76 FR 66076 - National Human Genome Research Institute; Notice of Closed Meeting

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2011-10-25

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Human Genome... Call). Contact Person: Camilla E. Day, PhD, Scientific Review Officer, CIDR, National Human Genome... Assistance Program Nos. 93.172, Human Genome Research, National Institutes of Health, HHS) Dated: October 19...

75 FR 80509 - National Human Genome Research Institute; Notice of Closed Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-22

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Human Genome... Call). Contact Person: Camilla E. Day, PhD, Scientific Review Officer, CIDR, National Human Genome... Assistance Program Nos. 93.172, Human Genome Research, National Institutes of Health, HHS) Dated: December 16...

Genome-wide prediction of vaccine targets for human herpes simplex viruses using Vaxign reverse vaccinology

PubMed Central

2013-01-01

Herpes simplex virus (HSV) types 1 and 2 (HSV-1 and HSV-2) are the most common infectious agents of humans. No safe and effective HSV vaccines have been licensed. Reverse vaccinology is an emerging and revolutionary vaccine development strategy that starts with the prediction of vaccine targets by informatics analysis of genome sequences. Vaxign (http://www.violinet.org/vaxign) is the first web-based vaccine design program based on reverse vaccinology. In this study, we used Vaxign to analyze 52 herpesvirus genomes, including 3 HSV-1 genomes, one HSV-2 genome, 8 other human herpesvirus genomes, and 40 non-human herpesvirus genomes. The HSV-1 strain 17 genome that contains 77 proteins was used as the seed genome. These 77 proteins are conserved in two other HSV-1 strains (strain F and strain H129). Two envelope glycoproteins gJ and gG do not have orthologs in HSV-2 or 8 other human herpesviruses. Seven HSV-1 proteins (including gJ and gG) do not have orthologs in all 40 non-human herpesviruses. Nineteen proteins are conserved in all human herpesviruses, including capsid scaffold protein UL26.5 (NP_044628.1). As the only HSV-1 protein predicted to be an adhesin, UL26.5 is a promising vaccine target. The MHC Class I and II epitopes were predicted by the Vaxign Vaxitop prediction program and IEDB prediction programs recently installed and incorporated in Vaxign. Our comparative analysis found that the two programs identified largely the same top epitopes but also some positive results predicted from one program might not be positive from another program. Overall, our Vaxign computational prediction provides many promising candidates for rational HSV vaccine development. The method is generic and can also be used to predict other viral vaccine targets. PMID:23514126

75 FR 62548 - National Human Genome Research Institute; Notice of Closed Meeting

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2010-10-12

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Human Genome... Call). Contact Person: Camilla E. Day, PhD, Scientific Review Officer, CIDR, National Human Genome...- 402-8837, [email protected] . Catalogue of Federal Domestic Assistance Program Nos. 93.172, Human...

76 FR 9031 - National Human Genome Research Institute; Notice of Closed Meeting

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2011-02-16

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Human Genome... Call). Contact Person: Camilla E. Day, PhD, Scientific Review Officer, CIDR, National Human Genome...- 402-8837, [email protected] . (Catalogue of Federal Domestic Assistance Program Nos. 93.172, Human...

76 FR 65204 - National Human Genome Research Institute; Notice of Meeting

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2011-10-20

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Human Genome..., National Human Genome Research Institute. The meeting will be open to the public as indicated below, with..., discussion, and evaluation of individual intramural programs and projects conducted by the National Human...

75 FR 60467 - National Human Genome Research Institute; Notice of Meeting

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2010-09-30

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77 FR 64816 - National Human Genome Research Institute; Notice of Closed Meeting

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2012-10-23

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Human Genome... Conference Call). Contact Person: Camilla E. Day, Ph.D., Scientific Review Officer, CIDR, National Human..., Human Genome Research, National Institutes of Health, HHS) Dated: October 16, 2012. David Clary, Program...

76 FR 50486 - National Human Genome Research Institute; Notice of Closed Meeting

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2011-08-15

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Human Genome... Conference Call). Contact Person: Camilla E. Day, PhD, Scientific Review Officer, CIDR, National Human Genome...- 402-8837, [email protected] . (Catalogue of Federal Domestic Assistance Program Nos. 93.172, Human...

Human Genome Program Report. Part 1, Overview and Progress

DOE R&D Accomplishments Database

1997-11-01

This report contains Part 1 of a two-part report to reflect research and progress in the U.S. Department of Energy Human Genome Program from 1994 through 1996, with specified updates made just before publication. Part 1 consists of the program overview and report on progress.

Human genome program report. Part 1, overview and progress

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

1997-11-01

This report contains Part 1 of a two-part report to reflect research and progress in the U.S. Department of Energy Human Genome Program from 1994 through 1996, with specified updates made just before publication. Part 1 consists of the program overview and report on progress.

The Ethical, Legal, and Social Implications Program of the National Human Genome Research Institute: reflections on an ongoing experiment.

PubMed

McEwen, Jean E; Boyer, Joy T; Sun, Kathie Y; Rothenberg, Karen H; Lockhart, Nicole C; Guyer, Mark S

2014-01-01

For more than 20 years, the Ethical, Legal, and Social Implications (ELSI) Program of the National Human Genome Research Institute has supported empirical and conceptual research to anticipate and address the ethical, legal, and social implications of genomics. As a component of the agency that funds much of the underlying science, the program has always been an experiment. The ever-expanding number of issues the program addresses and the relatively low level of commitment on the part of other funding agencies to support such research make setting priorities especially challenging. Program-supported studies have had a significant impact on the conduct of genomics research, the implementation of genomic medicine, and broader public policies. The program's influence is likely to grow as ELSI research, genomics research, and policy development activities become increasingly integrated. Achieving the benefits of increased integration while preserving the autonomy, objectivity, and intellectual independence of ELSI investigators presents ongoing challenges and new opportunities.

Primer on Molecular Genetics; DOE Human Genome Program

DOE R&D Accomplishments Database

1992-04-01

This report is taken from the April 1992 draft of the DOE Human Genome 1991--1992 Program Report, which is expected to be published in May 1992. The primer is intended to be an introduction to basic principles of molecular genetics pertaining to the genome project. The material contained herein is not final and may be incomplete. Techniques of genetic mapping and DNA sequencing are described.

Human Genome Program

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1993-01-01

The DOE Human Genome program has grown tremendously, as shown by the marked increase in the number of genome-funded projects since the last workshop held in 1991. The abstracts in this book describe the genome research of DOE-funded grantees and contractors and invited guests, and all projects are represented at the workshop by posters. The 3-day meeting includes plenary sessions on ethical, legal, and social issues pertaining to the availability of genetic data; sequencing techniques, informatics support; and chromosome and cDNA mapping and sequencing.

Genome Science: A Video Tour of the Washington University Genome Sequencing Center for High School and Undergraduate Students

ERIC Educational Resources Information Center

Flowers, Susan K.; Easter, Carla; Holmes, Andrea; Cohen, Brian; Bednarski, April E.; Mardis, Elaine R.; Wilson, Richard K.; Elgin, Sarah C. R.

2005-01-01

Sequencing of the human genome has ushered in a new era of biology. The technologies developed to facilitate the sequencing of the human genome are now being applied to the sequencing of other genomes. In 2004, a partnership was formed between Washington University School of Medicine Genome Sequencing Center's Outreach Program and Washington…

Human Genome Research: Decoding DNA

Science.gov Websites

instructions for making all the protein molecules for all the different kinds of cells of the human body dropdown arrow Site Map A-Z Index Menu Synopsis Human Genome Research: Decoding DNA Resources with DeLisi played a pivotal role in proposing and initiating the Human Genome Program in 1986. The U.S

The Saudi Human Genome Program: An oasis in the desert of Arab medicine is providing clues to genetic disease.

PubMed

Project Team, Saudi Genome

2015-01-01

Oil wells, endless deserts, stifling heat, masses of pilgrims, and wealthy-looking urban areas still dominate the widespread mental image of Saudi Arabia. Currently, this image is being extended to include a recent endeavor that is reserving a global share in the limelight as one of the top ten genomics projects currently underway: the Saudi Human Genome Program (SHGP). With sound funding, dedicated resources, and national determination, the SHGP targets the sequencing of 100,000 human genomes over the next five years to conduct world-class genomics-based biomedical research in the Saudi population. Why this project was conceived and thought to be feasible, what is the ultimate target, and how it operates are the questions we answer in this article.

Epidemiology & Genomics Research Program

Cancer.gov

The Epidemiology and Genomics Research Program, in the National Cancer Institute's Division of Cancer Control and Population Sciences, funds research in human populations to understand the determinants of cancer occurrence and outcomes.

Translational Genomics in Low and Middle Income Countries: Opportunities and Challenges

PubMed Central

Tekola-Ayele, Fasil; Rotimi, Charles N.

2015-01-01

Translation of genomic discoveries into patient care is slowly becoming a reality in developed economies around the world. In contrast, low and middle income countries (LMIC) have participated minimally in genomic research for several reasons including lack of coherent national policies, limited number of well-trained genomic scientists, poor research infrastructure, and local economic and cultural challenges. Recent initiatives such as the Human Heredity and Health in Africa (H3Africa), the Qatar Genome Project and the Mexico National Institute of Genomic Medicine (INMEGEN) that aim to address these problems through capacity building and empowerment of local researchers have sparked a paradigm shift. In this short communication, we describe experiences of small-scale medical genetics and translational genomics research programs in LMIC. The lessons drawn from these programs drive home the importance of addressing resource, policy, and socio-cultural dynamics to realize the promise of precision medicine driven by genomic science globally. By echoing lessons from a bench-to-community translational genomics research, we advocate that large-scale genomics research projects can be successfully linked with health care programs. To harness the benefits of genomics-led health care, LMIC governments should begin to develop national genomics policies that will address human and technology capacity development within the context of their national economic and socio-cultural uniqueness. These policies should encourage international collaboration and promote link between the public health program and genomics researchers. Finally, we highlight the potential catalytic roles of the global community to foster translational genomics in LMIC. PMID:26138992

Human genome program report. Part 2, 1996 research abstracts

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

This report contains Part 2 of a two-part report to reflect research and progress in the US Department of Energy Human Genome Program from 1994 through 1996, with specified updates made just before publication. Part 2 consists of 1996 research abstracts. Attention is focused on the following: sequencing; mapping; informatics; ethical, legal, and social issues; infrastructure; and small business innovation research.

Human Genome Program Report. Part 2, 1996 Research Abstracts

DOE R&D Accomplishments Database

1997-11-01

This report contains Part 2 of a two-part report to reflect research and progress in the US Department of Energy Human Genome Program from 1994 through 1996, with specified updates made just before publication. Part 2 consists of 1996 research abstracts. Attention is focused on the following: sequencing; mapping; informatics; ethical, legal, and social issues; infrastructure; and small business innovation research.

Information on a Major New Initiative: Mapping and Sequencing the Human Genome (1986 DOE Memorandum)

DOE R&D Accomplishments Database

DeLisi, Charles (Associate Director, Health and Environmental Research, DOE Office of Energy Research)

1986-05-06

In the history of the Human Genome Program, Dr. Charles DeLisi and Dr. Alvin Trivelpiece of the Department of Energy (DOE) were instrumental in moving the seeds of the program forward. This May 1986 memo from DeLisi to Trivelpiece, Director of DOE's Office of Energy Research, documents this fact. Following the March 1986 Santa Fe workshop on the subject of mapping and sequencing the human genome, DeLisi's memo outlines workshop conclusions, explains the relevance of this project to DOE and the importance of the Department's laboratories and capabilities, notes the critical experience of DOE in managing projects of this scale and potential magnitude, and recognizes the fact that the project will impact biomedical science in ways which could not be fully anticipated at the time. Subsequently, program guidance was further sought from the DOE Health Effects Research Advisory Committee (HERAC) and the April 1987 HERAC report recommended that DOE and the nation commit to a large, multidisciplinary, scientific and technological undertaking to map and sequence the human genome.

Translational Genomics in Low- and Middle-Income Countries: Opportunities and Challenges.

PubMed

Tekola-Ayele, Fasil; Rotimi, Charles N

2015-01-01

Translation of genomic discoveries into patient care is slowly becoming a reality in developed economies around the world. In contrast, low- and middle-income countries (LMIC) have participated minimally in genomic research for several reasons including the lack of coherent national policies, the limited number of well-trained genomic scientists, poor research infrastructure, and local economic and cultural challenges. Recent initiatives such as the Human Heredity and Health in Africa (H3Africa), the Qatar Genome Project, and the Mexico National Institute of Genomic Medicine (INMEGEN) that aim to address these problems through capacity building and empowerment of local researchers have sparked a paradigm shift. In this short communication, we describe experiences of small-scale medical genetics and translational genomic research programs in LMIC. The lessons drawn from these programs drive home the importance of addressing resource, policy, and sociocultural dynamics to realize the promise of precision medicine driven by genomic science globally. By echoing lessons from a bench-to-community translational genomic research, we advocate that large-scale genomic research projects can be successfully linked with health care programs. To harness the benefits of genomics-led health care, LMIC governments should begin to develop national genomics policies that will address human and technology capacity development within the context of their national economic and sociocultural uniqueness. These policies should encourage international collaboration and promote the link between the public health program and genomics researchers. Finally, we highlight the potential catalytic roles of the global community to foster translational genomics in LMIC. © 2015 S. Karger AG, Basel.

Multimedia Presentations on the Human Genome: Implementation and Assessment of a Teaching Program for the Introduction to Genome Science Using a Poster and Animations

ERIC Educational Resources Information Center

Kano, Kei; Yahata, Saiko; Muroi, Kaori; Kawakami, Masahiro; Tomoda, Mari; Miyaki, Koichi; Nakayama, Takeo; Kosugi, Shinji; Kato, Kazuto

2008-01-01

Genome science, including topics such as gene recombination, cloning, genetic tests, and gene therapy, is now an established part of our daily lives; thus we need to learn genome science to better equip ourselves for the present day. Learning from topics directly related to the human has been suggested to be more effective than learning from…

The Human Genome Project: applications in the diagnosis and treatment of neurologic disease.

PubMed

Evans, G A

1998-10-01

The Human Genome Project (HGP), an international program to decode the entire DNA sequence of the human genome in 15 years, represents the largest biological experiment ever conducted. This set of information will contain the blueprint for the construction and operation of a human being. While the primary driving force behind the genome project is the potential to vastly expand the amount of genetic information available for biomedical research, the ramifications for other fields of study in biological research, the biotechnology and pharmaceutical industry, our understanding of evolution, effects on agriculture, and implications for bioethics are likely to be profound.

snoSeeker: an advanced computational package for screening of guide and orphan snoRNA genes in the human genome.

PubMed

Yang, Jian-Hua; Zhang, Xiao-Chen; Huang, Zhan-Peng; Zhou, Hui; Huang, Mian-Bo; Zhang, Shu; Chen, Yue-Qin; Qu, Liang-Hu

2006-01-01

Small nucleolar RNAs (snoRNAs) represent an abundant group of non-coding RNAs in eukaryotes. They can be divided into guide and orphan snoRNAs according to the presence or absence of antisense sequence to rRNAs or snRNAs. Current snoRNA-searching programs, which are essentially based on sequence complementarity to rRNAs or snRNAs, exist only for the screening of guide snoRNAs. In this study, we have developed an advanced computational package, snoSeeker, which includes CDseeker and ACAseeker programs, for the highly efficient and specific screening of both guide and orphan snoRNA genes in mammalian genomes. By using these programs, we have systematically scanned four human-mammal whole-genome alignment (WGA) sequences and identified 54 novel candidates including 26 orphan candidates as well as 266 known snoRNA genes. Eighteen novel snoRNAs were further experimentally confirmed with four snoRNAs exhibiting a tissue-specific or restricted expression pattern. The results of this study provide the most comprehensive listing of two families of snoRNA genes in the human genome till date.

Origins of the Human Genome Project.

PubMed

Watson, J D; Cook-Deegan, R M

1991-01-01

The Human Genome Project has become a reality. Building on a debate that dates back to 1985, several genome projects are now in full stride around the world, and more are likely to form in the next several years. Italy began its genome program in 1987, and the United Kingdom and U.S.S.R. in 1988. The European communities mounted several genome projects on yeast, bacteria, Drosophila, and Arabidospis thaliana (a rapidly growing plant with a small genome) in 1988, and in 1990 commenced a new 2-year program on the human genome. In the United States, we have completed the first year of operation of the National Center for Human Genome Research at the National Institutes of Health (NIH), now the largest single funding source for genome research in the world. There have been dedicated budgets focused on genome-scale research at NIH, the U.S. Department of Energy, and the Howard Hughes Medical Institute for several years, and results are beginning to accumulate. There were three annual meetings on genome mapping and sequencing at Cold Spring Harbor, New York, in the spring of 1988, 1989, and 1990; the talks have shifted from a discussion about how to approach problems to presenting results from experiments already performed. We have finally begun to work rather than merely talk. The purpose of genome projects is to assemble data on the structure of DNA in human chromosomes and those of other organisms. A second goal is to develop new technologies to perform mapping and sequencing. There have been impressive technical advances in the past 5 years since the debate about the human genome project began. We are on the verge of beginning pilot projects to test several approaches to sequencing long stretches of DNA, using both automation and manual methods. Ordered sets of yeast artificial chromosome and cosmid clones have been assembled to span more than 2 million base pairs of several human chromosomes, and a region of 10 million base pairs has been assembled for Caenorhabditis elegans by a collaboration between Washington University and the Medical Research Council laboratory in Cambridge, U.K. This project is now turning to sequencing C. elegans DNA as a logical extension of this work. These are but the first fruits of the genome project. There is much more to come.

Brad Ozenberger, Ph.D., Presents the Achievements of The Cancer Genome Atlas During its Early Years - TCGA

Cancer.gov

Dr. Brad Ozenberger, former TCGA Program Director for the National Human Genome Research Institute, describes the goals and achievements of TCGA during its pilot phase, which involved the genomic characterization of brain, ovarian, and lung cancers.

Current Priorities for Public Health Practice in Addressing the Role of Human Genomics in Improving Population Health

PubMed Central

Khoury, Muin J.; Bowen, Michael S.; Burke, Wylie; Coates, Ralph J.; Dowling, Nicole F.; Evans, James P.; Reyes, Michele; St. Pierre, Jeannette

2017-01-01

In spite of accelerating human genome discoveries in a wide variety of diseases of public health significance, the promise of personalized health care and disease prevention based on genomics has lagged behind. In a time of limited resources, public health agencies must continue to focus on implementing programs that can improve health and prevent disease now. Nevertheless, public health has an important and assertive leadership role in addressing the promise and pitfalls of human genomics for population health. Such efforts are needed not only to implement what is known in genomics to improve health but also to reduce potential harm and create the infrastructure needed to derive health benefits in the future. PMID:21406285

Identification of a unique library of complex, but ordered, arrays of repetitive elements in the human genome and implication of their potential involvement in pathobiology.

PubMed

Lee, Kang-Hoon; Lee, Young-Kwan; Kwon, Deug-Nam; Chiu, Sophia; Chew, Victoria; Rah, Hyungchul; Kujawski, Gregory; Melhem, Ramzi; Hsu, Karen; Chung, Cecilia; Greenhalgh, David G; Cho, Kiho

2011-06-01

Approximately 2% of the human genome is reported to be occupied by genes. Various forms of repetitive elements (REs), both characterized and uncharacterized, are presumed to make up the vast majority of the rest of the genomes of human and other species. In conjunction with a comprehensive annotation of genes, information regarding components of genome biology, such as gene polymorphisms, non-coding RNAs, and certain REs, is found in human genome databases. However, the genome-wide profile of unique RE arrangements formed by different groups of REs has not been fully characterized yet. In this study, the entire human genome was subjected to an unbiased RE survey to establish a whole-genome profile of REs and their arrangements. Due to the limitation in query size within the bl2seq alignment program (National Center for Biotechnology Information [NCBI]) utilized for the RE survey, the entire NCBI reference human genome was fragmented into 6206 units of 0.5M nucleotides. A number of RE arrangements with varying complexities and patterns were identified throughout the genome. Each chromosome had unique profiles of RE arrangements and density, and high levels of RE density were measured near the centromere regions. Subsequently, 175 complex RE arrangements, which were selected throughout the genome, were subjected to a comparison analysis using five different human genome sequences. Interestingly, three of the five human genome databases shared the exactly same arrangement patterns and sequences for all 175 RE arrangement regions (a total of 12,765,625 nucleotides). The findings from this study demonstrate that a substantial fraction of REs in the human genome are clustered into various forms of ordered structures. Further investigations are needed to examine whether some of these ordered RE arrangements contribute to the human pathobiology as a functional genome unit. Copyright © 2011 Elsevier Inc. All rights reserved.

Whose genome is it, anyway?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marshall, E.

1996-09-27

The genome program has issued guidelines to ensure that sequencing is done on DNA from diverse sources who have given informed consent and are anonymous. Most current sources don`t meet those criteria. It may be the first question every nonexpert asks on learning about the Human Genome Project: Whose genome are we studying, anyway? It sounds naive, says one government scientist-so naive, in fact, that {open_quotes}we chuckle as we explain that we aren`t sequencing anyone`s genome in particular; we`re sequencing a representative genome{close_quotes} made up of a mosaic of DNA from a variety of anonymous sources. And Bruce Birren, amore » clone-maker now at the Massachusetts Institute of Technology`s (MIT`s) Whitehead Center for Genome Research says: {open_quotes}We spent many years pooh-poohing the question{close_quotes} of whose genome would be stored in the database. But now that labs have begun working on large stretches of human DNA-aiming to identify all 3 billion base pairs in the genetic code-the question no longer seems to laughable. To the distress of program managers in Bethesda, Maryland, the initial sources of DNA are not as diverse or as anonymous as they had assumed.« less

RNA-programmed genome editing in human cells

PubMed Central

Jinek, Martin; East, Alexandra; Cheng, Aaron; Lin, Steven; Ma, Enbo; Doudna, Jennifer

2013-01-01

Type II CRISPR immune systems in bacteria use a dual RNA-guided DNA endonuclease, Cas9, to cleave foreign DNA at specific sites. We show here that Cas9 assembles with hybrid guide RNAs in human cells and can induce the formation of double-strand DNA breaks (DSBs) at a site complementary to the guide RNA sequence in genomic DNA. This cleavage activity requires both Cas9 and the complementary binding of the guide RNA. Experiments using extracts from transfected cells show that RNA expression and/or assembly into Cas9 is the limiting factor for Cas9-mediated DNA cleavage. In addition, we find that extension of the RNA sequence at the 3′ end enhances DNA targeting activity in vivo. These results show that RNA-programmed genome editing is a facile strategy for introducing site-specific genetic changes in human cells. DOI: http://dx.doi.org/10.7554/eLife.00471.001 PMID:23386978

Democratizing Human Genome Project Information: A Model Program for Education, Information and Debate in Public Libraries.

ERIC Educational Resources Information Center

Pollack, Miriam

The "Mapping the Human Genome" project demonstrated that librarians can help whomever they serve in accessing information resources in the areas of biological and health information, whether it is the scientists who are developing the information or a member of the public who is using the information. Public libraries can guide library…

Teaching strategies to incorporate genomics education into academic nursing curricula.

PubMed

Quevedo Garcia, Sylvia P; Greco, Karen E; Loescher, Lois J

2011-11-01

The translation of genomic science into health care has expanded our ability to understand the effects of genomics on human health and disease. As genomic advances continue, nurses are expected to have the knowledge and skills to translate genomic information into improved patient care. This integrative review describes strategies used to teach genomics in academic nursing programs and their facilitators and barriers to inclusion in nursing curricula. The Learning Engagement Model and the Diffusion of Innovations Theory guided the interpretation of findings. CINAHL, Medline, and Web of Science were resources for articles published during the past decade that included strategies for teaching genomics in academic nursing programs. Of 135 articles, 13 met criteria for review. Examples of effective genomics teaching strategies included clinical application through case studies, storytelling, online genomics resources, student self-assessment, guest lecturers, and a genetics focus group. Most strategies were not evaluated for effectiveness. Copyright 2011, SLACK Incorporated.

Applying Genomic and Genetic Tools to Understand and Mitigate Damage from Exposure to Toxins

DTIC Science & Technology

2013-10-01

sequences to the human genome . Genome Biol 10, R25 (2009). 26 Award number: W81XWH-09-1-0715 Title: Applying Genomic and Genetic Tools to Understand...utilizing the high-throughput technology of mRNA-seq. BODY The goal of our research program (W81XWH-09-1-0715) was to utilize genetic and genomic ...also acquired the achetf222a * * * * * 5 Award number: W81XWH-09-1-0715 Title: Applying Genomic and Genetic Tools to Understand and Mitigate

Genetics for the Human Race

DOE Office of Scientific and Technical Information (OSTI.GOV)

Myles Axton; Francis Collins; Charles Rotimi

2004-11-01

This supplement has its origins on May 15, 2003, when the National Human Genome Center at Howard University held a small but important workshop in Washington DC. The workshop, Human Genome Variation and 'Race', and this special issue of Nature Genetics were proposed by scientists at Howard University and financially supported by the Genome Programs of the US Department of Energy, through its Office of Science; the Irving Harris Foundation; the National Institutes of Health, through the National Human Genome Research Institute; and Howard University. As summarized by Francis Collins, director of the National Human Genome Research Institute, the workshopmore » focused on several key questions: ''What does the current body of scientific information say about the connections among race, ethnicity, genetics and health? What remains unknown? What additional research is needed? How can this information be applied to benefit human health? How might this information be applied in nonmedical settings? How can we adopt policies that will achieve beneficial societal outcomes?'' This supplement, supported by the Department of Energy through a grant to Howard University, contains articles based on the presentations at this workshop.« less

Entering the Public Health Genomics Era: Why Must Health Educators Develop Genomic Competencies?

ERIC Educational Resources Information Center

Chen, Lei-Shih; Goodson, Patricia

2007-01-01

Although the completion of the Human Genome Project will offer new insight into diseases and help develop efficient, personalized treatment or prevention programs, it will also raise new and non-trivial public health issues. Many of these issues fall under the professional purview of public health workers. As members of the public health…

The Human Genome Project and Mental Retardation: An Educational Program. Final Progress Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Davis, Sharon

The Arc, a national organization on mental retardation, conducted an educational program for members, many of whom have a family member with a genetic condition causing mental retardation. The project informed members about the Human Genome scientific efforts, conducted training regarding ethical, legal and social implications and involved members in issue discussions. Short reports and fact sheets on genetic and ELSI topics were disseminated to 2,200 of the Arc's leaders across the country and to other interested individuals. Materials produced by the project can e found on the Arc's web site, TheArc.org.

Social Regulation of Human Gene Expression: Mechanisms and Implications for Public Health

PubMed Central

2013-01-01

Recent analyses have discovered broad alterations in the expression of human genes across different social environments. The emerging field of social genomics has begun to identify the types of genes sensitive to social regulation, the biological signaling pathways mediating these effects, and the genetic polymorphisms that modify their individual impact. The human genome appears to have evolved specific “social programs” to adapt molecular physiology to the changing patterns of threat and opportunity ancestrally associated with changing social conditions. In the context of the immune system, this programming now fosters many of the diseases that dominate public health. The embedding of individual genomes within a broader metagenomic network provides a framework for integrating molecular, physiologic, and social perspectives on human health. PMID:23927506

Opening plenary speaker: Human genomics, precision medicine, and advancing human health.

PubMed

Green, Eric D

2016-08-01

Starting with the launch of the Human Genome Project in 1990, the past quarter-century has brought spectacular achievements in genomics that dramatically empower the study of human biology and disease. The human genomics enterprise is now in the midst of an important transition, as the growing foundation of genomic knowledge is being used by researchers and clinicians to tackle increasingly complex problems in biomedicine. Of particular prominence is the use of revolutionary new DNA sequencing technologies for generating prodigious amounts of DNA sequence data to elucidate the complexities of genome structure, function, and evolution, as well as to unravel the genomic bases of rare and common diseases. Together, these developments are ushering in the era of genomic medicine. Augmenting the advances in human genomics have been innovations in technologies for measuring environmental and lifestyle information, electronic health records, and data science; together, these provide opportunities of unprecedented scale and scope for investigating the underpinnings of health and disease. To capitalize on these opportunities, U.S. President Barack Obama recently announced a major new research endeavor - the U.S. Precision Medicine Initiative. This bold effort will be framed around several key aims, which include accelerating the use of genomically informed approaches to cancer care, making important policy and regulatory changes, and establishing a large research cohort of >1 million volunteers to facilitate precision medicine research. The latter will include making the partnership with all participants a centerpiece feature in the cohort's design and development. The Precision Medicine Initiative represents a broad-based research program that will allow new approaches for individualized medical care to be rigorously tested, so as to establish a new evidence base for advancing clinical practice and, eventually, human health.

Megabase replication domains along the human genome: relation to chromatin structure and genome organisation.

PubMed

Audit, Benjamin; Zaghloul, Lamia; Baker, Antoine; Arneodo, Alain; Chen, Chun-Long; d'Aubenton-Carafa, Yves; Thermes, Claude

2013-01-01

In higher eukaryotes, the absence of specific sequence motifs, marking the origins of replication has been a serious hindrance to the understanding of (i) the mechanisms that regulate the spatio-temporal replication program, and (ii) the links between origins activation, chromatin structure and transcription. In this chapter, we review the partitioning of the human genome into megabased-size replication domains delineated as N-shaped motifs in the strand compositional asymmetry profiles. They collectively span 28.3% of the genome and are bordered by more than 1,000 putative replication origins. We recapitulate the comparison of this partition of the human genome with high-resolution experimental data that confirms that replication domain borders are likely to be preferential replication initiation zones in the germline. In addition, we highlight the specific distribution of experimental and numerical chromatin marks along replication domains. Domain borders correspond to particular open chromatin regions, possibly encoded in the DNA sequence, and around which replication and transcription are highly coordinated. These regions also present a high evolutionary breakpoint density, suggesting that susceptibility to breakage might be linked to local open chromatin fiber state. Altogether, this chapter presents a compartmentalization of the human genome into replication domains that are landmarks of the human genome organization and are likely to play a key role in genome dynamics during evolution and in pathological situations.

Back to the future: the human protein index (HPI) and the agenda for post-proteomic biology.

PubMed

Anderson, N G; Matheson, A; Anderson, N L

2001-01-01

The effort to produce an index of all human proteins (the human protein index, or HPI) began twenty years ago, before the initiation of the human genome program. Because DNA sequencing technology is inherently simpler and more scalable than protein analytical technology, and because the finiteness of genomes invited a spirit of rapid conquest, the notion of genome sequencing has displaced that of protein databases in the minds of most molecular biologists for the last decade. However, now that the human genome sequence is nearing completion, a major realignment is under way that brings proteins back to the center of biological thinking. Using an influx of new and improved protein technologies--from mass spectrometry to re-engineered two-dimensional (2-D) gel systems, the original objectives of the HPI have been expanded and the time frame for its execution radically shortened. Several additional large scale technology efforts flowing from the HPI are also described.

Cell Lines Expressing Nuclear and/or Mitochondrial RNAse H1 | NCI Technology Transfer Center | TTC

Cancer.gov

The National Institute of Child Health & Human Development (NICHD), Program in Genomics of Differentiation, seeks interested parties to further co-develop small molecule inhibitors of RNase H1, especially in regards to genome instability, transcription, and translation.

Interdisciplinary Models for Research and Clinical Endeavors in Genomic Medicine: A Scientific Statement From the American Heart Association.

PubMed

Musunuru, Kiran; Arora, Pankaj; Cooke, John P; Ferguson, Jane F; Hershberger, Ray E; Hickey, Kathleen T; Lee, Jin-Moo; Lima, João A C; Loscalzo, Joseph; Pereira, Naveen L; Russell, Mark W; Shah, Svati H; Sheikh, Farah; Wang, Thomas J; MacRae, Calum A

2018-06-01

The completion of the Human Genome Project has unleashed a wealth of human genomics information, but it remains unclear how best to implement this information for the benefit of patients. The standard approach of biomedical research, with researchers pursuing advances in knowledge in the laboratory and, separately, clinicians translating research findings into the clinic as much as decades later, will need to give way to new interdisciplinary models for research in genomic medicine. These models should include scientists and clinicians actively working as teams to study patients and populations recruited in clinical settings and communities to make genomics discoveries-through the combined efforts of data scientists, clinical researchers, epidemiologists, and basic scientists-and to rapidly apply these discoveries in the clinic for the prediction, prevention, diagnosis, prognosis, and treatment of cardiovascular diseases and stroke. The highly publicized US Precision Medicine Initiative, also known as All of Us, is a large-scale program funded by the US National Institutes of Health that will energize these efforts, but several ongoing studies such as the UK Biobank Initiative; the Million Veteran Program; the Electronic Medical Records and Genomics Network; the Kaiser Permanente Research Program on Genes, Environment and Health; and the DiscovEHR collaboration are already providing exemplary models of this kind of interdisciplinary work. In this statement, we outline the opportunities and challenges in broadly implementing new interdisciplinary models in academic medical centers and community settings and bringing the promise of genomics to fruition. © 2018 American Heart Association, Inc.

