability against misfolding occur in organisms with reduced genomes, like obligate intracellular bacteria. We argue that they are fixed because these organisms experience weaker purifying selection due to their small effective population sizes. This interpretation is supported by the observation of a high expression level of chaperones in these bacteria. Our results indicate that the mutational spectrum of a genome and the strength of selection significantly influence protein folding thermodynamics.     

Evidence That Personal Genome Testing Enhances Student Learning in a Course on Genomics and Personalized Medicine

An emerging debate in academic medical centers is not about the need for providing trainees with fundamental education on genomics, but rather the most effective educational models that should be deployed. At Stanford School of Medicine, a novel hands-on genomics course was developed in 2010 that provided students the option to undergo personal genome testing as part of the course curriculum. We hypothesized that use of personal genome testing in the classroom would enhance the learning experience of students. No data currently exist on how such methods impact student learning; thus, we surveyed students before and after the course to determine its impact. We analyzed responses using paired statistics from the 31 medical and graduate students who completed both pre-course and post-course surveys. Participants were stratified by those who did (N = 23) or did not (N = 8) undergo personal genome testing. In reflecting on the experience, 83% of students who underwent testing stated that they were pleased with their decision compared to 12.5% of students who decided against testing (P = 0.00058). Seventy percent of those who underwent personal genome testing self-reported a better understanding of human genetics on the basis of having undergone testing. Further, students who underwent personal genome testing demonstrated an average 31% increase in pre- to post-course scores on knowledge questions (P = 3.5×10⁻⁶); this was significantly higher (P = 0.003) than students who did not undergo testing, who showed a non-significant improvement. Undergoing personal genome testing and using personal genotype data in the classroom enhanced students'' self-reported and assessed knowledge of genomics, and did not appear to cause significant anxiety. At least for self-selected students, the incorporation of personal genome testing can be an effective educational tool to teach important concepts of clinical genomic testing.     

Women's understanding of abnormal cervical smear test results: a qualitative interview study.

OBJECTIVE: To describe how women interpret their experiences of diagnosis and treatment of a cervical abnormality and how healthcare services for such women can be improved. DESIGN: Qualitative study using detailed individual interviews. SETTING: Australian gynaecology clinics. SUBJECTS: 29 Women who had a cervical cytological abnormality and who attended a gynaecologist. MAIN OUTCOME MEASURES: Women''s views on their diagnosis and their information needs. RESULTS: Most women wanted to participate in decisions about their care but found it difficult to get the information they required from doctors because they were confused by what their doctors told them and felt unable to ask questions in the consultation. Medical terms such as wart virus and precancer were difficult to understand. Not being able to see their cervix also made it hard for women to understand what their abnormality meant and what treatment entailed. Most women tried to make sense of their abnormality in the context of their everyday lives. For some women their gynaecological care was not consistent with the way they understood their abnormality. CONCLUSIONS: The inherent power structure of medical practice combined with time pressures often make it difficult for doctors to give the detailed information and reassurance patients need when a diagnosis is distressing or when investigation and treatment are strange and upsetting.     

Interpretation of Dog Behavior by Children and Young Adults

This study investigates people's ability to interpret dog behavior. Inability to interpret dog behavior correctly may be a factor contributing to young children's higher likelihood of being bitten by dogs. Children (4- to 10-year-olds) and adults (total n = 550) watched videos of dogs displaying friendly, aggressive, and fearful behavior. They were asked to interpret the dogs' behaviors and to describe which features they had attended to in making their decision. Four- and 6-year-old children were unable to identify fearful dogs, while participants in all age groups were capable of identifying friendly and aggressive behavior (p < 0.001). Misinterpretations of fearful behavior were significantly associated with reports of attending to the dog's face rather than other features (χ² = 80.2, df = 1, p < 0.001). Four-year-olds were particularly likely to report looking at the dog's face and together with 6-year-olds they focused more on one feature rather than multiple features in order to make their decisions. The results show that younger children are less good at interpreting dog behavior, and that they are particularly poor at recognizing fear in dogs, while aggression is the most readily recognized behavior. Children's lower ability to interpret dog behavior seems to be due to the features they focus on. Younger children appear to focus on the dogs' most salient features and not the features that would allow them to correctly interpret the dogs' behavior. For example, 4- and 6-year-olds tended to report attending to the fearful dog's face rather than its tail and general posture. The results suggest it would be beneficial to include information about how to interpret dog behavior in dog-bite prevention programs.     

