1998 — 1999 |
Eichler, Evan |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Molecular Evolution of Pericentromeric Duplications Among Higher Primates @ Case Western Reserve University
9806913 Eichler Gene duplication is one of the primary forces of evolutionary change. It is by this process that new genes are believed to arise in the genome of an organism. Despite its importance in evolution, the mechanism by which this process occurs is not well understood. The objective of this proposal is to investigate one such mechanism that has been recently identified within the genomes of higher primates. An unusual bias for duplicating segments containing entire genes or gene-segments has been documented for regions near the centromeres of primate chromosomes. Dr. Eichler will conduct experiments to determine precisely what segments of the genome have been duplicated, when the duplication events occurred within an evolutionary timeframe, how large are the duplicated segments, where these duplication events have occurred and what molecular sequences define the breakpoints between ancestral and duplicated loci. Due to the unusually high degree of sequence similarity between these segments, the study will focus primarily on man and his most closely related species (chimpanzee, gorilla and orangutan). The chromosomes of multiple individuals from each species will be analyzed to determine if these events contribute to differences in the architecture of the genome both between species and within species. The results of this process should provide important clues in understanding the mechanism which has been responsible for the distribution of these segments across the primate genome and help to explain the bias for these events to occur near the centromeres of chromosomes. Furthermore, the results of these studies should shed light on the role of gene duplication in the evolution and organization of chromosomes in man and other primates.
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0.945 |
1999 — 2002 |
Eichler, Evan E. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanism &Instability of Pericentromeric Duplications @ Case Western Reserve University
DESCRIPTION (Adapted from the Investigator's Abstract): Gene duplication followed by functional and structural specialization is one of the primary forces of evolutionary change. Despite its importance in genome expansion, speciation and the generation of evolutionary diversity, such processes have been implicated in predisposition to human genetic disease by creating regions of sequence similarity capable of undergoing illegitimate recombination. Interestingly, an unusual functional property of the human genome has emerged in which large genomic segments have been predisposed to duplicate to the pericentromeric regions of chromosomes. The available data indicate that this process has occurred relatively recently (1-15 mya); that it involves the inter/ intrachromosomal transposition of genomic segments ranging from approximately 5-50kb in length and that it has contributed to considerable variation in the genomic architecture of these regions among the higher primates. The investigators hypothesize that this mechanism is an ongoing evolutionary process which results in considerable genomic variability and provides the molecular context for instability associated with these regions. The aim of this proposal is to 1) investigate the molecular mechanism responsible for such pericentromeric duplications and 2) to assess the impact of this process in contributing to heteromorphism of normal human chromosomes and chromosomes associated with pericentromeric instability. To this end, the proposal will focus on the comparative analysis of 670 kb of pericentromeric sequence from human cytogenetic band interval 16p11.1 which appears to have been the target of multiple pericentromeric duplication events. Combining large-scale comparative sequencing and FISH (fluorescent in situ hybridization) methods with other molecular biology techniques, this proposal will specially define the "domains" of paralogy within this 670kb interval, identify the sequence junctions for both the "ancestral" and duplicated loci, reconstruct the phylogeny of each duplication and address the impact of these events on normal and disease variation. Due to the recent nature of this phenomenon and a reference human genomic sequence, the results of this analysis provide a unique opportunity to investigate the molecular mechanism underlying this form of human genome evolution. In addition, these results should provide the framework for understanding the peculiar genomic architecture of pericentromeric regions of chromosomes and the involvement of this structure in creating genetic diversity as well as a proclivity to genomic instability associated with genetic disease.
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0.902 |
2003 — 2010 |
Eichler, Evan E. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanism and Instability of Segmental Duplications @ Case Western Reserve University
DESCRIPTION (provided by applicant): Segmental duplication and subsequent mutation of genetic material is one of the primary forces by which genomes evolve. While genomic duplication is fundamental to the emergence of genes with new functions, it is also a significant source of genomic instability associated with recurrent chromosomal structural rearrangement and disease. Our recent analysis of the human genome has revealed an extraordinary degree of recent evolutionary plasticity--at the level of both the genome and the gene. We hypothesize that the process of segmental duplication and the emergence of new gene function have been coordinated through processes of gene conversion and non-allelic homologous recombination. To test this model, this renewal application will focus on the comparative primate analysis of about 4 Mb of euchromatic sequence from human chromosome 16 which has been the target of a series of complex intrachromosomal duplication events as well as the site for the emergence of a novel human gene family. Combining large-scale comparative sequencing, phylogenetics, FISH, microarray comparative genomic hybridization and computational analysis, the proposal will address three fundamental questions: 1) How did such a complex architecture of chromosome-specific duplications evolve so rapidly? 2) How did this expansion correlate with the emergence of a novel gene family? 3) Does this architecture contribute to large-scale structural variation within and between contemporary primate populations? Due to the recent nature of these duplications and a reference human genome for comparison, the results of these studies provide a unique opportunity to investigate the molecular events and mechanisms(s) underlying this form of human genome evolution. Furthermore, these detailed studies should provide framework for a more global understanding of the impact of segmental duplications on large-scale genomic variation and disease.
