Genetic factors predict hybrid formation in the British flora.

Natural hybridization can have a profound evolutionary impact, with consequences ranging from the extinction of rare taxa to the origin of new species. Natural hybridization is particularly common in plants; however, our understanding of the general factors that promote or prevent hybridization is hampered by the highly variable outcomes in different lineages. Here, we quantify the influence of different predictors on hybrid formation across species from an entire flora. We combine estimates of hybridization with ecological attributes and a new species-level phylogeny for over 1,100 UK flowering plant species. Our results show that genetic factors, particularly parental genetic distance, as well as phylogenetic position and ploidy, are key determinants of hybrid formation, whereas many other factors such as range overlap and genus size explain much less variation in hybrid formation. Overall, intrinsic genetic factors shape the evolutionary and ecological consequences of natural hybridization across species in a flora.

Development and evaluation of a novel educational program for providers on the use of polygenic risk scores.

PURPOSE: This study aimed to develop an online educational program for using polygenic risk score (PRS) for breast and ovarian cancer risk assessments and to evaluate the impact on the attitudes, confidence, knowledge, and preparedness of genetic health care providers (GHPs). METHODS: The educational program comprises an online module that covers the theoretical aspects of PRS and a facilitated virtual workshop with prerecorded role-plays and case discussions. Data were collected in pre- and posteducation surveys. Eligible participants were GHPs working in Australian familial cancer clinics registered to recruit patients for a breast and ovarian cancer PRS clinical trial (n = 12). RESULTS: A total of 124 GHPs completed the PRS education, of whom 80 (64%) and 67 (41%) completed the pre- and posteducation surveys, respectively. Before education, GHPs reported limited experience, confidence, and preparedness using PRS, but they recognized its potential benefits. After education, GHPs indicated improved attitudes (P ≤ .001), confidence (P ≤ .001), knowledge (P ≤ .001), and preparedness (P ≤ .001) to use PRS. Most GHPs thought that the program entirely met their learning needs (73%) and was completely relevant to their clinical practice (88%). GHPs identified PRS implementation barriers, including limited funding models, diversity issues, and need for clinical guidelines. CONCLUSION: Our education program improved GHP attitudes, confidence, knowledge, and preparedness for using PRS/personalized risk and provides a framework for the development of future programs.

Comprehensive phylogenomic time tree of bryophytes reveals deep relationships and uncovers gene incongruences in the last 500 million years of diversification.

PREMISE: Bryophytes form a major component of terrestrial plant biomass, structuring ecological communities in all biomes. Our understanding of the evolutionary history of hornworts, liverworts, and mosses has been significantly reshaped by inferences from molecular data, which have highlighted extensive homoplasy in various traits and repeated bursts of diversification. However, the timing of key events in the phylogeny, patterns, and processes of diversification across bryophytes remain unclear. METHODS: Using the GoFlag probe set, we sequenced 405 exons representing 228 nuclear genes for 531 species from 52 of the 54 orders of bryophytes. We inferred the species phylogeny from gene tree analyses using concatenated and coalescence approaches, assessed gene conflict, and estimated the timing of divergences based on 29 fossil calibrations. RESULTS: The phylogeny resolves many relationships across the bryophytes, enabling us to resurrect five liverwort orders and recognize three more and propose 10 new orders of mosses. Most orders originated in the Jurassic and diversified in the Cretaceous or later. The phylogenomic data also highlight topological conflict in parts of the tree, suggesting complex processes of diversification that cannot be adequately captured in a single gene-tree topology. CONCLUSIONS: We sampled hundreds of loci across a broad phylogenetic spectrum spanning at least 450 Ma of evolution; these data resolved many of the critical nodes of the diversification of bryophytes. The data also highlight the need to explore the mechanisms underlying the phylogenetic ambiguity at specific nodes. The phylogenomic data provide an expandable framework toward reconstructing a comprehensive phylogeny of this important group of plants.

Psychiatric genetic counseling: A survey of Australian genetic counselors' practice and attitudes.