Anticipation of Personal Genomics Data Enhances Interest and Learning Environment in Genomics and Molecular Biology Undergraduate Courses

An important discussion at colleges is centered on determining more effective models for teaching undergraduates. As personalized genomics has become more common, we hypothesized it could be a valuable tool to make science education more hands on, personal, and engaging for college undergraduates. We hypothesized that providing students with personal genome testing kits would enhance the learning experience of students in two undergraduate courses at Brigham Young University: Advanced Molecular Biology and Genomics. These courses have an emphasis on personal genomics the last two weeks of the semester. Students taking these courses were given the option to receive personal genomics kits in 2014, whereas in 2015 they were not. Students sent their personal genomics samples in on their own and received the data after the course ended. We surveyed students in these courses before and after the two-week emphasis on personal genomics to collect data on whether anticipation of obtaining their own personal genomic data impacted undergraduate student learning. We also tested to see if specific personal genomic assignments improved the learning experience by analyzing the data from the undergraduate students who completed both the pre- and post-course surveys. Anticipation of personal genomic data significantly enhanced student interest and the learning environment based on the time students spent researching personal genomic material and their self-reported attitudes compared to those who did not anticipate getting their own data. Personal genomics homework assignments significantly enhanced the undergraduate student interest and learning based on the same criteria and a personal genomics quiz. We found that for the undergraduate students in both molecular biology and genomics courses, incorporation of personal genomic testing can be an effective educational tool in undergraduate science education.     

Genomics and privacy: implications of the new reality of closed data for the field

Open source and open data have been driving forces in bioinformatics in the past. However, privacy concerns may soon change the landscape, limiting future access to important data sets, including personal genomics data. Here we survey this situation in some detail, describing, in particular, how the large scale of the data from personal genomic sequencing makes it especially hard to share data, exacerbating the privacy problem. We also go over various aspects of genomic privacy: first, there is basic identifiability of subjects having their genome sequenced. However, even for individuals who have consented to be identified, there is the prospect of very detailed future characterization of their genotype, which, unanticipated at the time of their consent, may be more personal and invasive than the release of their medical records. We go over various computational strategies for dealing with the issue of genomic privacy. One can "slice" and reformat datasets to allow them to be partially shared while securing the most private variants. This is particularly applicable to functional genomics information, which can be largely processed without variant information. For handling the most private data there are a number of legal and technological approaches-for example, modifying the informed consent procedure to acknowledge that privacy cannot be guaranteed, and/or employing a secure cloud computing environment. Cloud computing in particular may allow access to the data in a more controlled fashion than the current practice of downloading and computing on large datasets. Furthermore, it may be particularly advantageous for small labs, given that the burden of many privacy issues falls disproportionately on them in comparison to large corporations and genome centers. Finally, we discuss how education of future genetics researchers will be important, with curriculums emphasizing privacy and data security. However, teaching personal genomics with identifiable subjects in the university setting will, in turn, create additional privacy issues and social conundrums.     

Genome-wide identification of novel genomic islands that contribute to Salmonella virulence in mouse systemic infection

Salmonella pathogenicity islands are inserted into the genome by horizontal gene transfer and are required for expression of full virulence. Here, we performed tRNA scanning of the genome of Salmonella enterica serovar Typhimurium and compared it with that of nonpathogenic Escherichia coli in order to identify genomic islands that contribute to Salmonella virulence. Using deletion analysis, we identified four genomic islands that are required for virulence in the mouse infection model. One of the newly identified pathogenicity islands was the pheV- tRNA-located genomic island, which is comprised of 26 126 bp, and encodes 22 putative genes, including STM3117–STM3138. We also showed that the pheV tRNA-located genomic island is widely distributed among different nontyphoid Salmonella serovars. Furthermore, genes including STM3118–STM3121 were identified as novel virulence-associated genes within the pheV- tRNA-located genomic island. These results indicate that a Salmonella -specific pheV- tRNA genomic island is involved in Salmonella pathogenesis among the nontyphoid Salmonella serovars.     

From sequence to function: using RNAi to elucidate mechanisms of human disease

RNA interference (RNAi) has emerged as one of the most powerful tools for functionally characterizing large sets of genomic data. Capabilities of RNAi place it at the forefront of high-throughput screens, which are able to span the human genome in search of novel targets. Although RNAi screens have been used to elucidate pathway components and discover potential drug targets in lower organisms, including Caenorhabditis elegans and Drosophila, only recently has the technology been advanced to a state in which large-scale screens can be performed in mammalian cells. In this review, we will evaluate the major advancements in the field of mammalian RNAi, specifically in terms of high-throughput assays. Crucial points of experimental design will be highlighted, as well as suggestions as to how to interpret and follow-up on potential cell death targets. Finally, we assess the prospective applications of high-throughput screens, the data they are capable of generating, and the potential for this technique to further our understanding of human disease.     