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1 |
2003 — 2007 |
Eichler, Evan E. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Segmental Aneusomy Between Blocks of Duplicated Dna @ Case Western Reserve University
[unreadable] DESCRIPTION (provided by applicant): One of the major goals of the field of human genetics is to define the relationship between human genotype and phenotype. Much of our assessment of genotypic variation has been focused on small scale, single nucleotide events. Our understanding of the molecular basis of disease, however, has begun to reveal that large-scale differences including micro duplications and micro deletions contribute significantly to childhood disease, disease susceptibility and normal variation in the population. Despite its importance, there has been no systematic study of this form of genotypic variation. The long-term objective of this proposal is to investigate the pattern and nature of this large-scale variation. Our approach will be directed to regions of the genome that contain highly homologous duplicated sequence and therefore have an increased probability of genomic gain and loss. This proposal is a collaborative effort that brings together expertise in genome structure, array comparative genomic hybridization technology and mental retardation. The specific aims of this proposal are (1) to identify and validate all intrachromosomally duplicated regions within the human genome, (2) to develop a set of large-insert clones bracketed by duplicated sequence to be placed on a CGH microarray platform for genome-wide screening, (3) to assess copy number variation within both normal individuals and children with idiopathic mental retardation and (4) to validate the extent, frequency and inheritance pattern of these large structural "polymorphisms". This project aims to address two fundamental questions; what is the nature and frequency of duplication-mediated structural polymorphisms within the human genome? Are there an excess of de novo events among children with mental retardation and congenital birth defects? [unreadable] [unreadable]
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0.958 |
2004 — 2006 |
Eichler, Evan E. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sequence and Assembly of Pericentromeric Duplication @ University of Washington
[unreadable] DESCRIPTION (provided by applicant): Biological research is increasingly dependent upon "finished" genome sequence as a baseline for further research. More than 99% of the targeted human genome is now represented as high quality finished sequence with each base ordered and orientated. Two major types of gaps remain: heterochromatic (estimated at _190 Mb) and euchromatic gaps (23.0 Mb). Within euchromatic regions 54.5% (168/308) of all assembly gaps are flanked by segmental duplication. The greatest gap density within the finished genome occurs within 2 Mb transition regions between the centromere and euchromatin DNA. We propose that duplications and large-scale structural variation have complicated sequence and assembly of these regions creating de facto gaps. This grant outlines a systematic strategy to target the sequence and assembly of pericentromeric DNA using genomic libraries of haploid complexity. Comparative sequence analysis of one pericentromeric region among primates will serve as a model to understand the pattern of structural variation as a function of evolutionary time. In addition, this competitive renewal develops a computational pipeline that provides support for the analysis of duplication content within other mammalian genomes. The results of this analysis will provide a framework for understanding these regions in other organisms as well as complement ongoing NHGRI-approved whole-genome shotgun sequencing efforts. The presence of recent segmental duplications remains the single most important predictor of gap location within euchromatic sequence. The resolution of these exceptional regions is, therefore, critical for accurate assembly and annotation of genomes. [unreadable] [unreadable]
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0.958 |
2007 — 2013 |
Eichler, Evan E. |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Genotyping @ University of Washington
Project 3: One of the major difficulties of characterizing structural variation in a large number of individuals has been the lack of an accurate, cost-effective, high-throughput genotyping method. This project focuses on developing methods for genotyping structural variation and assessing their genetic characteristics in the four major HapMap populations. Our strategy is to develop specific high-throughput assays according to the type of structural variation. During the course of this project, we propose to: 1) develop a robust assay to genotype -400 simple insertion/deletion events within 480 HapMap samples using a fluorescent oligonucleotide-extension microbead assay; 2) assess the utility of the oligonucleotide array comparative genomic hybridization by genotyping 300 structural variants within segmental duplications and calibrating these results against corresponding sequence; 3) develop PCR breakpoint assays to genotype 200 complex/inversion rearrangements and 4) assess linkage disequilibrium of structural variation and flanking SNPs. The results of this analysis will provide an assessment of heritability and allele frequency spectrum data for a large subset of structural variation. In addition, these data will allow integration of structural variation data in the HapMap and provide a set of experimentally validated genotyping assays for future disease association studies.
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1 |
2007 — 2009 |
Eichler, Evan |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Human Genome Structural Variation @ University of Washington
DESCRIPTION (provided by applicant): In the last three years there has been considerable progress in understanding the nature and pattern of single nucleotide variation within the human species. By contrast, a comprehensive understanding of human structural variation which includes deletion, insertion and inversion polymorphisms lags far behind. The structure, frequency and phenotypic impact of most of these events are not known. Recent studies, however, suggest that genome structural variation is common in the normal population, alters structure and copy number of genes and is associated with human disease/disease susceptibility factors. This program project develops a systematic approach to characterize common structural variation within the human genome. The specific aims of this proposal are 1) to identify all inversions, deletions and insertions (>6 kb in size) in nine human samples using an end-sequence-pair mapping strategy;2) to sequence the structure of each of these (n=~2000 variants) including breakpoints;and 3) to develop genotyping assays to assess their frequency in the human population. It is a collaborative effort which brings together expertise in genome sequencing, clone characterization and structural variation. The results of this work will generate the first high quality reference set of sequenced structural variants, provide insight into the molecular mechanisms underlying these events, and develop the genotyping platforms that will be needed to assess the phenotypic consequences in terms of human disease and adaptation.
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1 |
2007 — 2009 |
Eichler, Evan |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Identification of Structural Variation @ University of Washington
Project 3: One of the major difficulties of characterizing structural variation in a large number of individuals has been the lack of an accurate, cost-effective,high-throughput genotyping method. This project focuses on developing methods for genotyping structural variation and assessing their genetic characteristics in the four major HapMap populations. Our strategy is to develop specific high-throughput assays according to the type of structural variation. During the course of this project, we propose to: 1) develop a robust assay to genotype -400 simple insertion/deletion events within 480 HapMap samples using a fluorescent oligonucleotide-extension microbead assay;2) assess the utility of the oligonucleotide array comparative genomic hybridization by genotyping 300 structural variants within segmental duplications and calibrating these results against corresponding sequence;3) develop PCR breakpoint assays to genotype 200 complex/inversion rearrangements and 4) assess linkage disequilibrium of structural variation and flanking SNPs. The results of this analysis will provide an assessment of heritability and allele frequency spectrum data for a large subset of structural variation. In addition, these data will allow integration of structural variation data in the HapMap and provide a set of experimentally validated genotyping assays for future disease association studies.