Genetic counseling plays a critical role in supporting individuals and their families' adaption to psychiatric conditions, addressing the multifactorial nature of these conditions in a personally meaningful and empowering way. Yet data related to the practice and attitudes of Australian genetic counselors about psychiatric genetic counseling (PGC) is limited. This survey investigated the practice of Australian genetic counselors, and their attitudes toward PGC. Genetic counselors (N = 393) were invited to participate in an anonymous online survey between March and May 2022. Forty-four genetic counselors (response rate = 11%) from Australia and New Zealand responded. No respondents practice in psychiatric genetics as their speciality area; most respondents do not see any patients where the primary indication is a personal and/or family history of psychiatric disorders (91%). Greater than half of respondents (56%) believed there was sufficient evidence to support PGC, and 64% enquire about personal and/or family history of psychiatric disorders, but only 25% provide genetic counseling on this topic. Most respondents do not feel confident providing risk assessments for psychiatric disorders (72%), while the majority expressed interest in attending specialist training (95%), and in incorporating PGC into future practice (77%). Australian genetic counselors would benefit from psychiatric genetic education and training, and establishment of specialized PGC services would address this gap in patient care, while providing opportunities for genetic counselors to gain skills and experience in PGC.

Becoming and being a parent with an inherited predisposition to diffuse gastric cancer: A qualitative study of young adults with a CDH1 pathogenic variant.

PURPOSE: This study explored the experiences of young people with hereditary diffuse gastric cancer (HDGC), an inherited cancer predisposition syndrome, as they navigate becoming and being a parent. DESIGN: We used interpretive description and conducted semi-structured interviews with 13 young Australians (18-39 years) with a CDH1 pathogenic variant (PV). Data were analyzed using team-based, reflexive thematic analysis. FINDINGS: Participants' reproductive decisions centered on the perceived manageability of HDGC, namely via gastrectomy, and timing of their genetic testing. Participants yet to have children and those with challenging gastrectomy experiences favored using reproductive technologies to prevent passing on their PV. Parents who had children before genetic testing described complicated decisions about having more children. Gastrectomy was considered a parental responsibility but recovery diminished parenting abilities. CONCLUSION: Young people with HDGC face unique challenges navigating reproductive decision-making and parenting with gastrectomy. Findings lend credence to calls for longitudinal, developmentally sensitive genetic counseling services.

Young people's experiences of a CDH1 pathogenic variant: Decision-making about gastric cancer risk management.

The most effective option for gastric cancer risk management in individuals with a CDH1 germline pathogenic or likely pathogenic variant (PV) in Australia is prophylactic total gastrectomy (PTG). There is, however, increasing confidence in endoscopic surveillance as a risk management strategy thus affording individuals with a CDH1 PV with challenging decisions regarding their gastric cancer risk management. For young people, this decision-making comes at a complex development stage of emerging and young adulthood. This study aims to explore the factors that influence young people's decision-making about their gastric cancer risk management due to a CDH1 PV. Potential participants were identified and approached through the Parkville Familial Cancer Centre in Melbourne, Australia. Thematic analysis was used to interpret and analyze the data. Qualitative interviews were conducted with 13 people with a CDH1 PV aged 18 to 39 years, inclusive. The interviews found that participants' familial and shared experiences of cancer and risk management, perceived tolerance of uncertainty, and desire for control over their cancer risk were fundamental in their decision-making about their gastric cancer risk management. The participants' young adult life stage was also deemed particularly important in decisions about the timing of PTG. The findings of this study are vital to inform decisional counseling discussions with this unique population.

Assessing the acceptability, feasibility, and usefulness of a psychosocial screening tool to patients and clinicians in a clinical genetics service in Australia.

