NNT pseudoexon activation as a novel mechanism for disease in two siblings with familial glucocorticoid deficiency

CONTEXT: Intronic DNA frequently encodes potential exonic sequences called pseudoexons. In recent years, mutations resulting in aberrant pseudoexon inclusion have been increasingly recognized to cause disease. OBJECTIVES: To find the genetic cause of familial glucocorticoid deficiency (FGD) in two siblings. PATIENTS: The proband and his affected sibling, from nonconsanguineous parents of East Asian and South African origin, were diagnosed with FGD at the ages of 21 and 8 months, respectively. DESIGN: Whole exome sequencing was performed on genomic DNA (gDNA) of the siblings. Variants in genes known to cause FGD were assessed for causality. Further analysis of gDNA and cDNA was performed by PCR/RT-PCR followed by automated Sanger sequencing. RESULTS: Whole exome sequencing identified a single, novel heterozygous variant (p.Arg71*) in nicotinamide nucleotide transhydrogenase (NNT) in both affected individuals. Follow-up cDNA analysis in the proband identified a 69-bp pseudoexon inclusion event, and Sanger sequencing of his gDNA identified a 4-bp duplication responsible for its activation. The variants segregated with the disease: p.Arg71* was inherited from the mother, the pseudoexon change was inherited from the father, and an unaffected sibling had inherited only the p.Arg71* variant. CONCLUSIONS: FGD in these siblings is caused by compound heterozygous mutations in NNT; one causing pseudoexon inclusion in combination with another leading to Arg71*. Discovery of this pseudoexon activation mutation highlights the importance of identifying sequence changes in introns by cDNA analysis. The clinical implications of these findings include: facilitation of antenatal genetic diagnosis, early institution of potentially lifesaving therapy, and the possibility of preventative or curative interventio

Evolution of Genes Neighborhood Within Reconciled Phylogenies: An Ensemble Approach

Context The reconstruction of evolutionary scenarios for whole genomes in terms of genome rearrangements is a fundamental problem in evolutionary and comparative genomics. The DeCo algorithm, recently introduced by Bérard et al., computes parsimonious evolutionary scenarios for gene adjacencies, from pairs of reconciled gene trees. However, as for many combinatorial optimization algorithms, there can exist many co-optimal, or slightly sub-optimal, evolutionary scenarios that deserve to be considered. Contribution We extend the DeCo algorithm to sample evolutionary scenarios from the whole solution space under the Boltzmann distribution, and also to compute Boltzmann probabilities for specific ancestral adjacencies. Results We apply our algorithms to a dataset of mammalian gene trees and adjacencies, and observe a significant reduction of the number of syntenic conflicts observed in the resulting ancestral gene adjacencies

Likelihood Geometry

We study the critical points of monomial functions over an algebraic subset of the probability simplex. The number of critical points on the Zariski closure is a topological invariant of that embedded projective variety, known as its maximum likelihood degree. We present an introduction to this theory and its statistical motivations. Many favorite objects from combinatorial algebraic geometry are featured: toric varieties, A-discriminants, hyperplane arrangements, Grassmannians, and determinantal varieties. Several new results are included, especially on the likelihood correspondence and its bidegree. These notes were written for the second author's lectures at the CIME-CIRM summer course on Combinatorial Algebraic Geometry at Levico Terme in June 2013.Comment: 45 pages; minor changes and addition

Lassoing and corraling rooted phylogenetic trees

The construction of a dendogram on a set of individuals is a key component of a genomewide association study. However even with modern sequencing technologies the distances on the individuals required for the construction of such a structure may not always be reliable making it tempting to exclude them from an analysis. This, in turn, results in an input set for dendogram construction that consists of only partial distance information which raises the following fundamental question. For what subset of its leaf set can we reconstruct uniquely the dendogram from the distances that it induces on that subset. By formalizing a dendogram in terms of an edge-weighted, rooted phylogenetic tree on a pre-given finite set X with |X|>2 whose edge-weighting is equidistant and a set of partial distances on X in terms of a set L of 2-subsets of X, we investigate this problem in terms of when such a tree is lassoed, that is, uniquely determined by the elements in L. For this we consider four different formalizations of the idea of "uniquely determining" giving rise to four distinct types of lassos. We present characterizations for all of them in terms of the child-edge graphs of the interior vertices of such a tree. Our characterizations imply in particular that in case the tree in question is binary then all four types of lasso must coincide

Hot topics, urgent priorities, and ensuring success for racial/ethnic minority young investigators in academic pediatrics.

