An update on ECARUCA,the European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations

The European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations (ECARUCA, www.ecaruca.net) is an online database initiated in 2003 that collects and provides detailed, curated clinical and molecular information on rare unbalanced chromosome aberrations. ECARUCA now contains over 4800 cases with a total of more than 6600 genetic aberrations and has over 3000 account holders worldwide. Recently, the ECARUCA web site was renewed, including the presentation of interesting case reports in collaboration with the European Journal of Medical Genetics. This article gives an overview of the current status and future plans of the online ECARUCA database.     

Correlates of psychosocial well-being among overweight adolescents: the role of the family

An ethnically diverse sample of at-risk-for-overweight and overweight youths (body mass index greater than the 85th percentile for age and gender; n = 667 male participants, and n = 684 female participants) completed a school-based survey measuring family variables (connectedness, mealtime environment, and weight commentary), psychosocial well-being (depressed mood, body satisfaction, and self-esteem), and unhealthy weight-control behaviors; all measures were assessed concurrently. Hierarchical linear regression analyses revealed that measures of general family connectedness, priority of family meals, and positive mealtime environment were significantly positively associated with psychological well-being and inversely associated with depressive symptoms and unhealthy weight-control behaviors. Familial weight commentary (i.e., weight-based teasing and parental encouragement to diet) was associated with many indicators of poor psychological health. The authors conclude that greater psychosocial well-being and fewer unhealthy weight-control behaviors are associated with making family time at meals a priority, creating a positive mealtime atmosphere, and refraining from weight commentary.     

Setting priorities in global child health research investments: assessment of principles and practice

This article reviews theoretical and practical approaches for setting priorities in global child health research investments. It also provides an overview of previous attempts to develop appropriate tools and methodologies to define priorities in health research investments. A brief review of the most important theoretical concepts that should govern priority setting processes is undertaken, showing how different perspectives, such as medical, economical, legal, ethical, social, political, rational, philosophical, stakeholder driven, and others will necessarily conflict each other in determining priorities. We specially address present research agenda in global child health today and how it relates to United Nation's (UN) Millennium Development Goal 4, which is to reduce child mortality by two-thirds between 1990 and 2015. The outcomes of these former approaches are evaluated and their benefits and shortcomings presented. The case for a new methodology for setting priorities in health research investments is presented, as proposed by Child Health and Nutrition Research Initiative, and a need for its implementation in global child health is outlined. A transdisciplinary approach is needed to address all the perspectives from which investments into health research can be seen as priorities. This prioritization requires a process that is transparent, systematic, and that would take into account many perspectives and build on advantages of previous approaches.     

Y-chromosome short tandem repeat DYS458.2 non-consensus alleles occur independently in both binary haplogroups J1-M267 and R1b3-M405

Aim

To determine the human Y-chromosome haplogroup backgrounds of non-consensus DYS458.2 short tandem repeat alleles and evaluate their phylogenetic substructure and frequency in representative samples from the Middle East, Europe, and Pakistan.

Methods

Molecular characterization of lineages was achieved using a combination of Y-chromosome haplogroup defining binary polymorphisms and up to 37 short tandem repeat loci, including DYS388 to construct haplotypes. DNA sequencing of the DYS458 locus and median-joining network analyses were used to evaluate Y-chromosome lineages displaying the DYS458.2 motif.

Results

We showed that the DYS458.2 allelic innovation arose independently on at least two distinctive binary haplogroup backgrounds and possibly a third as well. The partial allele length pattern was fixed in all haplogroup J1 chromosomes examined, including its known rare sub-haplogroups. Within the alternative R1b3 associated M405 defined sub-haplogroup, both DYS458.0 and DYS458.2 allele classes occurred. A single chromosome also allocated to the R1b3-M269*(xM405) classification. The physical position of the partial insertion/deletion occurrence within the normal tetramer tract differed distinctly in each haplogroup context.