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1 |
2007 — 2021 |
Eichler, Evan E. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sequence and Assembly of Segmental Duplications @ University of Washington
[unreadable] DESCRIPTION (provided by applicant): Large-scale comparative sequencing of primate genomes promises to reconstruct the evolutionary history of the human genome and to highlight the functional genetic differences between human and non-human primates. Regions enriched for segmental duplication are not adequately resolved within preliminary working draft genome assemblies; however, these regions contribute significantly to disease, the emergence of novel genes and are a source of considerable genetic differences between and within primate species. The object of this four-year proposal is to a) identify and validate regions of segmental duplication and structural variation in five non-human primate species (chimpanzee, orangutan, gibbon, macaque and marmoset), b) to target large-insert clones for sequencing in order to provide high-quality sequence continuity across these genetically complex regions and c) to assess the extent of polymorphism within respective populations of each primate group. The data will significantly enhance the quality of forthcoming primate genome assemblies, improve our understanding of the frequency of de novo duplications events; provide insight into the mechanisms underlying segmental duplication and improve annotation of lineage-specific gene families that lack clear orthologues within outgroup species. Such targeted studies are essential to complete our understanding of the evolution of the human genome. [unreadable] [unreadable] [unreadable]
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1 |
2008 — 2009 |
Eichler, Evan E. Green, Philip P Nickerson, Deborah A [⬀] Shendure, Jay Ashok (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Seattleseq @ University of Washington
[unreadable] DESCRIPTION (provided by applicant): Deep resequencing of human genes has led to the discovery of rare, nonsynonymous sequence variants that are robustly associated with complex human phenotypes. Such studies have historically been rate-limited by the cost of DNA sequencing. Although a new generation of sequencing platforms is reducing costs by over two orders of magnitude, the routine sequencing of complete human genomes continues to be prohibitively expensive. Recently, methods have been developed to enable the efficient capture of specific subsets of the genome. With these methods, the cost of sequencing all of the protein-coding sequences (i.e. ~1% of the human genome split across ~180,000 discontiguous subsequences) may soon be on par with that of dense genotyping arrays. The goals of this proposal are to further the development of these targeting methods, and to integrate them into a scalable resequencing pipeline that relies on second-generation sequencing technology. Specifically, we will: (1) optimize and evaluate candidate strategies for multiplex capture, including array hybridization and gap-fill molecular inversion probes, while extending their application to the full protein-coding genome; (2) integrate optimized capture methods, second-generation sequencing technology, and sequence analysis software into a scalable resequencing pipeline; (3) develop the requisite computational tools for translating raw sequence data generated by new sequencing platforms into quality-tagged, consensus predictions of sequence variants; (4) make our data and methods broadly available, and facilitate the goals of this program through open communication with other investigators and the NIH. PUBLIC HEALTH RELEVANCE - As we enter an era of "personalized medicine", DNA sequencing technology will be increasingly important to public health, contributing towards the unraveling of the genetic basis of human disease, as well as serving an increasing role in clinical diagnostics. Next-generation sequencing technologies have the potential to markedly accelerate genetics research, but are hindered by the lack of equivalently powerful methods to target specific subsets of the human genome. We propose here to develop technologies that meet this critical need, focusing specifically on the development of a scalable resequencing pipeline that targets the ~1% of the genome that is protein-coding. [unreadable] [unreadable] The principal investigator (PI) proposes to evaluate two different methods that will capture approximately 1% of the human genome that represents the protein coding genome (PCG). [unreadable] [unreadable] [unreadable] [unreadable]
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1 |
2009 — 2010 |
Eichler, Evan E. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Genomic Identification of Autism Loci @ University of Washington
DESCRIPTION (provided by applicant): This proposal will explore the hypothesis that autism is caused by highly-penetrant, rare mutations using emerging technologies that screen regions for autism-specific copy- number variation (CNV) mutations and exonic point mutations. Our targeted focus will be 17 genomic regions (carrying 83 genes) and an additional 87 genes where copy-number changes and point mutations have been associated with autism. We propose three subprojects: 1) fine-scale CNV screening and validation to identify autism-specific structural changes;2) systematic assessment of high-impact point mutations in ~4000 coding exons using molecular inversion probe technology and next-generation sequencing;and 3) complete exome characterization of a subset of autism samples. Aims 1 and 2 will be applied to 1320 simplex and multiplex families (AGRE and SFARI Simplex Collection), while the third aim will focus on the comprehensive assessment of 20 autism genomes. Our goal is to identify and characterize specific genes associated with autism and we anticipate that we will pinpoint the genetic causation of 5-10% of autism. This is an interdisciplinary effort that brings together cutting-edge technology in next-generation sequencing and CNV characterization to identify genes associated with autism. PUBLIC HEALTH RELEVANCE: This proposal will advance human health by developing a systematic strategy for the identification of mutations and genes associated with autism and it will optimize new technology for the characterization of patient genomes for pathogenic copy-number variation and point mutations associated with complex genetic disease. The diagnostic impact of this study is particularly high and will lead to the early diagnosis of children with molecular lesions and the genetic classification of different causes of autism. Such subcategorizations of autism will significantly enhance phenotypic characterization leading to future downstream treatments and interventions for autism.
