MSY Breakpoint Mapper, a database of sequence-tagged sites useful in defining naturally occurring deletions in the human Y chromosome

Y chromosome deletions arise frequently in human populations, where they cause sex reversal and Turner syndrome and predispose individuals to infertility and germ cell cancer. Knowledge of the nucleotide sequence of the male-specific region of the Y chromosome (MSY) makes it possible to precisely demarcate such deletions and the repertoires of genes lost, offering insights into mechanisms of deletion and the molecular etiologies of associated phenotypes. Such deletion mapping is usually conducted using polymerase chain reaction (PCR) assays for the presence or absence of a series of Y-chromosomal DNA markers, or sequence-tagged sites (STSs). In the course of mapping intact and aberrant Y chromosomes during the past two decades, we and our colleagues have developed robust PCR assays for 1287 Y-specific STSs. These PCR assays amplify 1698 loci at an average spacing of <14 kb across the MSY euchromatin. To facilitate mapping of deletions, we have compiled a database of these STSs, MSY Breakpoint Mapper (http://breakpointmapper.wi.mit.edu/). When queried, this online database provides regionally targeted catalogs of STSs and nearby genes. MSY Breakpoint Mapper is useful for efficiently and systematically defining the breakpoint(s) of virtually any naturally occurring Y chromosome deletion.National Institutes of Health (U.S.)Howard Hughes Medical Institut

Chimpanzee and Human Y Chromosomes Are Remarkably Divergent in Structure and Gene Content

LetterThe human Y chromosome began to evolve from an autosome hundreds of millions of years ago, acquiring a sex-determining function and undergoing a series of inversions that suppressed crossing over with the X chromosome[1, 2]. Little is known about the recent evolution of the Y chromosome because only the human Y chromosome has been fully sequenced. Prevailing theories hold that Y chromosomes evolve by gene loss, the pace of which slows over time, eventually leading to a paucity of genes, and stasis [3, 4]. These theories have been buttressed by partial sequence data from newly emergent plant and animal Y chromosomes [5, 6, 7, 8], but they have not been tested in older, highly evolved Y chromosomes such as that of humans. Here we finished sequencing of the male-specific region of the Y chromosome (MSY) in our closest living relative, the chimpanzee, achieving levels of accuracy and completion previously reached for the human MSY. By comparing the MSYs of the two species we show that they differ radically in sequence structure and gene content, indicating rapid evolution during the past 6 million years. The chimpanzee MSY contains twice as many massive palindromes as the human MSY, yet it has lost large fractions of the MSY protein-coding genes and gene families present in the last common ancestor. We suggest that the extraordinary divergence of the chimpanzee and human MSYs was driven by four synergistic factors: the prominent role of the MSY in sperm production, ‘genetic hitchhiking’ effects in the absence of meiotic crossing over, frequent ectopic recombination within the MSY, and species differences in mating behaviour. Although genetic decay may be the principal dynamic in the evolution of newly emergent Y chromosomes, wholesale renovation is the paramount theme in the continuing evolution of chimpanzee, human and perhaps other older MSYs.National Institutes of Health (U.S.)Howard Hughes Medical Institut

Patient perspectives of managing fatigue in ankylosing spondylitis, and views on potential interventions: a qualitative study