GenomeVista

DOE Office of Scientific and Technical Information (OSTI.GOV)

Poliakov, Alexander; Couronne, Olivier

2002-11-04

Aligning large vertebrate genomes that are structurally complex poses a variety of problems not encountered on smaller scales. Such genomes are rich in repetitive elements and contain multiple segmental duplications, which increases the difficulty of identifying true orthologous SNA segments in alignments. The sizes of the sequences make many alignment algorithms designed for comparing single proteins extremely inefficient when processing large genomic intervals. We integrated both local and global alignment tools and developed a suite of programs for automatically aligning large vertebrate genomes and identifying conserved non-coding regions in the alignments. Our method uses the BLAT local alignment program tomore » find anchors on the base genome to identify regions of possible homology for a query sequence. These regions are postprocessed to find the best candidates which are then globally aligned using the AVID global alignment program. In the last step conserved non-coding segments are identified using VISTA. Our methods are fast and the resulting alignments exhibit a high degree of sensitivity, covering more than 90% of known coding exons in the human genome. The GenomeVISTA software is a suite of Perl programs that is built on a MySQL database platform. The scheduler gets control data from the database, builds a queve of jobs, and dispatches them to a PC cluster for execution. The main program, running on each node of the cluster, processes individual sequences. A Perl library acts as an interface between the database and the above programs. The use of a separate library allows the programs to function independently of the database schema. The library also improves on the standard Perl MySQL database interfere package by providing auto-reconnect functionality and improved error handling.« less

Genetics/genomics education for nongenetic health professionals: a systematic literature review.

PubMed

Talwar, Divya; Tseng, Tung-Sung; Foster, Margaret; Xu, Lei; Chen, Lei-Shih

2017-07-01

The completion of the Human Genome Project has enhanced avenues for disease prevention, diagnosis, and management. Owing to the shortage of genetic professionals, genetics/genomics training has been provided to nongenetic health professionals for years to establish their genomic competencies. We conducted a systematic literature review to summarize and evaluate the existing genetics/genomics education programs for nongenetic health professionals. Five electronic databases were searched from January 1990 to June 2016. Forty-four studies met our inclusion criteria. There was a growing publication trend. Program participants were mainly physicians and nurses. The curricula, which were most commonly provided face to face, included basic genetics; applied genetics/genomics; ethical, legal, and social implications of genetics/genomics; and/or genomic competencies/recommendations in particular professional fields. Only one-third of the curricula were theory-based. The majority of studies adopted a pre-/post-test design and lacked follow-up data collection. Nearly all studies reported participants' improvements in one or more of the following areas: knowledge, attitudes, skills, intention, self-efficacy, comfort level, and practice. However, most studies did not report participants' age, ethnicity, years of clinical practice, data validity, and data reliability. Many genetics/genomics education programs for nongenetic health professionals exist. Nevertheless, enhancement in methodological quality is needed to strengthen education initiatives.Genet Med advance online publication 20 October 2016.

A novel program to design siRNAs simultaneously effective to highly variable virus genomes.

PubMed

Lee, Hui Sun; Ahn, Jeonghyun; Jun, Eun Jung; Yang, Sanghwa; Joo, Chul Hyun; Kim, Yoo Kyum; Lee, Heuiran

2009-07-10

A major concern of antiviral therapy using small interfering RNAs (siRNAs) targeting RNA viral genome is high sequence diversity and mutation rate due to genetic instability. To overcome this problem, it is indispensable to design siRNAs targeting highly conserved regions. We thus designed CAPSID (Convenient Application Program for siRNA Design), a novel bioinformatics program to identify siRNAs targeting highly conserved regions within RNA viral genomes. From a set of input RNAs of diverse sequences, CAPSID rapidly searches conserved patterns and suggests highly potent siRNA candidates in a hierarchical manner. To validate the usefulness of this novel program, we investigated the antiviral potency of universal siRNA for various Human enterovirus B (HEB) serotypes. Assessment of antiviral efficacy using Hela cells, clearly demonstrates that HEB-specific siRNAs exhibit protective effects against all HEBs examined. These findings strongly indicate that CAPSID can be applied to select universal antiviral siRNAs against highly divergent viral genomes.

EGASP: the human ENCODE Genome Annotation Assessment Project

PubMed Central

Guigó, Roderic; Flicek, Paul; Abril, Josep F; Reymond, Alexandre; Lagarde, Julien; Denoeud, France; Antonarakis, Stylianos; Ashburner, Michael; Bajic, Vladimir B; Birney, Ewan; Castelo, Robert; Eyras, Eduardo; Ucla, Catherine; Gingeras, Thomas R; Harrow, Jennifer; Hubbard, Tim; Lewis, Suzanna E; Reese, Martin G

2006-01-01

Background We present the results of EGASP, a community experiment to assess the state-of-the-art in genome annotation within the ENCODE regions, which span 1% of the human genome sequence. The experiment had two major goals: the assessment of the accuracy of computational methods to predict protein coding genes; and the overall assessment of the completeness of the current human genome annotations as represented in the ENCODE regions. For the computational prediction assessment, eighteen groups contributed gene predictions. We evaluated these submissions against each other based on a 'reference set' of annotations generated as part of the GENCODE project. These annotations were not available to the prediction groups prior to the submission deadline, so that their predictions were blind and an external advisory committee could perform a fair assessment. Results The best methods had at least one gene transcript correctly predicted for close to 70% of the annotated genes. Nevertheless, the multiple transcript accuracy, taking into account alternative splicing, reached only approximately 40% to 50% accuracy. At the coding nucleotide level, the best programs reached an accuracy of 90% in both sensitivity and specificity. Programs relying on mRNA and protein sequences were the most accurate in reproducing the manually curated annotations. Experimental validation shows that only a very small percentage (3.2%) of the selected 221 computationally predicted exons outside of the existing annotation could be verified. Conclusion This is the first such experiment in human DNA, and we have followed the standards established in a similar experiment, GASP1, in Drosophila melanogaster. We believe the results presented here contribute to the value of ongoing large-scale annotation projects and should guide further experimental methods when being scaled up to the entire human genome sequence. PMID:16925836

Global Implementation of Genomic Medicine: We Are Not Alone

PubMed Central

Manolio, Teri A.; Abramowicz, Marc; Al-Mulla, Fahd; Anderson, Warwick; Balling, Rudi; Berger, Adam C.; Bleyl, Steven; Chakravarti, Aravinda; Chantratita, Wasun; Chisholm, Rex L.; Dissanayake, Vajira H. W.; Dunn, Michael; Dzau, Victor J.; Han, Bok-Ghee; Hubbard, Tim; Kolbe, Anne; Korf, Bruce; Kubo, Michiaki; Lasko, Paul; Leego, Erkki; Mahasirimongkol, Surakameth; Majumdar, Partha P.; Matthijs, Gert; McLeod, Howard L.; Metspalu, Andres; Meulien, Pierre; Miyano, Satoru; Naparstek, Yaakov; O’Rourke, P. Pearl; Patrinos, George P.; Rehm, Heidi L.; Relling, Mary V.; Rennert, Gad; Rodriguez, Laura Lyman; Roden, Dan M.; Shuldiner, Alan R.; Sinha, Sukdev; Tan, Patrick; Ulfendahl, Mats; Ward, Robyn; Williams, Marc S.; Wong, John E.L.; Green, Eric D.; Ginsburg, Geoffrey S.

2016-01-01

Advances in high-throughput genomic technologies coupled with a growing number of genomic results potentially useful in clinical care have led to ground-breaking genomic medicine implementation programs in various nations. Many of these innovative programs capitalize on unique local capabilities arising from the structure of their health care systems or their cultural or political milieu, as well as from unusual burdens of disease or risk alleles. Many such programs are being conducted in relative isolation and might benefit from sharing of approaches and lessons learned in other nations. The National Human Genome Research Institute recently brought together 25 of these groups from around the world to describe and compare projects, examine the current state of implementation and desired near-term capabilities, and identify opportunities for collaboration to promote the responsible implementation of genomic medicine. The wide variety of nascent programs in diverse settings demonstrates that implementation of genomic medicine is expanding globally in varied and highly innovative ways. Opportunities for collaboration abound in the areas of evidence generation, health information technology, education, workforce development, pharmacogenomics, and policy and regulatory issues. Several international organizations that are already facilitating effective research collaborations should engage to ensure implementation proceeds collaboratively without potentially wasteful duplication. Efforts to coalesce these groups around concrete but compelling signature projects, such as global eradication of genetically-mediated drug reactions or developing a truly global genomic variant data resource across a wide number of ethnicities, would accelerate appropriate implementation of genomics to improve clinical care world-wide. PMID:26041702

GEMINI: Integrative Exploration of Genetic Variation and Genome Annotations

PubMed Central

Paila, Umadevi; Chapman, Brad A.; Kirchner, Rory; Quinlan, Aaron R.

2013-01-01

Modern DNA sequencing technologies enable geneticists to rapidly identify genetic variation among many human genomes. However, isolating the minority of variants underlying disease remains an important, yet formidable challenge for medical genetics. We have developed GEMINI (GEnome MINIng), a flexible software package for exploring all forms of human genetic variation. Unlike existing tools, GEMINI integrates genetic variation with a diverse and adaptable set of genome annotations (e.g., dbSNP, ENCODE, UCSC, ClinVar, KEGG) into a unified database to facilitate interpretation and data exploration. Whereas other methods provide an inflexible set of variant filters or prioritization methods, GEMINI allows researchers to compose complex queries based on sample genotypes, inheritance patterns, and both pre-installed and custom genome annotations. GEMINI also provides methods for ad hoc queries and data exploration, a simple programming interface for custom analyses that leverage the underlying database, and both command line and graphical tools for common analyses. We demonstrate GEMINI's utility for exploring variation in personal genomes and family based genetic studies, and illustrate its ability to scale to studies involving thousands of human samples. GEMINI is designed for reproducibility and flexibility and our goal is to provide researchers with a standard framework for medical genomics. PMID:23874191

Evolution and Diversity of the Human Hepatitis D Virus Genome

PubMed Central

Huang, Chi-Ruei; Lo, Szecheng J.

2010-01-01

Human hepatitis delta virus (HDV) is the smallest RNA virus in genome. HDV genome is divided into a viroid-like sequence and a protein-coding sequence which could have originated from different resources and the HDV genome was eventually constituted through RNA recombination. The genome subsequently diversified through accumulation of mutations selected by interactions between the mutated RNA and proteins with host factors to successfully form the infectious virions. Therefore, we propose that the conservation of HDV nucleotide sequence is highly related with its functionality. Genome analysis of known HDV isolates shows that the C-terminal coding sequences of large delta antigen (LDAg) are the highest diversity than other regions of protein-coding sequences but they still retain biological functionality to interact with the heavy chain of clathrin can be selected and maintained. Since viruses interact with many host factors, including escaping the host immune response, how to design a program to predict RNA genome evolution is a great challenging work. PMID:20204073

Improving the Human Hazard Characterization of Chemicals: A Tox21 Update

EPA Science Inventory

Background: In 2008, the National Institute of Environmental Health Sciences/National Toxicology Program, the U.S. Environmental Protection Agency’s National Center for Computational Toxicology, and the National Human Genome Research Institute/National Institutes of Health ...

Genomic Perspectives of Transcriptional Regulation in Forebrain Development

DOE PAGES

Nord, Alex S.; Pattabiraman, Kartik; Visel, Axel; ...

2015-01-07

The forebrain is the seat of higher-order brain functions, and many human neuropsychiatric disorders are due to genetic defects affecting forebrain development, making it imperative to understand the underlying genetic circuitry. We report that recent progress now makes it possible to begin fully elucidating the genomic regulatory mechanisms that control forebrain gene expression. Here, we discuss the current knowledge of how transcription factors drive gene expression programs through their interactions with cis-acting genomic elements, such as enhancers; how analyses of chromatin and DNA modifications provide insights into gene expression states; and how these approaches yield insights into the evolution ofmore » the human brain.« less

Human Genome: DOE Origins

Science.gov Websites

Health and Environmental Research [OHER], the program that supported most Biology in the Department. The origins of DOE's biology program traced to the Manhattan Project, the World War II program that produced Technical Report; 1964 Impact of Radiation Biology on Fundamental Insights in Biology; DOE Technical Report

Genome-wide alterations of the DNA replication program during tumor progression

NASA Astrophysics Data System (ADS)

Arneodo, A.; Goldar, A.; Argoul, F.; Hyrien, O.; Audit, B.

2016-08-01

Oncogenic stress is a major driving force in the early stages of cancer development. Recent experimental findings reveal that, in precancerous lesions and cancers, activated oncogenes may induce stalling and dissociation of DNA replication forks resulting in DNA damage. Replication timing is emerging as an important epigenetic feature that recapitulates several genomic, epigenetic and functional specificities of even closely related cell types. There is increasing evidence that chromosome rearrangements, the hallmark of many cancer genomes, are intimately associated with the DNA replication program and that epigenetic replication timing changes often precede chromosomic rearrangements. The recent development of a novel methodology to map replication fork polarity using deep sequencing of Okazaki fragments has provided new and complementary genome-wide replication profiling data. We review the results of a wavelet-based multi-scale analysis of genomic and epigenetic data including replication profiles along human chromosomes. These results provide new insight into the spatio-temporal replication program and its dynamics during differentiation. Here our goal is to bring to cancer research, the experimental protocols and computational methodologies for replication program profiling, and also the modeling of the spatio-temporal replication program. To illustrate our purpose, we report very preliminary results obtained for the chronic myelogeneous leukemia, the archetype model of cancer. Finally, we discuss promising perspectives on using genome-wide DNA replication profiling as a novel efficient tool for cancer diagnosis, prognosis and personalized treatment.

Pairagon: a highly accurate, HMM-based cDNA-to-genome aligner.

PubMed

Lu, David V; Brown, Randall H; Arumugam, Manimozhiyan; Brent, Michael R

2009-07-01

The most accurate way to determine the intron-exon structures in a genome is to align spliced cDNA sequences to the genome. Thus, cDNA-to-genome alignment programs are a key component of most annotation pipelines. The scoring system used to choose the best alignment is a primary determinant of alignment accuracy, while heuristics that prevent consideration of certain alignments are a primary determinant of runtime and memory usage. Both accuracy and speed are important considerations in choosing an alignment algorithm, but scoring systems have received much less attention than heuristics. We present Pairagon, a pair hidden Markov model based cDNA-to-genome alignment program, as the most accurate aligner for sequences with high- and low-identity levels. We conducted a series of experiments testing alignment accuracy with varying sequence identity. We first created 'perfect' simulated cDNA sequences by splicing the sequences of exons in the reference genome sequences of fly and human. The complete reference genome sequences were then mutated to various degrees using a realistic mutation simulator and the perfect cDNAs were aligned to them using Pairagon and 12 other aligners. To validate these results with natural sequences, we performed cross-species alignment using orthologous transcripts from human, mouse and rat. We found that aligner accuracy is heavily dependent on sequence identity. For sequences with 100% identity, Pairagon achieved accuracy levels of >99.6%, with one quarter of the errors of any other aligner. Furthermore, for human/mouse alignments, which are only 85% identical, Pairagon achieved 87% accuracy, higher than any other aligner. Pairagon source and executables are freely available at http://mblab.wustl.edu/software/pairagon/

Fungal genome sequencing: basic biology to biotechnology.

PubMed

Sharma, Krishna Kant

2016-08-01

The genome sequences provide a first glimpse into the genomic basis of the biological diversity of filamentous fungi and yeast. The genome sequence of the budding yeast, Saccharomyces cerevisiae, with a small genome size, unicellular growth, and rich history of genetic and molecular analyses was a milestone of early genomics in the 1990s. The subsequent completion of fission yeast, Schizosaccharomyces pombe and genetic model, Neurospora crassa initiated a revolution in the genomics of the fungal kingdom. In due course of time, a substantial number of fungal genomes have been sequenced and publicly released, representing the widest sampling of genomes from any eukaryotic kingdom. An ambitious genome-sequencing program provides a wealth of data on metabolic diversity within the fungal kingdom, thereby enhancing research into medical science, agriculture science, ecology, bioremediation, bioenergy, and the biotechnology industry. Fungal genomics have higher potential to positively affect human health, environmental health, and the planet's stored energy. With a significant increase in sequenced fungal genomes, the known diversity of genes encoding organic acids, antibiotics, enzymes, and their pathways has increased exponentially. Currently, over a hundred fungal genome sequences are publicly available; however, no inclusive review has been published. This review is an initiative to address the significance of the fungal genome-sequencing program and provides the road map for basic and applied research.

Identifying Epigenetic Modulators of Resistance to ERK Signaling Inhibitors

DTIC Science & Technology

2015-08-01

1.8 cal months 07/01/2014 - 05/31/2016 Bayer Hemophilia Award Program Targeted conection of hemophilia A using CRISPR -mediated editing The Specific...Aims of the project are to: (1) Inse1t a human FVIII eDNA into the Rosa26locus of the mouse genome using the CRISPR -Cas9 system, and (2) Inse1t a...human FVIII eDNA into the AA VS 1 locus of the human genome using the CRISPR -Cas9 system. Role: PI RGP009/2014 (Brown) 1.8 cal months 06/01/2014 - 05

Single genome retrieval of context-dependent variability in mutation rates for human germline.

PubMed

Sahakyan, Aleksandr B; Balasubramanian, Shankar

2017-01-13

Accurate knowledge of the core components of substitution rates is of vital importance to understand genome evolution and dynamics. By performing a single-genome and direct analysis of 39,894 retrotransposon remnants, we reveal sequence context-dependent germline nucleotide substitution rates for the human genome. The rates are characterised through rate constants in a time-domain, and are made available through a dedicated program (Trek) and a stand-alone database. Due to the nature of the method design and the imposed stringency criteria, we expect our rate constants to be good estimates for the rates of spontaneous mutations. Benefiting from such data, we study the short-range nucleotide (up to 7-mer) organisation and the germline basal substitution propensity (BSP) profile of the human genome; characterise novel, CpG-independent, substitution prone and resistant motifs; confirm a decreased tendency of moieties with low BSP to undergo somatic mutations in a number of cancer types; and, produce a Trek-based estimate of the overall mutation rate in human. The extended set of rate constants we report may enrich our resources and help advance our understanding of genome dynamics and evolution, with possible implications for the role of spontaneous mutations in the emergence of pathological genotypes and neutral evolution of proteomes.

Comparative Genome Sequence Analysis of the Bpa/Str Region in Mouse and Man

PubMed Central

Mallon, A.-M.; Platzer, M.; Bate, R.; Gloeckner, G.; Botcherby, M.R.M.; Nordsiek, G.; Strivens, M.A.; Kioschis, P.; Dangel, A.; Cunningham, D.; Straw, R.N.A.; Weston, P.; Gilbert, M.; Fernando, S.; Goodall, K.; Hunter, G.; Greystrong, J.S.; Clarke, D.; Kimberley, C.; Goerdes, M.; Blechschmidt, K.; Rump, A.; Hinzmann, B.; Mundy, C.R.; Miller, W.; Poustka, A.; Herman, G.E.; Rhodes, M.; Denny, P.; Rosenthal, A.; Brown, S.D.M.

2000-01-01

The progress of human and mouse genome sequencing programs presages the possibility of systematic cross-species comparison of the two genomes as a powerful tool for gene and regulatory element identification. As the opportunities to perform comparative sequence analysis emerge, it is important to develop parameters for such analyses and to examine the outcomes of cross-species comparison. Our analysis used gene prediction and a database search of 430 kb of genomic sequence covering the Bpa/Str region of the mouse X chromosome, and 745 kb of genomic sequence from the homologous human X chromosome region. We identified 11 genes in mouse and 13 genes and two pseudogenes in human. In addition, we compared the mouse and human sequences using pairwise alignment and searches for evolutionary conserved regions (ECRs) exceeding a defined threshold of sequence identity. This approach aided the identification of at least four further putative conserved genes in the region. Comparative sequencing revealed that this region is a mosaic in evolutionary terms, with considerably more rearrangement between the two species than realized previously from comparative mapping studies. Surprisingly, this region showed an extremely high LINE and low SINE content, low G+C content, and yet a relatively high gene density, in contrast to the low gene density usually associated with such regions. [The sequence data described in this paper have been submitted to EMBL under the following accession nos.: Mouse Genomic Sequence: Mouse contig A (AL021127), Mouse contig B (AL049866), BAC41M10 (AL136328), PAC303O11(AL136329). Human Genomic Sequence: Human contig 1 (U82671, U82670), Human contig 2 (U82695).] PMID:10854409

Mapping Our Genes: The Genome Projects: How Big, How Fast

DOE R&D Accomplishments Database

1988-04-01

For the past 2 years, scientific and technical journals in biology and medicine have extensively covered a debate about whether and how to determine the function and order of human genes on human chromosomes and when to determine the sequence of molecular building blocks that comprise DNA in those chromosomes. In 1987, these issues rose to become part of the public agenda. The debate involves science, technology, and politics. Congress is responsible for ?writing the rules? of what various federal agencies do and for funding their work. This report surveys the points made so far in the debate, focusing on those that most directly influence the policy options facing the US Congress. Congressional interest focused on how to assess the rationales for conducting human genome projects, how to fund human genome projects (at what level and through which mechanisms), how to coordinate the scientific and technical programs of the several federal agencies and private interests already supporting various genome projects, and how to strike a balance regarding the impact of genome projects on international scientific cooperation and international economic competition in biotechnology. The Office of Technology Assessment (OTA) prepared this report with the assistance of several hundred experts throughout the world.

Literature and patent analysis of the cloning and identification of human functional genes in China.

PubMed

Xia, Yan; Tang, LiSha; Yao, Lei; Wan, Bo; Yang, XianMei; Yu, Long

2012-03-01

The Human Genome Project was launched at the end of the 1980s. Since then, the cloning and identification of functional genes has been a major focus of research across the world. In China too, the potentially profound impact of such studies on the life sciences and on human health was realized, and relevant studies were initiated in the 1990s. To advance China's involvement in the Human Genome Project, in the mid-1990s, Committee of Experts in Biology from National High Technology Research and Development Program of China (863 Program) proposed the "two 1%" goal. This goal envisaged China contributing 1% of the total sequencing work, and cloning and identifying 1% of the total human functional genes. Over the past 20 years, tremendous achievement has been accomplished by Chinese scientists. It is well known that scientists in China finished the 1% of sequencing work of the Human Genome Project, whereas, there is no comprehensive report about "whether China had finished cloning and identifying 1% of human functional genes". In the present study, the GenBank database at the National Center of Biotechnology Information, the PubMed search tool, and the patent database of the State Intellectual Property Office, China, were used to retrieve entries based on two screening standards: (i) Were the newly cloned and identified genes first reported by Chinese scientists? (ii) Were the Chinese scientists awarded the gene sequence patent? Entries were retrieved from the databases up to the cut-off date of 30 June 2011 and the obtained data were analyzed further. The results showed that 589 new human functional genes were first reported by Chinese scientists and 159 gene sequences were patented (http://gene.fudan.sh.cn/introduction/database/chinagene/chinagene.html). This study systematically summarizes China's contributions to human functional genomics research and answers the question "has China finished cloning and identifying 1% of human functional genes?" in the affirmative.

04-ERD-052-Final Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Loots, G G; Ovcharenko, I; Collette, N

2007-02-26

Generating the sequence of the human genome represents a colossal achievement for science and mankind. The technical use for the human genome project information holds great promise to cure disease, prevent bioterror threats, as well as to learn about human origins. Yet converting the sequence data into biological meaningful information has not been immediately obvious, and we are still in the preliminary stages of understanding how the genome is organized, what are the functional building blocks and how do these sequences mediate complex biological processes. The overarching goal of this program was to develop novel methods and high throughput strategiesmore » for determining the functions of ''anonymous'' human genes that are evolutionarily deeply conserved in other vertebrates. We coupled analytical tool development and computational predictions regarding gene function with novel high throughput experimental strategies and tested biological predictions in the laboratory. The tools required for comparative genomic data-mining are fundamentally the same whether they are applied to scientific studies of related microbes or the search for functions of novel human genes. For this reason the tools, conceptual framework and the coupled informatics-experimental biology paradigm we developed in this LDRD has many potential scientific applications relevant to LLNL multidisciplinary research in bio-defense, bioengineering, bionanosciences and microbial and environmental genomics.« less

Study reveals potentially prognostic gene, metabolism changes in kidney cancers | Center for Cancer Research

Cancer.gov

The Cancer Genome Atlas Research Network investigators, including CCR scientists, identified genetic and metabolic pathway changes linked to reduced survival of patients within and across subtypes of renal cell carcinoma (RCC), a type of kidney cancer. The study, published April 5, 2018, in Cell Reports, is part of The Cancer Genome Atlas (TCGA) Program, a joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI).

Genome Improvement at JGI-HAGSC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grimwood, Jane; Schmutz, Jeremy J.; Myers, Richard M.

Since the completion of the sequencing of the human genome, the Joint Genome Institute (JGI) has rapidly expanded its scientific goals in several DOE mission-relevant areas. At the JGI-HAGSC, we have kept pace with this rapid expansion of projects with our focus on assessing, assembling, improving and finishing eukaryotic whole genome shotgun (WGS) projects for which the shotgun sequence is generated at the Production Genomic Facility (JGI-PGF). We follow this by combining the draft WGS with genomic resources generated at JGI-HAGSC or in collaborator laboratories (including BAC end sequences, genetic maps and FLcDNA sequences) to produce an improved draft sequence.more » For eukaryotic genomes important to the DOE mission, we then add further information from directed experiments to produce reference genomic sequences that are publicly available for any scientific researcher. Also, we have continued our program for producing BAC-based finished sequence, both for adding information to JGI genome projects and for small BAC-based sequencing projects proposed through any of the JGI sequencing programs. We have now built our computational expertise in WGS assembly and analysis and have moved eukaryotic genome assembly from the JGI-PGF to JGI-HAGSC. We have concentrated our assembly development work on large plant genomes and complex fungal and algal genomes.« less

A genomic lifespan program that reorganises the young adult brain is targeted in schizophrenia.

PubMed

Skene, Nathan G; Roy, Marcia; Grant, Seth Gn

2017-09-12

The genetic mechanisms regulating the brain and behaviour across the lifespan are poorly understood. We found that lifespan transcriptome trajectories describe a calendar of gene regulatory events in the brain of humans and mice. Transcriptome trajectories defined a sequence of gene expression changes in neuronal, glial and endothelial cell-types, which enabled prediction of age from tissue samples. A major lifespan landmark was the peak change in trajectories occurring in humans at 26 years and in mice at 5 months of age. This species-conserved peak was delayed in females and marked a reorganization of expression of synaptic and schizophrenia-susceptibility genes. The lifespan calendar predicted the characteristic age of onset in young adults and sex differences in schizophrenia. We propose a genomic program generates a lifespan calendar of gene regulation that times age-dependent molecular organization of the brain and mutations that interrupt the program in young adults cause schizophrenia.

Implications of the Human Genome Project

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kitcher, P.

The Human Genome Project (HGP), launched in 1991, aims to map and sequence the human genome by 2006. During the fifteen-year life of the project, it is projected that $3 billion in federal funds will be allocated to it. The ultimate aims of spending this money are to analyze the structure of human DNA, to identify all human genes, to recognize the functions of those genes, and to prepare for the biology and medicine of the twenty-first century. The following summary examines some of the implications of the program, concentrating on its scientific import and on the ethical and socialmore » problems that it raises. Its aim is to expose principles that might be used in applying the information which the HGP will generate. There is no attempt here to translate the principles into detailed proposals for legislation. Arguments and discussion can be found in the full report, but, like this summary, that report does not contain any legislative proposals.« less

Transcriptionally Driven DNA Replication Program of the Human Parasite Leishmania major.

PubMed

Lombraña, Rodrigo; Álvarez, Alba; Fernández-Justel, José Miguel; Almeida, Ricardo; Poza-Carrión, César; Gomes, Fábia; Calzada, Arturo; Requena, José María; Gómez, María

2016-08-09

Faithful inheritance of eukaryotic genomes requires the orchestrated activation of multiple DNA replication origins (ORIs). Although origin firing is mechanistically conserved, how origins are specified and selected for activation varies across different model systems. Here, we provide a complete analysis of the nucleosomal landscape and replication program of the human parasite Leishmania major, building on a better evolutionary understanding of replication organization in Eukarya. We found that active transcription is a driving force for the nucleosomal organization of the L. major genome and that both the spatial and the temporal program of DNA replication can be explained as associated to RNA polymerase kinetics. This simple scenario likely provides flexibility and robustness to deal with the environmental changes that impose alterations in the genetic programs during parasitic life cycle stages. Our findings also suggest that coupling replication initiation to transcription elongation could be an ancient solution used by eukaryotic cells for origin maintenance. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Genome Science: A Video Tour of the Washington University Genome Sequencing Center for High School and Undergraduate Students

PubMed Central

2005-01-01

Sequencing of the human genome has ushered in a new era of biology. The technologies developed to facilitate the sequencing of the human genome are now being applied to the sequencing of other genomes. In 2004, a partnership was formed between Washington University School of Medicine Genome Sequencing Center's Outreach Program and Washington University Department of Biology Science Outreach to create a video tour depicting the processes involved in large-scale sequencing. “Sequencing a Genome: Inside the Washington University Genome Sequencing Center” is a tour of the laboratory that follows the steps in the sequencing pipeline, interspersed with animated explanations of the scientific procedures used at the facility. Accompanying interviews with the staff illustrate different entry levels for a career in genome science. This video project serves as an example of how research and academic institutions can provide teachers and students with access and exposure to innovative technologies at the forefront of biomedical research. Initial feedback on the video from undergraduate students, high school teachers, and high school students provides suggestions for use of this video in a classroom setting to supplement present curricula. PMID:16341256

Connecting genomic alterations to cancer biology with proteomics: the NCI Clinical Proteomic Tumor Analysis Consortium.

PubMed

Ellis, Matthew J; Gillette, Michael; Carr, Steven A; Paulovich, Amanda G; Smith, Richard D; Rodland, Karin K; Townsend, R Reid; Kinsinger, Christopher; Mesri, Mehdi; Rodriguez, Henry; Liebler, Daniel C

2013-10-01

The National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium is applying the latest generation of proteomic technologies to genomically annotated tumors from The Cancer Genome Atlas (TCGA) program, a joint initiative of the NCI and the National Human Genome Research Institute. By providing a fully integrated accounting of DNA, RNA, and protein abnormalities in individual tumors, these datasets will illuminate the complex relationship between genomic abnormalities and cancer phenotypes, thus producing biologic insights as well as a wave of novel candidate biomarkers and therapeutic targets amenable to verification using targeted mass spectrometry methods. ©2013 AACR.

MutSpec: a Galaxy toolbox for streamlined analyses of somatic mutation spectra in human and mouse cancer genomes.

PubMed

Ardin, Maude; Cahais, Vincent; Castells, Xavier; Bouaoun, Liacine; Byrnes, Graham; Herceg, Zdenko; Zavadil, Jiri; Olivier, Magali

2016-04-18

The nature of somatic mutations observed in human tumors at single gene or genome-wide levels can reveal information on past carcinogenic exposures and mutational processes contributing to tumor development. While large amounts of sequencing data are being generated, the associated analysis and interpretation of mutation patterns that may reveal clues about the natural history of cancer present complex and challenging tasks that require advanced bioinformatics skills. To make such analyses accessible to a wider community of researchers with no programming expertise, we have developed within the web-based user-friendly platform Galaxy a first-of-its-kind package called MutSpec. MutSpec includes a set of tools that perform variant annotation and use advanced statistics for the identification of mutation signatures present in cancer genomes and for comparing the obtained signatures with those published in the COSMIC database and other sources. MutSpec offers an accessible framework for building reproducible analysis pipelines, integrating existing methods and scripts developed in-house with publicly available R packages. MutSpec may be used to analyse data from whole-exome, whole-genome or targeted sequencing experiments performed on human or mouse genomes. Results are provided in various formats including rich graphical outputs. An example is presented to illustrate the package functionalities, the straightforward workflow analysis and the richness of the statistics and publication-grade graphics produced by the tool. MutSpec offers an easy-to-use graphical interface embedded in the popular Galaxy platform that can be used by researchers with limited programming or bioinformatics expertise to analyse mutation signatures present in cancer genomes. MutSpec can thus effectively assist in the discovery of complex mutational processes resulting from exogenous and endogenous carcinogenic insults.

Human Genome Replication Proceeds through Four Chromatin States

PubMed Central

Julienne, Hanna; Zoufir, Azedine; Audit, Benjamin; Arneodo, Alain

2013-01-01

Advances in genomic studies have led to significant progress in understanding the epigenetically controlled interplay between chromatin structure and nuclear functions. Epigenetic modifications were shown to play a key role in transcription regulation and genome activity during development and differentiation or in response to the environment. Paradoxically, the molecular mechanisms that regulate the initiation and the maintenance of the spatio-temporal replication program in higher eukaryotes, and in particular their links to epigenetic modifications, still remain elusive. By integrative analysis of the genome-wide distributions of thirteen epigenetic marks in the human cell line K562, at the 100 kb resolution of corresponding mean replication timing (MRT) data, we identify four major groups of chromatin marks with shared features. These states have different MRT, namely from early to late replicating, replication proceeds though a transcriptionally active euchromatin state (C1), a repressive type of chromatin (C2) associated with polycomb complexes, a silent state (C3) not enriched in any available marks, and a gene poor HP1-associated heterochromatin state (C4). When mapping these chromatin states inside the megabase-sized U-domains (U-shaped MRT profile) covering about 50% of the human genome, we reveal that the associated replication fork polarity gradient corresponds to a directional path across the four chromatin states, from C1 at U-domains borders followed by C2, C3 and C4 at centers. Analysis of the other genome half is consistent with early and late replication loci occurring in separate compartments, the former correspond to gene-rich, high-GC domains of intermingled chromatin states C1 and C2, whereas the latter correspond to gene-poor, low-GC domains of alternating chromatin states C3 and C4 or long C4 domains. This new segmentation sheds a new light on the epigenetic regulation of the spatio-temporal replication program in human and provides a framework for further studies in different cell types, in both health and disease. PMID:24130466

Human genome research and the public interest: Progress notes from an American Science Policy Experiment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Juengst, E.T.