Increasing demand for clinical genetic services may impact the resources and quality of genetic counseling, potentially impacting patient outcomes. Using a psychosocial screening tool may aid the provision of genetic counseling by reliably identifying patients' psychosocial needs. The Genetic Psychosocial Risk Instrument (GPRI) is a validated genetic-specific screening tool designed to identify psychological risk factors that predict distress in patients having genetic testing. This questionnaire-based study investigated the perceived acceptability, feasibility, and usefulness of the GPRI in patients and clinicians in routine clinical genetic practice. From December 2018 to January 2019, 154 patients attending an Australian clinical genetic service were invited to complete a paper-based survey that included the GPRI. The GPRI was scored and provided to the clinician for use in the appointment. In February 2019, clinicians completed an anonymous online survey regarding acceptability, feasibility, and usefulness of the GPRI. Descriptive statistics, chi-squared, t tests, and regression analyses were used to analyze the patient data, and descriptive statistics were employed for clinician surveys. A total of 145 patients participated (94% response rate). The average GPRI score was 46.3 (95% CI 43.6-49.0) with 41% of patients meeting the 50-point threshold indicating high risk for psychological distress. The GPRI was highly acceptable to patients, regardless of their level of psychosocial risk. Fourteen clinicians participated (54% response rate): 85% found the GPRI not too time consuming, and 86% believed it improved patient care by identifying patient needs. All were willing to use the GPRI routinely. The use of the GPRI is highly acceptable to patients and clinicians in this setting, assisting in identifying patients at risk for distress, prompting clinicians to address concerns, provide psychosocial support, and consider ongoing referral. As 41% of patients' scores indicated a high risk of distress, the GPRI is an important tool for potentially enhancing overall patient outcomes.

Reproduction and Genetic Responsibility: An Interpretive Description of Reproductive Decision-Making for Young People With Li-Fraumeni Syndrome.

The reproductive decision-making of young people (aged 15-39 years) with Li-Fraumeni syndrome (LFS), an early onset inherited cancer syndrome, has not been studied in depth. Using interpretive description methodology, we conducted semi-structured interviews with 30 young Australians (mean age 25.5 years) diagnosed with LFS or at 50% genetic risk. With reflexive thematic analysis, we show how young people's reproductive decision-making and ideals for family formation were shaped by a sense of genetic responsibility to ensure the health of future biological kin. Reproductive technology provided choices for family formation in the context of LFS and also complicated reproductive decisions, as these choices were difficult to understand, make, or carry out. We uphold that reproductive decision-making when living with LFS is a profoundly moral practice that may pose significant challenges for young people navigating their formative years. We offer genetic counseling practice recommendations to support individuals with LFS when making reproductive decisions.

Finding the five-year window: A qualitative study examining young women's decision-making and experience of using tamoxifen to reduce BRCA1/2 breast cancer risk.

OBJECTIVE: Tamoxifen has been demonstrated to reduce breast cancer risk in high-risk, premenopausal women. Yet, very few young women with hereditary breast and ovarian cancer syndrome in Australia use tamoxifen, despite this being a less-invasive option compared to risk-reducing mastectomy. This study aims to examine young women's decision-making about and experience of taking tamoxifen to reduce their breast cancer risk. METHODS: Young women with a BRCA1/2 mutation participated in semi-structured qualitative interviews, recruited mainly from a metropolitan clinical genetics service. Data were analysed using an inductive, team-based approach to thematic analysis. RESULTS: Forty interviews with women aged 20-40 years with a BRCA1/2 mutation were conducted. Eleven women could not recall discussing tamoxifen with their healthcare provider or were too young to commence cancer risk management. Twenty-three women chose not to use tamoxifen because it is contraindicated for pregnancy or because it did not offer immediate and great enough risk reduction compared to bilateral risk-reducing mastectomy. Six women who were definite about not wanting to have children during the following 5-year period chose to use tamoxifen, and most experienced none or transient side effects. CONCLUSIONS: Decision-making about tamoxifen was nuanced and informed by considerations characteristic of young adulthood, especially childbearing. Therefore, clinical discussions about tamoxifen with young women with a BRCA1/2 mutation must include consideration of their reproductive plans.

The art and science of recruitment to a cancer rapid autopsy programme: A qualitative study exploring patient and clinician experiences.