&lt;p&gt;Background: Fatigue is a major component of living with ankylosing spondylitis (AS), though it has been largely over-looked, and currently there are no specific agreed management strategies.&lt;/p&gt; &lt;p&gt;Methods: This qualitative exploratory study involved participants who are members of an existing population-based ankylosing spondylitis (PAS) cohort. Participants residing in South West Wales were invited to participate in a focus group to discuss; (1) effects of fatigue, (2) self-management strategies and (3) potential future interventions. The focus groups were audio-recorded and the transcripts were analysed using thematic analysis.&lt;/p&gt; &lt;p&gt;Results: Participants consisted of 3 males/4 females (group 1) and 4 males/3 females (group 2), aged between 35 and 73 years (mean age 53 years). Three main themes were identified: (1) The effects of fatigue were multi-dimensional with participants expressing feelings of being ‘drained’ (physical), ‘upset’ (emotional) and experiencing ‘low-mood’ (psychological); (2) The most commonly reported self-management strategy for fatigue was a balanced combination of activity (exercise) and rest. Medication was reluctantly taken due to side-effects and worries over dependency; (3) Participants expressed a preference for psychological therapies rather than pharmacological for managing fatigue. Information on Mindfulness-Based Stress Reduction (MBSR) was received with interest, with recommendations for delivery in a group format with the option of distance-based delivery for people who were not able to attend a group course.&lt;/p&gt; &lt;p&gt;Conclusions: Patients frequently try and manage their fatigue without any formal guidance or support. Our research indicates there is a need for future research to focus on psychological interventions to address the multi-faceted aspects of fatigue in AS.&lt;/p&gt

Intrachromosomal homologous recombination between inverted amplicons on opposing Y-chromosome arms

Amplicons – large, nearly identical repeats in direct or inverted orientation – are abundant in the male-specific region of the human Y chromosome (MSY) and provide targets for intrachromosomal non-allelic homologous recombination (NAHR). Thus far, NAHR events resulting in deletions, duplications, inversions, or isodicentric chromosomes have been reported only for amplicon pairs located exclusively on the short arm (Yp) or the long arm (Yq). Here we report our finding of four men with Y chromosomes that evidently formed by intrachromosomal NAHR between inverted repeat pairs comprising one amplicon on Yp and one amplicon on Yq. In two men with spermatogenic failure, sister-chromatid crossing-over resulted in pseudoisoYp chromosome formation and loss of distal Yq. In two men with normal spermatogenesis, intrachromatid crossing-over generated pericentric inversions. These findings highlight the recombinogenic nature of the MSY, as intrachromosomal NAHR occurs for nearly all Y-chromosome amplicon pairs, even those located on opposing chromosome arms.National Institutes of Health (U.S.)Netherlands Organization for Scientific ResearchAcademic Medical Center (University of Amsterdam

Nurturing Societal Values in and Through Health Innovations; Comment on “What Health System Challenges Should Responsible Innovation in Health Address?”

Aligning innovation processes in healthcare with health system demands is a societal objective, not always achieved. In line with earlier contributions, Lehoux et al outline priorities for research, public communication, and policy action to achieve this objective. We endorse setting these priorities, while also highlighting a ‘commitment gap’ in collectively addressing system-level challenges. To acknowledge that stakeholders engaged in dialogue with one another are addressing the commitment gap is not a small step but a giant leap towards realising a socially responsible innovation agenda. Translating system-level demand signals into innovation opportunities is, therefore, the task-cum-art of all stakeholders, one that often prompts them to innovate how they deal with innovations

Recombination dynamics of a human Y-chromosomal palindrome:rapid GC-biased gene conversion, multi-kilobase conversion tracts, and rare inversions

The male-specific region of the human Y chromosome (MSY) includes eight large inverted repeats (palindromes) in which arm-to-arm similarity exceeds 99.9%, due to gene conversion activity. Here, we studied one of these palindromes, P6, in order to illuminate the dynamics of the gene conversion process. We genotyped ten paralogous sequence variants (PSVs) within the arms of P6 in 378 Y chromosomes whose evolutionary relationships within the SNP-defined Y phylogeny are known. This allowed the identification of 146 historical gene conversion events involving individual PSVs, occurring at a rate of 2.9-8.4×10(-4) events per generation. A consideration of the nature of nucleotide change and the ancestral state of each PSV showed that the conversion process was significantly biased towards the fixation of G or C nucleotides (GC-biased), and also towards the ancestral state. Determination of haplotypes by long-PCR allowed likely co-conversion of PSVs to be identified, and suggested that conversion tract lengths are large, with a mean of 2068 bp, and a maximum in excess of 9 kb. Despite the frequent formation of recombination intermediates implied by the rapid observed gene conversion activity, resolution via crossover is rare: only three inversions within P6 were detected in the sample. An analysis of chimpanzee and gorilla P6 orthologs showed that the ancestral state bias has existed in all three species, and comparison of human and chimpanzee sequences with the gorilla outgroup confirmed that GC bias of the conversion process has apparently been active in both the human and chimpanzee lineages