1994-01-01

This essay reviews the efforts of the US Human Genome Project to anticipate and address the ethical, legal, and social implications of new advances in human genetics. Since 1990, approximately $10 million has been awarded by the National Institutes of Health and the DOE, in support of 65 research, education, and public discussion projects. These projects address four major areas of need: (1) the need for both client-centered assessments of new genetic services and for improved knowledge of the psychosocial and ethnocultural factors that shape clients' clinical genetic experiences; (2) the need for clear professional policies regarding human-subject research, clinicalmore » practical standards, and public health goals in human genetics; (3) the need for social policy protection against unfair access to and use of personal genetic information; (4) the need for improved public and professional understanding and discussion of these issues. The Human Genome Project's goal is to have defined, by 1995, policy options and programs capable of addressing these needs. 47 refs.« less

Mapping our genes: The genome projects: How big, how fast

DOE Office of Scientific and Technical Information (OSTI.GOV)

none,

For the past 2 years, scientific and technical journals in biology and medicine have extensively covered a debate about whether and how to determine the function and order of human genes on human chromosomes and when to determine the sequence of molecular building blocks that comprise DNA in those chromosomes. In 1987, these issues rose to become part of the public agenda. The debate involves science, technology, and politics. Congress is responsible for /open quotes/writing the rules/close quotes/ of what various federal agencies do and for funding their work. This report surveys the points made so far in the debate,more » focusing on those that most directly influence the policy options facing the US Congress. Congressional interest focused on how to assess the rationales for conducting human genome projects, how to fund human genome projects (at what level and through which mechanisms), how to coordinate the scientific and technical programs of the several federal agencies and private interests already supporting various genome projects, and how to strike a balance regarding the impact of genome projects on international scientific cooperation and international economic competition in biotechnology. OTA prepared this report with the assistance of several hundred experts throughout the world. 342 refs., 26 figs., 11 tabs.« less

Genome-scale CRISPR-Cas9 knockout screening in human cells.

PubMed

Shalem, Ophir; Sanjana, Neville E; Hartenian, Ella; Shi, Xi; Scott, David A; Mikkelson, Tarjei; Heckl, Dirk; Ebert, Benjamin L; Root, David E; Doench, John G; Zhang, Feng

2014-01-03

The simplicity of programming the CRISPR (clustered regularly interspaced short palindromic repeats)-associated nuclease Cas9 to modify specific genomic loci suggests a new way to interrogate gene function on a genome-wide scale. We show that lentiviral delivery of a genome-scale CRISPR-Cas9 knockout (GeCKO) library targeting 18,080 genes with 64,751 unique guide sequences enables both negative and positive selection screening in human cells. First, we used the GeCKO library to identify genes essential for cell viability in cancer and pluripotent stem cells. Next, in a melanoma model, we screened for genes whose loss is involved in resistance to vemurafenib, a therapeutic RAF inhibitor. Our highest-ranking candidates include previously validated genes NF1 and MED12, as well as novel hits NF2, CUL3, TADA2B, and TADA1. We observe a high level of consistency between independent guide RNAs targeting the same gene and a high rate of hit confirmation, demonstrating the promise of genome-scale screening with Cas9.

A Comparative Encyclopedia of DNA Elements in the Mouse Genome

PubMed Central

Yue, Feng; Cheng, Yong; Breschi, Alessandra; Vierstra, Jeff; Wu, Weisheng; Ryba, Tyrone; Sandstrom, Richard; Ma, Zhihai; Davis, Carrie; Pope, Benjamin D.; Shen, Yin; Pervouchine, Dmitri D.; Djebali, Sarah; Thurman, Bob; Kaul, Rajinder; Rynes, Eric; Kirilusha, Anthony; Marinov, Georgi K.; Williams, Brian A.; Trout, Diane; Amrhein, Henry; Fisher-Aylor, Katherine; Antoshechkin, Igor; DeSalvo, Gilberto; See, Lei-Hoon; Fastuca, Meagan; Drenkow, Jorg; Zaleski, Chris; Dobin, Alex; Prieto, Pablo; Lagarde, Julien; Bussotti, Giovanni; Tanzer, Andrea; Denas, Olgert; Li, Kanwei; Bender, M. A.; Zhang, Miaohua; Byron, Rachel; Groudine, Mark T.; McCleary, David; Pham, Long; Ye, Zhen; Kuan, Samantha; Edsall, Lee; Wu, Yi-Chieh; Rasmussen, Matthew D.; Bansal, Mukul S.; Keller, Cheryl A.; Morrissey, Christapher S.; Mishra, Tejaswini; Jain, Deepti; Dogan, Nergiz; Harris, Robert S.; Cayting, Philip; Kawli, Trupti; Boyle, Alan P.; Euskirchen, Ghia; Kundaje, Anshul; Lin, Shin; Lin, Yiing; Jansen, Camden; Malladi, Venkat S.; Cline, Melissa S.; Erickson, Drew T.; Kirkup, Vanessa M; Learned, Katrina; Sloan, Cricket A.; Rosenbloom, Kate R.; de Sousa, Beatriz Lacerda; Beal, Kathryn; Pignatelli, Miguel; Flicek, Paul; Lian, Jin; Kahveci, Tamer; Lee, Dongwon; Kent, W. James; Santos, Miguel Ramalho; Herrero, Javier; Notredame, Cedric; Johnson, Audra; Vong, Shinny; Lee, Kristen; Bates, Daniel; Neri, Fidencio; Diegel, Morgan; Canfield, Theresa; Sabo, Peter J.; Wilken, Matthew S.; Reh, Thomas A.; Giste, Erika; Shafer, Anthony; Kutyavin, Tanya; Haugen, Eric; Dunn, Douglas; Reynolds, Alex P.; Neph, Shane; Humbert, Richard; Hansen, R. Scott; De Bruijn, Marella; Selleri, Licia; Rudensky, Alexander; Josefowicz, Steven; Samstein, Robert; Eichler, Evan E.; Orkin, Stuart H.; Levasseur, Dana; Papayannopoulou, Thalia; Chang, Kai-Hsin; Skoultchi, Arthur; Gosh, Srikanta; Disteche, Christine; Treuting, Piper; Wang, Yanli; Weiss, Mitchell J.; Blobel, Gerd A.; Good, Peter J.; Lowdon, Rebecca F.; Adams, Leslie B.; Zhou, Xiao-Qiao; Pazin, Michael J.; Feingold, Elise A.; Wold, Barbara; Taylor, James; Kellis, Manolis; Mortazavi, Ali; Weissman, Sherman M.; Stamatoyannopoulos, John; Snyder, Michael P.; Guigo, Roderic; Gingeras, Thomas R.; Gilbert, David M.; Hardison, Ross C.; Beer, Michael A.; Ren, Bing

2014-01-01

Summary As the premier model organism in biomedical research, the laboratory mouse shares the majority of protein-coding genes with humans, yet the two mammals differ in significant ways. To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications, and replication domains throughout the mouse genome in diverse cell and tissue types. By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of other sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization. Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases. PMID:25409824

A comparative encyclopedia of DNA elements in the mouse genome.

PubMed

Yue, Feng; Cheng, Yong; Breschi, Alessandra; Vierstra, Jeff; Wu, Weisheng; Ryba, Tyrone; Sandstrom, Richard; Ma, Zhihai; Davis, Carrie; Pope, Benjamin D; Shen, Yin; Pervouchine, Dmitri D; Djebali, Sarah; Thurman, Robert E; Kaul, Rajinder; Rynes, Eric; Kirilusha, Anthony; Marinov, Georgi K; Williams, Brian A; Trout, Diane; Amrhein, Henry; Fisher-Aylor, Katherine; Antoshechkin, Igor; DeSalvo, Gilberto; See, Lei-Hoon; Fastuca, Meagan; Drenkow, Jorg; Zaleski, Chris; Dobin, Alex; Prieto, Pablo; Lagarde, Julien; Bussotti, Giovanni; Tanzer, Andrea; Denas, Olgert; Li, Kanwei; Bender, M A; Zhang, Miaohua; Byron, Rachel; Groudine, Mark T; McCleary, David; Pham, Long; Ye, Zhen; Kuan, Samantha; Edsall, Lee; Wu, Yi-Chieh; Rasmussen, Matthew D; Bansal, Mukul S; Kellis, Manolis; Keller, Cheryl A; Morrissey, Christapher S; Mishra, Tejaswini; Jain, Deepti; Dogan, Nergiz; Harris, Robert S; Cayting, Philip; Kawli, Trupti; Boyle, Alan P; Euskirchen, Ghia; Kundaje, Anshul; Lin, Shin; Lin, Yiing; Jansen, Camden; Malladi, Venkat S; Cline, Melissa S; Erickson, Drew T; Kirkup, Vanessa M; Learned, Katrina; Sloan, Cricket A; Rosenbloom, Kate R; Lacerda de Sousa, Beatriz; Beal, Kathryn; Pignatelli, Miguel; Flicek, Paul; Lian, Jin; Kahveci, Tamer; Lee, Dongwon; Kent, W James; Ramalho Santos, Miguel; Herrero, Javier; Notredame, Cedric; Johnson, Audra; Vong, Shinny; Lee, Kristen; Bates, Daniel; Neri, Fidencio; Diegel, Morgan; Canfield, Theresa; Sabo, Peter J; Wilken, Matthew S; Reh, Thomas A; Giste, Erika; Shafer, Anthony; Kutyavin, Tanya; Haugen, Eric; Dunn, Douglas; Reynolds, Alex P; Neph, Shane; Humbert, Richard; Hansen, R Scott; De Bruijn, Marella; Selleri, Licia; Rudensky, Alexander; Josefowicz, Steven; Samstein, Robert; Eichler, Evan E; Orkin, Stuart H; Levasseur, Dana; Papayannopoulou, Thalia; Chang, Kai-Hsin; Skoultchi, Arthur; Gosh, Srikanta; Disteche, Christine; Treuting, Piper; Wang, Yanli; Weiss, Mitchell J; Blobel, Gerd A; Cao, Xiaoyi; Zhong, Sheng; Wang, Ting; Good, Peter J; Lowdon, Rebecca F; Adams, Leslie B; Zhou, Xiao-Qiao; Pazin, Michael J; Feingold, Elise A; Wold, Barbara; Taylor, James; Mortazavi, Ali; Weissman, Sherman M; Stamatoyannopoulos, John A; Snyder, Michael P; Guigo, Roderic; Gingeras, Thomas R; Gilbert, David M; Hardison, Ross C; Beer, Michael A; Ren, Bing

2014-11-20

The laboratory mouse shares the majority of its protein-coding genes with humans, making it the premier model organism in biomedical research, yet the two mammals differ in significant ways. To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types. By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization. Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases.

[The interpretation and integration of traditional Chinese phytotherapy into Western-type medicine with the possession of knowledge of the human genome].

PubMed

Blázovics, Anna

2018-05-01

The terminology of traditional Chinese medicine (TCM) is hardly interpretable in the context of human genome, therefore the human genome program attracted attention towards the Western practice of medicine in China. In the last two decades, several important steps could be observed in China in relation to the approach of traditional Chinese and Western medicine. The Chinese government supports the realization of information databases for research in order to clarify the molecular biology level to detect associations between gene expression signal transduction pathways and protein-protein interactions, and the effects of bioactive components of Chinese drugs and their effectiveness. The values of TCM are becoming more and more important for Western medicine as well, because molecular biological therapies did not redeem themselves, e.g., in tumor therapy. Orv Hetil. 2018; 159(18): 696-702.

Aspergillus Niger Genomics: Past, Present and into the Future

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baker, Scott E.

2006-09-01

Aspergillus niger is a filamentous ascomycete fungus that is ubiquitous in the environment and has been implicated in opportunistic infections of humans. In addition to its role as an opportunistic human pathogen, A. niger is economically important as a fermentation organism used for the production of citric acid. Industrial citric acid production by A. niger represents one of the most efficient, highest yield bioprocesses in use currently by industry. The genome size of A. niger is estimated to be between 35.5 and 38.5 megabases (Mb) divided among eight chromosomes/linkage groups that vary in size from 3.5 - 6.6 Mb. Currently,more » there are three independent A. niger genome projects, an indication of the economic importance of this organism. The rich amount of data resulting from these multiple A. niger genome sequences will be used for basic and applied research programs applicable to fermentation process development, morphology and pathogenicity.« less

Interview: Professor Andrew Feinberg speaks to Epigenomics.

PubMed

Feinberg, Andrew

2009-10-01

Andrew Feinberg studied mathematics and humanities at Yale University (CT, USA) in the Directed Studies honors program, and he received his BA (1973) and MD (1976) from the accelerated medical program at Johns Hopkins University (MD, USA), as well as an MPH from Johns Hopkins (1981). He performed a postdoctoral fellowship in developmental biology at the University of California, San Diego (UCSD, CA, USA), clinical training in medicine and medical genetics at the University of Pennsylvania (PA, USA) and genetics research with Bert Vogelstein at Johns Hopkins, discovering altered DNA methylation in human cancer. Dr Feinberg continued to perform seminal work in cancer epigenetics as a Howard Hughes investigator at the University of Michigan (MI, USA), discovering human imprinted genes and loss of imprinting in cancer, and the molecular basis of Beckwith-Wiedemann syndrome. He returned to John Hopkins in 1994 as King Fahd Professor of Medicine, Molecular Biology & Genetics and Oncology, and he holds an Adjunct Professorship at the Karolinska Institute in Sweden. Dr Feinberg is Director of the Center for Epigenetics, a National Human Genome Research Institute-designated Center of Excellence in Genome Sciences. The Center is pioneering genome-scale tools in molecular, statistical and epidemiological epigenetics, and is applying them to the study of cancer, neuropsychiatric disease and aging. As part of the center, Dr Feinberg has organized a highly innovative program to bring gifted minority high-school students into genetics and genomics. Dr Feinberg has also invented a number of widely used molecular tools, including random priming. His honors include election to the American Society for Clinical Investigation, the Association of American Physicians, the Institute of Medicine of the National Academy of Sciences, and the American Academy of Arts and Sciences, as well as membership on the ISI most-cited authors list, a MERIT Award of the National Cancer Institute, a Doctor of Philosophy (Hon. Caus.) from Uppsala University (Sweden), and the President's Diversity Recognition Award of Johns Hopkins University.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nord, Alex S.; Pattabiraman, Kartik; Visel, Axel

The forebrain is the seat of higher-order brain functions, and many human neuropsychiatric disorders are due to genetic defects affecting forebrain development, making it imperative to understand the underlying genetic circuitry. We report that recent progress now makes it possible to begin fully elucidating the genomic regulatory mechanisms that control forebrain gene expression. Here, we discuss the current knowledge of how transcription factors drive gene expression programs through their interactions with cis-acting genomic elements, such as enhancers; how analyses of chromatin and DNA modifications provide insights into gene expression states; and how these approaches yield insights into the evolution ofmore » the human brain.« less

Universal Newborn Screening and Adverse Medical Outcomes: A Historical Note

ERIC Educational Resources Information Center

Brosco, Jeffrey P.; Seider, Michael I.; Dunn, Angela C.

2006-01-01

Universal newborn screening programs for metabolic disorders are typically described as a triumph of medicine and public policy in the US over the last 50 years. Advances in science and technology, including the Human Genome Project, offer the opportunity to expand universal newborn screening programs to include many additional metabolic and…

EGRP Privacy Policy & Disclaimers

Cancer.gov

The Epidemiology and Genomics Research Program complies with requirements for privacy and security established by the Office of Management and Budget, Department of Health and Human Services, the National Institutes of Health, and the National Cancer Institute.

The Einstein Center for Epigenomics: studying the role of epigenomic dysregulation in human disease.

PubMed

McLellan, Andrew S; Dubin, Robert A; Jing, Qiang; Maqbool, Shahina B; Olea, Raul; Westby, Gael; Broin, Pilib Ó; Fazzari, Melissa J; Zheng, Deyou; Suzuki, Masako; Greally, John M

2009-10-01

There is increasing interest in the role of epigenetic and transcriptional dysregulation in the pathogenesis of a range of human diseases, not just in the best-studied example of cancer. It is, however, quite difficult for an individual investigator to perform these studies, as they involve genome-wide molecular assays combined with sophisticated computational analytical approaches of very large datasets that may be generated from various resources and technologies. In 2008, the Albert Einstein College of Medicine in New York, USA established a Center for Epigenomics to facilitate the research programs of its investigators, providing shared resources for genome-wide assays and for data analysis. As a result, several avenues of research are now expanding, with cancer epigenomics being complemented by studies of the epigenomics of infectious disease and a neuroepigenomics program.

GIANT API: an application programming interface for functional genomics

PubMed Central

Roberts, Andrew M.; Wong, Aaron K.; Fisk, Ian; Troyanskaya, Olga G.

2016-01-01

GIANT API provides biomedical researchers programmatic access to tissue-specific and global networks in humans and model organisms, and associated tools, which includes functional re-prioritization of existing genome-wide association study (GWAS) data. Using tissue-specific interaction networks, researchers are able to predict relationships between genes specific to a tissue or cell lineage, identify the changing roles of genes across tissues and uncover disease-gene associations. Additionally, GIANT API enables computational tools like NetWAS, which leverages tissue-specific networks for re-prioritization of GWAS results. The web services covered by the API include 144 tissue-specific functional gene networks in human, global functional networks for human and six common model organisms and the NetWAS method. GIANT API conforms to the REST architecture, which makes it stateless, cacheable and highly scalable. It can be used by a diverse range of clients including web browsers, command terminals, programming languages and standalone apps for data analysis and visualization. The API is freely available for use at http://giant-api.princeton.edu. PMID:27098035

ActiveDriverDB: human disease mutations and genome variation in post-translational modification sites of proteins

PubMed Central

Krassowski, Michal; Paczkowska, Marta; Cullion, Kim; Huang, Tina; Dzneladze, Irakli; Ouellette, B F Francis; Yamada, Joseph T; Fradet-Turcotte, Amelie

2018-01-01

Abstract Interpretation of genetic variation is needed for deciphering genotype-phenotype associations, mechanisms of inherited disease, and cancer driver mutations. Millions of single nucleotide variants (SNVs) in human genomes are known and thousands are associated with disease. An estimated 21% of disease-associated amino acid substitutions corresponding to missense SNVs are located in protein sites of post-translational modifications (PTMs), chemical modifications of amino acids that extend protein function. ActiveDriverDB is a comprehensive human proteo-genomics database that annotates disease mutations and population variants through the lens of PTMs. We integrated >385,000 published PTM sites with ∼3.6 million substitutions from The Cancer Genome Atlas (TCGA), the ClinVar database of disease genes, and human genome sequencing projects. The database includes site-specific interaction networks of proteins, upstream enzymes such as kinases, and drugs targeting these enzymes. We also predicted network-rewiring impact of mutations by analyzing gains and losses of kinase-bound sequence motifs. ActiveDriverDB provides detailed visualization, filtering, browsing and searching options for studying PTM-associated mutations. Users can upload mutation datasets interactively and use our application programming interface in pipelines. Integrative analysis of mutations and PTMs may help decipher molecular mechanisms of phenotypes and disease, as exemplified by case studies of TP53, BRCA2 and VHL. The open-source database is available at https://www.ActiveDriverDB.org. PMID:29126202

HuMiChip: Development of a Functional Gene Array for the Study of Human Microbiomes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tu, Q.; Deng, Ye; Lin, Lu

Microbiomes play very important roles in terms of nutrition, health and disease by interacting with their hosts. Based on sequence data currently available in public domains, we have developed a functional gene array to monitor both organismal and functional gene profiles of normal microbiota in human and mouse hosts, and such an array is called human and mouse microbiota array, HMM-Chip. First, seed sequences were identified from KEGG databases, and used to construct a seed database (seedDB) containing 136 gene families in 19 metabolic pathways closely related to human and mouse microbiomes. Second, a mother database (motherDB) was constructed withmore » 81 genomes of bacterial strains with 54 from gut and 27 from oral environments, and 16 metagenomes, and used for selection of genes and probe design. Gene prediction was performed by Glimmer3 for bacterial genomes, and by the Metagene program for metagenomes. In total, 228,240 and 801,599 genes were identified for bacterial genomes and metagenomes, respectively. Then the motherDB was searched against the seedDB using the HMMer program, and gene sequences in the motherDB that were highly homologous with seed sequences in the seedDB were used for probe design by the CommOligo software. Different degrees of specific probes, including gene-specific, inclusive and exclusive group-specific probes were selected. All candidate probes were checked against the motherDB and NCBI databases for specificity. Finally, 7,763 probes covering 91.2percent (12,601 out of 13,814) HMMer confirmed sequences from 75 bacterial genomes and 16 metagenomes were selected. This developed HMM-Chip is able to detect the diversity and abundance of functional genes, the gene expression of microbial communities, and potentially, the interactions of microorganisms and their hosts.« less

Functional analysis and transcriptional output of the Göttingen minipig genome.

PubMed

Heckel, Tobias; Schmucki, Roland; Berrera, Marco; Ringshandl, Stephan; Badi, Laura; Steiner, Guido; Ravon, Morgane; Küng, Erich; Kuhn, Bernd; Kratochwil, Nicole A; Schmitt, Georg; Kiialainen, Anna; Nowaczyk, Corinne; Daff, Hamina; Khan, Azinwi Phina; Lekolool, Isaac; Pelle, Roger; Okoth, Edward; Bishop, Richard; Daubenberger, Claudia; Ebeling, Martin; Certa, Ulrich

2015-11-14

In the past decade the Göttingen minipig has gained increasing recognition as animal model in pharmaceutical and safety research because it recapitulates many aspects of human physiology and metabolism. Genome-based comparison of drug targets together with quantitative tissue expression analysis allows rational prediction of pharmacology and cross-reactivity of human drugs in animal models thereby improving drug attrition which is an important challenge in the process of drug development. Here we present a new chromosome level based version of the Göttingen minipig genome together with a comparative transcriptional analysis of tissues with pharmaceutical relevance as basis for translational research. We relied on mapping and assembly of WGS (whole-genome-shotgun sequencing) derived reads to the reference genome of the Duroc pig and predict 19,228 human orthologous protein-coding genes. Genome-based prediction of the sequence of human drug targets enables the prediction of drug cross-reactivity based on conservation of binding sites. We further support the finding that the genome of Sus scrofa contains about ten-times less pseudogenized genes compared to other vertebrates. Among the functional human orthologs of these minipig pseudogenes we found HEPN1, a putative tumor suppressor gene. The genomes of Sus scrofa, the Tibetan boar, the African Bushpig, and the Warthog show sequence conservation of all inactivating HEPN1 mutations suggesting disruption before the evolutionary split of these pig species. We identify 133 Sus scrofa specific, conserved long non-coding RNAs (lncRNAs) in the minipig genome and show that these transcripts are highly conserved in the African pigs and the Tibetan boar suggesting functional significance. Using a new minipig specific microarray we show high conservation of gene expression signatures in 13 tissues with biomedical relevance between humans and adult minipigs. We underline this relationship for minipig and human liver where we could demonstrate similar expression levels for most phase I drug-metabolizing enzymes. Higher expression levels and metabolic activities were found for FMO1, AKR/CRs and for phase II drug metabolizing enzymes in minipig as compared to human. The variability of gene expression in equivalent human and minipig tissues is considerably higher in minipig organs, which is important for study design in case a human target belongs to this variable category in the minipig. The first analysis of gene expression in multiple tissues during development from young to adult shows that the majority of transcriptional programs are concluded four weeks after birth. This finding is in line with the advanced state of human postnatal organ development at comparative age categories and further supports the minipig as model for pediatric drug safety studies. Genome based assessment of sequence conservation combined with gene expression data in several tissues improves the translational value of the minipig for human drug development. The genome and gene expression data presented here are important resources for researchers using the minipig as model for biomedical research or commercial breeding. Potential impact of our data for comparative genomics, translational research, and experimental medicine are discussed.

SNP-associations and phenotype predictions from hundreds of microbial genomes without genome alignments.

PubMed

Hall, Barry G

2014-01-01

SNP-association studies are a starting point for identifying genes that may be responsible for specific phenotypes, such as disease traits. The vast bulk of tools for SNP-association studies are directed toward SNPs in the human genome, and I am unaware of any tools designed specifically for such studies in bacterial or viral genomes. The PPFS (Predict Phenotypes From SNPs) package described here is an add-on to kSNP , a program that can identify SNPs in a data set of hundreds of microbial genomes. PPFS identifies those SNPs that are non-randomly associated with a phenotype based on the χ² probability, then uses those diagnostic SNPs for two distinct, but related, purposes: (1) to predict the phenotypes of strains whose phenotypes are unknown, and (2) to identify those diagnostic SNPs that are most likely to be causally related to the phenotype. In the example illustrated here, from a set of 68 E. coli genomes, for 67 of which the pathogenicity phenotype was known, there were 418,500 SNPs. Using the phenotypes of 36 of those strains, PPFS identified 207 diagnostic SNPs. The diagnostic SNPs predicted the phenotypes of all of the genomes with 97% accuracy. It then identified 97 SNPs whose probability of being causally related to the pathogenic phenotype was >0.999. In a second example, from a set of 116 E. coli genome sequences, using the phenotypes of 65 strains PPFS identified 101 SNPs that predicted the source host (human or non-human) with 90% accuracy.

Knowledge, attitudes, and values among physicians working with clinical genomics: a survey of medical oncologists.

PubMed

Chow-White, Peter; Ha, Dung; Laskin, Janessa

2017-06-27

It has been over a decade since the completion of the Human Genome Project (HGP), genomic sequencing technologies have yet to become parts of standard of care in Canada. This study investigates medical oncologists' (MOs) genomic literacy and their experiences based on their participation in a cancer genomics trial in British Columbia, Canada. The authors conducted a survey of MOs from British Columbia, Canada (n = 31, 52.5% response rate), who are actively involved in a clinical genomics trial called Personalized Onco-Genomics (POG). The authors also measured MOs' level of genomic knowledge and attitudes about clinical genomics in cancer medicine. The findings show a low to moderate level of genomic literacy among MOs. MOs located outside the Vancouver area (the major urban center) reported less knowledge about new genetics technologies compared to those located in the major metropolitan area (26.7 vs 73.3%, P < 0.07, Fisher exact test). Forty-two percent of all MOs thought medical training programs do not offer enough genomic training. The majority of the respondents thought genomics will have major impact on drug discovery (67.7%), and treatment selection (58%) in the next 5 years. They also thought the major challenges are cost (61.3%), patient genomic literacy (48.3%), and clinical utility of genomics (42%). The data suggest a high need to increase genomic literacy among MOs and other doctors in medical school training programs and beyond, especially to physicians in regional areas who may need more educational interventions. Initiatives like POG play a critical role in the education of MOs and the integration of big data clinical genomics into cancer care.

From genomics to mechanistic insight: a global perspective on molecular deficits induced by environmental agents.

PubMed

Ramos, Kenneth S; Steffen, Marlene C; Falahatpisheh, M H; Nanez, Adrian

2007-06-01

As the postgenomic era continues to unfold, a new wave of scientific investigation is upon us focusing on the application of genomic technologies to study the meanings encrypted on the DNA code and the responses of living organisms to changes in their environment. Recent functional genomics studies in this laboratory have focused on the role of the aryl hydrocarbon receptor, a ubiquitous transcription factor, in genetic programming during renal development. Also of interest is the application of genomics investigations to the study of chronic medical conditions associated with early life exposures to environmental contaminants. Molecular evidence is discussed in this review within the framework of human molecular medicine.

Postdoctoral Fellows | Center for Cancer Research

Cancer.gov

The Oncogenomics section of the Genetics Branch is a multidisciplinary and interdisciplinary translational research programmatic effort with the goal of utilizing genomics to develop novel immunotherapies for cancer. Our group is applying high throughput applied genomics methods including single cell RNAseq, single cell TCR sequencing, DNA sequencing, CRISPR/Cas9, bioinformatics combined with T cell based therapeutics to identify and develop novel immunotherapeutics for human cancer. We work with other investigators within the intramural program as well as industrial and pharmaceutical partners to rapidly translate our findings to the clinic. The program takes advantage of the uniqueness of the National Cancer Institute, (NCI), Center for Cancer Research (CCR) intramural program in that it spans high-risk basic discovery research in immunology, genomics and tumor biology, through preclinical translational research, to paradigm-shifting clinical trials. The position is available immediately. The appointment duration is up to 5 years. Stipends are commensurate with education and experience. Additional information can be found on Dr. Khan’s profile page: https://ccr.cancer.gov/Genetics-Branch/javed-khan

Genome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans

PubMed Central

Houtepen, Lotte C.; Vinkers, Christiaan H.; Carrillo-Roa, Tania; Hiemstra, Marieke; van Lier, Pol A.; Meeus, Wim; Branje, Susan; Heim, Christine M.; Nemeroff, Charles B.; Mill, Jonathan; Schalkwyk, Leonard C.; Creyghton, Menno P.; Kahn, René S.; Joëls, Marian; Binder, Elisabeth B.; Boks, Marco P. M.

2016-01-01

DNA methylation likely plays a role in the regulation of human stress reactivity. Here we show that in a genome-wide analysis of blood DNA methylation in 85 healthy individuals, a locus in the Kit ligand gene (KITLG; cg27512205) showed the strongest association with cortisol stress reactivity (P=5.8 × 10−6). Replication was obtained in two independent samples using either blood (N=45, P=0.001) or buccal cells (N=255, P=0.004). KITLG methylation strongly mediates the relationship between childhood trauma and cortisol stress reactivity in the discovery sample (32% mediation). Its genomic location, a CpG island shore within an H3K27ac enhancer mark, and the correlation between methylation in the blood and prefrontal cortex provide further evidence that KITLG methylation is functionally relevant for the programming of stress reactivity in the human brain. Our results extend preclinical evidence for epigenetic regulation of stress reactivity to humans and provide leads to enhance our understanding of the neurobiological pathways underlying stress vulnerability. PMID:26997371

Open chromatin encoded in DNA sequence is the signature of ‘master’ replication origins in human cells

PubMed Central

Audit, Benjamin; Zaghloul, Lamia; Vaillant, Cédric; Chevereau, Guillaume; d'Aubenton-Carafa, Yves; Thermes, Claude; Arneodo, Alain

2009-01-01

For years, progress in elucidating the mechanisms underlying replication initiation and its coupling to transcriptional activities and to local chromatin structure has been hampered by the small number (approximately 30) of well-established origins in the human genome and more generally in mammalian genomes. Recent in silico studies of compositional strand asymmetries revealed a high level of organization of human genes around 1000 putative replication origins. Here, by comparing with recently experimentally identified replication origins, we provide further support that these putative origins are active in vivo. We show that regions ∼300-kb wide surrounding most of these putative replication origins that replicate early in the S phase are hypersensitive to DNase I cleavage, hypomethylated and present a significant enrichment in genomic energy barriers that impair nucleosome formation (nucleosome-free regions). This suggests that these putative replication origins are specified by an open chromatin structure favored by the DNA sequence. We discuss how this distinctive attribute makes these origins, further qualified as ‘master’ replication origins, priviledged loci for future research to decipher the human spatio-temporal replication program. Finally, we argue that these ‘master’ origins are likely to play a key role in genome dynamics during evolution and in pathological situations. PMID:19671527

A programmable Cas9-serine recombinase fusion protein that operates on DNA sequences in mammalian cells

PubMed Central

Chaikind, Brian; Bessen, Jeffrey L.; Thompson, David B.; Hu, Johnny H.; Liu, David R.

2016-01-01

We describe the development of ‘recCas9’, an RNA-programmed small serine recombinase that functions in mammalian cells. We fused a catalytically inactive dCas9 to the catalytic domain of Gin recombinase using an optimized fusion architecture. The resulting recCas9 system recombines DNA sites containing a minimal recombinase core site flanked by guide RNA-specified sequences. We show that these recombinases can operate on DNA sites in mammalian cells identical to genomic loci naturally found in the human genome in a manner that is dependent on the guide RNA sequences. DNA sequencing reveals that recCas9 catalyzes guide RNA-dependent recombination in human cells with an efficiency as high as 32% on plasmid substrates. Finally, we demonstrate that recCas9 expressed in human cells can catalyze in situ deletion between two genomic sites. Because recCas9 directly catalyzes recombination, it generates virtually no detectable indels or other stochastic DNA modification products. This work represents a step toward programmable, scarless genome editing in unmodified cells that is independent of endogenous cellular machinery or cell state. Current and future generations of recCas9 may facilitate targeted agricultural breeding, or the study and treatment of human genetic diseases. PMID:27515511

Joint Estimation of Contamination, Error and Demography for Nuclear DNA from Ancient Humans

PubMed Central

Slatkin, Montgomery

2016-01-01

When sequencing an ancient DNA sample from a hominin fossil, DNA from present-day humans involved in excavation and extraction will be sequenced along with the endogenous material. This type of contamination is problematic for downstream analyses as it will introduce a bias towards the population of the contaminating individual(s). Quantifying the extent of contamination is a crucial step as it allows researchers to account for possible biases that may arise in downstream genetic analyses. Here, we present an MCMC algorithm to co-estimate the contamination rate, sequencing error rate and demographic parameters—including drift times and admixture rates—for an ancient nuclear genome obtained from human remains, when the putative contaminating DNA comes from present-day humans. We assume we have a large panel representing the putative contaminant population (e.g. European, East Asian or African). The method is implemented in a C++ program called ‘Demographic Inference with Contamination and Error’ (DICE). We applied it to simulations and genome data from ancient Neanderthals and modern humans. With reasonable levels of genome sequence coverage (>3X), we find we can recover accurate estimates of all these parameters, even when the contamination rate is as high as 50%. PMID:27049965

The human genome initiative: a statement of need.