BACKGROUND: CASCADE is a successful, Australia-first cancer rapid autopsy programme. Patients are recruited to the programme by their clinician once they understand that further treatment has only palliative intent. Despite its value, rapid autopsy is a rare research method owing partly to recruitment challenges. AIM: This research aimed to explore (1) how, in practice, clinicians select and recruit patients to the programme and (2) patient experiences of this process. DESIGN: This was a qualitative study grounded in phenomenology. CASCADE team members (clinicians and researchers) and patients participated in semi-structured interviews. Data were analysed using an inductive, team-based approach to thematic analysis. PARTICIPANTS: Interviews were conducted with 31 participants (11 patients and 20 CASCADE team members). RESULTS: Patient selection and recruitment to a rapid autopsy programme is both an art and science. In practice, patient selection is a subjective process that involves assessing a patient's psychosocial suitability for the programme. Trust and rapport are necessary for informing this assessment and to create an environment conducive to discussing rapid autopsy. Clinicians have also crafted their own ways of delivering information about CASCADE, with both clinicians and patients acknowledging that, if not handled sensitively, recruitment could cause distress. Overall, patients were satisfied with the way in which they were recruited. CONCLUSION: Findings provide insight into how clinicians successfully select and recruit patients to a rapid autopsy programme and suggests that discussing such topics are acceptable to end-of-life patients. This research also raises thought-provoking questions about the 'gatekeeping' role of clinicians in recruitment.

Mainstreaming genomics: training experience of hospital medical officers at the Royal Melbourne Hospital.

The rapid evolution and wide applicability of genomic testing means that medical practitioners outside the field are not appropriately skilled to understand the utility of genomics for their patients. Rotating junior doctors through genomic medicine provides them with the hands-on experience necessary to understand the complexities in this field. In this study, we analysed the training experience of 12 hospital medical officers who rotated through genomic medicine at the Royal Melbourne Hospital. Here, we demonstrate that immersion in clinical genomics aids in mainstreaming genomics knowledge.

Social media usage in family communication about genetic information: 'I no longer speak with my sister but she needed to know'.

The use of social media has become a ubiquitous form of communication. Little is known about whether social media is used in families to assist with the communication of genetic information. This study aimed to understand if and why individuals use social media to communicate genetic information to at-risk relatives. Individuals with either a pathogenic variant in a cancer-predisposing gene or a heterozygous pathogenic variant in an autosomal or X-linked recessive gene were surveyed about communicating genetic information to their at-risk relatives and their use of social media to assist this process. Surveys were sent to 323 individuals from a reproductive carrier screening program and 250 individuals from a familial cancer center. The 128 responses (response rate 25.2%) showed that while most participants (79.0%) did not use social media to communicate genetic information, those that did use social media (21.0%) found it to be helpful as it was easy, accessible and allowed individuals to overcome communication barriers. Genetic professionals should be aware that social media is being used by individuals to assist family communication about genetic information and should discuss this method of communication with individuals who are faced with communicating genetic information with their family.

Single-cell RNA-sequencing reveals transcriptional dynamics of estrogen-induced dysplasia in the ovarian surface epithelium.

Estrogen therapy increases the risk of ovarian cancer and exogenous estradiol accelerates the onset of ovarian cancer in mouse models. Both in vivo and in vitro, ovarian surface epithelial (OSE) cells exposed to estradiol develop a subpopulation that loses cell polarity, contact inhibition, and forms multi-layered foci of dysplastic cells with increased susceptibility to transformation. Here, we use single-cell RNA-sequencing to characterize this dysplastic subpopulation and identify the transcriptional dynamics involved in its emergence. Estradiol-treated cells were characterized by up-regulation of genes associated with proliferation, metabolism, and survival pathways. Pseudotemporal ordering revealed that OSE cells occupy a largely linear phenotypic spectrum that, in estradiol-treated cells, diverges towards cell state consistent with the dysplastic population. This divergence is characterized by the activation of various cancer-associated pathways including an increase in Greb1 which was validated in fallopian tube epithelium and human ovarian cancers. Taken together, this work reveals possible mechanisms by which estradiol increases epithelial cell susceptibility to tumour initiation.

"I need to know if I'm going to die young": Adolescent and young adult experiences of genetic testing for Li-Fraumeni syndrome.