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STUDY QUESTION: What is the cost-effectiveness of in vitro fertilization(IVF) with conventional ovarian stimulation, single embryotransfer (SET) and subsequent cryocycles or IVF in a modified natural cycle (MNC) compared with intrauterine insemination with controlled ovarian hyperstimulation (IUI-COH) as a first-line treatment in couples with unexplained subfertility and an unfavourable prognosis on natural conception?. SUMMARY ANSWER: Both IVF strategies are significantly more expensive when compared with IUI-COH, without being significantly more effective. In the comparison between IVF-MNC and IUI-COH, the latter is the dominant strategy. Whether IVF-SET is cost-effective depends on society's willingness to pay for an additional healthy child. WHAT IS KNOWN ALREADY: IUI-COH and IVF, either after conventional ovarian stimulation or in a MNC, are used as first-line treatments for couples with unexplained or mild male subfertility. As IUI-COH is less invasive, this treatment is usually offered before proceeding to IVF. Yet, as conventional IVF with SET may lead to higher pregnancy rates in fewer cycles for a lower multiple pregnancy rate, some have argued to start with IVF instead of IUI-COH. In addition, IVF in the MNC is considered to be a more patient friendly and less costly form of IVF. STUDY DESIGN, SIZE, DURATION: We performed a cost-effectiveness analysis alongside a randomized noninferiority trial. Between January 2009 and February 2012, 602 couples with unexplained infertility and a poor prognosis on natural conception were allocated to three cycles of IVF-SET including frozen embryo transfers, six cycles of IVF-MNC or six cycles of IUI-COH. These couples were followed until 12 months after randomization. PARTICIPANTS/MATERIALS, SETTING, METHODS: We collected data on resource use related to treatment, medication and pregnancy from the case report forms. We calculated unit costs from various sources. For each of the three strategies, we calculated the mean costs and effectiveness. Incremental cost-effectiveness ratios (ICER) were calculated for IVF-SET compared with IUI-COH and for IVF-MNC compared with IUI-COH. Nonparametric bootstrap resampling was used to investigate the effect of uncertainty in our estimates. MAIN RESULTS AND THE ROLE OF CHANCE: There were 104 healthy children (52%) born in the IVF-SET group, 83 (43%) the IVF-MNC group and 97 (47%) in the IUI-COH group. The mean costs per couple were (sic)7187 for IVF-SET, (sic)8206 for IVF-MNC and (sic)5070 for IUI-COH. Compared with IUI-COH, the costs for IVF-SET and IVF-MNC were significantly higher (mean differences (sic)2117; 95% CI: (sic)1544-(sic)2657 and (sic)3136, 95% CI: (sic)2519-(sic)3754, respectively). The ICER for IVF-SET compared with IUI-COH was (sic)43 375 for the birth of an additional healthy child. In the comparison of IVF-MNC to IUI-COH, the latter was the dominant strategy, i.e. more effective at lower costs. LIMITATIONS, REASONS FOR CAUTION: We only report on direct health care costs. The present analysis is limited to 12 months. WIDER IMPLICATIONS OF THE FINDINGS: Since we found no evidence in support of offering IVF as a first-line strategy in couples with unexplained and mild subfertility, IUI-COH should remain the treatment of first choice

What impact does written information about fatigue have on patients with autoimmune rheumatic diseases? : Findings from a qualitative study

