Core B - Sequencing, Genotyping and Automated Mapping
核心 B - 测序、基因分型和自动作图
基本信息
- 批准号:10642551
- 负责人:
- 金额:$ 93.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-06-13 至 2028-05-31
- 项目状态:未结题
- 来源:
- 关键词:AgeAllelesAttentionBar CodesBiological AssayBloodBlood capillariesBreedingCellsChemistryCodeComputer softwareComputersCustomDNADataDatabasesDetectionDevelopmentDiabetes MellitusEthylnitrosoureaFailureFemaleGenesGenomic DNAGenotypeGlycosuriaHeterozygoteHomozygoteImmune systemImmunologic TestsImmunologicsIndividualInduced MutationInsulin-Dependent Diabetes MellitusIonsLaboratory PersonnelLightMachine LearningMapsMeiosisMissionMusMutagenesisMutant Strains MiceMutationMutation DetectionNucleotidesPhenotypeProcessRNA SplicingSiteSoftware ToolsSplice-Site MutationTargeted ResequencingTechnologyTerminologyTrainingWeaningWritingarmcarrier statuscausal variantelectronic dataexome sequencingexperiencegenetic pedigreemutantparagonphenotypic dataprogramsscreeningsequencing platformtransmission process
项目摘要
PROJECT SUMMARY/ABSTRACT
Highly trained and experienced Core B laboratory personnel will be responsible for automated meiotic mapping
(AMM) of mutations that alter the T1D phenotype in NOD/NckH mice (either suppressing or augmenting the
normal course of T1D development). AMM is necessary for the rapid identification of single nucleotide changes
responsible for phenotypes. DNA will be sent from Core C by express mail at monthly intervals, and phenotyping
data will be transmitted by direct data upload on a weekly basis. Core B will first identify all coding/splicing
mutations in each pedigree. Then, within each pedigree, Core B will genotype DNA from all G2 and G3 mice at
pedigree-specific mutation sites to determine the zygosity of induced mutations in every mouse. Because two
separate sequencing platforms are used to detect mutations (Illumina) and to genotype mutations (Ion Torrent),
the latter process being performed on many individual mice, the rate of false positive mutations is essentially
zero. Genotyping errors are also exceedingly rare. Genotyping failure (as distinct from error) occurs for ~2-3%
of targeted loci, requiring a second attempt using capillary sequencing. The computational arm of Core B will
use statistical computation, carried out on a local computer with 192 parallel processors, to identify all mutations
causative of phenotype, whether they augment or suppress T1D. Software written for the parsing and display of
AMM data will assure that no causative mutation goes unnoticed. Using the machine-learning program
Candidate Explorer (CE), written for precisely this task, Core B will designate certain mutations for verification
studies (performed in Project 2) and mechanistic studies (performed in both Project 1 and Project 2). Core B
has also developed another mission-specific software tool that permits detection of epistatic interactions between
mutations. This program will determine whether interactions are additive, synergistic, or antagonistic. It will also
determine whether these effects are, in the case of each mutation, dominant, recessive or additive. The causative
mutations identified in Core B will be interpreted in light of phenotypic studies of >230,000 mutations presently
in the Mutagenetix database that were tested for immunologic effects. Just as a Coro1a mutation was shown to
abolish the development of T1D (see Overall), we anticipate that mutations in many lesser-known genes may
have inhibitory or augmenting effects. The Mutagenetix database will help guide our general approach to
mechanism across the P01. We will explore immunologically significant mutations mechanistically with the
hypothesis that they operate in cells of the immune system. The data developed in Core B will be publicly
available on the Mutagenetix database through the CE program. A public version of CE is already available to
display FACS data and will be adapted for the display of T1D modifier data in the course of this P01 project.