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1 |
2010 — 2013 |
Eichler, Evan |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Human Genome Sructural Variation @ University of Washington
DESCRIPTION (provided by applicant): The discovery of genome structural variants has increased exponentially with the application of next generation sequencing (NGS) technologies. The current approaches, however, are particularly biased against variants of a particular size and sequence context. Most notable is the skew against highly duplicated regions-regions enriched in genes and disease-causing variation. This program project will focus on the sequence characterization of more complex structural genetic variation with a particular emphasis on regions of biomedical relevance. The approach will be to leverage existing and new clone resources in combination with next-generation sequencing technologies to target variation that has not been adequately assessed for copy, content and structure. The specific aims of this proposal are to 1) discover, sequence and integrate novel insertion sequences, duplicated regions of high diversity, and recurrent structural variants into the human reference genome; 2) develop a next-generation sequencing based platform to accurately predict copy number and sequence content of duplicated genes for 2,000 genomes being analyzed as part of the 1000 Genomes Project; and 3) generate a BAC clone resource (n=18 individuals) and completely sequence and characterize structurally variant haplotypes for 20 biomedically relevant loci where structural variation predisposes to disease. This program project is a collaborative effort that brings together expertise in large scale genome sequencing, library production and structural variation. This work will provide fundamental information that will inform and complement efforts as part of the 1000 Genomes Project's Structural Variation Initiative and the Genome Reference Consortium. It will continue to develop the first high-quality reference set of sequenced variants, provide insight into the molecular mechanisms underlying these differences, and lead to the development of genot5rping platforms that will be needed to assess the phenotypic consequences of these regions in terms of human disease and adaptation.
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1 |
2010 — 2013 |
Eichler, Evan E. |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Discovery @ University of Washington
In this project, we propose to discover, sequence and integrate into the human genome three classes of refractory structural variation. This will include novel insertions not present with the reference sequence, regions of recurrent copy-number variation, and duplicated regions of high sequence diversity. Using an existing fosmid clone resource from 16 reference individuals, we will identify and subclone these regions, generate high-quality sequence commensurate with the human genome, and assess copy-number variation of these regions. We predict that this project will recover and characterize 1,575 loci that will be difficult to fully characterize by other experimental and computational approaches. The advantage of our approach is that it utilizes the entire sequence of the clone to determine the complete context of this variation. Our goal will be to integrate this high-quality sequence into the reference genome as alternate haplotypes that may be annotated and further characterized. This work will, thus, complement ongoing efforts as part of the 1000 Genomes Project and Genome Reference Consortium to comprehensively assess the complete spectrum of human genetic variation.
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1 |
2010 — 2013 |
Eichler, Evan |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Clone Characterization and Sequencing @ University of Washington
We will apply next-generation sequencing (NGS) technology to assess the genome-wide pattern of structural variation within large (>20 kbp), complex regions of segmental duplication. Combining read-depth and a single-base unique nucleotide (SUN) identifier map, we will generate absolute estimates of diploid copy-number and sequence content for duplicated regions and gene families. We propose to analyze all 2,000 individuals being analyzed as part of the 1000 Genomes Project and to validate regions by a combination of array comparative genomic hybridization (arrayCGH), clone-based sequencing and FISH-based approaches. This aim will provide the first genotypic assessment of copy and content of these complex regions facilitating future disease association studies.
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1 |
2011 — 2013 |
Eichler, Evan Mefford, Heather C (co-PI) [⬀] |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
7 of 7 Epi 4k: Copy Number Variants Project @ University of Washington
DESCRIPTION (provided by applicant): The primary goal of the Epi4K Center Without Walls is to increase understanding of the genetic basis of human epilepsy in order to improve the well-being of patients and family members living with these disorders. This improvement will come in the form of better diagnostics, treatments and cures. To accomplish this goal, Epi4K aims to analyze the genomes of a large number of well-phenotyped epilepsy patients and families collected by investigators from several major research groups. The specific goals of this project (7 of 7 - CNV Detection) are to discover copy number variants (CNVs) from exome and whole genome sequence data; to describe the CNV landscape in epilepsy patients compared to controls; and to evaluate the broader impact of a subset of CNVs in a large case-control comparison study. Dr. Evan Eichler of Genome Sciences and Dr. Heather Mefford of Pediatrics & Genetic Medicine will co-direct this project. The discovery of novel, disease-related CNVs in the Epi4K cohorts will further our understanding of epilepsy genetics and lead to the identification of new epilepsy genes and pathways.
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1 |
2011 |
Eichler, Evan E. Goldstein, David B. [⬀] Heinzen Cox, Erin L Mefford, Heather C (co-PI) [⬀] Shianna, Kevin |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
3 of 7 Epi4k: Sequencing, Biostatistics &Bioinformatics Core
DESCRIPTION (provided by applicant): The primary goal of the Epi4K Center Without Walls is to increase understanding of the genetic basis of human epilepsy in order to improve the well-being of patients and family members living with these disorders. This improvement will come in the form of better diagnostics, treatments and cures. To accomplish this goal, Epi4K aims to analyze the genomes of a large number of well-phenotyped epilepsy patients and families collected by investigators from several major research groups. The specific goals of this core (3 of 7 - Sequencing, Biostatistics, and Bioinformatics Core) are to 1) sequence and annotate 4,000 genomes, 2) develop computational procedures for calling CNVs in whole exome data, 3) identify and prioritize variants of interest for all three projects, 4) conduct follow up genotypin analyses in a cohort of additional cases and controls, and 5) quickly and efficiently share data among the Epi4K consortium. PUBLIC HEALTH RELEVANCE: Epilepsy is one of the most common human neurological disorders, affecting 3% of the population. Although it is clear that there is a strong genetic component for epilepsy, there are still only a few genes known. The Epi4K project will identify new genes and genetic pathways in epilepsy and will directly benefit individuals with epilepsy and their families through improved diagnostic, prognostic and recurrence risk information. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of th individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.
