Identification of rare de novo epigenetic variations in congenital disorders

Certain human traits such as neurodevelopmental disorders (NDs) and congenital anomalies (CAs) are believed to be primarily genetic in origin. However, even after whole-genome sequencing (WGS), a substantial fraction of such disorders remain unexplained. We hypothesize that some cases of ND-CA are caused by aberrant DNA methylation leading to dysregulated genome function. Comparing DNA methylation profiles from 489 individuals with ND-CAs against 1534 controls, we identify epivariations as a frequent occurrence in the human genome. De novo epivariations are significantly enriched in cases, while RNAseq analysis shows that epivariations often have an impact on gene expression comparable to loss-of-function mutations. Additionally, we detect and replicate an enrichment of rare sequence mutations overlapping CTCF binding sites close to epivariations, providing a rationale for interpreting non-coding variation. We propose that epivariations contribute to the pathogenesis of some patients with unexplained ND-CAs, and as such likely have diagnostic relevance.The authors are grateful to the patients and families who participated in this study and to the collaborators who supported patient recruitment. This work was supported by NIH grant HG006696 and research grant 6-FY13-92 from the March of Dimes to A.J.S., grant HL098123 to B.D.G. and A.J.S., Gulbenkian Programme for Advanced Medical Education and the Portuguese Foundation for Science and Technology (SFRH/BDINT/51549/ 2011, PIC/IC/83026/2007, PIC/IC/83013/2007, SFRH/BD/90167/2012, Portugal) to P.M., F.L., and M.B., by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013) to P.M., a Beatriu de Pinos Postdoctoral Fellowship to R.S.J. (2011BP-A00515), and a Seaver Foundation fellowship to S.D.R. The views expressed are those of the authors and do not necessarily reflect those of the National Heart, Lung, and Blood Institute or the National Institutes of Health. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD018522. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai.The authors are grateful to the patients and families who participated in this study and to the collaborators who supported patient recruitment. This work was supported by NIH grant HG006696 and research grant 6-FY13-92 from the March of Dimes to A.J.S., grant HL098123 to B.D.G. and A.J.S., Gulbenkian Programme for Advanced Medical Education and the Portuguese Foundation for Science and Technology (SFRH/BDINT/51549/ 2011, PIC/IC/83026/2007, PIC/IC/83013/2007, SFRH/BD/90167/2012, Portugal) to P.M., F.L., and M.B., by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013) to P.M., a Beatriu de Pinos Postdoctoral Fellowship to R.S.J. (2011BP-A00515), and a Seaver Foundation fellowship to S.D.R. The views expressed are those of the authors and do not necessarily reflect those of the National Heart, Lung, and Blood Institute or the National Institutes of Health. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD018522. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai

A comparison of SNP and STR loci for delineating population structure and performing individual genetic assignment

<p>Abstract</p> <p>Background</p> <p>Technological advances have lead to the rapid increase in availability of single nucleotide polymorphisms (SNPs) in a range of organisms, and there is a general optimism that SNPs will become the marker of choice for a range of evolutionary applications. Here, comparisons between 300 polymorphic SNPs and 14 short tandem repeats (STRs) were conducted on a data set consisting of approximately 500 Atlantic salmon arranged in 10 samples/populations.</p> <p>Results</p> <p>Global F_STranged from 0.033-0.115 and -0.002-0.316 for the 14 STR and 300 SNP loci respectively. Global F_STwas similar among 28 linkage groups when averaging data from mapped SNPs. With the exception of selecting a panel of SNPs taking the locus displaying the highest global F_STfor each of the 28 linkage groups, which inflated estimation of genetic differentiation among the samples, inferred genetic relationships were highly similar between SNP and STR data sets and variants thereof. The best 15 SNPs (30 alleles) gave a similar level of self-assignment to the best 4 STR loci (83 alleles), however, addition of further STR loci did not lead to a notable increase assignment whereas addition of up to 100 SNP loci increased assignment.</p> <p>Conclusion</p> <p>Whilst the optimal combinations of SNPs identified in this study are linked to the samples from which they were selected, this study demonstrates that identification of highly informative SNP loci from larger panels will provide researchers with a powerful approach to delineate genetic relationships at the individual and population levels.</p

Genetic Control of Resistance to Trypanosoma brucei brucei Infection in Mice

Trypanosoma brucei are extracellular protozoa transmitted to mammalian host by the tsetse fly. They developed several mechanisms that subvert host's immune defenses. Therefore analysis of genes affecting host's resistance to infection can reveal critical aspects of host-parasite interactions. Trypanosoma brucei brucei infects many animal species including livestock, with particularly severe effects in horses and dogs. Mouse strains differ greatly in susceptibility to T. b. brucei. However, genes controlling susceptibility to this parasite have not been mapped. We analyzed the genetic control of survival after T. b. brucei infection using CcS/Dem recombinant congenic (RC) strains, each of which contains a different random set of 12.5% genes of their donor parental strain STS/A on the BALB/c genetic background. The RC strain CcS-11 is even more susceptible to parasites than BALB/c or STS/A. In F2 hybrids between BALB/c and CcS-11 we detected and mapped four loci, Tbbr1-4 (Trypanosoma brucei brucei response 1–4), that control survival after T. b. brucei infection. Tbbr1 (chromosome 3) and Tbbr2 (chromosome 12) have independent effects, Tbbr3 (chromosome 7) and Tbbr4 (chromosome 19) were detected by their mutual inter-genic interaction. Tbbr2 was precision mapped to a segment of 2.15 Mb that contains 26 genes