项目总结/摘要
训练有素且经验丰富的Core B实验室人员将负责自动减数分裂图谱绘制
(AMM)在NOD/NckH小鼠中改变T1 D表型的突变(抑制或增强T1 D表型),
T1 D发展的正常过程)。AMM是快速鉴定单核苷酸变化所必需的
负责表型。DNA将通过快递邮件从核心C每月发送一次,
数据将通过每周直接上传数据的方式传送。核心B将首先识别所有编码/剪接
每个家系的突变。然后,在每个谱系内,核心B将对来自所有G2和G3小鼠的DNA进行基因分型,
谱系特异性突变位点,以确定每只小鼠中诱导突变的接合性。因为两
使用单独的测序平台来检测突变(Illumina)和对突变进行基因分型(IonTorrent),
后一过程在许多个体小鼠上进行,假阳性突变率基本上是
零.基因分型错误也非常罕见。基因分型失败(与错误不同)发生约2-3%
需要使用毛细管测序进行第二次尝试。核心B的计算臂将
使用统计计算,在具有192个并行处理器的本地计算机上进行,以识别所有突变
无论是增加还是抑制T1 D。为分析和显示
AMM数据将确保没有致病突变被忽视。使用机器学习程序
候选探索者(CE),正是为这一任务编写的,核心B将指定某些突变进行验证
研究(在项目2中进行)和机制研究(在项目1和项目2中进行)。核心B
还开发了另一种特定任务的软件工具,允许检测上位相互作用之间
突变。该程序将确定相互作用是相加的、协同的还是拮抗的。它还将
确定这些效应在每个突变的情况下是显性的、隐性的还是加性的。致病
核心B中鉴定的突变将根据目前> 230,000个突变的表型研究来解释
在Mutagenetix数据库中进行了免疫效果测试。正如Coro 1a突变被证明
消除T1 D的发展(见总体),我们预计,许多鲜为人知的基因突变可能
具有抑制或增强作用。Mutagenetix数据库将有助于指导我们的一般方法,
整个P01的机制。我们将探索免疫学上的重要突变机制,
假设它们在免疫系统的细胞中起作用。核心B中开发的数据将公开
通过CE程序在Mutagenetix数据库中提供。CE的公开版本已经提供给
显示FACS数据,并将在本P01项目过程中用于显示T1 D修饰数据。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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BRUCE A BEUTLER其他文献
BRUCE A BEUTLER的其他文献
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{{ truncateString('BRUCE A BEUTLER', 18)}}的其他基金
Modulation of NOD Strain Diabetes by ENU-Induced Mutations
ENU 诱导突变对 NOD 菌株糖尿病的调节
- 批准号:
10642549 - 财政年份:2023
- 资助金额:
$ 93.34万 - 项目类别:
Project 2 - Verification and Molecular Mechanisms of T1D Modifier Mutations
项目2-T1D修饰突变的验证和分子机制
- 批准号:
10642554 - 财政年份:2023
- 资助金额:
$ 93.34万 - 项目类别:
Automated Forward Genetic Analysis of Adaptive Immunity
适应性免疫的自动正向遗传分析
- 批准号:
9158963 - 财政年份:2016
- 资助金额:
$ 93.34万 - 项目类别:
Automated Forward Genetic Analysis of Adaptive Immunity
适应性免疫的自动正向遗传分析
- 批准号:
10623164 - 财政年份:2016
- 资助金额:
$ 93.34万 - 项目类别:
Automated Forward Genetic Analysis of Adaptive Immunity
适应性免疫的自动正向遗传分析
- 批准号:
10328571 - 财政年份:2016
- 资助金额:
$ 93.34万 - 项目类别:
Automated Forward Genetic Analysis of Adaptive Immunity
适应性免疫的自动正向遗传分析
- 批准号:
10209864 - 财政年份:2016
- 资助金额:
$ 93.34万 - 项目类别:
Genetic Analysis of TLR Signaling and Innate Resistance to Viral Infection
TLR 信号传导和病毒感染先天抵抗力的遗传分析
- 批准号:
10240688 - 财政年份:2012
- 资助金额:
$ 93.34万 - 项目类别:
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