133 research outputs found
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Modeling Rare Protein-Coding Variation to Identify Mutation-Intolerant Genes With Application to Disease
No full textSequencing exomes—the 1% of the genome that codes for proteins—has increased the rate at which the genetic basis of a patient’s disease is determined. Unfortunately, when a patient does not carry a well-established pathogenic variant, it is extremely challenging to establish which of the tens of thousands of variants identified in that individual is contributing to their disease. In these situations, variants must be prioritized to make further investigation more manageable. In this thesis, we have focused on creating statistical frameworks and models to aid in the interpretation of rare variants and towards establishing gene-level metrics for variant prioritization.
We developed a sensitive and specific workflow to detect newly arising (de novo) variants from exome sequencing data of parent-child trios, and created a sequence-context based mutational. This mutational model was the basis of a rigorous statistical framework to evaluate the significance of de novo variant burden not only globally, but also per gene. When we applied this framework to de novo variants identified in patients with an autism spectrum disorder, we found a global excess of de novo loss-of-function variants as well as two genes that harbored significantly more de novo loss-of-function variants than expected.
We also used the mutational model to predict the expected number of rare (minor allele frequency < 0.1%) variants in exome sequencing datasets of reference individuals. We found a significant depletion of missense and loss-of-function variants in a subset of genes, indicating that these genes are under strong evolutionary constraint. Specifically, we identified 3,230 genes that are intolerant of loss-of-function variation and that set of genes is enriched for established dominant and haploinsufficient disease genes. Similarly, we searched for regions within genes that were intolerant of missense variation. The most missense depleted 15% of the exome contains 83% of reported pathogenic variants found in haploinsufficient disease genes that cause severe disease. Additionally, both gene-level and region-level constraint metrics highlight a set of de novo variants from patients with a neurodevelopmental disorder that are more likely to be pathogenic, supporting the utility of these metrics when interpreting rare variants within the context of disease.Medical SciencesMedical Sciencesgenomics; exome; sequencing; mutation; de novo; autism; constrain
Substitution of fish meal by co-extruded soybean poultry by-product meal in practical diets for the Pacific white shrimp, Litopenaeus vannamei
No full textThe use of a co-extruded soybean poultry by-product meal with egg supplement was evaluated as a substitute for fish meal in a practical diet formulated to contain 32percent crude protein and 8percent lipid. The co-extruded product was substituted for menhaden fish meal on an iso-nitrogenous basis and offered to juvenile Litopenaeus vannamei (mean initial weight±standard deviation, 1.13±0.06 g) over a 6-week period. Inclusion levels ranged from 0percent (30 g fish meal-100 g diet) to 100percent replacement (0 g fish meal-100 g diet). A fifth diet was formulated to contain no fish meal and 1 g krill meal-100 g diet. Furthermore, a commercial shrimp feed was included in the study to allow for a commercial reference. At the conclusion of the growth trial, survival, final weight, percent weight gain and feed efficiency (FE) were not significantly different among treatments. The inclusion of krill meal did not appear to improve attractability or palatability of the diet. Co-extruded soybean poultry by-product meal with egg supplement appears suitable as a substitute for fish meal in L. vannamei diets. © 2004 Elsevier B.V. All rights reserved.Barlow S., 2000, ADVOCATE, V3, P85; Carver L.A., 1989, ASA TECH B, V3, P89; Davis DA, 2000, AQUACULTURE, V185, P291, DOI 10.1016-S0044-8486(99)00354-3; Eusebio PS, 1998, ISR J AQUACULT-BAMID, V50, P47; EUSEBIO PS, 1991, AQUACULTURE, V99, P297, DOI 10.1016-0044-8486(91)90250-B; Hardy R.W., 2001, AQUACULTURE MAGAZINE, V27, P57; LIM C, 1990, AQUACULTURE, V87, P53, DOI 10.1016-0044-8486(90)90210-E; Lim C, 1996, J WORLD AQUACULT SOC, V27, P402, DOI 10.1111-j.1749-7345.1996.tb00624.x; PENAFLORIDA VD, 1995, ISR J AQUACULT-BAMID, V47, P25; PIEDADPASCUAL F, 1990, AQUACULTURE, V89, P183, DOI 10.1016-0044-8486(90)90309-B; Spotte S, 1979, FISH INVERTEBRATE CU; Steel RG, 1980, PRINCIPLES PROCEDURE; SUDARYONO A, 1995, AQUACULTURE, V134, P313, DOI 10.1016-0044-8486(95)00047-6; Sudaryono A, 1999, AQUACULTURE, V171, P121, DOI 10.1016-S0044-8486(98)00424-4; Tacon AGJ, 1998, TROPICAL MARICULTURE, P171, DOI 10.1016-B978-012210845-7-50006-4; TACON AGJ, 1997, ADV WOR AQUAC, V6, P411; TIDWELL JH, 1993, AQUACULTURE, V118, P119, DOI 10.1016-0044-8486(93)90285-7; Webster C. D., 2002, NUTR REQUIREMENTS FE61605
Contribution of retrotransposition to developmental disorders