Conclusions

While unusual DYS458.2 alleles are informative, additional information for other linked polymorphic loci is required when using such non-conforming alleles to infer haplogroup background and common ancestry.Ever since Y-chromosome specific polymorphic short tandem repeat (Y-STR) or microsatellite loci were first developed as practical polymerase chain reaction (PCR)-based amplification assays in the early 1990s (1), these loci have become important reagents in the molecular genetic analysis of the non-recombining portion of this paternally transmitted haploid chromosome. Currently, several hundred potentially polymorphic short tandem repeat loci have been recognized on the human Y-chromosome (2). This abundance, combined with their high variability, makes them useful for studies of population substructure (3), temporality of population dynamics (4), forensic identification (5), and genealogical investigations (6), although homoplasy (ie, recurrent mutation) phenomena may alter true genetic distance, thereby creating potentially false evidence of actual affinity (7,8). Their development and extensive use have been facilitated, in part, by the availability of well-calibrated, standardized commercial multiplex PCR kits, compatible with capillary electrophoresis platforms and quantitative fragment sizing algorithms. These validated kits, that contain anywhere from 12-15 different Y-STR loci, are becoming more widely used throughout the genetic analysis community and will generate a substantial amount of population data for the particular loci involved. One such locus contained in the AmpFLSTR Y filer PCR amplification kit (Applied Biosystems, Foster City, CA, USA) is DYS458 (9) that is composed of a polymorphic tetra (GAAA) nucleotide repeat motif. Interestingly, null alleles at this locus have been associated with amelogenin allele negative men, caused by large scale (>1 Mb) deletions (10) that often correspond to specific Y-chromosome binary haplogroup affiliation (11) suggestive of common ancestry. Additionally, unusual partial DYS458.2 insertion/deletion alleles have been reported in Tunisian Berbers (12).The ability of Y-chromosome STR diversification to help our understanding of population substructure and group membership is fundamentally linked to our knowledge regarding the molecular resolution of the haploid binary marker defined phylogeny. During the past 10 years, significant progress in reconstructing the detailed branching order of the gene tree topology for the non-recombining portion of the Y-chromosome (13,14) has paralleled the developing understanding and application of Y-STR loci. This binary haplogroup defined gene tree is the scaffold upon which all Y-STR data are partitioned (15). As suggested by de Knijff (16), Y-chromosomes identified by STRs are designated haplotypes. Y-chromosomes that are defined only by biallelic markers are called haplogroups or clades, and the combination of biallelic markers and Y-STRs are called lineages.The occasional occurrence of an unusually short Y-STR allele that has lost or dramatically reduced its mutagenicity (and hence has properties approaching those of an evolutionary stable binary marker) has lead to reliable clues of the authentic affinity of Y-STR haplotypes. Some examples of such uncommon “short” alleles include DYS390 in Australian haplogroup C chromosomes (17) and DYS388 in a subset of J1-M267 Turkish chromosomes (7). Reduced allelic variability at microsatellite loci also results from nucleotide substitutions within the usual repetitive elements (18). In a similar manner, non-consensus partial insertion/deletion events within the repeat motif of loci like DYS458 have the potential to provide clues to common Y-chromosome lineal ancestries within STR haplotype-based data sets. While Y-STR mutation rates are exceptionally high relative to binary mutations, network analysis (19) provides a useful technique to help disentangle complex multi-locus haplotype data and potentially identify chromosomes with distinctively different evolutionary histories.During the evaluation of potential patterns in Y-STR haplotypes characterized by up to 37 loci in data from 17 646 samples generated by the Sorenson Molecular Genealogy Foundation (SMGF), a subset of chromosomes characterized by the presence of atypical DYS458.2 alleles was selected for further scrutiny. This allelic designation style follows recommended guidelines (20) in which the 0.2 label denotes the presence of allele repeats of intermediate size, in addition to variation in numbers of typical repeats. Such partial sized alleles arise by insertion/deletion events most probably caused by slipped-strand mis-pairing events within the locus during spermatogenesis (21).The trinucleotide locus DYS388 that was also included in the SMGF data set played an important role in framing the course of this investigation. This locus is known to deviate from the stepwise mutational process when the allele frequency spectrum is analyzed (22). Subsequently, the larger DYS388 allele size category in the bimodal distribution was shown to be affiliated with samples with geographic ancestry in the Middle East that displayed the derived allele for a binary marker (12f2.1) used to define haplogroup J (23) within the standardized nomenclature (24). While DYS388 short allele representatives are known to occur within a subset of J1-M267 derived chromosomes (7), the majority of haplogroup J1 representatives have DYS388 allele sizes ≥15 repeats (7,25,26). This article reports on the results of our explorations into haplogroup affiliations within DYS458.2 designated chromosomes from various European, Middle Eastern, and Pakistani populations.Although ambiguities caused by Y-STR homoplasmy can be mitigated by typing large numbers of such loci, especially in genealogical situations, this article illustrates how the intersection of binary haplogroups and Y-STR haplotypes in combination more clearly reveals authentic lineal relationships and underscores the vulnerability of using Y-STR data alone to infer common ancestry, even when unusual allelic variants are involved.     