PURPOSE: This study explored the genetic testing experiences of adolescents and young adults (AYAs; aged 15-39 years) with, or at 50% risk of, an early onset cancer predisposition syndrome: Li-Fraumeni syndrome (LFS). DESIGN: We used interpretive description and conducted semi-structured interviews with 30 AYAs (mean age 25.5 years): 26 with LFS and four at 50% risk. Findings were developed using team-based, inductive thematic analysis. FINDINGS: Participants reported genetic testing uptake to reduce uncertainty about their gene status and to access cancer risk management. Learning their gene status, however, introduced a new uncertainty about living with high multi-organ cancer risk. Participants preoccupied with surviving cancer during diagnostic testing underestimated the implications of LFS. Reliance on family at this life stage complicated decision-making for genetic testing, especially among adolescents. CONCLUSION: AYAs undergoing genetic testing for LFS have unique support needs based on their life stage and require developmentally appropriate psychosocial care.

Health professionals' practice for young people with, or at risk of, Li-Fraumeni syndrome: An Australasian survey.

Li-Fraumeni syndrome (LFS), a rare cancer syndrome caused by pathogenic germline variants in TP53, has serious implications for adolescents and young adults (AYAs; aged 15-39 years). The early-onset and multi-organ cancer risk associated with LFS means health professionals must concurrently contend with the developmental needs of individuals who are diagnosed from a young age, and recent changes in practice due to advances in whole-body cancer surveillance. To help understand how current practice meets the developmental needs of AYAs with, or at risk of, LFS, we conducted a national online survey to explore the experiences of health professionals who care for this population in Australia and New Zealand. Forty-three respondents completed the survey (56% genetic counselors), one-third of whom had facilitated predictive TP53 testing for minors (n = 14/43, 33%). In hypothetical scenarios describing 15-year-olds eligible for predictive TP53 testing, respondents were more supportive of testing for emotionally mature compared to immature minors (p = .009); and more supportive of adolescent wishes compared to parental wishes for testing (p = .020) when families held discordant views on testing. Genetic health professionals were more likely than oncology health professionals to address psychological (p = .017) and information needs about reproductive options for LFS during consultations than to refer them on (p = .004). All respondents supported comprehensive risk management for LFS, but noted important medical, logistical, and psychosocial limitations for AYAs. This study offers valuable insight into developmentally appropriate practices of Australasian health professionals who care for AYAs with, or at risk of, LFS. These findings suggest they may foster the autonomy of minors undergoing predictive TP53 genetic testing and be supportive of new whole-body risk management guidelines.

Men's experiences of recontact about a potential increased risk of prostate cancer due to Lynch Syndrome: "Just another straw on the stack".

The practice of recontacting patients to provide new health information is becoming increasingly common in clinical genetics, despite the limited research to evidence the patient experience. We explored how men with Lynch Syndrome (LS) understand and experience being recontacted about a potential increased risk of prostate cancer. Sixteen men with LS (Meanage 51 years) were recruited from an Australian screening study to undergo a semi-structured interview. A modified grounded theory approach was used to guide data collection and thematic analysis. Qualitative coding was shared by the research team to triangulate analysis. The practice of recontact was viewed by participants as acceptable and was associated with minimal emotional distress. The majority of men understood that they may be above population risk of prostate cancer, although evidence was still emerging. Men reported high engagement with personal and familial health, including regular screening practices and familial risk communication. Findings suggest that men's carrier status and beliefs about the actionability of the new cancer risk information influence their response to recontact. Recontact practices that include the offer of risk management strategies may lead to improved patient outcomes (e.g., reduced cancer worry and increased health engagement), if perceived as valuable by recipients.

Making Sense of SNPs: Women's Understanding and Experiences of Receiving a Personalized Profile of Their Breast Cancer Risks.