No full textMobile genetic Elements (MEs) are segments of DNA which can copy themselves and other transcribed sequences through the process of retrotransposition (RT). In humans several disorders have been attributed to RT, but the role of RT in severe developmental disorders (DD) has not yet been explored. Here we identify RT-derived events in 9738 exome sequenced trios with DD-affected probands. We ascertain 9 de novo MEs, 4 of which are likely causative of the patient’s symptoms (0.04%), as well as 2 de novo gene retroduplications. Beyond identifying likely diagnostic RT events, we estimate genome-wide germline ME mutation rate and selective constraint and demonstrate that coding RT events have signatures of purifying selection equivalent to those of truncating mutations. Overall, our analysis represents a comprehensive interrogation of the impact of retrotransposition on protein coding genes and a framework for future evolutionary and disease studies.</p
Potencial redox em sedimentos de viveiros de água doce e salgada: metodologia de determinação e comportamento
No full textDissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Agrárias. Programa de Pós-Graduação em Aquicultura.Pouco se conhece a respeito do comportamento do potencial redox em viveiros de cultivo e de sua relação com a produção. O uso deste recurso pode ser útil no manejo de viveiros para evitar a produção de substâncias potencialmente tóxicas. A dificuldade de se obter uma amostra que permita uma leitura do valor de redox dentro do horizonte desejado é um obstáculo a aquisição destes conhecimentos. Este trabalho propõe uma metodologia que utiliza um coletor de amostras voltado para as necessidades deste tipo de trabalho. O equipamento foi elaborado com materiais disponíveis, de fácil construção e passível de ser operado por uma única pessoa. O método permite a visualização da amostra para a introdução do eletrodo no horizonte desejado. O trabalho foi realizado em duas propriedades no estado de Santa Catarina sendo uma de cultivo de catfish e outra de camarões marinhos. Observou-se o comportamento do potencial redox por um período de 50 dias dentro de um ciclo de produção onde os viveiros foram amostrados em doze regiões. Verificou-se que o comportamento nos dois viveiros foi diferente e que o manejo diferenciado pode ter influencia sobre o comportamento dos valores de redox. Os valores de redox no viveiro de catfish comportaram-se de maneira estável porem, negativa. Já no viveiro de camarões houve uma forte baixa nos valores tendendo a estabilização após o 20 dia de observação
Evidence for 28 genetic disorders discovered by combining healthcare and research data
No full textDe novo mutations in protein-coding genes are a well-established cause of developmental disorders1. However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations1,2. Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent–offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of genes associated with developmental disorders
Author Correction: Transcript expression-aware annotation improves rare variant interpretation
No full textIn this Article, author Marquis P. Vawter was missing from the Genome Aggregation Database Consortium list. They are associated with the affiliation: ‘Department of Psychiatry & Human Behavior, University of California Irvine, Irvine, CA, USA’, and contributed to the generation of the primary data incorporated into the gnomAD resource. The original Article has been corrected online
Network Analysis of Genome-Wide Selective Constraint Reveals a Gene Network Active in Early Fetal Brain Intolerant of Mutation.
No full textUsing robust, integrated analysis of multiple genomic datasets, we show that genes depleted for non-synonymous de novo mutations form a subnetwork of 72 members under strong selective constraint. We further show this subnetwork is preferentially expressed in the early development of the human hippocampus and is enriched for genes mutated in neurological Mendelian disorders. We thus conclude that carefully orchestrated developmental processes are under strong constraint in early brain development, and perturbations caused by mutation have adverse outcomes subject to strong purifying selection. Our findings demonstrate that selective forces can act on groups of genes involved in the same process, supporting the notion that purifying selection can act coordinately on multiple genes. Our approach provides a statistically robust, interpretable way to identify the tissues and developmental times where groups of disease genes are active
Author Correction: The mutational constraint spectrum quantified from variation in 141,456 humanS
No full textIn this Article, author Marquis P. Vawter was missing from the Genome Aggregation Database Consortium list. They are associated with the affiliation: ‘Department of Psychiatry & Human Behavior, University of California Irvine, Irvine, CA, USA’, and contributed to the generation of the primary data incorporated into the gnomAD resource. In addition, in the legend to Fig. 1, ‘ten’ should have been ‘seven’ in the sentence: “a, Uniform manifold approximation and projection (UMAP)46,47 plot depicting the ancestral diversity of all individuals in gnomAD, using seven principal components.” The original Article has been corrected online
The contribution of X-linked coding variation to severe developmental disorders
No full textOver 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders.UK Research Ethics CommitteeCambridge South Research Ethics CommitteeRepublic of Ireland Research Ethics CommitteeHealth Innovation Challenge FundWellcome Trust and the UK Department of HealthWellcome Trust Sanger InstituteNational Institutes for Health Researc
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