PubMed

Watson, J D

1991-10-15

We may never have a complete understanding of the complex dynamics of the human organism, but we can and should know all our genes and begin to understand their role in the diseases that diminish our lives. A 15-year program has been projected and the specific, quantifiable goals in mapping and sequencing are outlined. Ethical, legal, and social implications are also discussed.

An Exact Algorithm to Compute the Double-Cut-and-Join Distance for Genomes with Duplicate Genes.

PubMed

Shao, Mingfu; Lin, Yu; Moret, Bernard M E

2015-05-01

Computing the edit distance between two genomes is a basic problem in the study of genome evolution. The double-cut-and-join (DCJ) model has formed the basis for most algorithmic research on rearrangements over the last few years. The edit distance under the DCJ model can be computed in linear time for genomes without duplicate genes, while the problem becomes NP-hard in the presence of duplicate genes. In this article, we propose an integer linear programming (ILP) formulation to compute the DCJ distance between two genomes with duplicate genes. We also provide an efficient preprocessing approach to simplify the ILP formulation while preserving optimality. Comparison on simulated genomes demonstrates that our method outperforms MSOAR in computing the edit distance, especially when the genomes contain long duplicated segments. We also apply our method to assign orthologous gene pairs among human, mouse, and rat genomes, where once again our method outperforms MSOAR.

GIANT API: an application programming interface for functional genomics.

PubMed

Roberts, Andrew M; Wong, Aaron K; Fisk, Ian; Troyanskaya, Olga G

2016-07-08

GIANT API provides biomedical researchers programmatic access to tissue-specific and global networks in humans and model organisms, and associated tools, which includes functional re-prioritization of existing genome-wide association study (GWAS) data. Using tissue-specific interaction networks, researchers are able to predict relationships between genes specific to a tissue or cell lineage, identify the changing roles of genes across tissues and uncover disease-gene associations. Additionally, GIANT API enables computational tools like NetWAS, which leverages tissue-specific networks for re-prioritization of GWAS results. The web services covered by the API include 144 tissue-specific functional gene networks in human, global functional networks for human and six common model organisms and the NetWAS method. GIANT API conforms to the REST architecture, which makes it stateless, cacheable and highly scalable. It can be used by a diverse range of clients including web browsers, command terminals, programming languages and standalone apps for data analysis and visualization. The API is freely available for use at http://giant-api.princeton.edu. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Structural and quantitative expression analyses of HERV gene family in human tissues.

PubMed

Ahn, Kung; Kim, Heui-Soo

2009-08-31

Human endogenous retroviruses (HERVs) have been implicated in the pathogenesis of several human diseases as multi-copy members in the human genome. Their gene expression profiling could provide us with important insights into the pathogenic relationship between HERVs and cancer. In this study, we have evaluated the genomic structure and quantitatively determined the expression patterns in the env gene of a variety of HERV family members located on six specific loci by the RetroTector 10 program, as well as real-time RT-PCR amplification. The env gene transcripts evidenced significant differences in the human tumor/normal adjacent tissues (colon, liver, uterus, lung and testis). As compared to the adjacent normal tissues, high levels of expression were noted in testis tumor tissues for HERV-K, in liver and lung tumor tissues for HERV-R, in liver, lung, and testis tumor tissues for HERV-H, and in colon and liver tumor tissues for HERV-P. These data warrant further studies with larger groups of patients to develop biomarkers for specific human cancers.

From ecology to base pairs: nursing and genetic science.

PubMed

Williams, J K; Tripp-Reimer, T

2001-07-01

With the mapping of the human genome has come the opportunity for nursing research to explore topics of concern to the maintenance, restoration, and attainment of genetic-related health. Initially, nursing research on genetic topics originated primarily from physical anthropology and from a clinical, disease-focused perspective. Nursing research subsequently focused on psychosocial aspects of genetic conditions for individuals and their family members. As findings emerge from current human genome discovery, new programs of genetic nursing research are originating from a biobehavioral interface, ranging from the investigations of the influence of specific molecular changes on gene function to social/ethical issues of human health and disease. These initiatives reflect nursing's response to discoveries of gene mutations related to phenotypic expression in both clinical and community-based populations. Genetic research programs are needed that integrate or adapt theoretical and methodological advances in epidemiology, family systems, anthropology, and ethics with those from nursing. Research programs must address not only populations with a specific disease but also community-based genetic health care issues. As genetic health care practice evolves, so will opportunities for research by nurses who can apply genetic concepts and interventions to improve the health of the public. This article presents an analysis of the evolution of genetic nursing research and challengesfor the future.

10. international mouse genome conference

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meisler, M.H.

Ten years after hosting the First International Mammalian Genome Conference in Paris in 1986, Dr. Jean-Louis Guenet presided over the Tenth Conference at the Pasteur Institute, October 7--10, 1996. The 1986 conference was a satellite to the Human Gene Mapping Workshop and had approximately 50 attendees. The 1996 meeting was attended by 300 scientists from around the world. In the interim, the number of mapped loci in the mouse increased from 1,000 to over 20,000. This report contains a listing of the program and its participants, and two articles that review the meeting and the role of the laboratory mousemore » in the Human Genome project. More than 200 papers were presented at the conference covering the following topics: International mouse chromosome committee meetings; Mutant generation and identification; Physical and genetic maps; New technology and resources; Chromatin structure and gene regulation; Rate and hamster genetic maps; Informatics and databases; and Quantitative trait analysis.« less

The anti-human immunodeficiency virus agent 3'-fluorothymidine induces DNA damage and apoptosis in human lymphoblastoid cells.

PubMed Central

Sundseth, R; Joyner, S S; Moore, J T; Dornsife, R E; Dev, I K

1996-01-01

Patients infected with the human immunodeficiency virus experienced severe hematopoietic toxicity after treatment with the deoxynucleoside analog 3'-fluorothymidine (FLT). Using several methods for the analysis of genome integrity, including histochemical staining of the 3' ends of DNA and both conventional and pulsed-field agarose gel electrophoresis, we demonstrated that FLT caused extensive DNA fragmentation in CEM cells that was not observed when these cells were treated with other, less toxic thymidine analogs. In addition, a distinctive pattern of small DNA fragments that is characteristic of cells in the process of programmed cell death was observed in the genomic DNA of CEM cells treated with FLT. We conclude that FLT induces DNA fragmentation and apoptosis in a human cell line of hematopoietic origin, and we offer this observation as a possible explanation for the severe toxicity of FLT observed in vivo. PMID:8834875

swga: a primer design toolkit for selective whole genome amplification.

PubMed

Clarke, Erik L; Sundararaman, Sesh A; Seifert, Stephanie N; Bushman, Frederic D; Hahn, Beatrice H; Brisson, Dustin

2017-07-15

Population genomic analyses are often hindered by difficulties in obtaining sufficient numbers of genomes for analysis by DNA sequencing. Selective whole-genome amplification (SWGA) provides an efficient approach to amplify microbial genomes from complex backgrounds for sequence acquisition. However, the process of designing sets of primers for this method has many degrees of freedom and would benefit from an automated process to evaluate the vast number of potential primer sets. Here, we present swga , a program that identifies primer sets for SWGA and evaluates them for efficiency and selectivity. We used swga to design and test primer sets for the selective amplification of Wolbachia pipientis genomic DNA from infected Drosophila melanogaster and Mycobacterium tuberculosis from human blood. We identify primer sets that successfully amplify each against their backgrounds and describe a general method for using swga for arbitrary targets. In addition, we describe characteristics of primer sets that correlate with successful amplification, and present guidelines for implementation of SWGA to detect new targets. Source code and documentation are freely available on https://www.github.com/eclarke/swga . The program is implemented in Python and C and licensed under the GNU Public License. ecl@mail.med.upenn.edu. Supplementary data are available at Bioinformatics online. © The Author(s) 2017. Published by Oxford University Press.

Building an International Initiative to Infuse Novel Cancer Models into the Research Community | Office of Cancer Genomics

Cancer.gov

My name is Caitlyn Barrett and I am the Scientific Program Manager for the Human Cancer Model Initiative (HCMI) in the Office of Cancer Genomics (OCG). In my role within the HCMI, I am helping to establish communication pathways and build the foundation for collaboration that will enable the completion of the Initiative’s aim to develop as many as 1000 next-generation cancer models, established from patient tumors and accompanied by clinical and molecular data.

Programmed DNA Elimination: Keeping Germline Genes in Their Place.

PubMed

Smith, Jeramiah J

2018-05-21

Each of our cells contains a full set of instructions needed to make an entire human: the genome. But a few special species buck this trend. A new study now identifies the first germline-specific gene in zebra finch, one of a small number of vertebrates that are known to undergo developmentally programmed DNA elimination. Copyright © 2018 Elsevier Ltd. All rights reserved.

Open versus Controlled-Access Data | Office of Cancer Genomics

Cancer.gov

OCG employs stringent human subjects’ protection and data access policies to protect the privacy and confidentiality of the research participants. Depending on the risk of patient identification, OCG programs data are available to the scientific community in two tiers: open or controlled access. Both types of data can be accessed through its corresponding OCG program-specific data matrix or portal. Open-access Data

Season of conception in rural Gambia affects DNA methylation at putative human metastable epialleles

USDA-ARS?s Scientific Manuscript database

Throughout most of the mammalian genome, genetically regulated developmental programming establishes diverse yet predictable epigenetic states across differentiated cells and tissues. At metastable epialleles (MEs), conversely, epigenotype is established stochastically in the early embryo then maint...

Integrating Genetics and Social Science: Genetic Risk Scores

PubMed Central

Belsky, Daniel W.; Israel, Salomon

2014-01-01

The sequencing of the human genome and the advent of low-cost genome-wide assays that generate millions of observations of individual genomes in a matter of hours constitute a disruptive innovation for social science. Many public-use social science datasets have or will soon add genome-wide genetic data. With these new data come technical challenges, but also new possibilities. Among these, the lowest hanging fruit and the most potentially disruptive to existing research programs is the ability to measure previously invisible contours of health and disease risk within populations. In this article, we outline why now is the time for social scientists to bring genetics into their research programs. We discuss how to select genetic variants to study. We explain how the polygenic architecture of complex traits and the low penetrance of individual genetic loci pose challenges to research integrating genetics and social science. We introduce genetic risk scores as a method of addressing these challenges and provide guidance on how genetic risk scores can be constructed. We conclude by outlining research questions that are ripe for social science inquiry. PMID:25343363

SGP-1: Prediction and Validation of Homologous Genes Based on Sequence Alignments

PubMed Central

Wiehe, Thomas; Gebauer-Jung, Steffi; Mitchell-Olds, Thomas; Guigó, Roderic

2001-01-01

Conventional methods of gene prediction rely on the recognition of DNA-sequence signals, the coding potential or the comparison of a genomic sequence with a cDNA, EST, or protein database. Reasons for limited accuracy in many circumstances are species-specific training and the incompleteness of reference databases. Lately, comparative genome analysis has attracted increasing attention. Several analysis tools that are based on human/mouse comparisons are already available. Here, we present a program for the prediction of protein-coding genes, termed SGP-1 (Syntenic Gene Prediction), which is based on the similarity of homologous genomic sequences. In contrast to most existing tools, the accuracy of SGP-1 depends little on species-specific properties such as codon usage or the nucleotide distribution. SGP-1 may therefore be applied to nonstandard model organisms in vertebrates as well as in plants, without the need for extensive parameter training. In addition to predicting genes in large-scale genomic sequences, the program may be useful to validate gene structure annotations from databases. To this end, SGP-1 output also contains comparisons between predicted and annotated gene structures in HTML format. The program can be accessed via a Web server at http://soft.ice.mpg.de/sgp-1. The source code, written in ANSI C, is available on request from the authors. PMID:11544202

Chemical Genomics Profiling of Environmental Chemical Modulation of Human Nuclear Receptors

EPA Science Inventory

The large and increasing number of chemicals released into the environment demand more efficient and cost effective approaches for assessing environmental chemical toxicity. The U.S. Tox21 program has responded to this challenge by proposing alternative strategies for toxicity te...

The NIH Undiagnosed Diseases Program | NIH MedlinePlus the Magazine

MedlinePlus

... to discover and understand rare diseases,” says Eric D. Green, M.D., Ph.D., director of the National Human Genome Research Institute ( ... interdisciplinary approach,” says NIH Director Francis S. Collins, M.D., Ph.D. “The disorder had long-evaded conventional ...

Integrating Public Health and Deliberative Public Bioethics: Lessons from the Human Genome Project Ethical, Legal, and Social Implications Program

PubMed Central

Meagher, Karen M.

2016-01-01

Public health policy works best when grounded in firm public health standards of evidence and widely shared social values. In this article, we argue for incorporating a specific method of ethical deliberation—deliberative public bioethics—into public health. We describe how deliberative public bioethics is a method of engagement that can be helpful in public health. Although medical, research, and public health ethics can be considered some of what bioethics addresses, deliberative public bioethics offers both a how and where. Using the Human Genome Project Ethical, Legal, and Social Implications program as an example of effective incorporation of deliberative processes to integrate ethics into public health policy, we examine how deliberative public bioethics can integrate both public health and bioethics perspectives into three areas of public health practice: research, education, and health policy. We then offer recommendations for future collaborations that integrate deliberative methods into public health policy and practice. PMID:26843669

Integrating Public Health and Deliberative Public Bioethics: Lessons from the Human Genome Project Ethical, Legal, and Social Implications Program.

PubMed

Meagher, Karen M; Lee, Lisa M

2016-01-01

Public health policy works best when grounded in firm public health standards of evidence and widely shared social values. In this article, we argue for incorporating a specific method of ethical deliberation--deliberative public bioethics--into public health. We describe how deliberative public bioethics is a method of engagement that can be helpful in public health. Although medical, research, and public health ethics can be considered some of what bioethics addresses, deliberative public bioethics offers both a how and where. Using the Human Genome Project Ethical, Legal, and Social Implications program as an example of effective incorporation of deliberative processes to integrate ethics into public health policy, we examine how deliberative public bioethics can integrate both public health and bioethics perspectives into three areas of public health practice: research, education, and health policy. We then offer recommendations for future collaborations that integrate deliberative methods into public health policy and practice.

Whole-genome regression and prediction methods applied to plant and animal breeding.

PubMed

de Los Campos, Gustavo; Hickey, John M; Pong-Wong, Ricardo; Daetwyler, Hans D; Calus, Mario P L

2013-02-01

Genomic-enabled prediction is becoming increasingly important in animal and plant breeding and is also receiving attention in human genetics. Deriving accurate predictions of complex traits requires implementing whole-genome regression (WGR) models where phenotypes are regressed on thousands of markers concurrently. Methods exist that allow implementing these large-p with small-n regressions, and genome-enabled selection (GS) is being implemented in several plant and animal breeding programs. The list of available methods is long, and the relationships between them have not been fully addressed. In this article we provide an overview of available methods for implementing parametric WGR models, discuss selected topics that emerge in applications, and present a general discussion of lessons learned from simulation and empirical data analysis in the last decade.

Whole-Genome Regression and Prediction Methods Applied to Plant and Animal Breeding

PubMed Central

de los Campos, Gustavo; Hickey, John M.; Pong-Wong, Ricardo; Daetwyler, Hans D.; Calus, Mario P. L.

2013-01-01

Genomic-enabled prediction is becoming increasingly important in animal and plant breeding and is also receiving attention in human genetics. Deriving accurate predictions of complex traits requires implementing whole-genome regression (WGR) models where phenotypes are regressed on thousands of markers concurrently. Methods exist that allow implementing these large-p with small-n regressions, and genome-enabled selection (GS) is being implemented in several plant and animal breeding programs. The list of available methods is long, and the relationships between them have not been fully addressed. In this article we provide an overview of available methods for implementing parametric WGR models, discuss selected topics that emerge in applications, and present a general discussion of lessons learned from simulation and empirical data analysis in the last decade. PMID:22745228

The Ruby UCSC API: accessing the UCSC genome database using Ruby.

PubMed

Mishima, Hiroyuki; Aerts, Jan; Katayama, Toshiaki; Bonnal, Raoul J P; Yoshiura, Koh-ichiro

2012-09-21

The University of California, Santa Cruz (UCSC) genome database is among the most used sources of genomic annotation in human and other organisms. The database offers an excellent web-based graphical user interface (the UCSC genome browser) and several means for programmatic queries. A simple application programming interface (API) in a scripting language aimed at the biologist was however not yet available. Here, we present the Ruby UCSC API, a library to access the UCSC genome database using Ruby. The API is designed as a BioRuby plug-in and built on the ActiveRecord 3 framework for the object-relational mapping, making writing SQL statements unnecessary. The current version of the API supports databases of all organisms in the UCSC genome database including human, mammals, vertebrates, deuterostomes, insects, nematodes, and yeast.The API uses the bin index-if available-when querying for genomic intervals. The API also supports genomic sequence queries using locally downloaded *.2bit files that are not stored in the official MySQL database. The API is implemented in pure Ruby and is therefore available in different environments and with different Ruby interpreters (including JRuby). Assisted by the straightforward object-oriented design of Ruby and ActiveRecord, the Ruby UCSC API will facilitate biologists to query the UCSC genome database programmatically. The API is available through the RubyGem system. Source code and documentation are available at https://github.com/misshie/bioruby-ucsc-api/ under the Ruby license. Feedback and help is provided via the website at http://rubyucscapi.userecho.com/.

The Ruby UCSC API: accessing the UCSC genome database using Ruby

PubMed Central

2012-01-01

Background The University of California, Santa Cruz (UCSC) genome database is among the most used sources of genomic annotation in human and other organisms. The database offers an excellent web-based graphical user interface (the UCSC genome browser) and several means for programmatic queries. A simple application programming interface (API) in a scripting language aimed at the biologist was however not yet available. Here, we present the Ruby UCSC API, a library to access the UCSC genome database using Ruby. Results The API is designed as a BioRuby plug-in and built on the ActiveRecord 3 framework for the object-relational mapping, making writing SQL statements unnecessary. The current version of the API supports databases of all organisms in the UCSC genome database including human, mammals, vertebrates, deuterostomes, insects, nematodes, and yeast. The API uses the bin index—if available—when querying for genomic intervals. The API also supports genomic sequence queries using locally downloaded *.2bit files that are not stored in the official MySQL database. The API is implemented in pure Ruby and is therefore available in different environments and with different Ruby interpreters (including JRuby). Conclusions Assisted by the straightforward object-oriented design of Ruby and ActiveRecord, the Ruby UCSC API will facilitate biologists to query the UCSC genome database programmatically. The API is available through the RubyGem system. Source code and documentation are available at https://github.com/misshie/bioruby-ucsc-api/ under the Ruby license. Feedback and help is provided via the website at http://rubyucscapi.userecho.com/. PMID:22994508

Are we Genomic Mosaics? Variations of the Genome of Somatic Cells can Contribute to Diversify our Phenotypes.

PubMed

Astolfi, P A; Salamini, F; Sgaramella, V

2010-09-01

Theoretical and experimental evidences support the hypothesis that the genomes and the epigenomes may be different in the somatic cells of complex organisms. In the genome, the differences range from single base substitutions to chromosome number; in the epigenome, they entail multiple postsynthetic modifications of the chromatin. Somatic genome variations (SGV) may accumulate during development in response both to genetic programs, which may differ from tissue to tissue, and to environmental stimuli, which are often undetected and generally irreproducible. SGV may jeopardize physiological cellular functions, but also create novel coding and regulatory sequences, to be exposed to intraorganismal Darwinian selection. Genomes acknowledged as comparatively poor in genes, such as humans', could thus increase their pristine informational endowment. A better understanding of SGV will contribute to basic issues such as the "nature vs nurture" dualism and the inheritance of acquired characters. On the applied side, they may explain the low yield of cloning via somatic cell nuclear transfer, provide clues to some of the problems associated with transdifferentiation, and interfere with individual DNA analysis. SGV may be unique in the different cells types and in the different developmental stages, and thus explain the several hundred gaps persisting in the human genomes "completed" so far. They may compound the variations associated to our epigenomes and make of each of us an "(epi)genomic" mosaic. An ensuing paradigm is the possibility that a single genome (the ephemeral one assembled at fertilization) has the capacity to generate several different brains in response to different environments.

BSP-01: Full Four-Digit Typing for Class I and II HLA Genes | Frederick National Laboratory for Cancer Research

Cancer.gov

The Basic Science Program will receive genomic DNA at a concentration of 50 ng/ul.Human leukocyte antigen (HLA) typing will be performed using atargeted next-generation sequencing (NGS) method.Briefly, locus-specific primers are use

Toxicity pathway-based mode of action modeling for risk assessment

EPA Science Inventory

In response to the 2007 NRC report on toxicity testing in the 21st century, the USEPA has entered into a memorandum of understanding with the National Human Genome Research Institute and the national Toxicology Program to jointly pursue ways to incorporate high throughput methods...

Genomes2Drugs: Identifies Target Proteins and Lead Drugs from Proteome Data

PubMed Central

Toomey, David; Hoppe, Heinrich C.; Brennan, Marian P.; Nolan, Kevin B.; Chubb, Anthony J.

2009-01-01

Background Genome sequencing and bioinformatics have provided the full hypothetical proteome of many pathogenic organisms. Advances in microarray and mass spectrometry have also yielded large output datasets of possible target proteins/genes. However, the challenge remains to identify new targets for drug discovery from this wealth of information. Further analysis includes bioinformatics and/or molecular biology tools to validate the findings. This is time consuming and expensive, and could fail to yield novel drugs if protein purification and crystallography is impossible. To pre-empt this, a researcher may want to rapidly filter the output datasets for proteins that show good homology to proteins that have already been structurally characterised or proteins that are already targets for known drugs. Critically, those researchers developing novel antibiotics need to select out the proteins that show close homology to any human proteins, as future inhibitors are likely to cross-react with the host protein, causing off-target toxicity effects later in clinical trials. Methodology/Principal Findings To solve many of these issues, we have developed a free online resource called Genomes2Drugs which ranks sequences to identify proteins that are (i) homologous to previously crystallized proteins or (ii) targets of known drugs, but are (iii) not homologous to human proteins. When tested using the Plasmodium falciparum malarial genome the program correctly enriched the ranked list of proteins with known drug target proteins. Conclusions/Significance Genomes2Drugs rapidly identifies proteins that are likely to succeed in drug discovery pipelines. This free online resource helps in the identification of potential drug targets. Importantly, the program further highlights proteins that are likely to be inhibited by FDA-approved drugs. These drugs can then be rapidly moved into Phase IV clinical studies under ‘change-of-application’ patents. PMID:19593435

The past, present, and future of Leishmania genomics and transcriptomics

PubMed Central

Cantacessi, Cinzia; Dantas-Torres, Filipe; Nolan, Matthew J.; Otranto, Domenico

2015-01-01

It has been nearly 10 years since the completion of the first entire genome sequence of a Leishmania parasite. Genomic and transcriptomic analyses have advanced our understanding of the biology of Leishmania, and shed new light on the complex interactions occurring within the parasite–host–vector triangle. Here, we review these advances and examine potential avenues for translation of these discoveries into treatment and control programs. In addition, we argue for a strong need to explore how disease in dogs relates to that in humans, and how an improved understanding in line with the ‘One Health’ concept may open new avenues for the control of these devastating diseases. PMID:25638444

Human genetics and genomics a decade after the release of the draft sequence of the human genome.

PubMed

Naidoo, Nasheen; Pawitan, Yudi; Soong, Richie; Cooper, David N; Ku, Chee-Seng

2011-10-01

Substantial progress has been made in human genetics and genomics research over the past ten years since the publication of the draft sequence of the human genome in 2001. Findings emanating directly from the Human Genome Project, together with those from follow-on studies, have had an enormous impact on our understanding of the architecture and function of the human genome. Major developments have been made in cataloguing genetic variation, the International HapMap Project, and with respect to advances in genotyping technologies. These developments are vital for the emergence of genome-wide association studies in the investigation of complex diseases and traits. In parallel, the advent of high-throughput sequencing technologies has ushered in the 'personal genome sequencing' era for both normal and cancer genomes, and made possible large-scale genome sequencing studies such as the 1000 Genomes Project and the International Cancer Genome Consortium. The high-throughput sequencing and sequence-capture technologies are also providing new opportunities to study Mendelian disorders through exome sequencing and whole-genome sequencing. This paper reviews these major developments in human genetics and genomics over the past decade.

Human genetics and genomics a decade after the release of the draft sequence of the human genome

PubMed Central

2011-01-01

Substantial progress has been made in human genetics and genomics research over the past ten years since the publication of the draft sequence of the human genome in 2001. Findings emanating directly from the Human Genome Project, together with those from follow-on studies, have had an enormous impact on our understanding of the architecture and function of the human genome. Major developments have been made in cataloguing genetic variation, the International HapMap Project, and with respect to advances in genotyping technologies. These developments are vital for the emergence of genome-wide association studies in the investigation of complex diseases and traits. In parallel, the advent of high-throughput sequencing technologies has ushered in the 'personal genome sequencing' era for both normal and cancer genomes, and made possible large-scale genome sequencing studies such as the 1000 Genomes Project and the International Cancer Genome Consortium. The high-throughput sequencing and sequence-capture technologies are also providing new opportunities to study Mendelian disorders through exome sequencing and whole-genome sequencing. This paper reviews these major developments in human genetics and genomics over the past decade. PMID:22155605

Widespread of horizontal gene transfer in the human genome.

PubMed

Huang, Wenze; Tsai, Lillian; Li, Yulong; Hua, Nan; Sun, Chen; Wei, Chaochun

2017-04-04

A fundamental concept in biology is that heritable material is passed from parents to offspring, a process called vertical gene transfer. An alternative mechanism of gene acquisition is through horizontal gene transfer (HGT), which involves movement of genetic materials between different species. Horizontal gene transfer has been found prevalent in prokaryotes but very rare in eukaryote. In this paper, we investigate horizontal gene transfer in the human genome. From the pair-wise alignments between human genome and 53 vertebrate genomes, 1,467 human genome regions (2.6 M bases) from all chromosomes were found to be more conserved with non-mammals than with most mammals. These human genome regions involve 642 known genes, which are enriched with ion binding. Compared to known horizontal gene transfer regions in the human genome, there were few overlapping regions, which indicated horizontal gene transfer is more common than we expected in the human genome. Horizontal gene transfer impacts hundreds of human genes and this study provided insight into potential mechanisms of HGT in the human genome.

DOE Office of Scientific and Technical Information (OSTI.GOV)

de Pruneda, J.H.

This issue pays tribute to Roger Batzel, the Laboratory's sixth and longest-tenured direct (1971-1988). The articles in this issue are: (1) ''Roger Batzel--A Leader and a Gentleman''. (2) ''A Career of Distinguished Achievement'' A superb manager with a quiet and self-effacing demeanor. Roger Batzel presided over a period of unprecedented growth and technical diversification at Lawrence Livermore. (3) ''From Dosimetry to Genomics'' Roger Batzel's support of Livermore's relatively new biomedical research program led to its growth into a major contributor to the worldwide Human Genome Project. (4) ''Swords into Plowshares and Beyond'' Under Roger Batzel's leadership, the Laboratory championed numerousmore » long-term, innovative alternative energy technologies to help address challenges not unlike those we are facing today. (5) ''Adapting to a Changing Weapons Program'' Roger Batzel's knowledge of the US weapons program and his much-trusted professional judgment served the Laboratory and the nation well as arms control and deterrence emerged as national priorities.« less

78 FR 56905 - National Human Genome Research Institute; Notice of Closed Meeting

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Simple and efficient identification of rare recessive pathologically important sequence variants from next generation exome sequence data.

PubMed

Carr, Ian M; Morgan, Joanne; Watson, Christopher; Melnik, Svitlana; Diggle, Christine P; Logan, Clare V; Harrison, Sally M; Taylor, Graham R; Pena, Sergio D J; Markham, Alexander F; Alkuraya, Fowzan S; Black, Graeme C M; Ali, Manir; Bonthron, David T

2013-07-01

Massively parallel ("next generation") DNA sequencing (NGS) has quickly become the method of choice for seeking pathogenic mutations in rare uncharacterized monogenic diseases. Typically, before DNA sequencing, protein-coding regions are enriched from patient genomic DNA, representing either the entire genome ("exome sequencing") or selected mapped candidate loci. Sequence variants, identified as differences between the patient's and the human genome reference sequences, are then filtered according to various quality parameters. Changes are screened against datasets of known polymorphisms, such as dbSNP and the 1000 Genomes Project, in the effort to narrow the list of candidate causative variants. An increasing number of commercial services now offer to both generate and align NGS data to a reference genome. This potentially allows small groups with limited computing infrastructure and informatics skills to utilize this technology. However, the capability to effectively filter and assess sequence variants is still an important bottleneck in the identification of deleterious sequence variants in both research and diagnostic settings. We have developed an approach to this problem comprising a user-friendly suite of programs that can interactively analyze, filter and screen data from enrichment-capture NGS data. These programs ("Agile Suite") are particularly suitable for small-scale gene discovery or for diagnostic analysis. © 2013 WILEY PERIODICALS, INC.

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BigQ: a NoSQL based framework to handle genomic variants in i2b2.

PubMed

Gabetta, Matteo; Limongelli, Ivan; Rizzo, Ettore; Riva, Alberto; Segagni, Daniele; Bellazzi, Riccardo

2015-12-29

Precision medicine requires the tight integration of clinical and molecular data. To this end, it is mandatory to define proper technological solutions able to manage the overwhelming amount of high throughput genomic data needed to test associations between genomic signatures and human phenotypes. The i2b2 Center (Informatics for Integrating Biology and the Bedside) has developed a widely internationally adopted framework to use existing clinical data for discovery research that can help the definition of precision medicine interventions when coupled with genetic data. i2b2 can be significantly advanced by designing efficient management solutions of Next Generation Sequencing data. We developed BigQ, an extension of the i2b2 framework, which integrates patient clinical phenotypes with genomic variant profiles generated by Next Generation Sequencing. A visual programming i2b2 plugin allows retrieving variants belonging to the patients in a cohort by applying filters on genomic variant annotations. We report an evaluation of the query performance of our system on more than 11 million variants, showing that the implemented solution scales linearly in terms of query time and disk space with the number of variants. In this paper we describe a new i2b2 web service composed of an efficient and scalable document-based database that manages annotations of genomic variants and of a visual programming plug-in designed to dynamically perform queries on clinical and genetic data. The system therefore allows managing the fast growing volume of genomic variants and can be used to integrate heterogeneous genomic annotations.

Revealing the missing expressed genes beyond the human reference genome by RNA-Seq.

PubMed

Chen, Geng; Li, Ruiyuan; Shi, Leming; Qi, Junyi; Hu, Pengzhan; Luo, Jian; Liu, Mingyao; Shi, Tieliu

2011-12-02

The complete and accurate human reference genome is important for functional genomics researches. Therefore, the incomplete reference genome and individual specific sequences have significant effects on various studies. we used two RNA-Seq datasets from human brain tissues and 10 mixed cell lines to investigate the completeness of human reference genome. First, we demonstrated that in previously identified ~5 Mb Asian and ~5 Mb African novel sequences that are absent from the human reference genome of NCBI build 36, ~211 kb and ~201 kb of them could be transcribed, respectively. Our results suggest that many of those transcribed regions are not specific to Asian and African, but also present in Caucasian. Then, we found that the expressions of 104 RefSeq genes that are unalignable to NCBI build 37 in brain and cell lines are higher than 0.1 RPKM. 55 of them are conserved across human, chimpanzee and macaque, suggesting that there are still a significant number of functional human genes absent from the human reference genome. Moreover, we identified hundreds of novel transcript contigs that cannot be aligned to NCBI build 37, RefSeq genes and EST sequences. Some of those novel transcript contigs are also conserved among human, chimpanzee and macaque. By positioning those contigs onto the human genome, we identified several large deletions in the reference genome. Several conserved novel transcript contigs were further validated by RT-PCR. Our findings demonstrate that a significant number of genes are still absent from the incomplete human reference genome, highlighting the importance of further refining the human reference genome and curating those missing genes. Our study also shows the importance of de novo transcriptome assembly. The comparative approach between reference genome and other related human genomes based on the transcriptome provides an alternative way to refine the human reference genome.

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Geneticizing Ethnicity and Diet: Anti-doping Science and Its Social Impact in the Age of Post-genomics.

PubMed

Hyun, Jaehwan

2017-01-01

While gene doping and other technological means of sport enhancement have become a topic of ethical debate, a major outcome from genomic research in sports is often linked to the regulation of doping. In particular, researchers within the field of anti-doping science, a regulatory science that aims to develop scientific solutions for regulating doped athletes, have conducted genomic research on anabolic-androgenic steroids. Genomic knowledge on anabolic-androgenic steroids, a knowledge base that has been produced to improve doping regulation, has caused the 'geneticization' of cultural objects such as ethnic identities and dietary habits. Through examining how anti-doping genomic knowledge and its media representation unnecessarily reify cultural objects in terms of genomics, I argue that Ethical, Legal, and Social Implications (ELSI) research programs in human enhancement should include the social impacts of anti-doping science in their discussions. Furthermore, this article will propose that ELSI scholars begin their academic analysis on anti-doping science by engaging with the recent ELSI scholarship on genomics and race and consider the regulatory and political natures of anti-doping research.