Chromosomal reinsertion of broken RSS ends during T cell development

The V(D)J recombinase catalyzes DNA transposition and translocation both in vitro and in vivo. Because lymphoid malignancies contain chromosomal translocations involving antigen receptor and protooncogene loci, it is critical to understand the types of "mistakes" made by the recombinase. Using a newly devised assay, we characterized 48 unique TCRbeta recombination signal sequence (RSS) end insertions in murine thymocyte and splenocyte genomic DNA samples. Nearly half of these events targeted "cryptic" RSS-like elements. In no instance did we detect target-site duplications, which is a hallmark of recombinase-mediated transposition in vitro. Rather, these insertions were most likely caused by either V(D)J recombination between a bona fide RSS and a cryptic RSS or the insertion of signal circles into chromosomal loci via a V(D)J recombination-like mechanism. Although wild-type, p53, p53 x scid, H2Ax, and ATM mutant thymocytes all showed similar levels of RSS end insertions, core-RAG2 mutant thymocytes showed a sevenfold greater frequency of such events. Thus, the noncore domain of RAG2 serves to limit the extent to which the integrity of the genome is threatened by mistargeting of V(D)J recombination.     

Adiponectin Is a Candidate Biomarker of Lower Extremity Bone Density in Men With Chronic Spinal Cord Injury

Adipose tissue is a major regulator of bone metabolism and in the general population obesity is associated with greater bone mineral density (BMD). However, bone‐fat interactions are multifactorial, and may involve pathways that influence both bone formation and resorption with competing effects on the skeleton. One such pathway involves adipocyte production of adipokines that regulate bone metabolism. In this study we determined the association between BMD, walking status, and circulating adipokines (adiponectin and leptin) in 149 men with chronic spinal cord injury (SCI). Although adipokine levels did not vary significantly based on walking status, there was a significant inverse association between adiponectin and BMD in wheelchair users independent of body composition. We found no association between adiponectin and BMD in the walkers and no association between leptin and BMD in either group. These findings suggest that for subjects with chronic SCI, walking may mitigate the effect of adiponectin mediated bone loss. For wheelchair users, adipose‐derived adiponectin may contribute to SCI‐induced osteoporosis because the osteoprotective benefits of obesity appear to require mechanical loading during ambulation. © 2014 American Society for Bone and Mineral Research.     

The past,present, and future of telemedicine for Parkinson's disease

Travel distance, growing disability, and uneven distribution of doctors limit access to care for most Parkinson's disease (PD) patients worldwide. Telemedicine, the use of telecommunications technology to deliver care at a distance, can help overcome these barriers. In this report, we describe the past, present, and likely future applications of telemedicine to PD. Historically, telemedicine has relied on expensive equipment to connect single patients to a specialist in pilot programs in wealthy nations. As the cost of video conferencing has plummeted, these efforts have expanded in scale and scope, now reaching larger parts of the world and extending the focus from care to training of remote providers. Policy, especially limited reimbursement, currently hinders the growth and adoption of these new care models. As these policies change and technology advances and spreads, the following will likely develop: integrated care networks that connect patients to a wide range of providers; education programs that support patients and health care providers; and new research applications that include remote monitoring and remote visits. Together, these developments will enable more individuals with PD to connect to care, increase access to expertise for patients and providers, and allow more‐extensive, less‐expensive participation in research. © 2014 International Parkinson and Movement Disorder Society