Short tandem repeats (STRs) and variable number tandem repeats (VNTRs) are important sources of natural and disease-causing variation, yet they have been problematic to resolve in reference genomes ...and genotype with short-read technology. We created a framework tomodel the evolution and instability of STRs and VNTRs in apes. We phased and assembled 3 ape genomes (chimpanzee, gorilla, and orangutan) using long-read and 10x Genomics linkedread sequence data for 21,442 human tandem repeats discovered in 6 haplotype-resolved assemblies of Yoruban, Chinese, and Puerto Rican origin. We define a set of 1,584 STRs/VNTRs expanded specifically in humans, including large tandem repeats affecting coding and noncoding portions of genes (e.g., MUC3A, CACNA1C). We show that short interspersed nuclear element–VNTR–Alu (SVA) retrotransposition is the main mechanism for distributing GC-rich human-specific tandem repeat expansions throughout the genome but with a bias against genes. In contrast, we observe that VNTRs not originating from retrotransposons have a propensity to cluster near genes, especially in the subtelomere. Using tissuespecific expression from human and chimpanzee brains, we identify genes where transcript isoform usage differs significantly, likely caused by cryptic splicing variation within VNTRs. Using single-cell expression from cerebral organoids, we observe a strong effect for genes associated with transcription profiles analogous to intermediate progenitor cells. Finally, we compare the sequence composition of some of the largest human-specific repeat expansions and identify 52 STRs/VNTRs with at least 40 uninterrupted pure tracts as candidates for genetically unstable regions associated with disease.
Genetic studies of autism spectrum disorder (ASD) have established that de novo duplications and deletions contribute to risk. However, ascertainment of structural variants (SVs) has been restricted ...by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping, and de novo assembly to genome sequencing of 235 subjects (71 affected individuals, 26 healthy siblings, and their parents), we compiled an atlas of 29,719 SV loci (5,213/genome), comprising 11 different classes. We found a high diversity of de novo mutations, the majority of which were undetectable by previous methods. In addition, we observed complex mutation clusters where combinations of de novo SVs, nucleotide substitutions, and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%) and propose that genetic risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs, but not an elevated rate of genome rearrangement.
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.
Large (> 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.
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.
Although DNA bending is crucial in genome packing and gene regulation, the relationship between the sequence of a DNA and its ability to adopt bent conformations remains incompletely understood. ...Several methods, including gel mobility assays, crystallography, and measuring ring closure probabilities, have been used to quantify the inherent bending of individual DNA sequences. However, these methods are insufficient to survey the vast number of unique sequences necessary to fully understand sequence-dependent bending. To address this problem, a protocol was devised to select for DNA molecules that efficiently form circles from a library of 126 base pair DNA fragments containing a central region of 90 randomized base pairs. After six rounds of selection, individual molecules from the library showed a 20- to 100-fold increases in j-factor values, validating the selection protocol. High-throughput sequencing of the enriched libraries identified a sinusoidal pattern of enrichment and de-enrichment of A/T dinucleotides in the random region with a 10.4 base pair period associated with the helical repeat of the DNA duplex. A similar, but more moderate pattern of C/G dinucleotides was offset by precisely half a helical turn. A sequence-by-sequence examination indicated that, while C/G dinucleotide enrichments were evenly distributed, A/T dinucleotide enrichments displayed a preference to cluster in individual DNA molecules. Analysis of the most highly enriched 10 base pair sequences in the random region revealed motifs containing adjacent blocks of A/T and C/G trinucleotides that appeared in some, but not all rapidly cyclizing molecules. The phased dinucleotide enrichments determined here are similar to those present in accurately mapped yeast nucleosomes, while a quantitative comparison between the neighbor pair frequencies of the two datasets identified 189 cases of significant difference. Mapping these discrepancies to nucleosome structures revealed that many occur at potential sequence-specific DNA-histone interactions including arginine and lysine insertions into the minor groove and targets of post-translational histone modifications. Additionally, most of the cases reside at locations of nucleosomal DNA distortions. Therefore, efficient wrapping by nucleosomal DNA sequences might be influenced by specific DNA-histone interactions in addition to a fragment's propensity to bend.
Los indicadores de sustentabilidad permiten evaluar los impactos ambientales relacionados con la estrategia del desarrollo sustentable. En este estudio realizado en Ciudad del Carmen, Campeche ...considerada una isla de barrera que se localiza al sureste de México. El municipio canaliza la disposición final de los residuos sólidos urbanos (RSU) a través de un relleno sanitario el cual se encuentra ubicado en una zona de manglar, teniendo un impacto negativo en el medio ambiente lo que incide negativamente en el desarrollo sustentable. Mediante el análisis sedimentológico del subsuelo, se obtuvieron resultados que identificaron la dominancia de arenas carbonatadas, lo que permitió definir un rango de porosidad del 20,2 al 40,1%, y permeabilidad de ±10-2-10-4 m/s darcys, es decir, los sedimentos presentan una buena porosidad y una permeabilidad alta. Por su parte, mediante un análisis de la calidad del agua, se detectaron concentraciones de Demanda Bioquímica de Oxígeno (DBO5) y Demanda Química de Oxígeno (DQO) de 63,06 y 1,338.13 mg/L, respectivamente, así como la presencia de concentraciones traza de algunos metales pesados. Estos valores permitieron clasificarlo como un cuerpo de agua fuertemente contaminado.
Los indicadores de sustentabilidad permiten evaluar los impactos ambientales relacionados con la estrategia del desarrollo sustentable. Este estudio se realizó en Ciudad del Carmen, Campeche, que es ...considerada una isla de barrera que se localiza al sureste de México. El municipio canaliza la disposición final de los residuos sólidos urbanos (RSU) a través de un relleno sanitario el cual se encuentra ubicado en una zona de manglar, teniendo un impacto negativo en el medio ambiente lo que incide negativamente en el desarrollo sustentable. Mediante el análisis sedimentológico del subsuelo, se obtuvieron resultados que identificaron la dominancia de arenas carbonatadas, lo que permitió definir un rango de porosidad del 20,2 al 40,1%, y permeabilidad de + ó - 10-2-10-4 ms.sup.-1 darcys, es decir, los sedimentos presentan una buena porosidad y una permeabilidad alta. Por su parte, mediante un análisis de la calidad del agua se detectaron concentraciones de Demanda Bioquímica de Oxígeno (DBO5) y Demanda Química de Oxígeno (DQO) de 63,06 y 1338,13 mg L-1, respectivamente, así como la presencia de concentraciones de trazas de algunos metales pesados. Estos valores permitieron clasificarlo como un cuerpo de agua fuertemente contaminado.
PDF