Geneticizing Ethnicity and Diet: Anti-doping Science and Its Social Impact in the Age of Post-genomics

PubMed Central

Hyun, Jaehwan

2017-01-01

While gene doping and other technological means of sport enhancement have become a topic of ethical debate, a major outcome from genomic research in sports is often linked to the regulation of doping. In particular, researchers within the field of anti-doping science, a regulatory science that aims to develop scientific solutions for regulating doped athletes, have conducted genomic research on anabolic-androgenic steroids. Genomic knowledge on anabolic-androgenic steroids, a knowledge base that has been produced to improve doping regulation, has caused the ‘geneticization’ of cultural objects such as ethnic identities and dietary habits. Through examining how anti-doping genomic knowledge and its media representation unnecessarily reify cultural objects in terms of genomics, I argue that Ethical, Legal, and Social Implications (ELSI) research programs in human enhancement should include the social impacts of anti-doping science in their discussions. Furthermore, this article will propose that ELSI scholars begin their academic analysis on anti-doping science by engaging with the recent ELSI scholarship on genomics and race and consider the regulatory and political natures of anti-doping research. PMID:28536601

Human Contamination in Public Genome Assemblies.

PubMed

Kryukov, Kirill; Imanishi, Tadashi

2016-01-01

Contamination in genome assembly can lead to wrong or confusing results when using such genome as reference in sequence comparison. Although bacterial contamination is well known, the problem of human-originated contamination received little attention. In this study we surveyed 45,735 available genome assemblies for evidence of human contamination. We used lineage specificity to distinguish between contamination and conservation. We found that 154 genome assemblies contain fragments that with high confidence originate as contamination from human DNA. Majority of contaminating human sequences were present in the reference human genome assembly for over a decade. We recommend that existing contaminated genomes should be revised to remove contaminated sequence, and that new assemblies should be thoroughly checked for presence of human DNA before submitting them to public databases.

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iDoComp: a compression scheme for assembled genomes

PubMed Central

Ochoa, Idoia; Hernaez, Mikel; Weissman, Tsachy

2015-01-01

Motivation: With the release of the latest next-generation sequencing (NGS) machine, the HiSeq X by Illumina, the cost of sequencing a Human has dropped to a mere $4000. Thus we are approaching a milestone in the sequencing history, known as the $1000 genome era, where the sequencing of individuals is affordable, opening the doors to effective personalized medicine. Massive generation of genomic data, including assembled genomes, is expected in the following years. There is crucial need for compression of genomes guaranteed of performing well simultaneously on different species, from simple bacteria to humans, which will ease their transmission, dissemination and analysis. Further, most of the new genomes to be compressed will correspond to individuals of a species from which a reference already exists on the database. Thus, it is natural to propose compression schemes that assume and exploit the availability of such references. Results: We propose iDoComp, a compressor of assembled genomes presented in FASTA format that compresses an individual genome using a reference genome for both the compression and the decompression. In terms of compression efficiency, iDoComp outperforms previously proposed algorithms in most of the studied cases, with comparable or better running time. For example, we observe compression gains of up to 60% in several cases, including H.sapiens data, when comparing with the best compression performance among the previously proposed algorithms. Availability: iDoComp is written in C and can be downloaded from: http://www.stanford.edu/~iochoa/iDoComp.html (We also provide a full explanation on how to run the program and an example with all the necessary files to run it.). Contact: iochoa@stanford.edu Supplementary information: Supplementary Data are available at Bioinformatics online. PMID:25344501

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Programs | Office of Cancer Genomics

Cancer.gov

OCG facilitates cancer genomics research through a series of highly-focused programs. These programs generate and disseminate genomic data for use by the cancer research community. OCG programs also promote advances in technology-based infrastructure and create valuable experimental reagents and tools. OCG programs encourage collaboration by interconnecting with other genomics and cancer projects in order to accelerate translation of findings into the clinic. Below are OCG’s current, completed, and initiated programs:

Bacteria-Human Somatic Cell Lateral Gene Transfer Is Enriched in Cancer Samples

PubMed Central

Robinson, Kelly M.; White, James Robert; Ganesan, Ashwinkumar; Nourbakhsh, Syrus; Dunning Hotopp, Julie C.

2013-01-01

There are 10× more bacterial cells in our bodies from the microbiome than human cells. Viral DNA is known to integrate in the human genome, but the integration of bacterial DNA has not been described. Using publicly available sequence data from the human genome project, the 1000 Genomes Project, and The Cancer Genome Atlas (TCGA), we examined bacterial DNA integration into the human somatic genome. Here we present evidence that bacterial DNA integrates into the human somatic genome through an RNA intermediate, and that such integrations are detected more frequently in (a) tumors than normal samples, (b) RNA than DNA samples, and (c) the mitochondrial genome than the nuclear genome. Hundreds of thousands of paired reads support random integration of Acinetobacter-like DNA in the human mitochondrial genome in acute myeloid leukemia samples. Numerous read pairs across multiple stomach adenocarcinoma samples support specific integration of Pseudomonas-like DNA in the 5′-UTR and 3′-UTR of four proto-oncogenes that are up-regulated in their transcription, consistent with conversion to an oncogene. These data support our hypothesis that bacterial integrations occur in the human somatic genome and may play a role in carcinogenesis. We anticipate that the application of our approach to additional cancer genome projects will lead to the more frequent detection of bacterial DNA integrations in tumors that are in close proximity to the human microbiome. PMID:23840181

Integrating cancer genomic data into electronic health records.

PubMed

Warner, Jeremy L; Jain, Sandeep K; Levy, Mia A

2016-10-26

The rise of genomically targeted therapies and immunotherapy has revolutionized the practice of oncology in the last 10-15 years. At the same time, new technologies and the electronic health record (EHR) in particular have permeated the oncology clinic. Initially designed as billing and clinical documentation systems, EHR systems have not anticipated the complexity and variety of genomic information that needs to be reviewed, interpreted, and acted upon on a daily basis. Improved integration of cancer genomic data with EHR systems will help guide clinician decision making, support secondary uses, and ultimately improve patient care within oncology clinics. Some of the key factors relating to the challenge of integrating cancer genomic data into EHRs include: the bioinformatics pipelines that translate raw genomic data into meaningful, actionable results; the role of human curation in the interpretation of variant calls; and the need for consistent standards with regard to genomic and clinical data. Several emerging paradigms for integration are discussed in this review, including: non-standardized efforts between individual institutions and genomic testing laboratories; "middleware" products that portray genomic information, albeit outside of the clinical workflow; and application programming interfaces that have the potential to work within clinical workflow. The critical need for clinical-genomic knowledge bases, which can be independent or integrated into the aforementioned solutions, is also discussed.

VCFtoTree: a user-friendly tool to construct locus-specific alignments and phylogenies from thousands of anthropologically relevant genome sequences.

PubMed

Xu, Duo; Jaber, Yousef; Pavlidis, Pavlos; Gokcumen, Omer

2017-09-26

Constructing alignments and phylogenies for a given locus from large genome sequencing studies with relevant outgroups allow novel evolutionary and anthropological insights. However, no user-friendly tool has been developed to integrate thousands of recently available and anthropologically relevant genome sequences to construct complete sequence alignments and phylogenies. Here, we provide VCFtoTree, a user friendly tool with a graphical user interface that directly accesses online databases to download, parse and analyze genome variation data for regions of interest. Our pipeline combines popular sequence datasets and tree building algorithms with custom data parsing to generate accurate alignments and phylogenies using all the individuals from the 1000 Genomes Project, Neanderthal and Denisovan genomes, as well as reference genomes of Chimpanzee and Rhesus Macaque. It can also be applied to other phased human genomes, as well as genomes from other species. The output of our pipeline includes an alignment in FASTA format and a tree file in newick format. VCFtoTree fulfills the increasing demand for constructing alignments and phylogenies for a given loci from thousands of available genomes. Our software provides a user friendly interface for a wider audience without prerequisite knowledge in programming. VCFtoTree can be accessed from https://github.com/duoduoo/VCFtoTree_3.0.0 .

Human Genome Sequencing in Health and Disease

PubMed Central

Gonzaga-Jauregui, Claudia; Lupski, James R.; Gibbs, Richard A.

2013-01-01

Following the “finished,” euchromatic, haploid human reference genome sequence, the rapid development of novel, faster, and cheaper sequencing technologies is making possible the era of personalized human genomics. Personal diploid human genome sequences have been generated, and each has contributed to our better understanding of variation in the human genome. We have consequently begun to appreciate the vastness of individual genetic variation from single nucleotide to structural variants. Translation of genome-scale variation into medically useful information is, however, in its infancy. This review summarizes the initial steps undertaken in clinical implementation of personal genome information, and describes the application of whole-genome and exome sequencing to identify the cause of genetic diseases and to suggest adjuvant therapies. Better analysis tools and a deeper understanding of the biology of our genome are necessary in order to decipher, interpret, and optimize clinical utility of what the variation in the human genome can teach us. Personal genome sequencing may eventually become an instrument of common medical practice, providing information that assists in the formulation of a differential diagnosis. We outline herein some of the remaining challenges. PMID:22248320

Identifying micro-inversions using high-throughput sequencing reads.

PubMed

He, Feifei; Li, Yang; Tang, Yu-Hang; Ma, Jian; Zhu, Huaiqiu

2016-01-11

The identification of inversions of DNA segments shorter than read length (e.g., 100 bp), defined as micro-inversions (MIs), remains challenging for next-generation sequencing reads. It is acknowledged that MIs are important genomic variation and may play roles in causing genetic disease. However, current alignment methods are generally insensitive to detect MIs. Here we develop a novel tool, MID (Micro-Inversion Detector), to identify MIs in human genomes using next-generation sequencing reads. The algorithm of MID is designed based on a dynamic programming path-finding approach. What makes MID different from other variant detection tools is that MID can handle small MIs and multiple breakpoints within an unmapped read. Moreover, MID improves reliability in low coverage data by integrating multiple samples. Our evaluation demonstrated that MID outperforms Gustaf, which can currently detect inversions from 30 bp to 500 bp. To our knowledge, MID is the first method that can efficiently and reliably identify MIs from unmapped short next-generation sequencing reads. MID is reliable on low coverage data, which is suitable for large-scale projects such as the 1000 Genomes Project (1KGP). MID identified previously unknown MIs from the 1KGP that overlap with genes and regulatory elements in the human genome. We also identified MIs in cancer cell lines from Cancer Cell Line Encyclopedia (CCLE). Therefore our tool is expected to be useful to improve the study of MIs as a type of genetic variant in the human genome. The source code can be downloaded from: http://cqb.pku.edu.cn/ZhuLab/MID .

Genomic Hypomethylation in the Human Germline Associates with Selective Structural Mutability in the Human Genome

PubMed Central

Li, Jian; Harris, R. Alan; Cheung, Sau Wai; Coarfa, Cristian; Jeong, Mira; Goodell, Margaret A.; White, Lisa D.; Patel, Ankita; Kang, Sung-Hae; Shaw, Chad; Chinault, A. Craig; Gambin, Tomasz; Gambin, Anna; Lupski, James R.; Milosavljevic, Aleksandar

2012-01-01

The hotspots of structural polymorphisms and structural mutability in the human genome remain to be explained mechanistically. We examine associations of structural mutability with germline DNA methylation and with non-allelic homologous recombination (NAHR) mediated by low-copy repeats (LCRs). Combined evidence from four human sperm methylome maps, human genome evolution, structural polymorphisms in the human population, and previous genomic and disease studies consistently points to a strong association of germline hypomethylation and genomic instability. Specifically, methylation deserts, the ∼1% fraction of the human genome with the lowest methylation in the germline, show a tenfold enrichment for structural rearrangements that occurred in the human genome since the branching of chimpanzee and are highly enriched for fast-evolving loci that regulate tissue-specific gene expression. Analysis of copy number variants (CNVs) from 400 human samples identified using a custom-designed array comparative genomic hybridization (aCGH) chip, combined with publicly available structural variation data, indicates that association of structural mutability with germline hypomethylation is comparable in magnitude to the association of structural mutability with LCR–mediated NAHR. Moreover, rare CNVs occurring in the genomes of individuals diagnosed with schizophrenia, bipolar disorder, and developmental delay and de novo CNVs occurring in those diagnosed with autism are significantly more concentrated within hypomethylated regions. These findings suggest a new connection between the epigenome, selective mutability, evolution, and human disease. PMID:22615578

A comprehensive transcript index of the human genome generated using microarrays and computational approaches

PubMed Central

Schadt, Eric E; Edwards, Stephen W; GuhaThakurta, Debraj; Holder, Dan; Ying, Lisa; Svetnik, Vladimir; Leonardson, Amy; Hart, Kyle W; Russell, Archie; Li, Guoya; Cavet, Guy; Castle, John; McDonagh, Paul; Kan, Zhengyan; Chen, Ronghua; Kasarskis, Andrew; Margarint, Mihai; Caceres, Ramon M; Johnson, Jason M; Armour, Christopher D; Garrett-Engele, Philip W; Tsinoremas, Nicholas F; Shoemaker, Daniel D

2004-01-01

Background Computational and microarray-based experimental approaches were used to generate a comprehensive transcript index for the human genome. Oligonucleotide probes designed from approximately 50,000 known and predicted transcript sequences from the human genome were used to survey transcription from a diverse set of 60 tissues and cell lines using ink-jet microarrays. Further, expression activity over at least six conditions was more generally assessed using genomic tiling arrays consisting of probes tiled through a repeat-masked version of the genomic sequence making up chromosomes 20 and 22. Results The combination of microarray data with extensive genome annotations resulted in a set of 28,456 experimentally supported transcripts. This set of high-confidence transcripts represents the first experimentally driven annotation of the human genome. In addition, the results from genomic tiling suggest that a large amount of transcription exists outside of annotated regions of the genome and serves as an example of how this activity could be measured on a genome-wide scale. Conclusions These data represent one of the most comprehensive assessments of transcriptional activity in the human genome and provide an atlas of human gene expression over a unique set of gene predictions. Before the annotation of the human genome is considered complete, however, the previously unannotated transcriptional activity throughout the genome must be fully characterized. PMID:15461792

Genomic prediction unifies animal and plant breeding programs to form platforms for biological discovery.

PubMed

Hickey, John M; Chiurugwi, Tinashe; Mackay, Ian; Powell, Wayne

2017-08-30

The rate of annual yield increases for major staple crops must more than double relative to current levels in order to feed a predicted global population of 9 billion by 2050. Controlled hybridization and selective breeding have been used for centuries to adapt plant and animal species for human use. However, achieving higher, sustainable rates of improvement in yields in various species will require renewed genetic interventions and dramatic improvement of agricultural practices. Genomic prediction of breeding values has the potential to improve selection, reduce costs and provide a platform that unifies breeding approaches, biological discovery, and tools and methods. Here we compare and contrast some animal and plant breeding approaches to make a case for bringing the two together through the application of genomic selection. We propose a strategy for the use of genomic selection as a unifying approach to deliver innovative 'step changes' in the rate of genetic gain at scale.

Genomic research and data-mining technology: implications for personal privacy and informed consent.

PubMed

Tavani, Herman T

2004-01-01

This essay examines issues involving personal privacy and informed consent that arise at the intersection of information and communication technology (ICT) and population genomics research. I begin by briefly examining the ethical, legal, and social implications (ELSI) program requirements that were established to guide researchers working on the Human Genome Project (HGP). Next I consider a case illustration involving deCODE Genetics, a privately owned genetic company in Iceland, which raises some ethical concerns that are not clearly addressed in the current ELSI guidelines. The deCODE case also illustrates some ways in which an ICT technique known as data mining has both aided and posed special challenges for researchers working in the field of population genomics. On the one hand, data-mining tools have greatly assisted researchers in mapping the human genome and in identifying certain "disease genes" common in specific populations (which, in turn, has accelerated the process of finding cures for diseases tha affect those populations). On the other hand, this technology has significantly threatened the privacy of research subjects participating in population genomics studies, who may, unwittingly, contribute to the construction of new groups (based on arbitrary and non-obvious patterns and statistical correlations) that put those subjects at risk for discrimination and stigmatization. In the final section of this paper I examine some ways in which the use of data mining in the context of population genomics research poses a critical challenge for the principle of informed consent, which traditionally has played a central role in protecting the privacy interests of research subjects participating in epidemiological studies.

[The human variome project and its progress].

PubMed

Gao, Shan; Zhang, Ning; Zhang, Lei; Duan, Guang-You; Zhang, Tao

2010-11-01

The main goal of post genomics is to explain how the genome, the map of which has been constructed in the Human Genome Project, affacts activities of life. This leads to generate multiple "omics": structural genomics, functional genomics, proteomics, metabonomics, et al. In Jun. 2006, Melbourne, Australia, Human Genome Variation Society (HGVS) initiated the Human Variome Project (HVP) to collect all the sequence variation and polymorphism data worldwidely. HVP is to search and determine those mutations related with human diseases by association study between genetype and phenotype on the scale of genome level and other methods. Those results will be translated into clinical application. Considering the potential effects of this project on human health, this paper introduced its origin and main content in detail and discussed its meaning and prospect.

Molecular characterization of two rare human G8P[14] rotavirus strains, detected in Italy in 2012.

PubMed

Delogu, Roberto; Ianiro, Giovanni; Morea, Anna; Chironna, Maria; Fiore, Lucia; Ruggeri, Franco M

2016-10-01

Since 2007, the Italian Rotavirus Surveillance Program (RotaNet-Italy) has monitored the diversity and distribution of genotypes identified in children hospitalized with rotavirus acute gastroenteritis. We report the genomic characterization of two rare human G8P[14] rotavirus strains, identified in two children hospitalized with acute gastroenteritis in the southern Italian region of Apulia during rotavirus strain surveillance in 2012. Both strains showed a G8-P[14]-I2-R2-C2-M2-A11-N2-T6-E2-H3 genomic constellation (DS-1-like genomic background). Phylogenetic analysis of each genome segment revealed a mixed configuration of genes of animal and zoonotic human origin, indicating that genetic reassortment events generated these unusual human strains. Eight out of 11 genes (VP1, VP2, VP3, VP6, VP7, NSP3, NSP4 and NSP5) of the Italian G8P[14] strains exhibited close identity with a Spanish sheep strain, whereas the remaining genes (VP4, NSP1 and NSP2) were more closely related to human strains. The amino acid sequences of the antigenic regions of outer capsid proteins VP4 and VP7 were compared with vaccine and field strains, showing high conservation between the amino acid sequences of Apulia G8P[14] strains and human and animal strains bearing G8 and/or P[14] proteins, and revealing many substitutions with respect to the RotaTeq™ and Rotarix™ vaccine strains. Conversely, the amino acid analysis of the four antigenic sites of VP6 revealed a high degree of conservation between the two Apulia strains and the human and animal strains analyzed. These results reinforce the potential role of interspecies transmission and reassortment in generating novel rotavirus strains that might not be fully contrasted by current vaccines. Copyright © 2016 Elsevier B.V. All rights reserved.

HIPAA's Individual Right of Access to Genomic Data: Reconciling Safety and Civil Rights.

PubMed

Evans, Barbara J

2018-01-04

In 2014, the United States granted individuals a right of access to their own laboratory test results, including genomic data. Many observers feel that this right is in tension with regulatory and bioethical standards designed to protect the safety of people who undergo genomic testing. This commentary attributes this tension to growing pains within an expanding federal regulatory program for genetic and genomic testing. The Genetic Information Nondiscrimination Act of 2008 expanded the regulatory agenda to encompass civil rights and consumer safety. The individual access right, as it applies to genomic data, is best understood as a civil-rights regulation. Competing regulatory objectives-safety and civil rights-were not successfully integrated during the initial rollout of genomic civil-rights regulations after 2008. Federal law clarifies how to prioritize safety and civil rights when the two come into conflict, although with careful policy design, the two need not collide. This commentary opens a dialog about possible solutions to advance safety and civil rights together. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

75 FR 26846 - Genomic Medicine Program Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-12

... DEPARTMENT OF VETERANS AFFAIRS Genomic Medicine Program Advisory Committee; Notice of Meeting The...) that the Genomic Medicine Program Advisory Committee will meet on May 21, 2010, at the Westin... appropriate ethical oversight and protecting the privacy of Veterans; presentations on genomic medicine...

A survey of tools for variant analysis of next-generation genome sequencing data

PubMed Central

Pabinger, Stephan; Dander, Andreas; Fischer, Maria; Snajder, Rene; Sperk, Michael; Efremova, Mirjana; Krabichler, Birgit; Speicher, Michael R.; Zschocke, Johannes

2014-01-01

Recent advances in genome sequencing technologies provide unprecedented opportunities to characterize individual genomic landscapes and identify mutations relevant for diagnosis and therapy. Specifically, whole-exome sequencing using next-generation sequencing (NGS) technologies is gaining popularity in the human genetics community due to the moderate costs, manageable data amounts and straightforward interpretation of analysis results. While whole-exome and, in the near future, whole-genome sequencing are becoming commodities, data analysis still poses significant challenges and led to the development of a plethora of tools supporting specific parts of the analysis workflow or providing a complete solution. Here, we surveyed 205 tools for whole-genome/whole-exome sequencing data analysis supporting five distinct analytical steps: quality assessment, alignment, variant identification, variant annotation and visualization. We report an overview of the functionality, features and specific requirements of the individual tools. We then selected 32 programs for variant identification, variant annotation and visualization, which were subjected to hands-on evaluation using four data sets: one set of exome data from two patients with a rare disease for testing identification of germline mutations, two cancer data sets for testing variant callers for somatic mutations, copy number variations and structural variations, and one semi-synthetic data set for testing identification of copy number variations. Our comprehensive survey and evaluation of NGS tools provides a valuable guideline for human geneticists working on Mendelian disorders, complex diseases and cancers. PMID:23341494

Genome-wide protective response used by group A Streptococcus to evade destruction by human polymorphonuclear leukocytes.

PubMed

Voyich, Jovanka M; Sturdevant, Daniel E; Braughton, Kevin R; Kobayashi, Scott D; Lei, Benfang; Virtaneva, Kimmo; Dorward, David W; Musser, James M; DeLeo, Frank R

2003-02-18

Group A Streptococcus (GAS) evades polymorphonuclear leukocyte (PMN) phagocytosis and killing to cause human disease, including pharyngitis and necrotizing fasciitis (flesh-eating syndrome). We show that GAS genes differentially regulated during phagocytic interaction with human PMNs comprise a global pathogen-protective response to innate immunity. GAS prophage genes and genes involved in virulence, oxidative stress, cell wall biosynthesis, and gene regulation were up-regulated during PMN phagocytosis. Genes encoding novel secreted proteins were up-regulated, and the proteins were produced during human GAS infections. We discovered an essential role for the Ihk-Irr two-component regulatory system in evading PMN-mediated killing and promoting host-cell lysis, processes that would facilitate GAS pathogenesis. Importantly, the irr gene was highly expressed during human GAS pharyngitis. We conclude that a complex pathogen genetic program circumvents human innate immunity to promote disease. The gene regulatory program revealed by our studies identifies previously undescribed potential vaccine antigens and targets for therapeutic interventions designed to control GAS infections.

Automated eukaryotic gene structure annotation using EVidenceModeler and the Program to Assemble Spliced Alignments

PubMed Central

Haas, Brian J; Salzberg, Steven L; Zhu, Wei; Pertea, Mihaela; Allen, Jonathan E; Orvis, Joshua; White, Owen; Buell, C Robin; Wortman, Jennifer R

2008-01-01

EVidenceModeler (EVM) is presented as an automated eukaryotic gene structure annotation tool that reports eukaryotic gene structures as a weighted consensus of all available evidence. EVM, when combined with the Program to Assemble Spliced Alignments (PASA), yields a comprehensive, configurable annotation system that predicts protein-coding genes and alternatively spliced isoforms. Our experiments on both rice and human genome sequences demonstrate that EVM produces automated gene structure annotation approaching the quality of manual curation. PMID:18190707

De novo assembly of a haplotype-resolved human genome.

PubMed

Cao, Hongzhi; Wu, Honglong; Luo, Ruibang; Huang, Shujia; Sun, Yuhui; Tong, Xin; Xie, Yinlong; Liu, Binghang; Yang, Hailong; Zheng, Hancheng; Li, Jian; Li, Bo; Wang, Yu; Yang, Fang; Sun, Peng; Liu, Siyang; Gao, Peng; Huang, Haodong; Sun, Jing; Chen, Dan; He, Guangzhu; Huang, Weihua; Huang, Zheng; Li, Yue; Tellier, Laurent C A M; Liu, Xiao; Feng, Qiang; Xu, Xun; Zhang, Xiuqing; Bolund, Lars; Krogh, Anders; Kristiansen, Karsten; Drmanac, Radoje; Drmanac, Snezana; Nielsen, Rasmus; Li, Songgang; Wang, Jian; Yang, Huanming; Li, Yingrui; Wong, Gane Ka-Shu; Wang, Jun

2015-06-01

The human genome is diploid, and knowledge of the variants on each chromosome is important for the interpretation of genomic information. Here we report the assembly of a haplotype-resolved diploid genome without using a reference genome. Our pipeline relies on fosmid pooling together with whole-genome shotgun strategies, based solely on next-generation sequencing and hierarchical assembly methods. We applied our sequencing method to the genome of an Asian individual and generated a 5.15-Gb assembled genome with a haplotype N50 of 484 kb. Our analysis identified previously undetected indels and 7.49 Mb of novel coding sequences that could not be aligned to the human reference genome, which include at least six predicted genes. This haplotype-resolved genome represents the most complete de novo human genome assembly to date. Application of our approach to identify individual haplotype differences should aid in translating genotypes to phenotypes for the development of personalized medicine.

The human genome contracts again.

PubMed

Pavlichin, Dmitri S; Weissman, Tsachy; Yona, Golan

2013-09-01

The number of human genomes that have been sequenced completely for different individuals has increased rapidly in recent years. Storing and transferring complete genomes between computers for the purpose of applying various applications and analysis tools will soon become a major hurdle, hindering the analysis phase. Therefore, there is a growing need to compress these data efficiently. Here, we describe a technique to compress human genomes based on entropy coding, using a reference genome and known Single Nucleotide Polymorphisms (SNPs). Furthermore, we explore several intrinsic features of genomes and information in other genomic databases to further improve the compression attained. Using these methods, we compress James Watson's genome to 2.5 megabytes (MB), improving on recent work by 37%. Similar compression is obtained for most genomes available from the 1000 Genomes Project. Our biologically inspired techniques promise even greater gains for genomes of lower organisms and for human genomes as more genomic data become available. Code is available at sourceforge.net/projects/genomezip/

All about the Human Genome Project (HGP)

MedlinePlus

... CSER), and Genome Sequencing Informatics Tools (GS-IT) Comparative Genomics Background information prepared for the media on ... other species to the human sequence. Background on Comparative Genomic Analysis New Process to Prioritize Animal Genomes ...

78 FR 68856 - National Human Genome Research Institute; Notice of Closed Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-15

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Human Genome... Nakamura, Ph.D., Scientific Review Officer, Scientific Review Branch, National Human Genome Research...-402-0838. [[Page 68857

Transcriptome Analysis of Human Immune Responses Following Live Vaccine Strain (LVS) Francisella Tularensis Vaccination

DTIC Science & Technology

2007-03-08

with CD3D 50848 PAR1/UBE3A Prader–Willi syndrome chromosome region 1, GMCSFRalpha precursor, IL3Ralpha precursor (CD123) Brain development...intervention programs justifiable? Emerg. Infect. Dis. 3, 83–94. iebel, U., Kindler , B., Pepperkok, R., 2004. ‘Harvester’: a fast meta search engine of human...protein resources. Bioinformatics 20, 1962–1963. iebel, U., Kindler , B., Pepperkok, R., 2005. Bioinformatic “Harvester”: a search engine for genome

Learning about the Human Genome. Part 2: Resources for Science Educators. ERIC Digest.

ERIC Educational Resources Information Center

Haury, David L.

This ERIC Digest identifies how the human genome project fits into the "National Science Education Standards" and lists Human Genome Project Web sites found on the World Wide Web. It is a resource companion to "Learning about the Human Genome. Part 1: Challenge to Science Educators" (Haury 2001). The Web resources and…

Population-Sequencing as a Biomarker of Burkholderia mallei and Burkholderia pseudomallei Evolution through Microbial Forensic Analysis.

PubMed

Jakupciak, John P; Wells, Jeffrey M; Karalus, Richard J; Pawlowski, David R; Lin, Jeffrey S; Feldman, Andrew B

2013-01-01

Large-scale genomics projects are identifying biomarkers to detect human disease. B. pseudomallei and B. mallei are two closely related select agents that cause melioidosis and glanders. Accurate characterization of metagenomic samples is dependent on accurate measurements of genetic variation between isolates with resolution down to strain level. Often single biomarker sensitivity is augmented by use of multiple or panels of biomarkers. In parallel with single biomarker validation, advances in DNA sequencing enable analysis of entire genomes in a single run: population-sequencing. Potentially, direct sequencing could be used to analyze an entire genome to serve as the biomarker for genome identification. However, genome variation and population diversity complicate use of direct sequencing, as well as differences caused by sample preparation protocols including sequencing artifacts and mistakes. As part of a Department of Homeland Security program in bacterial forensics, we examined how to implement whole genome sequencing (WGS) analysis as a judicially defensible forensic method for attributing microbial sample relatedness; and also to determine the strengths and limitations of whole genome sequence analysis in a forensics context. Herein, we demonstrate use of sequencing to provide genetic characterization of populations: direct sequencing of populations.

Population-Sequencing as a Biomarker of Burkholderia mallei and Burkholderia pseudomallei Evolution through Microbial Forensic Analysis

PubMed Central

Jakupciak, John P.; Wells, Jeffrey M.; Karalus, Richard J.; Pawlowski, David R.; Lin, Jeffrey S.; Feldman, Andrew B.

2013-01-01

Large-scale genomics projects are identifying biomarkers to detect human disease. B. pseudomallei and B. mallei are two closely related select agents that cause melioidosis and glanders. Accurate characterization of metagenomic samples is dependent on accurate measurements of genetic variation between isolates with resolution down to strain level. Often single biomarker sensitivity is augmented by use of multiple or panels of biomarkers. In parallel with single biomarker validation, advances in DNA sequencing enable analysis of entire genomes in a single run: population-sequencing. Potentially, direct sequencing could be used to analyze an entire genome to serve as the biomarker for genome identification. However, genome variation and population diversity complicate use of direct sequencing, as well as differences caused by sample preparation protocols including sequencing artifacts and mistakes. As part of a Department of Homeland Security program in bacterial forensics, we examined how to implement whole genome sequencing (WGS) analysis as a judicially defensible forensic method for attributing microbial sample relatedness; and also to determine the strengths and limitations of whole genome sequence analysis in a forensics context. Herein, we demonstrate use of sequencing to provide genetic characterization of populations: direct sequencing of populations. PMID:24455204

Genomic sequencing of Pleistocene cave bears

DOE Office of Scientific and Technical Information (OSTI.GOV)

Noonan, James P.; Hofreiter, Michael; Smith, Doug

2005-04-01

Despite the information content of genomic DNA, ancient DNA studies to date have largely been limited to amplification of mitochondrial DNA due to technical hurdles such as contamination and degradation of ancient DNAs. In this study, we describe two metagenomic libraries constructed using unamplified DNA extracted from the bones of two 40,000-year-old extinct cave bears. Analysis of {approx}1 Mb of sequence from each library showed that, despite significant microbial contamination, 5.8 percent and 1.1 percent of clones in the libraries contain cave bear inserts, yielding 26,861 bp of cave bear genome sequence. Alignment of this sequence to the dog genome,more » the closest sequenced genome to cave bear in terms of evolutionary distance, revealed roughly the expected ratio of cave bear exons, repeats and conserved noncoding sequences. Only 0.04 percent of all clones sequenced were derived from contamination with modern human DNA. Comparison of cave bear with orthologous sequences from several modern bear species revealed the evolutionary relationship of these lineages. Using the metagenomic approach described here, we have recovered substantial quantities of mammalian genomic sequence more than twice as old as any previously reported, establishing the feasibility of ancient DNA genomic sequencing programs.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liphardt, Jan

In April 1953, Watson and Crick largely defined the program of 20th century biology: obtaining the blueprint of life encoded in the DNA. Fifty years later, in 2003, the sequencing of the human genome was completed. Like any major scientific breakthrough, the sequencing of the human genome raised many more questions than it answered. I'll brief you on some of the big open problems in cell and developmental biology, and I'll explain why approaches, tools, and ideas from the physical sciences are currently reshaping biological research. Super-resolution light microscopies are revealing the intricate spatial organization of cells, single-molecule methods showmore » how molecular machines function, and new probes are clarifying the role of mechanical forces in cell and tissue function. At the same time, Physics stands to gain beautiful new problems in soft condensed matter, quantum mechanics, and non-equilibrium thermodynamics.« less

The Intersection of Physics and Biology

ScienceCinema

Liphardt, Jan

2017-12-22

In April 1953, Watson and Crick largely defined the program of 20th century biology: obtaining the blueprint of life encoded in the DNA. Fifty years later, in 2003, the sequencing of the human genome was completed. Like any major scientific breakthrough, the sequencing of the human genome raised many more questions than it answered. I'll brief you on some of the big open problems in cell and developmental biology, and I'll explain why approaches, tools, and ideas from the physical sciences are currently reshaping biological research. Super-resolution light microscopies are revealing the intricate spatial organization of cells, single-molecule methods show how molecular machines function, and new probes are clarifying the role of mechanical forces in cell and tissue function. At the same time, Physics stands to gain beautiful new problems in soft condensed matter, quantum mechanics, and non-equilibrium thermodynamics.