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0.928 |
2012 — 2018 |
Eichler, Evan Goldstein, David B. [⬀] Heinzen Cox, Erin L Mefford, Heather C |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
3 of 7 Epi4k: Sequencing, Biostatistics & Bioinformatics Core @ Columbia University Health Sciences
DESCRIPTION (provided by applicant): The primary goal of the Epi4K Center Without Walls is to increase understanding of the genetic basis of human epilepsy in order to improve the well-being of patients and family members living with these disorders. This improvement will come in the form of better diagnostics, treatments and cures. To accomplish this goal, Epi4K aims to analyze the genomes of a large number of well-phenotyped epilepsy patients and families collected by investigators from several major research groups. The specific goals of this core (3 of 7 - Sequencing, Biostatistics, and Bioinformatics Core) are to 1) sequence and annotate 4,000 genomes, 2) develop computational procedures for calling CNVs in whole exome data, 3) identify and prioritize variants of interest for all three projects, 4) conduct follow up genotypin analyses in a cohort of additional cases and controls, and 5) quickly and efficiently share data among the Epi4K consortium.
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0.97 |
2013 — 2016 |
Eichler, Evan |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sporadic Mutations and Autism Spectrum Disorders @ University of Washington
DESCRIPTION (provided by applicant): Sporadic point mutations and large copy number variants (CNVs) contribute significantly to the etiology of autism but relatively few genes have been proven to be pathogenic. The goal of this project is to identify genes responsible for autism spectrum disorder (ASD) and developmental delay. We will apply an integrated approach combining exome sequence data and detailed ab initio CNV analysis to pinpoint likely candidate genes. We will test these candidates for an excess of de novo disruptive mutations in case versus control trios. There are three specific aims: 1) Expand our existing CNV morbidity map to include data from >40,000 cases of developmental delay versus 20,000 controls and integrate these data with emerging exome data to identify likely haploinsufficient genes; 2) Assess whether the burden of disruptive de novo mutations in these genes is significantly enriched in ASD families by molecular inversion probe (MIP) resequencing of approximately 6,200 cases and 6,200 controls; and 3) Select ten genes with the highest burden of de novo mutations for further clinical evaluation, phenotypic variability, and comprehensive genetic characterization. The end product of this analysis will be the identification and characterization of highly penetran genic mutations that contribute significantly to etiology of autism, providing targets for clinical diagnostics and future therapeutics.
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1 |
2014 |
Eichler, Evan Goldstein, David B. [⬀] Heinzen Cox, Erin L Mefford, Heather C (co-PI) [⬀] |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
3 of 7 Epi4k: Gene Discovery in 4,000 Epilepsy Genomes
DESCRIPTION (provided by applicant): The primary goal of the Epi4K Center Without Walls is to increase understanding of the genetic basis of human epilepsy in order to improve the well-being of patients and family members living with these disorders. This improvement will come in the form of better diagnostics, treatments and cures. To accomplish this goal, Epi4K aims to analyze the genomes of a large number of well-phenotyped epilepsy patients and families collected by investigators from several major research groups. The specific goals of this core (3 of 7 - Sequencing, Biostatistics, and Bioinformatics Core) are to 1) sequence and annotate 4,000 genomes, 2) develop computational procedures for calling CNVs in whole exome data, 3) identify and prioritize variants of interest for all three projects, 4) conduct follow up genotypin analyses in a cohort of additional cases and controls, and 5) quickly and efficiently share data among the Epi4K consortium.
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0.97 |
2016 — 2018 |
Dutcher, Susan K [⬀] Eichler, Evan |
U24Activity Code Description: To support research projects contributing to improvement of the capability of resources to serve biomedical research. |
High Quality Human and Non-Human Primate Genome Assemblies
? DESCRIPTION (provided by applicant): A collection of diverse and highly accurate primate genomes are critical to further our understanding of human variation and the evolutionary context of genetic disease. The main goal of this proposal is to generate high quality reference genomes that better represent the complexity of human diversity (i.e., continental human reference genomes) and that significantly improve the quality of index non-human primate (NHP) genomes, reaching a quality level more in line with the current human genome (GRCh38). We have selected 8 human genomes and 8 NHP for de novo sequencing and assembly using single molecule real-time sequencing followed by extensive higher-level resolution using experimental approaches. The end-result will be a set of NHP genomes that represent a >10-20 fold improvement in assembly continuity and representation of each and human genomes where >95% of euchromatic unique regions are fully sequenced, annotated, and phased. This project includes a special emphasis on gaps and gene-rich complex sequence structure, which have been the most intractable euchromatic regions of primate genomes. While there are many metrics of genome assembly completion and sequencing, ours is a practical one. The goal of this project is complete euchromatic sequence where >95% of the bases are ordered and oriented, and >95% of gene models are complete and annotated. Assemblies based on improved genome scaffolding or simple phasing of short read data using synthetic long reads add value but do not meet the needs of most researchers who are interested in studying gene models, gene regulation, and genetic variation. The community requires that sequence gaps are resolved and each genome is assembled at high contiguity. Our strategy is to deliver quality over quantity, and as such we are focused on a smaller subset of genomes delivered at the highest quality, building upon very recent advances in sequencing technology and assembly.
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1 |
2017 — 2021 |
Eichler, Evan |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Rare Mutations and Autism Spectrum Disorders @ University of Washington
ABSTRACT Sporadic point mutations and large copy number variants (CNVs) contribute significantly to the etiology of autism but most of the genetic architecture has not yet been understood. Most CNVs associated with autism are large and the majority of pathogenic genes have not been proven. The goal of this proposal is to significantly increase the yield of high-impact autism mutations by focusing on the discovery of understudied classes of rare variants from whole-genome sequence data being generated from 35,000 samples from autism families. This proposal focuses on rare, gene-disruptive mutations and leverages the additional sensitivity afforded by whole-genome shotgun sequencing data, novel CNV discovery methods, and particular patterns of gene-disruptive and missense mutation to increase yield of pathogenic mutations. Our target will include the discovery and validation of smaller and more complex structural variants (including CNVs), clustered de novo missense mutations, and private, gene-disruptive mutations transmitted preferentially from mothers to sons. We will test these candidates by rapid targeted sequencing in 15,000 additional cases where patient recontact and familial follow-up is possible. We propose to select 10 genes with the highest burden of mutation for further clinical evaluation, phenotypic variability, and comprehensive genetic characterization. This proposal specifically focuses on application of novel genomic methods, recurrent mutations, and inheritance patterns to discover pathogenic variants in order to develop a more sophisticated model to explain the genetic architecture of autism. As part of this effort, we will quantify and compare the risk of different classes of mutation for autism and investigate transmission disequilibrium differences depending on the parent of origin and gender of proband. The end product of this analysis will be the identification and characterization of new classes of highly penetrant genic mutations that contribute significantly to etiology of autism, providing targets for clinical diagnostics and future therapeutics.