The association between rheumatoid arthritis and periodontal disease

Chronic, plaque-associated inflammation of the gingiva and the periodontium are among the most common oral diseases. Periodontitis (PD) is characterized by the inflammatory destruction of the periodontal attachment and alveolar bone, and its clinical appearance can be influenced by congenital as well as acquired factors. The existence of a rheumatic or other inflammatory systemic disease may promote PD in both its emergence and progress. However, there is evidence that PD maintains systemic diseases. Nevertheless, many mechanisms in the pathogenesis have not yet been examined sufficiently, so that a final explanatory model is still under discussion, and we hereby present arguments in favor of this. In this review, we also discuss in detail the fact that oral bacterial infections and inflammation seem to be linked directly to the etiopathogenesis of rheumatoid arthritis (RA). There are findings that support the hypothesis that oral infections play a role in RA pathogenesis. Of special importance are the impact of periodontal pathogens, such as Porphyromonas gingivalis on citrullination, and the association of PD in RA patients with seropositivity toward rheumatoid factor and the anti-cyclic citrullinated peptide antibody

Advances in understanding and treating ADHD

Attention deficit hyperactivity disorder (ADHD) is a neurocognitive behavioral developmental disorder most commonly seen in childhood and adolescence, which often extends to the adult years. Relative to a decade ago, there has been extensive research into understanding the factors underlying ADHD, leading to far more treatment options available for both adolescents and adults with this disorder. Novel stimulant formulations have made it possible to tailor treatment to the duration of efficacy required by patients, and to help mitigate the potential for abuse, misuse and diversion. Several new non-stimulant options have also emerged in the past few years. Among these, cognitive behavioral interventions have proven popular in the treatment of adult ADHD, especially within the adult population who cannot or will not use medications, along with the many medication-treated patients who continue to show residual disability

Pregnancy-related pelvic girdle pain: an update

A large number of scientists from a wide range of medical and surgical disciplines have reported on the existence and characteristics of the clinical syndrome of pelvic girdle pain during or after pregnancy. This syndrome refers to a musculoskeletal type of persistent pain localised at the anterior and/or posterior aspect of the pelvic ring. The pain may radiate across the hip joint and the thigh bones. The symptoms may begin either during the first trimester of pregnancy, at labour or even during the postpartum period. The physiological processes characterising this clinical entity remain obscure. In this review, the definition and epidemiology, as well as a proposed diagnostic algorithm and treatment options, are presented. Ongoing research is desirable to establish clear management strategies that are based on the pathophysiologic mechanisms responsible for the escalation of the syndrome's symptoms to a fraction of the population of pregnant women

The impact of diabetes on the pathogenesis of sepsis

Diabetes is associated with an increased susceptibility to infection and sepsis. Conflicting data exist on whether the mortality of patients with sepsis is influenced by the presence of diabetes, fuelling the ongoing debate on the benefit of tight glucose regulation in patients with sepsis. The main reason for which diabetes predisposes to infection appears to be abnormalities of the host response, particularly in neutrophil chemotaxis, adhesion and intracellular killing, defects that have been attributed to the effect of hyperglycaemia. There is also evidence for defects in humoral immunity, and this may play a larger role than previously recognised. We review the literature on the immune response in diabetes and its potential contribution to the pathogenesis of sepsis. In addition, the effect of diabetes treatment on the immune response is discussed, with specific reference to insulin, metformin, sulphonylureas and thiazolidinediones

Mapping and validation of a major QTL affecting resistance to pancreas disease (salmonid alphavirus) in Atlantic salmon (Salmo salar)

Pancreas disease (PD), caused by a salmonid alphavirus (SAV), has a large negative economic and animal welfare impact on Atlantic salmon aquaculture. Evidence for genetic variation in host resistance to this disease has been reported, suggesting that selective breeding may potentially form an important component of disease control. The aim of this study was to explore the genetic architecture of resistance to PD, using survival data collected from two unrelated populations of Atlantic salmon; one challenged with SAV as fry in freshwater (POP 1) and one challenged with SAV as post-smolts in sea water (POP 2). Analyses of the binary survival data revealed a moderate-to-high heritability for host resistance to PD in both populations (fry POP 1 h(2)~0.5; post-smolt POP 2 h(2)~0.4). Subsets of both populations were genotyped for single nucleotide polymorphism markers, and six putative resistance quantitative trait loci (QTL) were identified. One of these QTL was mapped to the same location on chromosome 3 in both populations, reaching chromosome-wide significance in both the sire- and dam-based analyses in POP 1, and genome-wide significance in a combined analysis in POP 2. This independently verified QTL explains a significant proportion of host genetic variation in resistance to PD in both populations, suggesting a common underlying mechanism for genetic resistance across lifecycle stages. Markers associated with this QTL are being incorporated into selective breeding programs to improve PD resistance