Nuclear chromosome locations dictate segregation error frequencies.

Chromosome segregation errors during cell divisions generate aneuploidies and micronuclei, which can undergo extensive chromosomal rearrangements such as chromothripsis1-5. Selective pressures then shape distinct aneuploidy and rearrangement patterns-for example, in cancer6,7-but it is unknown whether initial biases in segregation errors and micronucleation exist for particular chromosomes. Using single-cell DNA sequencing8 after an error-prone mitosis in untransformed, diploid cell lines and organoids, we show that chromosomes have different segregation error frequencies that result in non-random aneuploidy landscapes. Isolation and sequencing of single micronuclei from these cells showed that mis-segregating chromosomes frequently also preferentially become entrapped in micronuclei. A similar bias was found in naturally occurring micronuclei of two cancer cell lines. We find that segregation error frequencies of individual chromosomes correlate with their location in the interphase nucleus, and show that this is highest for peripheral chromosomes behind spindle poles. Randomization of chromosome positions, Cas9-mediated live tracking and forced repositioning of individual chromosomes showed that a greater distance from the nuclear centre directly increases the propensity to mis-segregate. Accordingly, chromothripsis in cancer genomes9 and aneuploidies in early development10 occur more frequently for larger chromosomes, which are preferentially located near the nuclear periphery. Our findings reveal a direct link between nuclear chromosome positions, segregation error frequencies and micronucleus content, with implications for our understanding of tumour genome evolution and the origins of specific aneuploidies during development.

Educating for Responsible Research Practice in Biomedical Sciences: Towards Learning Goals.

New developments in the field of biomedicine can have extensive implications for society. To steer research efforts in a responsible direction, biomedical scientists should contribute to a forward-looking ethical, and societal evaluation of new developments. However, the question remains how to equip students sufficiently with the skills they need to contribute to this evaluation. In this paper, we examine how the four dimensions of Responsible Research and Innovation (anticipation, reflexivity, inclusivity, and responsiveness) inform the identification of learning goals and teaching approaches that contribute to developing these skills in biomedical scientists. We suggest that these educational approaches focus on the skills to anticipate intended and unintended outcomes, reflect on the epistemological and moral aspects of research practice, and be inclusive of the variety of voices in society. We argue that if these dimensions are properly integrated into biomedical curricula, they will help students develop the attitudinal aspects necessary for becoming responsive, and prepare them for implementing the dimensions of responsible research into their daily practice. This paper focuses specifically on skills biomedical scientists need for the responsible conduct of research. Therefore, our analysis results, at least in part, in domain-specific recommendations. We invite educators from other disciplines to do the same exercise, as we believe this could lead to tailored educational approaches by which students from various disciplinary backgrounds learn how they each have a role in contributing to socially robust and morally responsible research practice.

Simulating the Genetics Clinic of the Future - whether undergoing whole-genome sequencing shapes professional attitudes.

Whole-genome sequencing (WGS) can provide valuable health insight for research participants or patients. Opportunities to be sequenced are increasing as direct-to-consumer (DTC) testing becomes more prevalent, but it is still fairly unusual to have been sequenced. We offered WGS to fourteen professionals with pre-existing familiarity with an interest in human genetics - healthcare, science, policy and art. Participants received a hard drive containing their personal sequence data files (.BAM,.gvcf), without further explanation or obligation, to consider how experiencing WGS firsthand might influence their professional attitudes. We performed semi-structured pre- and post-sequencing interviews with each participant to identify key themes that they raised after being sequenced. To evaluate how their experience of the procedure evolved over time, we also conducted a questionnaire to gather their views 3 years after receiving their genomic data. Participants were generally satisfied with the experience (all 14 participants would choose to participate again). They mostly decided to participate out of curiosity (personal) and to learn from the experience (professional). Whereas most participants slightly developed their original perspective on genetic data, a small selection of them radically changed their views over the course of the project. We conclude that personal experience of sequencing provides an interesting alternative perspective for experts involved in leading, planning, implementing or researching genome sequencing services. Moreover, the personal experience may provide professionals with a better understanding of the challenges visitors of the Genetics Clinic of the Future may face.

[Direct-to-consumer genetic tests in the consulting room]. / Direct-to-consumer genetische tests in de spreekkamer.

Rapid developments in genome technology and a growing interest in personalized healthcare have led to a large rise in the range and use of commercial DNA tests, the so-called direct-to-consumer genetic tests (DTC-GT). DTC-GT can be of a non-medical (e.g. for external characteristics) or medical nature; medical tests mostly indicate relative risks of disease e.g. Alzheimer's disease or certain forms of cancer. Low clinical validity and frequently unknown analytical validity of DTC-GT make it difficult to estimate the clinical usefulness of test results. From an ethical perspective, an increase in autonomy and possible health benefits must be weighed against loss of privacy, inadequate provision of information and the risk of misinterpretation of results, over-diagnosis, overtreatment and higher healthcare costs. It is unclear whether providing and implementing DTC-GT require authorisation under Dutch law in the Population Screening Act (Wet op het Bevolkingsonderzoek) or the Special Medical Procedures Act (Wet op BijzondereMedischeVerrichtingen). Clinical utility of DTC-GT can only increase if there is greater clarity on interpretation and scope of the law and regulations, when DTC-GT companies provide better information and guidance for consumers and when there is more focus on DTC-GT in education and training programmes for healthcare professionals.