HomeResearchExtramural ResearchThe Large-Scale Genome Sequencing Program LSGS: Center Initiated Projects

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Large-scale Genome Sequencing Program

Medical Sequencing Cancer Sequencing Project Mendelian Disorders X-Linked Disorders Allelic Spectrum of Common Disease Center Initiated Projects

Structural Variation

Pathogens and Vectors (with NIAID)

Annotating the Human Genome Multiple Mammalian Genomes for Comparative Annotation Primate Genomes Y chromosomes Individual Species Center Initiated Projects

Comparative Genome Evolution Sequencing the Human Microbiome Origins of Multicellularity Evolution of the Human Proteome Individual Species

Allied Sequencing Programs The Cancer Genome Atlas (with NCI) Genes, Environment, and Health Initiative (trans-NIH)

Center Initiated Projects

Program Rationale

Most of the sequencing targets for the National Human Genome Research Institute (NHGRI) Large-Scale Sequencing Program are selected and approved by mechanisms independent of the funding of the large-scale sequencing centers. However, the sequencing centers may undertake their own projects using up to 10 percent of their annual funds.

All Center Initiated Projects (CIPs) are subject to approval by NHGRI staff. These projects allow the centers to engage in sequencing-related research that the centers are uniquely capable of approaching.

CIPs are subject to the same data release and human subjects policies as all other NHGRI-funded large-scale sequencing projects.

Active Center Initiated Projects

The Breast Cancer Genome Atlas Project - Pilot Phase

Washington University Genome Sequencing Center [genome.wustl.edu]

Breast cancer affects thousands of individuals in the United States every year. While new therapeutic advances have reduced the mortality rate, some patients still have poor outcomes with standard multidisciplinary breast cancer therapy. Breast cancer exists as several distinct subtypes that exhibit diverse clinical phenotypes and associated genetic anomalies. Breast cancer subtype has been correlated with responsiveness to therapy and outcome.

The Breast Cancer Genome Atlas aims to better understand the molecular basis of poor breast cancer outcomes by comparing the sequences of genes known or suspected to be involved in breast cancer between normal tissue, and several cancer subtypes.

Examples of questions that may be answered based on knowledge of the gene sequence differences between different breast cancer subtypes are the following:

• Are there common genetic factors that affect outcome across breast cancer subtypes?
• Does each breast cancer subtype have a specific genetic profile?
• Can researchers predict treatment response based on genetic factors of the tumor?

In this pilot phase, researchers will develop and validate new techniques designed to overcome difficulties with obtaining and interpreting genome sequence information from breast cancer samples. Specifically, the pilot will develop new laser capture micro dissection (LCM) and whole genome amplification (WGA) techniques to overcome tumor heterogeneity and low genomic yield issues that can be prevalent in many kinds of tumors. The pilot phase will entail sequencing of three genes that are typically mutated in breast cancer (PTEN, PIK3CA, and TP53) in 94 well-characterized tumor blocks representing diverse subtypes of breast cancer that range from 30 to greater than 90 percent neoplastic cellularity. Sequencing of pilot phase samples will be used to evaluate the relative potential for mutation detection in LCM and non-LCM samples based on the proportion of neoplastic cells in the samples to establish a standard for future studies. If the pilot phase is successful, a proposal will be developed for an expanded effort to sequence many more genes in a larger, subtype-specific collection of samples.

Studying Balancing Selection in the Human Lineage by Medical Sequencing

NIH Intramural Sequencing Center (NISC) [www.nisc.nih.gov]

An initial study of balancing selection (maintenance of polymorphism frequencies within a population) showed population-specific patterns of selection between African-American and European-American populations. If these population-specific patterns of selection are found within disease-related genes, they may be responsible for differing disease risk among human populations. Understanding the global patterns of variation in the genes, the origin of their variants and the evolutionary forces that shape polymorphism levels in human populations may provide insight into disease risk assessment and diagnosis.

Researchers will expand upon their initial study by examining putative targets of balancing selection in the context of different populations worldwide. The first phase of this study will focus on 3 genes involved in histocompatability and immunity (AKAP13, ERAP1/ARTS1 and ERAP2/LRAP). The second phase will involve genes with signals of balancing selection in African-Americans that have been lost in European-Americans. In each phase, there will be a pilot project in which 48 individuals will be sequenced. Sequencing an additional 122 diverse individuals is conditional on the results of the pilot phase.

Skin Microbiome Sequencing

NIH Intramural Sequencing Center (NISC) [www.nisc.nih.gov]

The Human Microbiome Project (HMP), approved as part of the trans-NIH Roadmap Initiative in May 2007, seeks to develop a reference set of microbial genomes to serve as the basis for future metagenomic studies of the human body. Intramural investigators at the National Institutes of Health have completed a pilot study of the human skin microbiome and have prepared a clinical protocol for further investigations modeled around Atopic dermatitis (AD). AD is an inflammatory skin disease that affects around 15 percent of children and over 15 million people total in the United States. Studies have begun to focus on microbial interactions that may affect AD. The goal of this study will be to define parameters for the study of the interaction between the human skin microbiome and disease through 16S sequencing.

Researchers will complete a set of four pilot projects based on the data from the preliminary pilot study. These pilot projects will include various sampling sites and methods in healthy volunteers, volunteers with AD and animal models. The first pilot project will be an effort to determine the number of sites needed to define a core skin microbiome and compare sampling methods. The second pilot project involves a comparison of bacterial cell culturing strategies to select for a dominant set of skin bacteria. The third pilot project is a longitudinal survey of the mouse skin microbiome. The last pilot project is planned as a characterization of skin microflora in humans affected by AD.

Population Genetics and Evolution of CD33-related Siglecs in Hominids

NIH Intramural Sequencing Center (NISC) [www.nisc.nih.gov]

Siglecs are a family of sialic-acid-binding immunoglobulin-like lectins that have the potential to mediate both cell-cell interactions and signaling functions in immune systems of various species. There have been 15 primate Siglecs identified in previous research. In particular, CD33-related Siglecs have shown rapid evolution through multiple processes. Studies have shown evidence that Siglecs are active in mammalian inflammatory and immune response.

Researchers will study the cluster of seven Siglec genes on human chromosome 19 in human, chimpanzee, gorilla and orangutan samples to understand the evolutionary forces that have driven the diversification of Siglecs in the human lineage to provide insight into the genetic basis of pathogen infections and prevalent human autoimmune diseases.

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Last Updated: August 12, 2008