Epigenomic programing: a future way to health?

PubMed

Shenderov, Boris A; Midtvedt, Tore

2014-01-01

It is now generally accepted that the 'central genome dogma' (i.e. a causal chain going from DNA to RNA to proteins and downstream to biological functions) should be replaced by the 'fluid genome dogma', that is, complex feed-forward and feed-back cycles that interconnect organism and environment by epigenomic programing - and reprograming - throughout life and at all levels, sometimes also down the generations. The epigenomic programing is the net sum of interactions derived from own metabolism and microbiota as well as external factors such as diet, pharmaceuticals, environmental compounds, and so on. It is a growing body of results indicating that many chronic metabolic and degenerative disorders and diseases - often called 'civilization diseases' - are initiated and/or influenced upon by non-optimal epigenomic programing, often taking place early in life. In this context, the first 1,000 days of life - from conception into early infancy - is often called the most important period of life. The following sections present some major mechanisms for epigenomic programing as well as some factors assumed to be of importance. The need for more information about own genome and metagenome, as well as a substantial lack of adequate information regarding dietary and environmental databases are also commented upon. However, the mere fact that we can influence epigenomic health programing opens up the way for prophylactic and therapeutic interventions. The authors underline the importance of creating a 'Human Gut Microbiota and Epigenomic Platform' in order to facilitate interdisciplinary collaborations among scientists and clinicians engaged in host microbial ecology, nutrition, metagenomics, epigenomics and metabolomics as well as in disease epidemiology, prevention and treatment.

Interpreting Mammalian Evolution using Fugu Genome Comparisons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stubbs, L; Ovcharenko, I; Loots, G G

2004-04-02

Comparative sequence analysis of the human and the pufferfish Fugu rubripes (fugu) genomes has revealed several novel functional coding and noncoding regions in the human genome. In particular, the fugu genome has been extremely valuable for identifying transcriptional regulatory elements in human loci harboring unusually high levels of evolutionary conservation to rodent genomes. In such regions, the large evolutionary distance between human and fishes provides an additional filter through which functional noncoding elements can be detected with high efficiency.

The IQ Quantitative Trait Loci Project: A Critique.

ERIC Educational Resources Information Center

King, David

1998-01-01

Describes the IQ Quantitative Trait Loci (QTL) project, an attempt to identify genes underlying IQ score variations using maps from the Human Genome Project. The essay argues against funding the IQ QTL project because it will end the debates about the genetic basis of intelligence and may lead directly to eugenic programs of genetic testing. (SLD)

The human genome: Mutating from science fiction to reality.

PubMed

Heymann, Warren R

2008-01-01

Dialogues in Dermatology, a monthly audio program from the American Academy of Dermatology, contains discussions between dermatologists on timely topics. Commentaries from Dialogues Editor-in-Chief Warren R. Heymann, MD, are provided after each discussion as a topic summary and are provided here as a special service to readers of the Journal of the American Academy of Dermatology.

Achieving World-Class Schools: Mastering School Improvement Using a Genetic Model.

ERIC Educational Resources Information Center

Kimmelman, Paul L.; Kroeze, David J.

In providing its program for education reform, this book uses, as an analogy, the genetic model taken from the Human Genome project. In the first part, "Theoretical Underpinnings," the book explains why a genetic model can be used to improve school systems; describes the critical components of a world-class school system; and details the…

Maternal adiposity in the absence of excessive gestational weight gain is associated with distinct changes in DNA methylation patterns in umbilical cords of infants

USDA-ARS?s Scientific Manuscript database

Maternal obesity has been hypothesized to lead to developmental programming of excessive weight and adiposity in offspring. In addition, excessive gestational weight gain (GWG) is also a demonstrated determinant of later-life adiposity. We examined genome-wide DNA methylation (Infinium® HumanMethyla...

Natural mutagenesis of human genomes by endogenous retrotransposons.

PubMed

Iskow, Rebecca C; McCabe, Michael T; Mills, Ryan E; Torene, Spencer; Pittard, W Stephen; Neuwald, Andrew F; Van Meir, Erwin G; Vertino, Paula M; Devine, Scott E

2010-06-25

Two abundant classes of mobile elements, namely Alu and L1 elements, continue to generate new retrotransposon insertions in human genomes. Estimates suggest that these elements have generated millions of new germline insertions in individual human genomes worldwide. Unfortunately, current technologies are not capable of detecting most of these young insertions, and the true extent of germline mutagenesis by endogenous human retrotransposons has been difficult to examine. Here, we describe technologies for detecting these young retrotransposon insertions and demonstrate that such insertions indeed are abundant in human populations. We also found that new somatic L1 insertions occur at high frequencies in human lung cancer genomes. Genome-wide analysis suggests that altered DNA methylation may be responsible for the high levels of L1 mobilization observed in these tumors. Our data indicate that transposon-mediated mutagenesis is extensive in human genomes and is likely to have a major impact on human biology and diseases.

Minimal Absent Words in Four Human Genome Assemblies

PubMed Central

Garcia, Sara P.; Pinho, Armando J.

2011-01-01

Minimal absent words have been computed in genomes of organisms from all domains of life. Here, we aim to contribute to the catalogue of human genomic variation by investigating the variation in number and content of minimal absent words within a species, using four human genome assemblies. We compare the reference human genome GRCh37 assembly, the HuRef assembly of the genome of Craig Venter, the NA12878 assembly from cell line GM12878, and the YH assembly of the genome of a Han Chinese individual. We find the variation in number and content of minimal absent words between assemblies more significant for large and very large minimal absent words, where the biases of sequencing and assembly methodologies become more pronounced. Moreover, we find generally greater similarity between the human genome assemblies sequenced with capillary-based technologies (GRCh37 and HuRef) than between the human genome assemblies sequenced with massively parallel technologies (NA12878 and YH). Finally, as expected, we find the overall variation in number and content of minimal absent words within a species to be generally smaller than the variation between species. PMID:22220210

Database resources of the National Center for Biotechnology Information: 2002 update

PubMed Central

Wheeler, David L.; Church, Deanna M.; Lash, Alex E.; Leipe, Detlef D.; Madden, Thomas L.; Pontius, Joan U.; Schuler, Gregory D.; Schriml, Lynn M.; Tatusova, Tatiana A.; Wagner, Lukas; Rapp, Barbara A.

2002-01-01

In addition to maintaining the GenBank nucleic acid sequence database, the National Center for Biotechnology Information (NCBI) provides data analysis and retrieval resources that operate on the data in GenBank and a variety of other biological data made available through NCBI’s web site. NCBI data retrieval resources include Entrez, PubMed, LocusLink and the Taxonomy Browser. Data analysis resources include BLAST, Electronic PCR, OrfFinder, RefSeq, UniGene, HomoloGene, Database of Single Nucleotide Polymorphisms (dbSNP), Human Genome Sequencing, Human MapViewer, Human¡VMouse Homology Map, Cancer Chromosome Aberration Project (CCAP), Entrez Genomes, Clusters of Orthologous Groups (COGs) database, Retroviral Genotyping Tools, SAGEmap, Gene Expression Omnibus (GEO), Online Mendelian Inheritance in Man (OMIM), the Molecular Modeling Database (MMDB) and the Conserved Domain Database (CDD). Augmenting many of the web applications are custom implementations of the BLAST program optimized to search specialized data sets. All of the resources can be accessed through the NCBI home page at http://www.ncbi.nlm.nih.gov. PMID:11752242

An ethnically relevant consensus Korean reference genome is a step towards personal reference genomes

PubMed Central

Cho, Yun Sung; Kim, Hyunho; Kim, Hak-Min; Jho, Sungwoong; Jun, JeHoon; Lee, Yong Joo; Chae, Kyun Shik; Kim, Chang Geun; Kim, Sangsoo; Eriksson, Anders; Edwards, Jeremy S.; Lee, Semin; Kim, Byung Chul; Manica, Andrea; Oh, Tae-Kwang; Church, George M.; Bhak, Jong

2016-01-01

Human genomes are routinely compared against a universal reference. However, this strategy could miss population-specific and personal genomic variations, which may be detected more efficiently using an ethnically relevant or personal reference. Here we report a hybrid assembly of a Korean reference genome (KOREF) for constructing personal and ethnic references by combining sequencing and mapping methods. We also build its consensus variome reference, providing information on millions of variants from 40 additional ethnically homogeneous genomes from the Korean Personal Genome Project. We find that the ethnically relevant consensus reference can be beneficial for efficient variant detection. Systematic comparison of human assemblies shows the importance of assembly quality, suggesting the necessity of new technologies to comprehensively map ethnic and personal genomic structure variations. In the era of large-scale population genome projects, the leveraging of ethnicity-specific genome assemblies as well as the human reference genome will accelerate mapping all human genome diversity. PMID:27882922

Database resources of the National Center for Biotechnology Information

PubMed Central

Wheeler, David L.; Church, Deanna M.; Lash, Alex E.; Leipe, Detlef D.; Madden, Thomas L.; Pontius, Joan U.; Schuler, Gregory D.; Schriml, Lynn M.; Tatusova, Tatiana A.; Wagner, Lukas; Rapp, Barbara A.

2001-01-01

In addition to maintaining the GenBank® nucleic acid sequence database, the National Center for Biotechnology Information (NCBI) provides data analysis and retrieval resources that operate on the data in GenBank and a variety of other biological data made available through NCBI’s Web site. NCBI data retrieval resources include Entrez, PubMed, LocusLink and the Taxonomy Browser. Data analysis resources include BLAST, Electronic PCR, OrfFinder, RefSeq, UniGene, HomoloGene, Database of Single Nucleotide Polymorphisms (dbSNP), Human Genome Sequencing, Human MapViewer, GeneMap’99, Human–Mouse Homology Map, Cancer Chromosome Aberration Project (CCAP), Entrez Genomes, Clusters of Orthologous Groups (COGs) database, Retroviral Genotyping Tools, Cancer Genome Anatomy Project (CGAP), SAGEmap, Gene Expression Omnibus (GEO), Online Mendelian Inheri­tance in Man (OMIM), the Molecular Modeling Database (MMDB) and the Conserved Domain Database (CDD). Augmenting many of the Web applications are custom implementations of the BLAST program optimized to search specialized data sets. All of the resources can be accessed through the NCBI home page at: http://www.ncbi.nlm.nih.gov. PMID:11125038

Prediction of Steps in the Evolution of Variola Virus Host Range

PubMed Central

Smithson, Chad; Purdy, Alex; Verster, Adrian J.; Upton, Chris

2014-01-01

Variola virus, the agent of smallpox, has a severely restricted host range (humans) but a devastatingly high mortality rate. Although smallpox has been eradicated by a World Health Organization vaccination program, knowledge of the evolutionary processes by which human super-pathogens such as variola virus arise is important. By analyzing the evolution of variola and other closely related poxviruses at the level of single nucleotide polymorphisms we detected a hotspot of genome variation within the smallpox ortholog of the vaccinia virus O1L gene, which is known to be necessary for efficient replication of vaccinia virus in human cells. These mutations in the variola virus ortholog and the subsequent loss of the functional gene from camelpox virus and taterapox virus, the two closest relatives of variola virus, strongly suggest that changes within this region of the genome may have played a key role in the switch to humans as a host for the ancestral virus and the subsequent host-range restriction that must have occurred to create the phenotype exhibited by smallpox. PMID:24626337

Prediction of steps in the evolution of variola virus host range.

PubMed

Smithson, Chad; Purdy, Alex; Verster, Adrian J; Upton, Chris

2014-01-01

Variola virus, the agent of smallpox, has a severely restricted host range (humans) but a devastatingly high mortality rate. Although smallpox has been eradicated by a World Health Organization vaccination program, knowledge of the evolutionary processes by which human super-pathogens such as variola virus arise is important. By analyzing the evolution of variola and other closely related poxviruses at the level of single nucleotide polymorphisms we detected a hotspot of genome variation within the smallpox ortholog of the vaccinia virus O1L gene, which is known to be necessary for efficient replication of vaccinia virus in human cells. These mutations in the variola virus ortholog and the subsequent loss of the functional gene from camelpox virus and taterapox virus, the two closest relatives of variola virus, strongly suggest that changes within this region of the genome may have played a key role in the switch to humans as a host for the ancestral virus and the subsequent host-range restriction that must have occurred to create the phenotype exhibited by smallpox.

Circular RNAs Are the Predominant Transcript Isoform from Hundreds of Human Genes in Diverse Cell Types

PubMed Central

Wang, Peter Lincoln; Lacayo, Norman; Brown, Patrick O.

2012-01-01

Most human pre-mRNAs are spliced into linear molecules that retain the exon order defined by the genomic sequence. By deep sequencing of RNA from a variety of normal and malignant human cells, we found RNA transcripts from many human genes in which the exons were arranged in a non-canonical order. Statistical estimates and biochemical assays provided strong evidence that a substantial fraction of the spliced transcripts from hundreds of genes are circular RNAs. Our results suggest that a non-canonical mode of RNA splicing, resulting in a circular RNA isoform, is a general feature of the gene expression program in human cells. PMID:22319583

Human genome and philosophy: what ethical challenge will human genome studies bring to the medical practices in the 21st century?

PubMed

Renzong, Q

2001-12-01

A human being or person cannot be reduced to a set of human genes, or human genome. Genetic essentialism is wrong, because as a person the entity should have self-conscious and social interaction capacity which is grown in an interpersonal relationship. Genetic determinism is wrong too, the relationship between a gene and a trait is not a linear model of causation, but rather a non-linear one. Human genome is a complexity system and functions in a complexity system of human body and a complexity of systems of natural/social environment. Genetic determinism also caused the issue of how much responsibility an agent should take for her/his action, and how much degrees of freedom will a human being have. Human genome research caused several conceptual issues. Can we call a gene 'good' or 'bad', 'superior' of 'inferior'? Is a boy who is detected to have the gene of Huntington's chorea or Alzheimer disease a patient? What should the term 'eugenics' mean? What do the terms such as 'gene therapy', 'treatment' and 'enhancement' and 'human cloning' mean etc.? The research of human genome and its application caused and will cause ethical issues. Can human genome research and its application be used for eugenics, or only for the treatment and prevention of diseases? Must the principle of informed consent/choice be insisted in human genome research and its application? How to protecting gene privacy and combating the discrimination on the basis of genes? How to promote the quality between persons, harmony between ethnic groups and peace between countries? How to establish a fair, just, equal and equitable relationship between developing and developed countries in regarding to human genome research and its application?

Secure Genomic Computation through Site-Wise Encryption

PubMed Central

Zhao, Yongan; Wang, XiaoFeng; Tang, Haixu

2015-01-01

Commercial clouds provide on-demand IT services for big-data analysis, which have become an attractive option for users who have no access to comparable infrastructure. However, utilizing these services for human genome analysis is highly risky, as human genomic data contains identifiable information of human individuals and their disease susceptibility. Therefore, currently, no computation on personal human genomic data is conducted on public clouds. To address this issue, here we present a site-wise encryption approach to encrypt whole human genome sequences, which can be subject to secure searching of genomic signatures on public clouds. We implemented this method within the Hadoop framework, and tested it on the case of searching disease markers retrieved from the ClinVar database against patients’ genomic sequences. The secure search runs only one order of magnitude slower than the simple search without encryption, indicating our method is ready to be used for secure genomic computation on public clouds. PMID:26306278

Secure Genomic Computation through Site-Wise Encryption.

PubMed

Zhao, Yongan; Wang, XiaoFeng; Tang, Haixu

2015-01-01

Commercial clouds provide on-demand IT services for big-data analysis, which have become an attractive option for users who have no access to comparable infrastructure. However, utilizing these services for human genome analysis is highly risky, as human genomic data contains identifiable information of human individuals and their disease susceptibility. Therefore, currently, no computation on personal human genomic data is conducted on public clouds. To address this issue, here we present a site-wise encryption approach to encrypt whole human genome sequences, which can be subject to secure searching of genomic signatures on public clouds. We implemented this method within the Hadoop framework, and tested it on the case of searching disease markers retrieved from the ClinVar database against patients' genomic sequences. The secure search runs only one order of magnitude slower than the simple search without encryption, indicating our method is ready to be used for secure genomic computation on public clouds.

Mapping and Sequencing the Human Genome: Science, Ethics, and Public Policy.

ERIC Educational Resources Information Center

Cutter, Mary Ann G.; Drexler, Edward; McCullough, Laurence B.; McInerney, Joseph D.; Murray, Jeffrey C.; Rossiter, Belinda; Zola, John

The human genome project started in 1989 with the collaboration of the National Institutes of Health (NIH) and the U.S. Department of Energy (DOE). This document aims to develop an understanding among students of the human genome project and relevant issues. Topics include the science and technology of the human genome project, and the ethical and…

Whole-Genome Screening of Newborns? The Constitutional Boundaries of State Newborn Screening Programs

PubMed Central

King, Jaime S.; Smith, Monica E.

2016-01-01

State newborn screening (NBS) programs routinely screen nearly all of the 4 million newborns in the United States each year for ~30 primary conditions and a number of secondary conditions. NBS could be on the cusp of an unprecedented expansion as a result of advances in whole-genome sequencing (WGS). As WGS becomes cheaper and easier and as our knowledge and understanding of human genetics expand, the question of whether WGS has a role to play in state NBS programs becomes increasingly relevant and complex. As geneticists and state public health officials begin to contemplate the technical and procedural details of whether WGS could benefit existing NBS programs, this is an opportune time to revisit the legal framework of state NBS programs. In this article, we examine the constitutional underpinnings of state-mandated NBS and explore the range of current state statutes and regulations that govern the programs. We consider the legal refinements that will be needed to keep state NBS programs within constitutional bounds, focusing on 2 areas of concern: consent procedures and the criteria used to select new conditions for NBS panels. We conclude by providing options for states to consider when contemplating the use of WGS for NBS. PMID:26729704

78 FR 11898 - National Human Genome Research Institute; Notice of Closed Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-20

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Human Genome... Conference Call). Contact Person: Camilla E. Day, Ph.D., Scientific Review Officer CIDR, National Human....172, Human Genome Research, National Institutes of Health, HHS) Dated: February 13, 2013. David Clary...

78 FR 77477 - National Human Genome Research Institute; Notice of Closed Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-23

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Human Genome... Conference Call). Contact Person: Camilla E. Day, Ph.D., Scientific Review Officer, CIDR, National Human..., Human Genome Research, National Institutes of Health, HHS). Dated: December 17, 2013. David Clary...

75 FR 2147 - National Human Genome Research Institute; Notice of Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-14

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Human Genome... Council for Human Genome Research. The meetings will be open to the public as indicated below, with... clearly unwarranted invasion of personal privacy. Name of Committee: National Advisory Council for Human...

Prophage Integrase Typing Is a Useful Indicator of Genomic Diversity in Salmonella enterica

PubMed Central

Colavecchio, Anna; D’Souza, Yasmin; Tompkins, Elizabeth; Jeukens, Julie; Freschi, Luca; Emond-Rheault, Jean-Guillaume; Kukavica-Ibrulj, Irena; Boyle, Brian; Bekal, Sadjia; Tamber, Sandeep; Levesque, Roger C.; Goodridge, Lawrence D.

2017-01-01

Salmonella enterica is a bacterial species that is a major cause of illness in humans and food-producing animals. S. enterica exhibits considerable inter-serovar diversity, as evidenced by the large number of host adapted serovars that have been identified. The development of methods to assess genome diversity in S. enterica will help to further define the limits of diversity in this foodborne pathogen. Thus, we evaluated a PCR assay, which targets prophage integrase genes, as a rapid method to investigate S. enterica genome diversity. To evaluate the PCR prophage integrase assay, 49 isolates of S. enterica were selected, including 19 clinical isolates from clonal serovars (Enteritidis and Heidelberg) that commonly cause human illness, and 30 isolates from food-associated Salmonella serovars that rarely cause human illness. The number of integrase genes identified by the PCR assay was compared to the number of integrase genes within intact prophages identified by whole genome sequencing and phage finding program PHASTER. The PCR assay identified a total of 147 prophage integrase genes within the 49 S. enterica genomes (79 integrase genes in the food-associated Salmonella isolates, 50 integrase genes in S. Enteritidis, and 18 integrase genes in S. Heidelberg). In comparison, whole genome sequencing and PHASTER identified a total of 75 prophage integrase genes within 102 intact prophages in the 49 S. enterica genomes (44 integrase genes in the food-associated Salmonella isolates, 21 integrase genes in S. Enteritidis, and 9 integrase genes in S. Heidelberg). Collectively, both the PCR assay and PHASTER identified the presence of a large diversity of prophage integrase genes in the food-associated isolates compared to the clinical isolates, thus indicating a high degree of diversity in the food-associated isolates, and confirming the clonal nature of S. Enteritidis and S. Heidelberg. Moreover, PHASTER revealed a diversity of 29 different types of prophages and 23 different integrase genes within the food-associated isolates, but only identified four different phages and integrase genes within clonal isolates of S. Enteritidis and S. Heidelberg. These results demonstrate the potential usefulness of PCR based detection of prophage integrase genes as a rapid indicator of genome diversity in S. enterica. PMID:28740489

Prophage Integrase Typing Is a Useful Indicator of Genomic Diversity in Salmonella enterica.

PubMed

Colavecchio, Anna; D'Souza, Yasmin; Tompkins, Elizabeth; Jeukens, Julie; Freschi, Luca; Emond-Rheault, Jean-Guillaume; Kukavica-Ibrulj, Irena; Boyle, Brian; Bekal, Sadjia; Tamber, Sandeep; Levesque, Roger C; Goodridge, Lawrence D

2017-01-01

Salmonella enterica is a bacterial species that is a major cause of illness in humans and food-producing animals. S. enterica exhibits considerable inter-serovar diversity, as evidenced by the large number of host adapted serovars that have been identified. The development of methods to assess genome diversity in S. enterica will help to further define the limits of diversity in this foodborne pathogen. Thus, we evaluated a PCR assay, which targets prophage integrase genes, as a rapid method to investigate S. enterica genome diversity. To evaluate the PCR prophage integrase assay, 49 isolates of S. enterica were selected, including 19 clinical isolates from clonal serovars (Enteritidis and Heidelberg) that commonly cause human illness, and 30 isolates from food-associated Salmonella serovars that rarely cause human illness. The number of integrase genes identified by the PCR assay was compared to the number of integrase genes within intact prophages identified by whole genome sequencing and phage finding program PHASTER. The PCR assay identified a total of 147 prophage integrase genes within the 49 S. enterica genomes (79 integrase genes in the food-associated Salmonella isolates, 50 integrase genes in S . Enteritidis, and 18 integrase genes in S . Heidelberg). In comparison, whole genome sequencing and PHASTER identified a total of 75 prophage integrase genes within 102 intact prophages in the 49 S. enterica genomes (44 integrase genes in the food-associated Salmonella isolates, 21 integrase genes in S . Enteritidis, and 9 integrase genes in S . Heidelberg). Collectively, both the PCR assay and PHASTER identified the presence of a large diversity of prophage integrase genes in the food-associated isolates compared to the clinical isolates, thus indicating a high degree of diversity in the food-associated isolates, and confirming the clonal nature of S . Enteritidis and S . Heidelberg. Moreover, PHASTER revealed a diversity of 29 different types of prophages and 23 different integrase genes within the food-associated isolates, but only identified four different phages and integrase genes within clonal isolates of S. Enteritidis and S. Heidelberg. These results demonstrate the potential usefulness of PCR based detection of prophage integrase genes as a rapid indicator of genome diversity in S. enterica .

Company profile: Complete Genomics Inc.

PubMed

Reid, Clifford

2011-02-01

Complete Genomics Inc. is a life sciences company that focuses on complete human genome sequencing. It is taking a completely different approach to DNA sequencing than other companies in the industry. Rather than building a general-purpose platform for sequencing all organisms and all applications, it has focused on a single application - complete human genome sequencing. The company's Complete Genomics Analysis Platform (CGA™ Platform) comprises an integrated package of biochemistry, instrumentation and software that sequences human genomes at the highest quality, lowest cost and largest scale available. Complete Genomics offers a turnkey service that enables customers to outsource their human genome sequencing to the company's genome sequencing center in Mountain View, CA, USA. Customers send in their DNA samples, the company does all the library preparation, DNA sequencing, assembly and variant analysis, and customers receive research-ready data that they can use for biological discovery.

77 FR 50140 - National Human Genome Research Institute; Notice of Closed Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-20

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Human Genome..., Human Genome Research, National Institutes of Health, HHS) Dated: August 13, 2012. Anna Snouffer, Deputy..., Bethesda, MD 20892. Contact Person: Camilla E. Day, Ph.D., Scientific Review Officer, CIDR, National Human...

Identification of estrogen-responsive genes using a genome-wide analysis of promoter elements for transcription factor binding sites.

PubMed

Kamalakaran, Sitharthan; Radhakrishnan, Senthil K; Beck, William T

2005-06-03

We developed a pipeline to identify novel genes regulated by the steroid hormone-dependent transcription factor, estrogen receptor, through a systematic analysis of upstream regions of all human and mouse genes. We built a data base of putative promoter regions for 23,077 human and 19,984 mouse transcripts from National Center for Biotechnology Information annotation and 8793 human and 6785 mouse promoters from the Data Base of Transcriptional Start Sites. We used this data base of putative promoters to identify potential targets of estrogen receptor by identifying estrogen response elements (EREs) in their promoters. Our program correctly identified EREs in genes known to be regulated by estrogen in addition to several new genes whose putative promoters contained EREs. We validated six genes (KIAA1243, NRIP1, MADH9, NME3, TPD52L, and ABCG2) to be estrogen-responsive in MCF7 cells using reverse transcription PCR. To allow for extensibility of our program in identifying targets of other transcription factors, we have built a Web interface to access our data base and programs. Our Web-based program for Promoter Analysis of Genome, PAGen@UIC, allows a user to identify putative target genes for vertebrate transcription factors through the analysis of their upstream sequences. The interface allows the user to search the human and mouse promoter data bases for potential target genes containing one or more listed transcription factor binding sites (TFBSs) in their upstream elements, using either regular expression-based consensus or position weight matrices. The data base can also be searched for promoters harboring user-defined TFBSs given as a consensus or a position weight matrix. Furthermore, the user can retrieve putative promoter sequences for any given gene together with identified TFBSs located on its promoter. Orthologous promoters are also analyzed to determine conserved elements.

Viral symbiosis and the holobiontic nature of the human genome.

PubMed

Ryan, Francis Patrick

2016-01-01

The human genome is a holobiontic union of the mammalian nuclear genome, the mitochondrial genome and large numbers of endogenized retroviral genomes. This article defines and explores this symbiogenetic pattern of evolution, looking at the implications for human genetics, epigenetics, embryogenesis, physiology and the pathogenesis of inborn errors of metabolism and many other diseases. © 2016 APMIS. Published by John Wiley & Sons Ltd.

GaussianCpG: a Gaussian model for detection of CpG island in human genome sequences.

PubMed

Yu, Ning; Guo, Xuan; Zelikovsky, Alexander; Pan, Yi

2017-05-24

As crucial markers in identifying biological elements and processes in mammalian genomes, CpG islands (CGI) play important roles in DNA methylation, gene regulation, epigenetic inheritance, gene mutation, chromosome inactivation and nuclesome retention. The generally accepted criteria of CGI rely on: (a) %G+C content is ≥ 50%, (b) the ratio of the observed CpG content and the expected CpG content is ≥ 0.6, and (c) the general length of CGI is greater than 200 nucleotides. Most existing computational methods for the prediction of CpG island are programmed on these rules. However, many experimentally verified CpG islands deviate from these artificial criteria. Experiments indicate that in many cases %G+C is < 50%, CpG obs /CpG exp varies, and the length of CGI ranges from eight nucleotides to a few thousand of nucleotides. It implies that CGI detection is not just a straightly statistical task and some unrevealed rules probably are hidden. A novel Gaussian model, GaussianCpG, is developed for detection of CpG islands on human genome. We analyze the energy distribution over genomic primary structure for each CpG site and adopt the parameters from statistics of Human genome. The evaluation results show that the new model can predict CpG islands efficiently by balancing both sensitivity and specificity over known human CGI data sets. Compared with other models, GaussianCpG can achieve better performance in CGI detection. Our Gaussian model aims to simplify the complex interaction between nucleotides. The model is computed not by the linear statistical method but by the Gaussian energy distribution and accumulation. The parameters of Gaussian function are not arbitrarily designated but deliberately chosen by optimizing the biological statistics. By using the pseudopotential analysis on CpG islands, the novel model is validated on both the real and artificial data sets.

The Human Genome Project: how do we protect Australians?

PubMed

Stott Despoja, N

It is the moon landing of the nineties: the ambitious Human Genome Project--identifying the up to 100,000 genes that make up human DNA and the sequences of the three billion base-pairs that comprise the human genome. However, unlike the moon landing, the effects of the genome project will have a fundamental impact on the way we see ourselves and each other.

Advances in Exercise, Fitness, and Performance Genomics in 2015.

PubMed

Sarzynski, Mark A; Loos, Ruth J F; Lucia, Alejandro; Pérusse, Louis; Roth, Stephen M; Wolfarth, Bernd; Rankinen, Tuomo; Bouchard, Claude

2016-10-01

This review of the exercise genomics literature encompasses the highest-quality articles published in 2015 across seven broad topics: physical activity behavior, muscular strength and power, cardiorespiratory fitness and endurance performance, body weight and adiposity, insulin and glucose metabolism, lipid and lipoprotein metabolism, and hemodynamic traits. One study used a quantitative trait locus for wheel running in mice to identify single nucleotide polymorphisms (SNPs) in humans associated with physical activity levels. Two studies examined the association of candidate gene ACTN3 R577X genotype on muscular performance. Several studies examined gene-physical activity interactions on cardiometabolic traits. One study showed that physical inactivity exacerbated the body mass index (BMI)-increasing effect of an FTO SNP but only in individuals of European ancestry, whereas another showed that high-density lipoprotein cholesterol (HDL-C) SNPs from genome-wide association studies exerted a smaller effect in active individuals. Increased levels of moderate-to-vigorous-intensity physical activity were associated with higher Matsuda insulin sensitivity index in PPARG Ala12 carriers but not Pro12 homozygotes. One study combined genome-wide and transcriptome-wide profiling to identify genes and SNPs associated with the response of triglycerides (TG) to exercise training. The genome-wide association study results showed that four SNPs accounted for all of the heritability of △TG, whereas the baseline expression of 11 genes predicted 27% of △TG. A composite SNP score based on the top eight SNPs derived from the genomic and transcriptomic analyses was the strongest predictor of ΔTG, explaining 14% of the variance. The review concludes with a discussion of a conceptual framework defining some of the critical conditions for exercise genomics studies and highlights the importance of the recently launched National Institutes of Health Common Fund program titled "Molecular Transducers of Physical Activity in Humans."

A genome resource to address mechanisms of developmental programming: determination of the fetal sheep heart transcriptome.

PubMed

Cox, Laura A; Glenn, Jeremy P; Spradling, Kimberly D; Nijland, Mark J; Garcia, Roy; Nathanielsz, Peter W; Ford, Stephen P

2012-06-15

The pregnant sheep has provided seminal insights into reproduction related to animal and human development (ovarian function, fertility, implantation, fetal growth, parturition and lactation). Fetal sheep physiology has been extensively studied since 1950, contributing significantly to the basis for our understanding of many aspects of fetal development and behaviour that remain in use in clinical practice today. Understanding mechanisms requires the combination of systems approaches uniquely available in fetal sheep with the power of genomic studies. Absence of the full range of sheep genomic resources has limited the full realization of the power of this model, impeding progress in emerging areas of pregnancy biology such as developmental programming. We have examined the expressed fetal sheep heart transcriptome using high-throughput sequencing technologies. In so doing we identified 36,737 novel transcripts and describe genes, gene variants and pathways relevant to fundamental developmental mechanisms. Genes with the highest expression levels and with novel exons in the fetal heart transcriptome are known to play central roles in muscle development. We show that high-throughput sequencing methods can generate extensive transcriptome information in the absence of an assembled and annotated genome for that species. The gene sequence data obtained provide a unique genomic resource for sheep specific genetic technology development and, combined with the polymorphism data, augment annotation and assembly of the sheep genome. In addition, identification and pathway analysis of novel fetal sheep heart transcriptome splice variants is a first step towards revealing mechanisms of genetic variation and gene environment interactions during fetal heart development.

A Bacillus anthracis Genome Sequence from the Sverdlovsk 1979 Autopsy Specimens

PubMed Central

Sahl, Jason W.; Pearson, Talima; Okinaka, Richard; Schupp, James M.; Gillece, John D.; Heaton, Hannah; Birdsell, Dawn; Hepp, Crystal; Fofanov, Viacheslav; Noseda, Ramón; Fasanella, Antonio; Hoffmaster, Alex; Wagner, David M.