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1 |
2018 |
Dutcher, Susan K [⬀] Eichler, Evan |
U24Activity Code Description: To support research projects contributing to improvement of the capability of resources to serve biomedical research. |
Improving Detection and Interpretation of Clinically Relevant Structural Variation
Project Summary At present, funding for improving the human reference (U24 HG009081 and U41 HG00763504) has produced 2 haploid (hydatidiform moles) and 15 collapsed diploid human genomes using PacBio sequencing together with Bionano physical maps and 10X Genomics data. Efforts are currently underway to resolve these collapsed genomes into haplotype-resolved assemblies. The goal will be to generate a broader spectrum of human genetic variation with haplotype- resolved genomes. For this supplement, we propose to sample additional cell lines that will help to increase the human reference diversity through efforts at The McDonnell Genome Institute at Washington University, The University of Washington, and Nationwide Children?s Hospital.
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1 |
2018 — 2021 |
Eichler, Evan |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sequence-Resolved Structural Variation of Human Genomes @ University of Washington
Understanding the genetic basis of human disease requires a comprehensive assessment of the full spectrum of human genetic variation. Genome structural variation, including larger deletions, insertions, and inversions (>50 bp), has been more difficult to characterize due to the association with repetitive DNA. The majority of structural variation, including common structural variants or SVs, has not yet been discovered using short-read whole-genome datasets and standard SV callers. Advances in sequencing technology over the last three years, however, have made the systematic discovery of this variation possible for the first time. This proposal focuses on the discovery, sequence resolution, and genotyping of the most complex and under-ascertained forms of human genetic variation, including multi-copy number variants (mCNVs), inversions, and intermediate- size insertions and deletions. We target a diversity panel of 34 human genomes and partition long-read single- molecule, real-time sequencing data using 10X linked reads and Strand-seq data in order to fully phase and sequence-resolve SVs on each human haplotype. Using these long-read sequence data, we further develop a computational graph-based approach to distinguish and assemble distinct copies underlying large mCNVs mapping to high-identity segmental duplications. Finally, we take advantage of the sequence structure, including breakpoints and sequence differences among the copies, to more accurately genotype these variants in a diversity panel of >2,800 human genomes where short-read whole-genome sequence data are already available. The work will develop new methods to characterize more complex forms of human genetic variation and provide fundamental insight into their diversity, mechanism of origin, and mutational properties. This research has the additional benefit that it will improve genome assembly, characterize new human genome sequence, identify a large class of missing genetic variation, and provide us with the ability to systematically explore this form of human genetic variation as part of disease-association studies.
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1 |
2019 — 2021 |
Eichler, Evan Jarvik, Gail Pairitz (co-PI) [⬀] Nickerson, Deborah A [⬀] |
OT2Activity Code Description: A single-component research award that is not a grant, cooperative agreement or contract using Other Transaction Authorities |
Northwest Genomics Center For All of Us @ University of Washington
The goal of the Northwest Genomics Center for All of Us (NWGC) is to provide high-throughput genotyping and whole genome sequencing (WGS) for individuals enrolled in the All of Us Research Program using a highly successful pipeline that has produced genotyping on nearly two hundred thousand samples and tens of thousands of high quality human genomes. The Northwest Genomics Center brings together three internationally recognized PIs (Nickerson (Contact), Eichler, and Jarvik), with decades of expertise in high-throughput clinical genomics and, together with their Co-Investigators, have returned tens of thousands of variant interpretations to patients. As we have done in the past with other NIH programs, we will coordinate our efforts with the All of Us program team in the National Center for Advancing Translational Sciences (NCATS), the other centers in the program such as the Data and Research Center (DRC) and the Biobank, and other Genome Centers if selected. To advance the goals and objectives of the All of Us Research Program we will produce and interpret variants from genotyping arrays for up to 100,000 samples in year 1 and up to 200,000 samples in years 2 - 5. We will also produce and interpret variants on more than 10,000 samples by WGS in year 1; up to 100,000 samples in year 2; and up to 200,000 samples in years 3-5 using the Illumina NovaSeq platform. To accomplish this, we will: 1- Work with the All of Us program, the DRC, the Biobank, and other groups to deliver an efficient and effective process for evaluating and completing high-throughput genotyping and WGS, call variants, and interpret the impact of variants in the ACMG 59 genes and other genes as indicated by the program in a CLIA-certified environment. 2- Interact directly with the Biobank to carefully develop the logistics and methods for preparing and receiving samples. 3- Track all samples and data transfers for all samples at every stage of the process (from project initiation to data delivery using our secure, completely interactive, and integrated laboratory information management system (LIMS)) and provide reports to the program, the DRC, and other groups as required. 4- Provide genotype and WGS data of the highest quality, in formats required by the program such as IDAT files for genotyping and CRAMs and VCFs for WGS. 5- Provide a team of specialized personnel and staff versed in the workflow of a well-established high-throughput CLIA-certified genome center. These include individuals specifically trained in DNA sample receipt, quality control, and large-scale bioinformatics analysis and variant interpretation. 6- Assist as needed with additional data interpretation (beyond the ACMG genes), with publications (i.e., materials and methods), and other activities as required for the program. 7- Provide secure backup of raw sequence data from the samples and all metadata associated with the project (i.e., sample tracking, storage, and QC information). The NWGC has worked successfully for more than 20 years with the NIH on a number of impactful, large-scale projects, and has a highly experienced team with a proven track record that is empowered by a robust administrative, computational, and instrumentation infrastructure that is state-of-the-art and can rapidly facilitate the goals of the All of Us Research Program. Depending on the needs of All of Us, the NWGC is flexible to handle the minimum number of samples proposed in all years while also being able to quickly scale to accommodate the maximum throughput needed by the All of Us Research Program (Table 1). The NWGC has extensive experience scaling in a short timeframe and has always met project goals and deadlines. The NWGC has a complete understanding of the requirements needed to be a full partner for the All of Us program and is fully capable and prepared.