Genome wide association studies have identified a number of common genetic variants - single nucleotide polymorphisms (SNPs) - that combine to increase breast cancer risk. SNP profiling may enhance the accuracy of risk assessment and provides a personalized risk estimate. SNP testing for breast cancer risks may supplement other genetic tests in the future, however, before it can be implemented in the clinic we need to know how it will be perceived and received. Semi-structured qualitative interviews were conducted with 39 women who had previously had a breast cancer diagnosis and undergone BRCA1/2 testing, participated in the Variants in Practice (ViP) study and received personalized risk (SNP) profiles. Interviews explored their understanding and experiences of receiving this SNP information. Women reported feeling positive about receiving their personalized risk profile, because it: provided an explanation for their previous diagnosis of cancer, vindicated previous risk management decisions and clarified their own and other family members' risks. A small group was initially shocked to learn of the increased risk of a second primary breast cancer. This study suggests that the provision of personalized risk information about breast cancer generated by SNP profiling is understood and well received. However, a model of genetic counseling that incorporates monogenic and polygenic genetic information will need to be developed prior to clinical implementation.

Divergence times and the evolution of morphological complexity in an early land plant lineage (Marchantiopsida) with a slow molecular rate.

We present a complete generic-level phylogeny of the complex thalloid liverworts, a lineage that includes the model system Marchantia polymorpha. The complex thalloids are remarkable for their slow rate of molecular evolution and for being the only extant plant lineage to differentiate gas exchange tissues in the gametophyte generation. We estimated the divergence times and analyzed the evolutionary trends of morphological traits, including air chambers, rhizoids and specialized reproductive structures. A multilocus dataset was analyzed using maximum likelihood and Bayesian approaches. Relative rates were estimated using local clocks. Our phylogeny cements the early branching in complex thalloids. Marchantia is supported in one of the earliest divergent lineages. The rate of evolution in organellar loci is slower than for other liverwort lineages, except for two annual lineages. Most genera diverged in the Cretaceous. Marchantia polymorpha diversified in the Late Miocene, giving a minimum age estimate for the evolution of its sex chromosomes. The complex thalloid ancestor, excluding Blasiales, is reconstructed as a plant with a carpocephalum, with filament-less air chambers opening via compound pores, and without pegged rhizoids. Our comprehensive study of the group provides a temporal framework for the analysis of the evolution of critical traits essential for plants during land colonization.

MD/PhD Training in Canada: Results from a national trainee and program director review.

PURPOSE: There has been limited examination of clinician scientist training in Canada, particularly regarding training integration and funding. This study assessed program structure, funding, tuition and mentorship structures available at Canadian MD/PhD programs. METHODS: Clinician Investigator Trainee Association of Canada administered an anonymous survey to current trainees and program directors that captured program structure, trainee funding, tuition and mentorship opportunities and needs across institutions. RESULTS: In June 2015, 101/228 (44%) trainees and 9/13 (69%) program directors completed the online survey. In all programs, students completed the PhD degree prior to clerkship training. Seven programs offered research training upon completion of pre-clerkship, four offered concurrent clinical and research training, and three offered alternative structures. Nine held seminars exposing students to clinical and research integration and two offered clinician scientist skills courses. Stipend funding and tuition varied, especially during clinical training years. Regarding mentorship, all programs held regular meetings, though eight programs do not have formal mentorship opportunities. Both trainees and program directors identified the need for further career planning and development support as a student priority. CONCLUSION: MD/PhD programs varied by program structure, funding, tuition and mentorship opportunities. Mechanisms to share and spread program innovations should be instated. Students may benefit from concurrent research and clinical training as well as courses specific to clinician scientist skill development. Decreasing debt burden may attract and retain trainees in this demanding path. To ensure mentorship programs align with trainee priorities, program directors should directly collaborate with students in their development and evaluation.

Population-based carrier screening for cystic fibrosis: a systematic review of 23 years of research.

Cystic fibrosis is the most common severe autosomal recessive disease, with a prevalence of 1 in 2,500-3,500 live births and a carrier frequency of 1 in 25 among Northern Europeans. Population-based carrier screening for cystic fibrosis has been possible since CFTR, the disease-causing gene, was identified in 1989. This review provides a systematic evaluation of the literature from the past 23 years on population-based carrier screening for cystic fibrosis, focusing on the following: uptake of testing; how to offer screening; attitudes, opinions, and knowledge; factors influencing decision making; and follow-up after screening. Recommendations are given for the implementation and evaluation of future carrier-screening programs.