BackgroundThe number of racial/ethnic minority children will exceed the number of white children in the USA by 2018. Although 38% of Americans are minorities, only 12% of pediatricians, 5% of medical-school faculty, and 3% of medical-school professors are minorities. Furthermore, only 5% of all R01 applications for National Institutes of Health grants are from African-American, Latino, and American Indian investigators. Prompted by the persistent lack of diversity in the pediatric and biomedical research workforces, the Academic Pediatric Association Research in Academic Pediatrics Initiative on Diversity (RAPID) was initiated in 2012. RAPID targets applicants who are members of an underrepresented minority group (URM), disabled, or from a socially, culturally, economically, or educationally disadvantaged background. The program, which consists of both a research project and career and leadership development activities, includes an annual career-development and leadership conference which is open to any resident, fellow, or junior faculty member from an URM, disabled, or disadvantaged background who is interested in a career in academic general pediatrics.MethodsAs part of the annual RAPID conference, a Hot Topic Session is held in which the young investigators spend several hours developing a list of hot topics on the most useful faculty and career-development issues. These hot topics are then posed in the form of six "burning questions" to the RAPID National Advisory Committee (comprised of accomplished, nationally recognized senior investigators who are seasoned mentors), the RAPID Director and Co-Director, and the keynote speaker.Results/conclusionsThe six compelling questions posed by the 10 young investigators-along with the responses of the senior conference leadership-provide a unique resource and "survival guide" for ensuring the academic success and optimal career development of young investigators in academic pediatrics from diverse backgrounds. A rich conversation ensued on the topics addressed, consisting of negotiating for protected research time, career trajectories as academic institutions move away from an emphasis on tenure-track positions, how "non-academic" products fit into career development, racism and discrimination in academic medicine and how to address them, coping with isolation as a minority faculty member, and how best to mentor the next generation of academic physicians

Shape-based peak identification for ChIP-Seq

We present a new algorithm for the identification of bound regions from ChIP-seq experiments. Our method for identifying statistically significant peaks from read coverage is inspired by the notion of persistence in topological data analysis and provides a non-parametric approach that is robust to noise in experiments. Specifically, our method reduces the peak calling problem to the study of tree-based statistics derived from the data. We demonstrate the accuracy of our method on existing datasets, and we show that it can discover previously missed regions and can more clearly discriminate between multiple binding events. The software T-PIC (Tree shape Peak Identification for ChIP-Seq) is available at http://math.berkeley.edu/~vhower/tpic.htmlComment: 12 pages, 6 figure

Recognizing Treelike k-Dissimilarities

A k-dissimilarity D on a finite set X, |X| >= k, is a map from the set of size k subsets of X to the real numbers. Such maps naturally arise from edge-weighted trees T with leaf-set X: Given a subset Y of X of size k, D(Y) is defined to be the total length of the smallest subtree of T with leaf-set Y . In case k = 2, it is well-known that 2-dissimilarities arising in this way can be characterized by the so-called "4-point condition". However, in case k > 2 Pachter and Speyer recently posed the following question: Given an arbitrary k-dissimilarity, how do we test whether this map comes from a tree? In this paper, we provide an answer to this question, showing that for k >= 3 a k-dissimilarity on a set X arises from a tree if and only if its restriction to every 2k-element subset of X arises from some tree, and that 2k is the least possible subset size to ensure that this is the case. As a corollary, we show that there exists a polynomial-time algorithm to determine when a k-dissimilarity arises from a tree. We also give a 6-point condition for determining when a 3-dissimilarity arises from a tree, that is similar to the aforementioned 4-point condition.Comment: 18 pages, 4 figure

Healthcare System Priorities for Successful Integration of Genomics: An Australian Focus

This paper examines key considerations for the successful integration of genomic technologies into healthcare systems. All healthcare systems strive to introduce new technologies that are effective and affordable, but genomics offers particular challenges, given the rapid evolution of the technology. In this context we frame internationally relevant discussion points relating to effective and sustainable implementation of genomic testing within the strategic priority areas of the recently endorsed Australian National Health Genomics Policy Framework. The priority areas are services, data, workforce, finances, and person-centred care. In addition, we outline recommendations from a government perspective through the lens of the Australian health system, and argue that resources should be allocated not to just genomic testing alone, but across the five strategic priority areas for full effectiveness

Optimality regions and fluctuations for Bernoulli last passage models

We study the sequence alignment problem and its independent version,the discrete Hammersley process with an exploration penalty. We obtain rigorous upper bounds for the number of optimality regions in both models near the soft edge.At zero penalty the independent model becomes an exactly solvable model and we identify cases for which the law of the last passage time converges to a Tracy-Widom law