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1 |
2019 |
Eichler, Evan Hall, Ira M Haussler, David H [⬀] |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Center For Human Reference Genome Diversity @ University of California Santa Cruz
Project Abstract The goal of our Center for Human Reference Genome Diversity is to generate as error-free, gapless, complete, and correctly haplotype-phased genome assemblies as possible from a set of 350 persons comprehensively capturing the full extent of human diversity. We aim to capture >99% of allelic variants with >1% allele frequency, and to provide these genomes as a resource to the international community to enable genomic medicine and research addressing fundamental unanswered questions in biology and disease. We will employ a multi-platform approach using cutting-edge long read and linked read technologies to obtain the highest quality phased genomes. Aim 1 will focus on sample collection and procuring cell lines from at least 350 individuals with a specific emphasis on filling in gaps in human diversity. Aim 2 will generate highly contiguous chromosomal level assemblies that are over 99% haplotype-phased for at least 700 haploid genomes from 350 diploid samples. Aim 3 will finish these genomes to be gapless from telomere-to-telomere (T2T) for each chromosome. Aim 4 will evaluate the genomes for accuracy and completeness and perform initial variant calling to assess the level of human diversity. We will use a novel combination of technologies, sequencing strategies, and algorithms that we and others developed to produce the highest quality and most complete genome assemblies to date. Our effort will specifically target regions that have been excluded by other efforts, including segmental duplications, centromeres, and acrocentric DNA. To achieve these aims we have assembled an exceptional team consisting of leaders from around the world in consent ethics, sample collection, sample extraction, and high-quality genome sequencing, assembly, finishing and evaluation. The team also has expertise in using genomic technologies to address a broad range of scientific questions, so is highly cognizant of the practical needs of biomedical researchers who will use this resource. The high-quality genomes produced will be passed to the Human Reference Genome Center (HGRC) and Genome Reference Representation (GRR) groups for curation and release. The result will be a pan-human genome reference, representing important human diversity not present in the current reference genome. The data we generate will enable a fundamental shift in human genetics, fostering new discoveries from the single-nucleotide to chromosomal levels and revealing a more accurate and global view of the human population.
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0.94 |
2020 — 2021 |
Chaisson, Mark [⬀] Eichler, Evan Marschall, Tobias |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Representing Structural Haplotypes and Complex Genetic Variation in Pan-Genome Graphs @ University of Southern California
Title: Representing structural haplotypes and complex genetic variation in pan-genome graphs. PROJECT SUMMARY A pan-genome graph (PGG) reference must faithfully reflect structural haplotypes that differ in copy number, order, and orientation, which are currently poorly represented in a linear reference sequence. This effort focuses on the most copy variable and complex regions, including segmental duplications (SDs), inversions, short tandem repeats/variable number tandem repeats (copy-number-variable repeats, CNVRs) and combinations thereof that are frequently excluded or collapsed in reference genomes. The overarching goal of this project is to develop the tool infrastructure enabling the construction of whole-chromosome reference haplotypes that include all of these difficult classes of sequence. There are four specific aims. First, we will develop methods to construct PGGs from haplotype-phased de novo assemblies, ensuring the graph reflects both copy number variation and repeat structure, including CNVRs and SD. Second, we will develop software that will expand SD assembly methods to facilitate the curation of SD loci in PGGs. We will use SD assembly to detect variants specific to individual copies of a duplication, called paralog-specific variants (PSVs), and provide software to reconstruct local haplotype paths through the PGG that describe the different copies. Third, we will design novel methods to exploit single-cell template strand DNA sequencing data (Strand-seq) mapped to PGGs in order to thread chromosome-length structural haplotypes through the graph. Therefore, our software tool will allow the physical resolution of haplotypes comprising the full spectrum of structural variation, including inversions and inverted duplications. By virtue of the PSVs, the structural haplotypes will also embed sequence-resolved SDs. Fourth, we will develop a scalable open-source software framework to systematically assess how the inclusion of single-nucleotide variants, short indels, and structural variant classes in the PGG affects variant detection with short-read data. This will enable the optimization of the complexity encoded in the PGG for short-read variant detection. It will additionally provide a comprehensive view on polymorphic and fixed k-mers in human populations. We will develop tools to detect allele-specific k-mers and demonstrate how that enables the rapid genotyping of variants in the PGG based on k-mer composition of a short-read dataset. Once the framework for enhanced genome representation is established, we will focus on improving efficiency, scalability, and computational ease to cater to the needs of a broad range of users in genetics and genome science. This proposal will ensure that the most complex regions of the human genome are encoded into the PGG and that underlying genetic variation is ultimately assessed for association with disease. ?
