The effects of common structural variants on 3D chromatin structure

Background Three-dimensional spatial organization of chromosomes is defined by highly self-interacting regions 0.1-1 Mb in size termed Topological Associating Domains (TADs). Genetic factors that explain dynamic variation in TAD structure are not understood. We hypothesize that common structural variation (SV) in the human population can disrupt regulatory sequences and thereby influence TAD formation. To determine the effects of SVs on 3D chromatin organization, we performed chromosome conformation capture sequencing (Hi-C) of lymphoblastoid cell lines from 19 subjects for which SVs had been previously characterized in the 1000 genomes project. We tested the effects of common deletion polymorphisms on TAD structure by linear regression analysis of nearby quantitative chromatin interactions (contacts) within 240 kb of the deletion, and we specifically tested the hypothesis that deletions at TAD boundaries (TBs) could result in large-scale alterations in chromatin conformation. Results Large (&gt; 10 kb) deletions had significant effects on long-range chromatin interactions. Deletions were associated with increased contacts that span the deleted region and this effect was driven by large deletions that were not located within a TAD boundary (nonTB). Some deletions at TBs, including a 80 kb deletion of the genes CFHR1 and CFHR3, had detectable effects on chromatin contacts. However for TB deletions overall, we did not detect a pattern of effects that was consistent in magnitude or direction. Large inversions in the population had a distinguishable signature characterized by a rearrangement of contacts that span its breakpoints. Conclusions Our study demonstrates that common SVs in the population impact long-range chromatin structure, and deletions and inversions have distinct signatures. However, the effects that we observe are subtle and variable between loci. Genome-wide analysis of chromatin conformation in large cohorts will be needed to quantify the influence of common SVs on chromatin structure.</p

DECENTRALIZATION IN UGANDA

The theory of fiscal federalism provides several reasons to expect better public service delivery if government is decentralized. Demand for public services is expected to vary across jurisdictions, and local government officials are expected to match supply of public services with demand more effectively than if public services were centrally provided. Households are expected to have higher participation rates in elections and to vote for better reasons (the candidates&apos; experience, agenda or political affiliation, rather than bribery or the candidates&apos; race, religion etc.) at the local level, and to have better access to information about local affairs than about national politics. Finally, mobility across jurisdictions is expected to induce local governments to be more efficient. We review the decentralization process in Uganda and provide evidence on all these mechanisms. There turns out to be little support for the relevance of these hypotheses to Uganda

Rare copy number variation in posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10-8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further

The Effects of Structural Variation on 3D Chromatin Structure

Three-dimensional spatial organization of chromosomes is defined by highly self-interacting regions 0.1-1 Mb in size termed Topological Associating Domains (TADs). Genetic factors that explain dynamic variation in TAD structure are not understood. We hypothesize that common structural variation (SV) in the human population; including deletions, insertions and inversions of &gt;50 bp; can disrupt regulatory sequences and thereby influence TAD formation. To determine the effects of SVs on 3D chromatin organization, we performed chromosome conformation capture sequencing (Hi-C) of lymphoblastoid cell lines from 19 subjects for which SVs had been previously characterized in the 1000 genomes project. Large (&gt;10kb) deletions had significant effects on long-range chromatin interactions. Deletions overall were associated with increased contacts that span the deleted region but had a modest effect on contacts in adjacent regions. Deletions at TAD boundaries were associated with diminished contacts in the adjacent domains, consistent with the structure of TADs being dependent on regulatory sequences at their boundaries. Large inversions in the population had a common signature characterized by a rearrangement of contacts that span its breakpoints. Our results suggest that common SVs in the population impact long range chromatin structure

The Effects of Structural Variation on 3D Chromatin Structure

Three-dimensional spatial organization of chromosomes is defined by highly self-interacting regions 0.1-1 Mb in size termed Topological Associating Domains (TADs). Genetic factors that explain dynamic variation in TAD structure are not understood. We hypothesize that common structural variation (SV) in the human population; including deletions, insertions and inversions of &gt;50 bp; can disrupt regulatory sequences and thereby influence TAD formation. To determine the effects of SVs on 3D chromatin organization, we performed chromosome conformation capture sequencing (Hi-C) of lymphoblastoid cell lines from 19 subjects for which SVs had been previously characterized in the 1000 genomes project. Large (&gt;10kb) deletions had significant effects on long-range chromatin interactions. Deletions overall were associated with increased contacts that span the deleted region but had a modest effect on contacts in adjacent regions. Deletions at TAD boundaries were associated with diminished contacts in the adjacent domains, consistent with the structure of TADs being dependent on regulatory sequences at their boundaries. Large inversions in the population had a common signature characterized by a rearrangement of contacts that span its breakpoints. Our results suggest that common SVs in the population impact long range chromatin structure

Neural-Enhanced Universal Ride at Low-cost (N.E.U.R.A.L.)

Goal StatementTo design a low-cost brain-controlled (EEG) wheelchair which will providemobility to people who have experienced spinal cord injuries, were born unable to move, or have been permanently paralyzed Team Members: Camilo Aguilar (EE), Cesar Becerril (EE), David Hong (CpE), Omar Shanta (EE)Advisor: Professor Lee Swindlehurs

Neural-Enhanced Universal Ride at Low-cost (N.E.U.R.A.L.)

Goal StatementTo design a low-cost brain-controlled (EEG) wheelchair which will providemobility to people who have experienced spinal cord injuries, were born unable to move, or have been permanently paralyzed Team Members: Camilo Aguilar (EE), Cesar Becerril (EE), David Hong (CpE), Omar Shanta (EE)Advisor: Professor Lee Swindlehurs

Oligogenic Effects of 16p11.2 Copy-Number Variation on Craniofacial Development

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