Predicting biological networks from genomic data

Continuing improvements in DNA sequencing technologies are providing us with vast amounts of genomic data from an ever-widening range of organisms. The resulting challenge for bioinformatics is to interpret this deluge of data and place it back into its biological context. Biological networks provide a conceptual framework with which we can describe part of this context, namely the different interactions that occur between the molecular components of a cell. Here, we review the computational methods available to predict biological networks from genomic sequence data and discuss how they relate to high-throughput experimental methods.     

Wer denkt,der Mensch oder sein Gehirn?

Who decides – humans or their brains? Philosophers' justify their criticism of how brain researchers interpret their results primarily on the basis of the classical philosophical approach of the definition of terms. For instance, they argue that it is nonsensical to assert that the brain is capable of thought, since only a human being possesses this faculty. Brain research has shown, however, that the processes taking place within the brain are necessary and sufficient in order to explain how we think. The author contends that the definition of terms does not advance our knowledge of brain function, the reason being that during a language's development those terms reflect the world‐view current at the time. If terms coined earlier are still used today, they may be outdated and hence, when defined, misleading.     

The Path to Enlightenment： Making Sense of Genomic and Proteomic Information

Whereas genomics describes the study of genome, mainly represented by its gene expression on the DNA or RNA level, the term proteomics denotes the study of the proteome, which is the protein complement encoded by the genome. In recent years, the number of proteomic experiments increased tremendously. While all fields of proteomics have made major technological advances, the biggest step was seen in bioinformatics. Biological information management relies on sequence and structure databases and powerful software tools to translate experimental results into meaningful biological hypotheses and answers. In this resource article, I provide a collection of databases and software available on the Internet that are useful to interpret genomic and proteomic data. The article is a toolbox for researchers who have genomic or proteomic datasets and need to put their findings into a biological context.     

Long Span DNA Paired-End-Tag (DNA-PET) Sequencing Strategy for the Interrogation of Genomic Structural Mutations and Fusion-Point-Guided Reconstruction of Amplicons

Structural variations (SVs) contribute significantly to the variability of the human genome and extensive genomic rearrangements are a hallmark of cancer. While genomic DNA paired-end-tag (DNA-PET) sequencing is an attractive approach to identify genomic SVs, the current application of PET sequencing with short insert size DNA can be insufficient for the comprehensive mapping of SVs in low complexity and repeat-rich genomic regions. We employed a recently developed procedure to generate PET sequencing data using large DNA inserts of 10–20 kb and compared their characteristics with short insert (1 kb) libraries for their ability to identify SVs. Our results suggest that although short insert libraries bear an advantage in identifying small deletions, they do not provide significantly better breakpoint resolution. In contrast, large inserts are superior to short inserts in providing higher physical genome coverage for the same sequencing cost and achieve greater sensitivity, in practice, for the identification of several classes of SVs, such as copy number neutral and complex events. Furthermore, our results confirm that large insert libraries allow for the identification of SVs within repetitive sequences, which cannot be spanned by short inserts. This provides a key advantage in studying rearrangements in cancer, and we show how it can be used in a fusion-point-guided-concatenation algorithm to study focally amplified regions in cancer.     

Recombinase technology: applications and possibilities

The use of recombinases for genomic engineering is no longer a new technology. In fact, this technology has entered its third decade since the initial discovery that recombinases function in heterologous systems (Sauer in Mol Cell Biol 7(6):2087–2096, 1987). The random insertion of a transgene into a plant genome by traditional methods generates unpredictable expression patterns. This feature of transgenesis makes screening for functional lines with predictable expression labor intensive and time consuming. Furthermore, an antibiotic resistance gene is often left in the final product and the potential escape of such resistance markers into the environment and their potential consumption raises consumer concern. The use of site-specific recombination technology in plant genome manipulation has been demonstrated to effectively resolve complex transgene insertions to single copy, remove unwanted DNA, and precisely insert DNA into known genomic target sites. Recombinases have also been demonstrated capable of site-specific recombination within non-nuclear targets, such as the plastid genome of tobacco. Here, we review multiple uses of site-specific recombination and their application toward plant genomic engineering. We also provide alternative strategies for the combined use of multiple site-specific recombinase systems for genome engineering to precisely insert transgenes into a pre-determined locus, and removal of unwanted selectable marker genes.     

From lab to lifestyle: translating genomics into healthcare practices

Contemporary genomic sciences are uncovering genetic factors implicated in common complex diseases such as type 2 diabetes. It is suggested that such knowledge could be developed into tests for susceptibility to the disease that would allow preventive action through lifestyle modification. This paper presents research on responses to this suggestion by genetic specialists, diabetologists, and general practitioners – three groups of health professionals whose practices are likely to be affected by such testing services. It shows how the responses of the different groups are related to the professional culture of practice. I suggest that the perspective a profession has of its potential role in relation to the emerging technology can illuminate the early stages of co-constitution by which the technology that is used and the community of practice that use it are mutually reshaped.