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0.943 |
2020 — 2021 |
Eichler, Evan |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Interdisciplinary Training in Genome Sciences @ University of Washington
ABSTRACT We request funds to continue the interdisciplinary training program in genomics at the University of Washington and affiliated institutions. The program focuses on preparing pre- and postdoctoral trainees for a research career in genomics and computational biology with an emphasis on translational research. Trainees will engage in projects that include discovering how a genome encodes the information for RNAs, proteins and its own structure and replication; measuring and analyzing sequence variation; developing technologies for high-throughput experimental assays including-next generation sequencing; and generating computational tools to analyze genomic variants and their impact on mRNA and protein function. As these research challenges demand interdisciplinary approaches and multidisciplinary collaborations, one goal of this program is to attract individuals trained in computer science, statistics, physics, and engineering to biological research. Another goal is to train cellular and molecular biologists to incorporate genomic- based quantitative analyses in their research to allow them to effectively collaborate at this interdisciplinary interface. Given the wide diversity in educational backgrounds and career goals among our trainees, the program emphasizes highly individualized training programs and interdisciplinary research. A multidisciplinary group of 51 faculty, selected for their involvement in genome analysis and their strong record of collaborative interactions, comprises the training team. Research experience is complemented with a variety of didactic courses and electives. The trainees are also exposed to discussions on ethical research conduct and the ethical, legal, and social implications of genomic research. Breadth of knowledge and program cohesion are achieved through trainee participation in two seminar series that feature genomic research and computational biology, journal clubs, and research reports. In the coming five years, we will continue to expand our program in genomics, proteomics, instrumentation development, computational biology, and statistical genomics. We request funds to train 12 predoctoral and 4 postdoctoral fellows per year. The trainees will emerge with the skills necessary for success in the academic and biomedical research environment of the 21st century made possible by advances in genomics.
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1 |
2020 |
Eichler, Evan |
R25Activity Code Description: For support to develop and/or implement a program as it relates to a category in one or more of the areas of education, information, training, technical assistance, coordination, or evaluation. |
Diversity Action Plan: Uw Genom Project @ University of Washington
ABSTRACT The overarching goal of the UW GenOM Project is to sustain and continue to develop a comprehensive umbrella program for undergraduates at the University of Washington to coordinate recruitment, retention and training activities for groups that are significantly underrepresented in genomic sciences and genetic medicine. The program will focus on Blacks/African Americans, Hispanic/Latinx Americans, Native Americans, Alaska Natives, Native Hawaiians, and Pacific Islanders. Additional emphases will be on serving students who come from disadvantaged backgrounds (rural, low income, students with disabilities, and those who come from low resource schools). The proposal will build upon the success of the UW GenOM Project to date, affiliated on- campus resources for underrepresented minority and underserved students, as well as the expertise of the scientists and faculty in the University of Washington?s department of Genome Sciences, the UW Genome Training Grant, other NIH-funded research centers and training grants, and other relevant departments on campus. The program will increase the numbers of genomic-science focused students from underrepresented minority and underserved populations who graduate with a bachelor?s degree and matriculate into graduate programs in genomic sciences, genetic medicine, and allied fields.
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1 |
2021 |
Bamshad, Michael Joseph Eichler, Evan Nickerson, Deborah A [⬀] |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
University of Washington Mendelian Genomics Research Center (Uw-Mgrc) @ University of Washington
PROJECT SUMMARY/ABSTRACT The genetic basis of >2,920 Mendelian conditions (MCs) remains unknown, and hundreds of novel MCs are described each year. Our group has, in partnership with 2,379 investigators from 656 institutions in 55 countries, assessed 15,387 samples from 5,675 families and has, over the past decade, identified genes for 1379 MCs, including 915 novel discoveries. The translation and impact of these discoveries on diagnostics and clinical care has been immediate and substantial. Additionally, we have developed multiple new analytical tools including CADD, PRIMUS, CoNIFER, SMRT-SV, RV-TDT, as well as methodological innovations including MIPs, smMIPs, and approaches for low input exome and genome sequencing (ES/WGS). We are also deeply committed to open data sharing with rolling submission of exome and genome data to the AnVIL (1,439 deposited); development of a MatchMaker Exchange node (http://MyGene2.org) that enables public sharing of genotype and phenotypic data among families, researchers, and clinicians; and creation of a public data browser (http://geno2mp.gs.washington.edu) that links de-identified, individual-level genotypes from over 18,000 exomes/genomes to individual phenotypes. In this application, we build upon these successes to establish the University of Washington Mendelian Genomics Research Center (UW-MGRC) with the overarching goal to maximize novel gene discovery for MCs, with an emphasis on canonical MCs that have gone unsolved using ES/WGS, and noncoding variants underlying MCs. To this end, we will develop novel approaches to inform variant interpretation and functional validation for the human genetics community at-large and disseminate results, data, and tools openly. We will capitalize on immediate access to sequence-ready samples from ~300 MCs (>26,000 samples), 1,500 samples suspected of harboring a causal noncoding variant for a MC, and an aggressive sample solicitation plan in partnership with industry, academic centers, and other NIH programs. We propose three specific aims: (1) maximize novel gene discovery for MCs by solicitation, sequencing, and analysis of families with unexplained (i.e., no known underlying gene) MCs; classic MCs considered high priority by the clinical genetics community and that have been recalcitrant to gene discovery efforts; and cases that remain unsolved after prior exome or genome sequencing. (2) Develop new strategies for gene discovery for unsolved MCs caused by variants that are difficult to detect or of unknown functional effects (e.g., structural variants, repeat expansions, cryptic splice, regulatory, etc.), and/or unusual modes of inheritance, and, in doing so, characterize the genetic architecture of pathogenic noncoding variants underlying MCs. Implement high- throughput screening and targeted follow-up functional studies to prioritize and validate assertions of pathogenicity of candidate noncoding variants. (3) Take a leadership role to openly and publicly, when feasible, share sequencing and rich phenotypic metadata, methods, and knowledge, to empower investigators worldwide and accelerate the pace of gene discovery.
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1 |