2016-01-01

ABSTRACT Anthrax is a zoonotic disease that occurs naturally in wild and domestic animals but has been used by both state-sponsored programs and terrorists as a biological weapon. A Soviet industrial production facility in Sverdlovsk, USSR, proved deficient in 1979 when a plume of spores was accidentally released and resulted in one of the largest known human anthrax outbreaks. In order to understand this outbreak and others, we generated a Bacillus anthracis population genetic database based upon whole-genome analysis to identify all single-nucleotide polymorphisms (SNPs) across a reference genome. Phylogenetic analysis has defined three major clades (A, B, and C), B and C being relatively rare compared to A. The A clade has numerous subclades, including a major polytomy named the trans-Eurasian (TEA) group. The TEA radiation is a dominant evolutionary feature of B. anthracis, with many contemporary populations having resulted from a large spatial dispersal of spores from a single source. Two autopsy specimens from the Sverdlovsk outbreak were deep sequenced to produce draft B. anthracis genomes. This allowed the phylogenetic placement of the Sverdlovsk strain into a clade with two Asian live vaccine strains, including the Russian Tsiankovskii strain. The genome was examined for evidence of drug resistance manipulation or other genetic engineering, but none was found. The Soviet Sverdlovsk strain genome is consistent with a wild-type strain from Russia that had no evidence of genetic manipulation during its industrial production. This work provides insights into the world’s largest biological weapons program and provides an extensive B. anthracis phylogenetic reference. PMID:27677796

A genome resource to address mechanisms of developmental programming: determination of the fetal sheep heart transcriptome

PubMed Central

Cox, Laura A; Glenn, Jeremy P; Spradling, Kimberly D; Nijland, Mark J; Garcia, Roy; Nathanielsz, Peter W; Ford, Stephen P

2012-01-01

The pregnant sheep has provided seminal insights into reproduction related to animal and human development (ovarian function, fertility, implantation, fetal growth, parturition and lactation). Fetal sheep physiology has been extensively studied since 1950, contributing significantly to the basis for our understanding of many aspects of fetal development and behaviour that remain in use in clinical practice today. Understanding mechanisms requires the combination of systems approaches uniquely available in fetal sheep with the power of genomic studies. Absence of the full range of sheep genomic resources has limited the full realization of the power of this model, impeding progress in emerging areas of pregnancy biology such as developmental programming. We have examined the expressed fetal sheep heart transcriptome using high-throughput sequencing technologies. In so doing we identified 36,737 novel transcripts and describe genes, gene variants and pathways relevant to fundamental developmental mechanisms. Genes with the highest expression levels and with novel exons in the fetal heart transcriptome are known to play central roles in muscle development. We show that high-throughput sequencing methods can generate extensive transcriptome information in the absence of an assembled and annotated genome for that species. The gene sequence data obtained provide a unique genomic resource for sheep specific genetic technology development and, combined with the polymorphism data, augment annotation and assembly of the sheep genome. In addition, identification and pathway analysis of novel fetal sheep heart transcriptome splice variants is a first step towards revealing mechanisms of genetic variation and gene environment interactions during fetal heart development. PMID:22508961

CRISPR-Cas9 Targeting of PCSK9 in Human Hepatocytes In Vivo-Brief Report.

PubMed

Wang, Xiao; Raghavan, Avanthi; Chen, Tao; Qiao, Lyon; Zhang, Yongxian; Ding, Qiurong; Musunuru, Kiran

2016-05-01

Although early proof-of-concept studies of somatic in vivo genome editing of the mouse ortholog of proprotein convertase subtilisin/kexin type 9 (Pcsk9) in mice have established its therapeutic potential for the prevention of cardiovascular disease, the unique nature of genome-editing technology-permanent alteration of genomic DNA sequences-mandates that it be tested in vivo against human genes in normal human cells with human genomes to give reliable preclinical insights into the efficacy (on-target mutagenesis) and safety (lack of off-target mutagenesis) of genome-editing therapy before it can be used in patients. We used a clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) 9 genome-editing system to target the human PCSK9 gene in chimeric liver-humanized mice bearing human hepatocytes. We demonstrated high on-target mutagenesis (approaching 50%), greatly reduced blood levels of human PCSK9 protein, and minimal off-target mutagenesis. This work yields important information on the efficacy and safety of CRISPR-Cas9 therapy targeting the human PCSK9 gene in human hepatocytes in vivo, and it establishes humanized mice as a useful platform for the preclinical assessment of applications of somatic in vivo genome editing. © 2016 American Heart Association, Inc.

GenomeCAT: a versatile tool for the analysis and integrative visualization of DNA copy number variants.

PubMed

Tebel, Katrin; Boldt, Vivien; Steininger, Anne; Port, Matthias; Ebert, Grit; Ullmann, Reinhard

2017-01-06

The analysis of DNA copy number variants (CNV) has increasing impact in the field of genetic diagnostics and research. However, the interpretation of CNV data derived from high resolution array CGH or NGS platforms is complicated by the considerable variability of the human genome. Therefore, tools for multidimensional data analysis and comparison of patient cohorts are needed to assist in the discrimination of clinically relevant CNVs from others. We developed GenomeCAT, a standalone Java application for the analysis and integrative visualization of CNVs. GenomeCAT is composed of three modules dedicated to the inspection of single cases, comparative analysis of multidimensional data and group comparisons aiming at the identification of recurrent aberrations in patients sharing the same phenotype, respectively. Its flexible import options ease the comparative analysis of own results derived from microarray or NGS platforms with data from literature or public depositories. Multidimensional data obtained from different experiment types can be merged into a common data matrix to enable common visualization and analysis. All results are stored in the integrated MySQL database, but can also be exported as tab delimited files for further statistical calculations in external programs. GenomeCAT offers a broad spectrum of visualization and analysis tools that assist in the evaluation of CNVs in the context of other experiment data and annotations. The use of GenomeCAT does not require any specialized computer skills. The various R packages implemented for data analysis are fully integrated into GenomeCATs graphical user interface and the installation process is supported by a wizard. The flexibility in terms of data import and export in combination with the ability to create a common data matrix makes the program also well suited as an interface between genomic data from heterogeneous sources and external software tools. Due to the modular architecture the functionality of GenomeCAT can be easily extended by further R packages or customized plug-ins to meet future requirements.

High-efficiency generation of induced pluripotent mesenchymal stem cells from human dermal fibroblasts using recombinant proteins.

PubMed

Chen, Fanfan; Zhang, Guoqiang; Yu, Ling; Feng, Yanye; Li, Xianghui; Zhang, Zhijun; Wang, Yongting; Sun, Dapeng; Pradhan, Sriharsa

2016-07-30

Induced pluripotent mesenchymal stem cells (iPMSCs) are novel candidates for drug screening, regenerative medicine, and cell therapy. However, introduction of transcription factor encoding genes for induced pluripotent stem cell (iPSC) generation which could be used to generate mesenchymal stem cells is accompanied by the risk of insertional mutations in the target cell genome. We demonstrate a novel method using an inactivated viral particle to package and deliver four purified recombinant Yamanaka transcription factors (Sox2, Oct4, Klf4, and c-Myc) resulting in reprogramming of human primary fibroblasts. Whole genome bisulfite sequencing was used to analyze genome-wide CpG methylation of human iPMSCs. Western blot, quantitative PCR, immunofluorescence, and in-vitro differentiation were used to assess the pluripotency of iPMSCs. The resulting reprogrammed fibroblasts show high-level expression of stem cell markers. The human fibroblast-derived iPMSC genome showed gains in DNA methylation in low to medium methylated regions and concurrent loss of methylation in previously hypermethylated regions. Most of the differentially methylated regions are close to transcription start sites and many of these genes are pluripotent pathway associated. We found that DNA methylation of these genes is regulated by the four iPSC transcription factors, which functions as an epigenetic switch during somatic reprogramming as reported previously. These iPMSCs successfully differentiate into three embryonic germ layer cells, both in vitro and in vivo. Following multipotency induction in our study, the delivered transcription factors were degraded, leading to an improved efficiency of subsequent programmed differentiation. Recombinant transcription factor based reprogramming and derivatization of iPMSC offers a novel high-efficiency approach for regenerative medicine from patient-derived cells.

Functional assessment of human enhancer activities using whole-genome STARR-sequencing.

PubMed

Liu, Yuwen; Yu, Shan; Dhiman, Vineet K; Brunetti, Tonya; Eckart, Heather; White, Kevin P

2017-11-20

Genome-wide quantification of enhancer activity in the human genome has proven to be a challenging problem. Recent efforts have led to the development of powerful tools for enhancer quantification. However, because of genome size and complexity, these tools have yet to be applied to the whole human genome.  In the current study, we use a human prostate cancer cell line, LNCaP as a model to perform whole human genome STARR-seq (WHG-STARR-seq) to reliably obtain an assessment of enhancer activity. This approach builds upon previously developed STARR-seq in the fly genome and CapSTARR-seq techniques in targeted human genomic regions. With an improved library preparation strategy, our approach greatly increases the library complexity per unit of starting material, which makes it feasible and cost-effective to explore the landscape of regulatory activity in the much larger human genome. In addition to our ability to identify active, accessible enhancers located in open chromatin regions, we can also detect sequences with the potential for enhancer activity that are located in inaccessible, closed chromatin regions. When treated with the histone deacetylase inhibitor, Trichostatin A, genes nearby this latter class of enhancers are up-regulated, demonstrating the potential for endogenous functionality of these regulatory elements. WHG-STARR-seq provides an improved approach to current pipelines for analysis of high complexity genomes to gain a better understanding of the intricacies of transcriptional regulation.

Germline genome-editing research and its socioethical implications.

PubMed

Ishii, Tetsuya

2015-08-01

Genetically modifying eggs, sperm, and zygotes ('germline' modification) can impact on the entire body of the resulting individual and on subsequent generations. With the advent of genome-editing technology, human germline gene modification is no longer theoretical. Owing to increasing concerns about human germline gene modification, a voluntary moratorium on human genome-editing research and/or the clinical application of human germline genome editing has recently been called for. However, whether such research should be suspended or encouraged warrants careful consideration. The present article reviews recent research on mammalian germline genome editing, discusses the importance of public dialogue on the socioethical implications of human germline genome-editing research, and considers the relevant guidelines and legislation in different countries. Copyright © 2015 Elsevier Ltd. All rights reserved.

Commentary: The Materials Project: A materials genome approach to accelerating materials innovation

NASA Astrophysics Data System (ADS)

Jain, Anubhav; Ong, Shyue Ping; Hautier, Geoffroy; Chen, Wei; Richards, William Davidson; Dacek, Stephen; Cholia, Shreyas; Gunter, Dan; Skinner, David; Ceder, Gerbrand; Persson, Kristin A.

2013-07-01

Accelerating the discovery of advanced materials is essential for human welfare and sustainable, clean energy. In this paper, we introduce the Materials Project (www.materialsproject.org), a core program of the Materials Genome Initiative that uses high-throughput computing to uncover the properties of all known inorganic materials. This open dataset can be accessed through multiple channels for both interactive exploration and data mining. The Materials Project also seeks to create open-source platforms for developing robust, sophisticated materials analyses. Future efforts will enable users to perform ``rapid-prototyping'' of new materials in silico, and provide researchers with new avenues for cost-effective, data-driven materials design.

Scanning the human genome at kilobase resolution.

PubMed

Chen, Jun; Kim, Yeong C; Jung, Yong-Chul; Xuan, Zhenyu; Dworkin, Geoff; Zhang, Yanming; Zhang, Michael Q; Wang, San Ming

2008-05-01

Normal genome variation and pathogenic genome alteration frequently affect small regions in the genome. Identifying those genomic changes remains a technical challenge. We report here the development of the DGS (Ditag Genome Scanning) technique for high-resolution analysis of genome structure. The basic features of DGS include (1) use of high-frequent restriction enzymes to fractionate the genome into small fragments; (2) collection of two tags from two ends of a given DNA fragment to form a ditag to represent the fragment; (3) application of the 454 sequencing system to reach a comprehensive ditag sequence collection; (4) determination of the genome origin of ditags by mapping to reference ditags from known genome sequences; (5) use of ditag sequences directly as the sense and antisense PCR primers to amplify the original DNA fragment. To study the relationship between ditags and genome structure, we performed a computational study by using the human genome reference sequences as a model, and analyzed the ditags experimentally collected from the well-characterized normal human DNA GM15510 and the leukemic human DNA of Kasumi-1 cells. Our studies show that DGS provides a kilobase resolution for studying genome structure with high specificity and high genome coverage. DGS can be applied to validate genome assembly, to compare genome similarity and variation in normal populations, and to identify genomic abnormality including insertion, inversion, deletion, translocation, and amplification in pathological genomes such as cancer genomes.

Human centromere genomics: now it's personal.

PubMed

Hayden, Karen E

2012-07-01

Advances in human genomics have accelerated studies in evolution, disease, and cellular regulation. However, centromere sequences, defining the chromosomal interface with spindle microtubules, remain largely absent from ongoing genomic studies and disconnected from functional, genome-wide analyses. This disparity results from the challenge of predicting the linear order of multi-megabase-sized regions that are composed almost entirely of near-identical satellite DNA. Acknowledging these challenges, the field of human centromere genomics possesses the potential to rapidly advance given the availability of individual, or personalized, genome projects matched with the promise of long-read sequencing technologies. Here I review the current genomic model of human centromeres in consideration of those studies involving functional datasets that examine the role of sequence in centromere identity.

Comparative Genomic Analyses of the Human NPHP1 Locus Reveal Complex Genomic Architecture and Its Regional Evolution in Primates

PubMed Central

Yuan, Bo; Liu, Pengfei; Gupta, Aditya; Beck, Christine R.; Tejomurtula, Anusha; Campbell, Ian M.; Gambin, Tomasz; Simmons, Alexandra D.; Withers, Marjorie A.; Harris, R. Alan; Rogers, Jeffrey; Schwartz, David C.; Lupski, James R.

2015-01-01

Many loci in the human genome harbor complex genomic structures that can result in susceptibility to genomic rearrangements leading to various genomic disorders. Nephronophthisis 1 (NPHP1, MIM# 256100) is an autosomal recessive disorder that can be caused by defects of NPHP1; the gene maps within the human 2q13 region where low copy repeats (LCRs) are abundant. Loss of function of NPHP1 is responsible for approximately 85% of the NPHP1 cases—about 80% of such individuals carry a large recurrent homozygous NPHP1 deletion that occurs via nonallelic homologous recombination (NAHR) between two flanking directly oriented ~45 kb LCRs. Published data revealed a non-pathogenic inversion polymorphism involving the NPHP1 gene flanked by two inverted ~358 kb LCRs. Using optical mapping and array-comparative genomic hybridization, we identified three potential novel structural variant (SV) haplotypes at the NPHP1 locus that may protect a haploid genome from the NPHP1 deletion. Inter-species comparative genomic analyses among primate genomes revealed massive genomic changes during evolution. The aggregated data suggest that dynamic genomic rearrangements occurred historically within the NPHP1 locus and generated SV haplotypes observed in the human population today, which may confer differential susceptibility to genomic instability and the NPHP1 deletion within a personal genome. Our study documents diverse SV haplotypes at a complex LCR-laden human genomic region. Comparative analyses provide a model for how this complex region arose during primate evolution, and studies among humans suggest that intra-species polymorphism may potentially modulate an individual’s susceptibility to acquiring disease-associated alleles. PMID:26641089

Heteroplasmy in the Mitochondrial Genomes of Human Lice and Ticks Revealed by High Throughput Sequencing

PubMed Central

Xiong, Haoyu; Barker, Stephen C.; Burger, Thomas D.; Raoult, Didier; Shao, Renfu

2013-01-01

The typical mitochondrial (mt) genomes of bilateral animals consist of 37 genes on a single circular chromosome. The mt genomes of the human body louse, Pediculus humanus, and the human head louse, Pediculus capitis, however, are extensively fragmented and contain 20 minichromosomes, with one to three genes on each minichromosome. Heteroplasmy, i.e. nucleotide polymorphisms in the mt genome within individuals, has been shown to be significantly higher in the mt cox1 gene of human lice than in humans and other animals that have the typical mt genomes. To understand whether the extent of heteroplasmy in human lice is associated with mt genome fragmentation, we sequenced the entire coding regions of all of the mt minichromosomes of six human body lice and six human head lice from Ethiopia, China and France with an Illumina HiSeq platform. For comparison, we also sequenced the entire coding regions of the mt genomes of seven species of ticks, which have the typical mitochondrial genome organization of bilateral animals. We found that the level of heteroplasmy varies significantly both among the human lice and among the ticks. The human lice from Ethiopia have significantly higher level of heteroplasmy than those from China and France (Pt<0.05). The tick, Amblyomma cajennense, has significantly higher level of heteroplasmy than other ticks (Pt<0.05). Our results indicate that heteroplasmy level can be substantially variable within a species and among closely related species, and does not appear to be determined by single factors such as genome fragmentation. PMID:24058467

Heteroplasmy in the mitochondrial genomes of human lice and ticks revealed by high throughput sequencing.

PubMed

Xiong, Haoyu; Barker, Stephen C; Burger, Thomas D; Raoult, Didier; Shao, Renfu

2013-01-01

The typical mitochondrial (mt) genomes of bilateral animals consist of 37 genes on a single circular chromosome. The mt genomes of the human body louse, Pediculus humanus, and the human head louse, Pediculus capitis, however, are extensively fragmented and contain 20 minichromosomes, with one to three genes on each minichromosome. Heteroplasmy, i.e. nucleotide polymorphisms in the mt genome within individuals, has been shown to be significantly higher in the mt cox1 gene of human lice than in humans and other animals that have the typical mt genomes. To understand whether the extent of heteroplasmy in human lice is associated with mt genome fragmentation, we sequenced the entire coding regions of all of the mt minichromosomes of six human body lice and six human head lice from Ethiopia, China and France with an Illumina HiSeq platform. For comparison, we also sequenced the entire coding regions of the mt genomes of seven species of ticks, which have the typical mitochondrial genome organization of bilateral animals. We found that the level of heteroplasmy varies significantly both among the human lice and among the ticks. The human lice from Ethiopia have significantly higher level of heteroplasmy than those from China and France (Pt<0.05). The tick, Amblyomma cajennense, has significantly higher level of heteroplasmy than other ticks (Pt<0.05). Our results indicate that heteroplasmy level can be substantially variable within a species and among closely related species, and does not appear to be determined by single factors such as genome fragmentation.

2012 U.S. Department of Energy: Joint Genome Institute: Progress Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gilbert, David

2013-01-01

The mission of the U.S. Department of Energy Joint Genome Institute (DOE JGI) is to serve the diverse scientific community as a user facility, enabling the application of large-scale genomics and analysis of plants, microbes, and communities of microbes to address the DOE mission goals in bioenergy and the environment. The DOE JGI's sequencing efforts fall under the Eukaryote Super Program, which includes the Plant and Fungal Genomics Programs; and the Prokaryote Super Program, which includes the Microbial Genomics and Metagenomics Programs. In 2012, several projects made news for their contributions to energy and environment research.

The Evolution of the Human Genome

PubMed Central

Simonti, Corinne N.; Capra, John A.

2015-01-01

Human genomes hold a record of the evolutionary forces that have shaped our species. Advances in DNA sequencing, functional genomics, and population genetic modeling have deepened our understanding of human demographic history, natural selection, and many other long-studied topics. These advances have also revealed many previously underappreciated factors that influence the evolution of the human genome, including functional modifications to DNA and histones, conserved 3D topological chromatin domains, structural variation, and heterogeneous mutation patterns along the genome. Using evolutionary theory as a lens to study these phenomena will lead to significant breakthroughs in understanding what makes us human and why we get sick. PMID:26338498

Combinations of chromosome transfer and genome editing for the development of cell/animal models of human disease and humanized animal models.

PubMed

Uno, Narumi; Abe, Satoshi; Oshimura, Mitsuo; Kazuki, Yasuhiro

2018-02-01

Chromosome transfer technology, including chromosome modification, enables the introduction of Mb-sized or multiple genes to desired cells or animals. This technology has allowed innovative developments to be made for models of human disease and humanized animals, including Down syndrome model mice and humanized transchromosomic (Tc) immunoglobulin mice. Genome editing techniques are developing rapidly, and permit modifications such as gene knockout and knockin to be performed in various cell lines and animals. This review summarizes chromosome transfer-related technologies and the combined technologies of chromosome transfer and genome editing mainly for the production of cell/animal models of human disease and humanized animal models. Specifically, these include: (1) chromosome modification with genome editing in Chinese hamster ovary cells and mouse A9 cells for efficient transfer to desired cell types; (2) single-nucleotide polymorphism modification in humanized Tc mice with genome editing; and (3) generation of a disease model of Down syndrome-associated hematopoiesis abnormalities by the transfer of human chromosome 21 to normal human embryonic stem cells and the induction of mutation(s) in the endogenous gene(s) with genome editing. These combinations of chromosome transfer and genome editing open up new avenues for drug development and therapy as well as for basic research.

The Translational Potential of Research on the Ethical, Legal and Social Implications of Genomics

PubMed Central

Burke, Wylie; Appelbaum, Paul; Dame, Lauren; Marshall, Patricia; Press, Nancy; Pyeritz, Reed; Sharp, Richard; Juengst, Eric

2014-01-01

Federally funded research on the ethical, legal and social implications of genomics (“ELSI” research) includes a programmatic charge to consider policy-relevant questions and to communicate findings in venues that help inform the policy-making process. In addressing this goal, investigators must consider the range of policies that are relevant to human genetics, how foundational research in bioethics, law, and the social sciences might inform those policies, and the potential professional issues that this translational imperative raises for ELSI investigators. We review these questions in the light of experiences from a consortium of federally funded Centers of Excellence in ELSI Research, and offer a set of policy recommendations for program design and evaluation of ELSI research. We conclude that it would be a mistake to require that ELSI research programs demonstrate a direct impact on science or health policy; however, ELSI researchers can take steps to increase the relevance of their work to policy makers. Similarly, funders of ELSI research concerned to facilitate policy development can help by building cross-disciplinary translational research capacities, and universities can take steps to make policy-relevant research more rewarding for scholars in the humanities, social sciences, and law. PMID:24946153

Sarilumab for the treatment of rheumatoid arthritis.

PubMed

Cooper, Simon

2016-01-01

Simon Cooper has >18 years of global experience in the pharmaceutical industry. He joined Sanofi in July 2014 as the Vice President, Global Project Head. In his current position at Sanofi, Dr Cooper is responsible for the clinical development of sarilumab and the worldwide submission in rheumatoid arthritis. He joined Sanofi after serving as the Global Program Medical Director at Novartis since 2012. In this role, Dr Cooper acted as the clinical lead for secukinumab psoriasis submission. Prior to Novartis, Dr Cooper held various posts at Human Genome Sciences, USA, including Executive Director of Clinical Research, Senior Director of Clinical Research and Director of Clinical Research. During his tenure at Human Genome Sciences, USA, Dr Cooper was involved in the submission of belimumab leading to its approval for SLE, and was responsible for its subsequent clinical development program. Dr Cooper has also previously held positions at MedImmune Ltd, UK, Roche, Napp Pharmaceutical Research Ltd, Wyeth Research and Medeval Ltd. In these roles, his responsibilities ranged from medical oversight of clinical trials to medical support for commercial, medical affairs and business development. He received a Bachelor of Medicine and Bachelor of Surgery from University of Newcastle upon Tyne Medical School.

The spotted gar genome illuminates vertebrate evolution and facilitates human-teleost comparisons.

PubMed

Braasch, Ingo; Gehrke, Andrew R; Smith, Jeramiah J; Kawasaki, Kazuhiko; Manousaki, Tereza; Pasquier, Jeremy; Amores, Angel; Desvignes, Thomas; Batzel, Peter; Catchen, Julian; Berlin, Aaron M; Campbell, Michael S; Barrell, Daniel; Martin, Kyle J; Mulley, John F; Ravi, Vydianathan; Lee, Alison P; Nakamura, Tetsuya; Chalopin, Domitille; Fan, Shaohua; Wcisel, Dustin; Cañestro, Cristian; Sydes, Jason; Beaudry, Felix E G; Sun, Yi; Hertel, Jana; Beam, Michael J; Fasold, Mario; Ishiyama, Mikio; Johnson, Jeremy; Kehr, Steffi; Lara, Marcia; Letaw, John H; Litman, Gary W; Litman, Ronda T; Mikami, Masato; Ota, Tatsuya; Saha, Nil Ratan; Williams, Louise; Stadler, Peter F; Wang, Han; Taylor, John S; Fontenot, Quenton; Ferrara, Allyse; Searle, Stephen M J; Aken, Bronwen; Yandell, Mark; Schneider, Igor; Yoder, Jeffrey A; Volff, Jean-Nicolas; Meyer, Axel; Amemiya, Chris T; Venkatesh, Byrappa; Holland, Peter W H; Guiguen, Yann; Bobe, Julien; Shubin, Neil H; Di Palma, Federica; Alföldi, Jessica; Lindblad-Toh, Kerstin; Postlethwait, John H

2016-04-01

To connect human biology to fish biomedical models, we sequenced the genome of spotted gar (Lepisosteus oculatus), whose lineage diverged from teleosts before teleost genome duplication (TGD). The slowly evolving gar genome has conserved in content and size many entire chromosomes from bony vertebrate ancestors. Gar bridges teleosts to tetrapods by illuminating the evolution of immunity, mineralization and development (mediated, for example, by Hox, ParaHox and microRNA genes). Numerous conserved noncoding elements (CNEs; often cis regulatory) undetectable in direct human-teleost comparisons become apparent using gar: functional studies uncovered conserved roles for such cryptic CNEs, facilitating annotation of sequences identified in human genome-wide association studies. Transcriptomic analyses showed that the sums of expression domains and expression levels for duplicated teleost genes often approximate the patterns and levels of expression for gar genes, consistent with subfunctionalization. The gar genome provides a resource for understanding evolution after genome duplication, the origin of vertebrate genomes and the function of human regulatory sequences.

The spotted gar genome illuminates vertebrate evolution and facilitates human-to-teleost comparisons

PubMed Central

Braasch, Ingo; Gehrke, Andrew R.; Smith, Jeramiah J.; Kawasaki, Kazuhiko; Manousaki, Tereza; Pasquier, Jeremy; Amores, Angel; Desvignes, Thomas; Batzel, Peter; Catchen, Julian; Berlin, Aaron M.; Campbell, Michael S.; Barrell, Daniel; Martin, Kyle J.; Mulley, John F.; Ravi, Vydianathan; Lee, Alison P.; Nakamura, Tetsuya; Chalopin, Domitille; Fan, Shaohua; Wcisel, Dustin; Cañestro, Cristian; Sydes, Jason; Beaudry, Felix E. G.; Sun, Yi; Hertel, Jana; Beam, Michael J.; Fasold, Mario; Ishiyama, Mikio; Johnson, Jeremy; Kehr, Steffi; Lara, Marcia; Letaw, John H.; Litman, Gary W.; Litman, Ronda T.; Mikami, Masato; Ota, Tatsuya; Saha, Nil Ratan; Williams, Louise; Stadler, Peter F.; Wang, Han; Taylor, John S.; Fontenot, Quenton; Ferrara, Allyse; Searle, Stephen M. J.; Aken, Bronwen; Yandell, Mark; Schneider, Igor; Yoder, Jeffrey A.; Volff, Jean-Nicolas; Meyer, Axel; Amemiya, Chris T.; Venkatesh, Byrappa; Holland, Peter W. H.; Guiguen, Yann; Bobe, Julien; Shubin, Neil H.; Di Palma, Federica; Alföldi, Jessica; Lindblad-Toh, Kerstin; Postlethwait, John H.

2016-01-01

To connect human biology to fish biomedical models, we sequenced the genome of spotted gar (Lepisosteus oculatus), whose lineage diverged from teleosts before the teleost genome duplication (TGD). The slowly evolving gar genome conserved in content and size many entire chromosomes from bony vertebrate ancestors. Gar bridges teleosts to tetrapods by illuminating the evolution of immunity, mineralization, and development (e.g., Hox, ParaHox, and miRNA genes). Numerous conserved non-coding elements (CNEs, often cis-regulatory) undetectable in direct human-teleost comparisons become apparent using gar: functional studies uncovered conserved roles of such cryptic CNEs, facilitating annotation of sequences identified in human genome-wide association studies. Transcriptomic analyses revealed that the sum of expression domains and levels from duplicated teleost genes often approximate patterns and levels of gar genes, consistent with subfunctionalization. The gar genome provides a resource for understanding evolution after genome duplication, the origin of vertebrate genomes, and the function of human regulatory sequences. PMID:26950095

The Simons Genome Diversity Project: 300 genomes from 142 diverse populations.

PubMed

Mallick, Swapan; Li, Heng; Lipson, Mark; Mathieson, Iain; Gymrek, Melissa; Racimo, Fernando; Zhao, Mengyao; Chennagiri, Niru; Nordenfelt, Susanne; Tandon, Arti; Skoglund, Pontus; Lazaridis, Iosif; Sankararaman, Sriram; Fu, Qiaomei; Rohland, Nadin; Renaud, Gabriel; Erlich, Yaniv; Willems, Thomas; Gallo, Carla; Spence, Jeffrey P; Song, Yun S; Poletti, Giovanni; Balloux, Francois; van Driem, George; de Knijff, Peter; Romero, Irene Gallego; Jha, Aashish R; Behar, Doron M; Bravi, Claudio M; Capelli, Cristian; Hervig, Tor; Moreno-Estrada, Andres; Posukh, Olga L; Balanovska, Elena; Balanovsky, Oleg; Karachanak-Yankova, Sena; Sahakyan, Hovhannes; Toncheva, Draga; Yepiskoposyan, Levon; Tyler-Smith, Chris; Xue, Yali; Abdullah, M Syafiq; Ruiz-Linares, Andres; Beall, Cynthia M; Di Rienzo, Anna; Jeong, Choongwon; Starikovskaya, Elena B; Metspalu, Ene; Parik, Jüri; Villems, Richard; Henn, Brenna M; Hodoglugil, Ugur; Mahley, Robert; Sajantila, Antti; Stamatoyannopoulos, George; Wee, Joseph T S; Khusainova, Rita; Khusnutdinova, Elza; Litvinov, Sergey; Ayodo, George; Comas, David; Hammer, Michael F; Kivisild, Toomas; Klitz, William; Winkler, Cheryl A; Labuda, Damian; Bamshad, Michael; Jorde, Lynn B; Tishkoff, Sarah A; Watkins, W Scott; Metspalu, Mait; Dryomov, Stanislav; Sukernik, Rem; Singh, Lalji; Thangaraj, Kumarasamy; Pääbo, Svante; Kelso, Janet; Patterson, Nick; Reich, David

2016-10-13

Here we report the Simons Genome Diversity Project data set: high quality genomes from 300 individuals from 142 diverse populations. These genomes include at least 5.8 million base pairs that are not present in the human reference genome. Our analysis reveals key features of the landscape of human genome variation, including that the rate of accumulation of mutations has accelerated by about 5% in non-Africans compared to Africans since divergence. We show that the ancestors of some pairs of present-day human populations were substantially separated by 100,000 years ago, well before the archaeologically attested onset of behavioural modernity. We also demonstrate that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans; instead, their modern human ancestry is consistent with coming from the same source as that of other non-Africans.

The Simons Genome Diversity Project: 300 genomes from 142 diverse populations

PubMed Central

Mallick, Swapan; Li, Heng; Lipson, Mark; Mathieson, Iain; Gymrek, Melissa; Racimo, Fernando; Zhao, Mengyao; Chennagiri, Niru; Nordenfelt, Susanne; Tandon, Arti; Skoglund, Pontus; Lazaridis, Iosif; Sankararaman, Sriram; Fu, Qiaomei; Rohland, Nadin; Renaud, Gabriel; Erlich, Yaniv; Willems, Thomas; Gallo, Carla; Spence, Jeffrey P.; Song, Yun S.; Poletti, Giovanni; Balloux, Francois; van Driem, George; de Knijff, Peter; Romero, Irene Gallego; Jha, Aashish R.; Behar, Doron M.; Bravi, Claudio M.; Capelli, Cristian; Hervig, Tor; Moreno-Estrada, Andres; Posukh, Olga L.; Balanovska, Elena; Balanovsky, Oleg; Karachanak-Yankova, Sena; Sahakyan, Hovhannes; Toncheva, Draga; Yepiskoposyan, Levon; Tyler-Smith, Chris; Xue, Yali; Abdullah, M. Syafiq; Ruiz-Linares, Andres; Beall, Cynthia M.; Di Rienzo, Anna; Jeong, Choongwon; Starikovskaya, Elena B.; Metspalu, Ene; Parik, Jüri; Villems, Richard; Henn, Brenna M.; Hodoglugil, Ugur; Mahley, Robert; Sajantila, Antti; Stamatoyannopoulos, George; Wee, Joseph T. S.; Khusainova, Rita; Khusnutdinova, Elza; Litvinov, Sergey; Ayodo, George; Comas, David; Hammer, Michael; Kivisild, Toomas; Klitz, William; Winkler, Cheryl; Labuda, Damian; Bamshad, Michael; Jorde, Lynn B.; Tishkoff, Sarah A.; Watkins, W. Scott; Metspalu, Mait; Dryomov, Stanislav; Sukernik, Rem; Singh, Lalji; Thangaraj, Kumarasamy; Pääbo, Svante; Kelso, Janet; Patterson, Nick; Reich, David

2016-01-01

We report the Simons Genome Diversity Project (SGDP) dataset: high quality genomes from 300 individuals from 142 diverse populations. These genomes include at least 5.8 million base pairs that are not present in the human reference genome. Our analysis reveals key features of the landscape of human genome variation, including that the rate of accumulation of mutations has accelerated by about 5% in non-Africans compared to Africans since divergence. We show that the ancestors of some pairs of present-day human populations were substantially separated by 100,000 years ago, well before the archaeologically attested onset of behavioral modernity. We also demonstrate that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans; instead, their modern human ancestry is consistent with coming from the same source as that in other non-Africans. PMID:27654912

Genome engineering in human cells.