Objectives Although fatigue is a common symptom for people with rheumatic diseases, limited support is available. This study explored the impact of written information about fatigue, focusing on a booklet, Fatigue and arthritis. Methods Thirteen patients with rheumatic disease and fatigue were recruited purposively from a rheumatology outpatient service. They were interviewed before and after receiving the fatigue booklet. Two patients, plus six professionals with relevant interests, participated in a focus group. Transcripts were analysed thematically and a descriptive summary was produced. Results Interviewees consistently reported that fatigue made life more challenging, and none had previously received any support to manage it. Reflecting on the booklet, most said that it had made a difference to how they thought about fatigue, and that this had been valuable. Around half also said that it had affected, or would affect, how they managed fatigue. No one reported any impact on fatigue itself. Comments from interviewees and focus group members alike suggested that the research process may have contributed to the changes in thought and behaviour reported. Its key contributions appear to have been: clarifying the booklet's relevance; prompting reflection on current management; and introducing accountability. Conclusions This study indicated that written information can make a difference to how people think about fatigue and may also prompt behaviour change. However, context appeared to be important: it seems likely that the research process played a part and that the impact of the booklet may have been less if read in isolation. Aspects of the research appearing to facilitate impact could be integrated into routine care, providing a pragmatic (relatively low-cost) response to an unmet need

The importance of genetic parenthood for infertile men and women

STUDY QUESTION: Do men and women beginning to attend a fertility clinic prefer genetic over non-genetic parenthood? SUMMARY ANSWER: Nearly, all infertile men and women prefer genetic parenthood. WHAT IS KNOWN ALREADY: Clinicians assume that all infertile couples prefer genetic parenthood over non-genetic parenthood and, therefore, consider treatments with donor gametes an option of last resort. Previous studies of the desire for parenthood identified 30 motivations for genetic parenthood, and 51 motivations for which having a genetically related child is not strictly necessary but might be deemed required. The exact strength of the preference of infertile men and women for genetic parenthood remains unclear, as does the importance of the various motivations. STUDY DESIGN, SIZE, DURATION: A questionnaire was developed based on a literature review. It was assessed by professionals and pilot tested among patients. The coded paper-pencil questionnaire was disseminated among both partners of 201 heterosexual infertile couples after their first consultation at one of two Belgian fertility clinics between October 2015 and May 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: The survey addressed: (i) the preference for genetic parenthood for themselves and for their partner, (ii) the importance of 30 motivations for genetic parenthood and (iii) the importance of 51 other motivations for parenthood and whether these motivations require being the genetic parent of their child to be fulfilled. To simplify presentation of the results, all 81 motivations were grouped into reliable categories of motivations using psychometric analyses. MAIN RESULTS AND THE ROLE OF CHANCE: The survey was completed by 104 women and 91 men (response rate: 49%). Almost all respondents (98%) favored genetic over non-genetic parenthood for both their partner and themselves. One-third of the respondents stated they only wanted to parent their own genetically related child. Achieving genetic parenthood for their partner was considered significantly more important than achieving genetic parenthood for themselves. Within couples, men had a stronger preference for genetic parenthood (P = 0.004), but this was not significant after correction for educational level, which was significantly associated with the preference of both men and women. The 30 motivations for becoming a genetic parent clustered into 11 categories of which 'to experience a natural process' was deemed most important. The 51 motivations for becoming a parent for which having a genetically related child is not strictly necessary clustered into 14 categories of which 'to contribute to a child's well-being' and 'to experience the love of a child' were most important. Respondents deemed they would need to be the genetic parent of their child to fulfill nearly all their motivations for parenthood. LIMITATIONS REASONS FOR CAUTION: We included couples that visited the fertility clinic for the first time, and the preference for genetic parenthood might change throughout a fertility treatment trajectory. Moreover, what prospective parents expect to be important for their future well-being might not really define parents' well-being. WIDER IMPLICATIONS OF THE FINDINGS: The presumed preference of couples for genetic parenthood was confirmed. Resistance against using donor gametes is more likely among lower educated individuals. Researching whether non-genetic parents actually feel they cannot fulfill the 51 motivations for parenthood, could be a basis for developing patient informatio