PubMed

Song, Minjung; Kim, Young-Hoon; Kim, Jin-Soo; Kim, Hyongbum

2014-01-01

Genome editing in human cells is of great value in research, medicine, and biotechnology. Programmable nucleases including zinc-finger nucleases, transcription activator-like effector nucleases, and RNA-guided engineered nucleases recognize a specific target sequence and make a double-strand break at that site, which can result in gene disruption, gene insertion, gene correction, or chromosomal rearrangements. The target sequence complexities of these programmable nucleases are higher than 3.2 mega base pairs, the size of the haploid human genome. Here, we briefly introduce the structure of the human genome and the characteristics of each programmable nuclease, and review their applications in human cells including pluripotent stem cells. In addition, we discuss various delivery methods for nucleases, programmable nickases, and enrichment of gene-edited human cells, all of which facilitate efficient and precise genome editing in human cells.

Strategies for implementation of an effective pharmacogenomics program in pharmacy education.

PubMed

Rao, U Subrahmanyeswara; Mayhew, Susan L; Rao, Prema S

2015-07-01

Sequencing of the human genome and the evidence correlating specific genetic variations to diseases have opened up the potential of genomics to more effective and less harmful interventions of human diseases. A wealth of pharmacogenomics knowledge is in place for the practice of precision medicine. However, this knowledge is not fully realized in clinical practice. One reason for this impasse is the lack of in-depth understanding of the potential of pharmacogenomics among the healthcare professionals. Pharmacists are the point-of-care providers and are expected to advise clinicians on matters relating to the implementation of pharmacogenomics in patient care. However, current pharmacogenomics instruction in pharmacy schools fails to produce pharmacists with the required knowledge or practical training in this discipline. In this perspective, we provide several strategies to overcome limitations faced by pharmacy schools. Once implemented, pharmacy schools will produce precision medicine-ready pharmacists.

The Past, Present, and Future of Human Centromere Genomics

PubMed Central

Aldrup-MacDonald, Megan E.; Sullivan, Beth A.

2014-01-01

The centromere is the chromosomal locus essential for chromosome inheritance and genome stability. Human centromeres are located at repetitive alpha satellite DNA arrays that compose approximately 5% of the genome. Contiguous alpha satellite DNA sequence is absent from the assembled reference genome, limiting current understanding of centromere organization and function. Here, we review the progress in centromere genomics spanning the discovery of the sequence to its molecular characterization and the work done during the Human Genome Project era to elucidate alpha satellite structure and sequence variation. We discuss exciting recent advances in alpha satellite sequence assembly that have provided important insight into the abundance and complex organization of this sequence on human chromosomes. In light of these new findings, we offer perspectives for future studies of human centromere assembly and function. PMID:24683489

The 'morbid anatomy' of the human genome: tracing the observational and representational approaches of postwar genetics and biomedicine the William Bynum Prize Essay.

PubMed

Hogan, Andrew J

2014-07-01

This paper explores evolving conceptions and depictions of the human genome among human and medical geneticists during the postwar period. Historians of science and medicine have shown significant interest in the use of informational approaches in postwar genetics, which treat the genome as an expansive digital data set composed of three billion DNA nucleotides. Since the 1950s, however, geneticists have largely interacted with the human genome at the microscopically visible level of chromosomes. Mindful of this, I examine the observational and representational approaches of postwar human and medical genetics. During the 1970s and 1980s, the genome increasingly came to be understood as, at once, a discrete part of the human anatomy and a standardised scientific object. This paper explores the role of influential medical geneticists in recasting the human genome as being a visible, tangible, and legible entity, which was highly relevant to traditional medical thinking and practice. I demonstrate how the human genome was established as an object amenable to laboratory and clinical research, and argue that the observational and representational approaches of postwar medical genetics reflect, more broadly, the interdisciplinary efforts underlying the development of contemporary biomedicine.

Functional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer.

PubMed

Mason, Jacqueline M; Wei, Xin; Fletcher, Graham C; Kiarash, Reza; Brokx, Richard; Hodgson, Richard; Beletskaya, Irina; Bray, Mark R; Mak, Tak W

2017-03-21

Loss of cell-cycle control is a hallmark of human cancer. Cell-cycle checkpoints are essential for maintaining genome integrity and balanced growth and division. They are specifically deregulated in cancer cells and contain regulators that represent potential therapeutic targets. Monopolar spindle 1 (Mps1; also known as TTK protein kinase) is a core component of the spindle assembly checkpoint (SAC), a genome-surveillance mechanism that is important for cell survival, and has emerged as a candidate target for anticancer therapy. Here, we report the cellular and antitumor effects of CFI-402257, a potent (Mps1 K i = 0.09 ± 0.02 nM; cellular Mps1 EC 50 = 6.5 ± 0.5 nM), highly selective, and orally active small-molecule inhibitor of Mps1 that was identified through a drug-discovery program. Human cancer cells treated with CFI-402257 exhibit effects consistent with Mps1 kinase inhibition, specifically SAC inactivation, leading to chromosome missegregation, aneuploidy, and ultimately cell death. Oral administration of CFI-402257 in monotherapy or in combination with an anti-programmed cell death 1 (PD-1) antibody in mouse models of human cancer results in inhibition of tumor growth at doses that are well-tolerated. Our findings provide a rationale for the clinical evaluation of CFI-402257 in patients with solid tumors.

Functional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer

PubMed Central

Mason, Jacqueline M.; Wei, Xin; Fletcher, Graham C.; Kiarash, Reza; Brokx, Richard; Hodgson, Richard; Beletskaya, Irina; Bray, Mark R.; Mak, Tak W.

2017-01-01

Loss of cell-cycle control is a hallmark of human cancer. Cell-cycle checkpoints are essential for maintaining genome integrity and balanced growth and division. They are specifically deregulated in cancer cells and contain regulators that represent potential therapeutic targets. Monopolar spindle 1 (Mps1; also known as TTK protein kinase) is a core component of the spindle assembly checkpoint (SAC), a genome-surveillance mechanism that is important for cell survival, and has emerged as a candidate target for anticancer therapy. Here, we report the cellular and antitumor effects of CFI-402257, a potent (Mps1 Ki = 0.09 ± 0.02 nM; cellular Mps1 EC50 = 6.5 ± 0.5 nM), highly selective, and orally active small-molecule inhibitor of Mps1 that was identified through a drug-discovery program. Human cancer cells treated with CFI-402257 exhibit effects consistent with Mps1 kinase inhibition, specifically SAC inactivation, leading to chromosome missegregation, aneuploidy, and ultimately cell death. Oral administration of CFI-402257 in monotherapy or in combination with an anti-programmed cell death 1 (PD-1) antibody in mouse models of human cancer results in inhibition of tumor growth at doses that are well-tolerated. Our findings provide a rationale for the clinical evaluation of CFI-402257 in patients with solid tumors. PMID:28270606

Race and Ethnicity in the Genome Era: The Complexity of the Constructs

ERIC Educational Resources Information Center

Bonham, Vence L.; Warshauer-Baker, Esther; Collins, Francis S.

2005-01-01

The vast amount of biological information that is now available through the completion of the Human Genome Project presents opportunities and challenges. The genomic era has the potential to advance an understanding of human genetic variation and its role in human health and disease. A challenge for genomics research is to understand the…

Understanding the Human Genome Project -- A Fact Sheet

MedlinePlus

... cost of sequencing whole exomes or genomes, groundbreaking comparative genomic studies are now identifiying the causes of ... the role of ethical, legal, and social implications research more important than ever. National Human Genome Research ...

DOE Research and Development Accomplishments

Science.gov Websites

sector to explore the possibility of sequencing the human genome. This Workshop was sponsored by DOE and approach to sequence the human genome. The Human Genome Project (HGP) was formalized in mid-February 1990

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

This volume contains the proceedings of the fourth Contractor-Grantee Workshop for the Department of Energy (DOE) Human Genome Program. Of the 204 abstracts in this book, some 200 describe the genome research of DOE-funded grantees and contractors located at the multidisciplinary centers at Lawrence Berkeley Laboratory, Lawrence Livermore National Laboratory, and Los Alamos National Laboratory; other DOE-supported laboratories; and more than 54 universities, research organizations, and companies in the United States and abroad. Included are 16 abstracts from ongoing projects in the Ethical, Legal, and Social Issues (ELSI) component, an area that continues to attract considerable attention from a widemore » variety of interested parties. Three abstracts summarize work in the new Microbial Genome Initiative launched this year by the Office of Health and Environmental Research (OHER) to provide genome sequence and mapping data on industrially important microorganisms and those that live under extreme conditions. Many of the projects will be discussed at plenary sessions held throughout the workshop, and all are represented in the poster sessions.« less

Multimode drug inducible CRISPR/Cas9 devices for transcriptional activation and genome editing

PubMed Central

Lu, Jia; Zhao, Chen; Zhao, Yingze; Zhang, Jingfang; Zhang, Yue; Chen, Li; Han, Qiyuan; Ying, Yue; Peng, Shuai; Ai, Runna; Wang, Yu

2018-01-01

Abstract Precise investigation and manipulation of dynamic biological processes often requires molecular modulation in a controlled inducible manner. The clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) has emerged as a versatile tool for targeted gene editing and transcriptional programming. Here, we designed and vigorously optimized a series of Hybrid drug Inducible CRISPR/Cas9 Technologies (HIT) for transcriptional activation by grafting a mutated human estrogen receptor (ERT2) to multiple CRISPR/Cas9 systems, which renders them 4-hydroxytamoxifen (4-OHT) inducible for the access of genome. Further, extra functionality of simultaneous genome editing was achieved with one device we named HIT2. Optimized terminal devices herein delivered advantageous performances in comparison with several existing designs. They exerted selective, titratable, rapid and reversible response to drug induction. In addition, these designs were successfully adapted to an orthogonal Cas9. HIT systems developed in this study can be applied for controlled modulation of potentially any genomic loci in multiple modes. PMID:29237052

Extensive sequencing of seven human genomes to characterize benchmark reference materials

PubMed Central

Zook, Justin M.; Catoe, David; McDaniel, Jennifer; Vang, Lindsay; Spies, Noah; Sidow, Arend; Weng, Ziming; Liu, Yuling; Mason, Christopher E.; Alexander, Noah; Henaff, Elizabeth; McIntyre, Alexa B.R.; Chandramohan, Dhruva; Chen, Feng; Jaeger, Erich; Moshrefi, Ali; Pham, Khoa; Stedman, William; Liang, Tiffany; Saghbini, Michael; Dzakula, Zeljko; Hastie, Alex; Cao, Han; Deikus, Gintaras; Schadt, Eric; Sebra, Robert; Bashir, Ali; Truty, Rebecca M.; Chang, Christopher C.; Gulbahce, Natali; Zhao, Keyan; Ghosh, Srinka; Hyland, Fiona; Fu, Yutao; Chaisson, Mark; Xiao, Chunlin; Trow, Jonathan; Sherry, Stephen T.; Zaranek, Alexander W.; Ball, Madeleine; Bobe, Jason; Estep, Preston; Church, George M.; Marks, Patrick; Kyriazopoulou-Panagiotopoulou, Sofia; Zheng, Grace X.Y.; Schnall-Levin, Michael; Ordonez, Heather S.; Mudivarti, Patrice A.; Giorda, Kristina; Sheng, Ying; Rypdal, Karoline Bjarnesdatter; Salit, Marc

2016-01-01

The Genome in a Bottle Consortium, hosted by the National Institute of Standards and Technology (NIST) is creating reference materials and data for human genome sequencing, as well as methods for genome comparison and benchmarking. Here, we describe a large, diverse set of sequencing data for seven human genomes; five are current or candidate NIST Reference Materials. The pilot genome, NA12878, has been released as NIST RM 8398. We also describe data from two Personal Genome Project trios, one of Ashkenazim Jewish ancestry and one of Chinese ancestry. The data come from 12 technologies: BioNano Genomics, Complete Genomics paired-end and LFR, Ion Proton exome, Oxford Nanopore, Pacific Biosciences, SOLiD, 10X Genomics GemCode WGS, and Illumina exome and WGS paired-end, mate-pair, and synthetic long reads. Cell lines, DNA, and data from these individuals are publicly available. Therefore, we expect these data to be useful for revealing novel information about the human genome and improving sequencing technologies, SNP, indel, and structural variant calling, and de novo assembly. PMID:27271295

Post-Genome Era Pedagogy: How a BS Biotechnology Program Benefits the Liberal Arts Institution

ERIC Educational Resources Information Center

Eden, Peter

2005-01-01

Genomics profoundly affects society, because genome sequence information is widely used in such areas as genetic testing, genomic medicine/vaccine development, and so forth. Therefore, a responsibility to modernize science curricula exists for "post-genome era" educators. At my university, we developed a BS biotechnology program within a…

Overview of NASARTI (NASA Radiation Track Image) Program: Highlights of the Model Improvement and the New Results

NASA Technical Reports Server (NTRS)

Ponomarev, Artem L.; Plante, I.; George, Kerry; Cornforth, M. N.; Loucas, B. D.; Wu, Honglu

2014-01-01

This presentation summarizes several years of research done by the co-authors developing the NASARTI (NASA Radiation Track Image) program and supporting it with scientific data. The goal of the program is to support NASA mission to achieve a safe space travel for humans despite the perils of space radiation. The program focuses on selected topics in radiation biology that were deemed important throughout this period of time, both for the NASA human space flight program and to academic radiation research. Besides scientific support to develop strategies protecting humans against an exposure to deep space radiation during space missions, and understanding health effects from space radiation on astronauts, other important ramifications of the ionizing radiation were studied with the applicability to greater human needs: understanding the origins of cancer, the impact on human genome, and the application of computer technology to biological research addressing the health of general population. The models under NASARTI project include: the general properties of ionizing radiation, such as particular track structure, the effects of radiation on human DNA, visualization and the statistical properties of DSBs (DNA double-strand breaks), DNA damage and repair pathways models and cell phenotypes, chromosomal aberrations, microscopy data analysis and the application to human tissue damage and cancer models. The development of the GUI and the interactive website, as deliverables to NASA operations teams and tools for a broader research community, is discussed. Most recent findings in the area of chromosomal aberrations and the application of the stochastic track structure are also presented.

Inferring Selective Constraint from Population Genomic Data Suggests Recent Regulatory Turnover in the Human Brain

PubMed Central

Schrider, Daniel R.; Kern, Andrew D.

2015-01-01

The comparative genomics revolution of the past decade has enabled the discovery of functional elements in the human genome via sequence comparison. While that is so, an important class of elements, those specific to humans, is entirely missed by searching for sequence conservation across species. Here we present an analysis based on variation data among human genomes that utilizes a supervised machine learning approach for the identification of human-specific purifying selection in the genome. Using only allele frequency information from the complete low-coverage 1000 Genomes Project data set in conjunction with a support vector machine trained from known functional and nonfunctional portions of the genome, we are able to accurately identify portions of the genome constrained by purifying selection. Our method identifies previously known human-specific gains or losses of function and uncovers many novel candidates. Candidate targets for gain and loss of function along the human lineage include numerous putative regulatory regions of genes essential for normal development of the central nervous system, including a significant enrichment of gain of function events near neurotransmitter receptor genes. These results are consistent with regulatory turnover being a key mechanism in the evolution of human-specific characteristics of brain development. Finally, we show that the majority of the genome is unconstrained by natural selection currently, in agreement with what has been estimated from phylogenetic methods but in sharp contrast to estimates based on transcriptomics or other high-throughput functional methods. PMID:26590212

Significance of functional disease-causal/susceptible variants identified by whole-genome analyses for the understanding of human diseases.

PubMed

Hitomi, Yuki; Tokunaga, Katsushi

2017-01-01

Human genome variation may cause differences in traits and disease risks. Disease-causal/susceptible genes and variants for both common and rare diseases can be detected by comprehensive whole-genome analyses, such as whole-genome sequencing (WGS), using next-generation sequencing (NGS) technology and genome-wide association studies (GWAS). Here, in addition to the application of an NGS as a whole-genome analysis method, we summarize approaches for the identification of functional disease-causal/susceptible variants from abundant genetic variants in the human genome and methods for evaluating their functional effects in human diseases, using an NGS and in silico and in vitro functional analyses. We also discuss the clinical applications of the functional disease causal/susceptible variants to personalized medicine.

LINE-1 Elements in Structural Variation and Disease

PubMed Central

Beck, Christine R.; Garcia-Perez, José Luis; Badge, Richard M.; Moran, John V.

2014-01-01

The completion of the human genome reference sequence ushered in a new era for the study and discovery of human transposable elements. It now is undeniable that transposable elements, historically dismissed as junk DNA, have had an instrumental role in sculpting the structure and function of our genomes. In particular, long interspersed element-1 (LINE-1 or L1) and short interspersed elements (SINEs) continue to affect our genome, and their movement can lead to sporadic cases of disease. Here, we briefly review the types of transposable elements present in the human genome and their mechanisms of mobility. We next highlight how advances in DNA sequencing and genomic technologies have enabled the discovery of novel retrotransposons in individual genomes. Finally, we discuss how L1-mediated retrotransposition events impact human genomes. PMID:21801021

Comparative Genomics in Homo sapiens.

PubMed

Oti, Martin; Sammeth, Michael

2018-01-01

Genomes can be compared at different levels of divergence, either between species or within species. Within species genomes can be compared between different subpopulations, such as human subpopulations from different continents. Investigating the genomic differences between different human subpopulations is important when studying complex diseases that are affected by many genetic variants, as the variants involved can differ between populations. The 1000 Genomes Project collected genome-scale variation data for 2504 human individuals from 26 different populations, enabling a systematic comparison of variation between human subpopulations. In this chapter, we present step-by-step a basic protocol for the identification of population-specific variants employing the 1000 Genomes data. These variants are subsequently further investigated for those that affect the proteome or RNA splice sites, to investigate potentially biologically relevant differences between the populations.

The human genome: a multifractal analysis

PubMed Central

2011-01-01

Background Several studies have shown that genomes can be studied via a multifractal formalism. Recently, we used a multifractal approach to study the genetic information content of the Caenorhabditis elegans genome. Here we investigate the possibility that the human genome shows a similar behavior to that observed in the nematode. Results We report here multifractality in the human genome sequence. This behavior correlates strongly on the presence of Alu elements and to a lesser extent on CpG islands and (G+C) content. In contrast, no or low relationship was found for LINE, MIR, MER, LTRs elements and DNA regions poor in genetic information. Gene function, cluster of orthologous genes, metabolic pathways, and exons tended to increase their frequencies with ranges of multifractality and large gene families were located in genomic regions with varied multifractality. Additionally, a multifractal map and classification for human chromosomes are proposed. Conclusions Based on these findings, we propose a descriptive non-linear model for the structure of the human genome, with some biological implications. This model reveals 1) a multifractal regionalization where many regions coexist that are far from equilibrium and 2) this non-linear organization has significant molecular and medical genetic implications for understanding the role of Alu elements in genome stability and structure of the human genome. Given the role of Alu sequences in gene regulation, genetic diseases, human genetic diversity, adaptation and phylogenetic analyses, these quantifications are especially useful. PMID:21999602

Mating programs including genomic relationships and dominance effects

USDA-ARS?s Scientific Manuscript database

Breed associations, artificial-insemination organizations, and on-farm software providers need new computerized mating programs for genomic selection so that genomic inbreeding could be minimized by comparing genotypes of potential mates. Efficient methods for transferring elements of the genomic re...

A 1463 Gene Cattle–Human Comparative Map With Anchor Points Defined by Human Genome Sequence Coordinates

PubMed Central

Everts-van der Wind, Annelie; Kata, Srinivas R.; Band, Mark R.; Rebeiz, Mark; Larkin, Denis M.; Everts, Robin E.; Green, Cheryl A.; Liu, Lei; Natarajan, Shreedhar; Goldammer, Tom; Lee, Jun Heon; McKay, Stephanie; Womack, James E.; Lewin, Harris A.

2004-01-01

A second-generation 5000 rad radiation hybrid (RH) map of the cattle genome was constructed primarily using cattle ESTs that were targeted to gaps in the existing cattle–human comparative map, as well as to sparsely populated map intervals. A total of 870 targeted markers were added, bringing the number of markers mapped on the RH5000 panel to 1913. Of these, 1463 have significant BLASTN hits (E < e–5) against the human genome sequence. A cattle–human comparative map was created using human genome sequence coordinates of the paired orthologs. One-hundred and ninety-five conserved segments (defined by two or more genes) were identified between the cattle and human genomes, of which 31 are newly discovered and 34 were extended singletons on the first-generation map. The new map represents an improvement of 20% genome-wide comparative coverage compared with the first-generation map. Analysis of gene content within human genome regions where there are gaps in the comparative map revealed gaps with both significantly greater and significantly lower gene content. The new, more detailed cattle–human comparative map provides an improved resource for the analysis of mammalian chromosome evolution, the identification of candidate genes for economically important traits, and for proper alignment of sequence contigs on cattle chromosomes. PMID:15231756

Sequence space coverage, entropy of genomes and the potential to detect non-human DNA in human samples

PubMed Central

Liu, Zhandong; Venkatesh, Santosh S; Maley, Carlo C

2008-01-01

Background Genomes store information for building and maintaining organisms. Complete sequencing of many genomes provides the opportunity to study and compare global information properties of those genomes. Results We have analyzed aspects of the information content of Homo sapiens, Mus musculus, Drosophila melanogaster, Caenorhabditis elegans, Arabidopsis thaliana, Saccharomyces cerevisiae, and Escherichia coli (K-12) genomes. Virtually all possible (> 98%) 12 bp oligomers appear in vertebrate genomes while < 2% of 19 bp oligomers are present. Other species showed different ranges of > 98% to < 2% of possible oligomers in D. melanogaster (12–17 bp), C. elegans (11–17 bp), A. thaliana (11–17 bp), S. cerevisiae (10–16 bp) and E. coli (9–15 bp). Frequencies of unique oligomers in the genomes follow similar patterns. We identified a set of 2.6 M 15-mers that are more than 1 nucleotide different from all 15-mers in the human genome and so could be used as probes to detect microbes in human samples. In a human sample, these probes would detect 100% of the 433 currently fully sequenced prokaryotes and 75% of the 3065 fully sequenced viruses. The human genome is significantly more compact in sequence space than a random genome. We identified the most frequent 5- to 20-mers in the human genome, which may prove useful as PCR primers. We also identified a bacterium, Anaeromyxobacter dehalogenans, which has an exceptionally low diversity of oligomers given the size of its genome and its GC content. The entropy of coding regions in the human genome is significantly higher than non-coding regions and chromosomes. However chromosomes 1, 2, 9, 12 and 14 have a relatively high proportion of coding DNA without high entropy, and chromosome 20 is the opposite with a low frequency of coding regions but relatively high entropy. Conclusion Measures of the frequency of oligomers are useful for designing PCR assays and for identifying chromosomes and organisms with hidden structure that had not been previously recognized. This information may be used to detect novel microbes in human tissues. PMID:18973670

Sequence space coverage, entropy of genomes and the potential to detect non-human DNA in human samples.

PubMed

Liu, Zhandong; Venkatesh, Santosh S; Maley, Carlo C

2008-10-30

Genomes store information for building and maintaining organisms. Complete sequencing of many genomes provides the opportunity to study and compare global information properties of those genomes. We have analyzed aspects of the information content of Homo sapiens, Mus musculus, Drosophila melanogaster, Caenorhabditis elegans, Arabidopsis thaliana, Saccharomyces cerevisiae, and Escherichia coli (K-12) genomes. Virtually all possible (> 98%) 12 bp oligomers appear in vertebrate genomes while < 2% of 19 bp oligomers are present. Other species showed different ranges of > 98% to < 2% of possible oligomers in D. melanogaster (12-17 bp), C. elegans (11-17 bp), A. thaliana (11-17 bp), S. cerevisiae (10-16 bp) and E. coli (9-15 bp). Frequencies of unique oligomers in the genomes follow similar patterns. We identified a set of 2.6 M 15-mers that are more than 1 nucleotide different from all 15-mers in the human genome and so could be used as probes to detect microbes in human samples. In a human sample, these probes would detect 100% of the 433 currently fully sequenced prokaryotes and 75% of the 3065 fully sequenced viruses. The human genome is significantly more compact in sequence space than a random genome. We identified the most frequent 5- to 20-mers in the human genome, which may prove useful as PCR primers. We also identified a bacterium, Anaeromyxobacter dehalogenans, which has an exceptionally low diversity of oligomers given the size of its genome and its GC content. The entropy of coding regions in the human genome is significantly higher than non-coding regions and chromosomes. However chromosomes 1, 2, 9, 12 and 14 have a relatively high proportion of coding DNA without high entropy, and chromosome 20 is the opposite with a low frequency of coding regions but relatively high entropy. Measures of the frequency of oligomers are useful for designing PCR assays and for identifying chromosomes and organisms with hidden structure that had not been previously recognized. This information may be used to detect novel microbes in human tissues.

Signatures of positive selection in East African Shorthorn Zebu: A genome-wide single nucleotide polymorphism analysis

PubMed Central

Bahbahani, Hussain; Clifford, Harry; Wragg, David; Mbole-Kariuki, Mary N; Van Tassell, Curtis; Sonstegard, Tad; Woolhouse, Mark; Hanotte, Olivier

2015-01-01

The small East African Shorthorn Zebu (EASZ) is the main indigenous cattle across East Africa. A recent genome wide SNP analysis revealed an ancient stable African taurine x Asian zebu admixture. Here, we assess the presence of candidate signatures of positive selection in their genome, with the aim to provide qualitative insights about the corresponding selective pressures. Four hundred and twenty-five EASZ and four reference populations (Holstein-Friesian, Jersey, N’Dama and Nellore) were analysed using 46,171 SNPs covering all autosomes and the X chromosome. Following FST and two extended haplotype homozygosity-based (iHS and Rsb) analyses 24 candidate genome regions within 14 autosomes and the X chromosome were revealed, in which 18 and 4 were previously identified in tropical-adapted and commercial breeds, respectively. These regions overlap with 340 bovine QTL. They include 409 annotated genes, in which 37 were considered as candidates. These genes are involved in various biological pathways (e.g. immunity, reproduction, development and heat tolerance). Our results support that different selection pressures (e.g. environmental constraints, human selection, genome admixture constrains) have shaped the genome of EASZ. We argue that these candidate regions represent genome landmarks to be maintained in breeding programs aiming to improve sustainable livestock productivity in the tropics. PMID:26130263

The NIH Roadmap Epigenomics Program data resource

PubMed Central

Chadwick, Lisa Helbling

2012-01-01

The NIH Roadmap Reference Epigenome Mapping Consortium is developing a community resource of genome-wide epigenetic maps in a broad range of human primary cells and tissues. There are large amounts of data already available, and a number of different options for viewing and analyzing the data. This report will describe key features of the websites where users will find data, protocols and analysis tools developed by the consortium, and provide a perspective on how this unique resource will facilitate and inform human disease research, both immediately and in the future. PMID:22690667

The NIH Roadmap Epigenomics Program data resource.

PubMed

Chadwick, Lisa Helbling

2012-06-01

The NIH Roadmap Reference Epigenome Mapping Consortium is developing a community resource of genome-wide epigenetic maps in a broad range of human primary cells and tissues. There are large amounts of data already available, and a number of different options for viewing and analyzing the data. This report will describe key features of the websites where users will find data, protocols and analysis tools developed by the consortium, and provide a perspective on how this unique resource will facilitate and inform human disease research, both immediately and in the future.

Tempo and mode of genomic mutations unveil human evolutionary history.

PubMed

Hara, Yuichiro

2015-01-01

Mutations that have occurred in human genomes provide insight into various aspects of evolutionary history such as speciation events and degrees of natural selection. Comparing genome sequences between human and great apes or among humans is a feasible approach for inferring human evolutionary history. Recent advances in high-throughput or so-called 'next-generation' DNA sequencing technologies have enabled the sequencing of thousands of individual human genomes, as well as a variety of reference genomes of hominids, many of which are publicly available. These sequence data can help to unveil the detailed demographic history of the lineage leading to humans as well as the explosion of modern human population size in the last several thousand years. In addition, high-throughput sequencing illustrates the tempo and mode of de novo mutations, which are producing human genetic variation at this moment. Pedigree-based human genome sequencing has shown that mutation rates vary significantly across the human genome. These studies have also provided an improved timescale of human evolution, because the mutation rate estimated from pedigree analysis is half that estimated from traditional analyses based on molecular phylogeny. Because of the dramatic reduction in sequencing cost, sequencing on-demand samples designed for specific studies is now also becoming popular. To produce data of sufficient quality to meet the requirements of the study, it is necessary to set an explicit sequencing plan that includes the choice of sample collection methods, sequencing platforms, and number of sequence reads.

The Arab genome: Health and wealth.

PubMed

Zayed, Hatem

2016-11-05

The 22 Arab nations have a unique genetic structure, which reflects both conserved and diverse gene pools due to the prevalent endogamous and consanguineous marriage culture and the long history of admixture among different ethnic subcultures descended from the Asian, European, and African continents. Human genome sequencing has enabled large-scale genomic studies of different populations and has become a powerful tool for studying disease predictions and diagnosis. Despite the importance of the Arab genome for better understanding the dynamics of the human genome, discovering rare genetic variations, and studying early human migration out of Africa, it is poorly represented in human genome databases, such as HapMap and the 1000 Genomes Project. In this review, I demonstrate the significance of sequencing the Arab genome and setting an Arab genome reference(s) for better understanding the molecular pathogenesis of genetic diseases, discovering novel/rare variants, and identifying a meaningful genotype-phenotype correlation for complex diseases. Copyright © 2016. Published by Elsevier B.V.

gmos: Rapid Detection of Genome Mosaicism over Short Evolutionary Distances.

PubMed

Domazet-Lošo, Mirjana; Domazet-Lošo, Tomislav

2016-01-01

Prokaryotic and viral genomes are often altered by recombination and horizontal gene transfer. The existing methods for detecting recombination are primarily aimed at viral genomes or sets of loci, since the expensive computation of underlying statistical models often hinders the comparison of complete prokaryotic genomes. As an alternative, alignment-free solutions are more efficient, but cannot map (align) a query to subject genomes. To address this problem, we have developed gmos (Genome MOsaic Structure), a new program that determines the mosaic structure of query genomes when compared to a set of closely related subject genomes. The program first computes local alignments between query and subject genomes and then reconstructs the query mosaic structure by choosing the best local alignment for each query region. To accomplish the analysis quickly, the program mostly relies on pairwise alignments and constructs multiple sequence alignments over short overlapping subject regions only when necessary. This fine-tuned implementation achieves an efficiency comparable to an alignment-free tool. The program performs well for simulated and real data sets of closely related genomes and can be used for fast recombination detection; for instance, when a new prokaryotic pathogen is discovered. As an example, gmos was used to detect genome mosaicism in a pathogenic Enterococcus faecium strain compared to seven closely related genomes. The analysis took less than two minutes on a single 2.1 GHz processor. The output is available in fasta format and can be visualized using an accessory program, gmosDraw (freely available with gmos).

gmos: Rapid Detection of Genome Mosaicism over Short Evolutionary Distances

PubMed Central

Domazet-Lošo, Mirjana; Domazet-Lošo, Tomislav

2016-01-01

Prokaryotic and viral genomes are often altered by recombination and horizontal gene transfer. The existing methods for detecting recombination are primarily aimed at viral genomes or sets of loci, since the expensive computation of underlying statistical models often hinders the comparison of complete prokaryotic genomes. As an alternative, alignment-free solutions are more efficient, but cannot map (align) a query to subject genomes. To address this problem, we have developed gmos (Genome MOsaic Structure), a new program that determines the mosaic structure of query genomes when compared to a set of closely related subject genomes. The program first computes local alignments between query and subject genomes and then reconstructs the query mosaic structure by choosing the best local alignment for each query region. To accomplish the analysis quickly, the program mostly relies on pairwise alignments and constructs multiple sequence alignments over short overlapping subject regions only when necessary. This fine-tuned implementation achieves an efficiency comparable to an alignment-free tool. The program performs well for simulated and real data sets of closely related genomes and can be used for fast recombination detection; for instance, when a new prokaryotic pathogen is discovered. As an example, gmos was used to detect genome mosaicism in a pathogenic Enterococcus faecium strain compared to seven closely related genomes. The analysis took less than two minutes on a single 2.1 GHz processor. The output is available in fasta format and can be visualized using an accessory program, gmosDraw (freely available with gmos). PMID:27846272

76 FR 65738 - National Human Genome Research Institute; Amended Notice of Meeting

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2011-10-24

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Amended Notice of Meeting Notice is hereby given of a change in the meeting of the National Human Genome Research Institute Special Emphasis Panel, November 29, 2011, 8 a.m. to November 29...

77 FR 67385 - National Human Genome Research Institute; Amended Notice of Meeting

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78 FR 65342 - National Human Genome Research Institute; Amended Notice of Meeting

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2011-11-18

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Amended Notice of Meeting Notice is hereby given of a change in the meeting of the National Human Genome Research Institute Special Emphasis Panel, November 22, 2011, 12 p.m. to November 22...

77 FR 55853 - National Human Genome Research Institute; Amended Notice of Meeting

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... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Human Genome Research Institute; Amended Notice of Meeting Notice is hereby given of a change in the meeting of the National Advisory Council for Human Genome Research, September 10, 2012, 8:30 a.m. to September 11, 2012, 5...

Pacific Northwest Laboratory annual report for 1990 to the DOE Office of Energy Research

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, J.F.

This report summarizes progress on OHER human health, biological, and general life sciences research programs conducted at PNL in FY 1990. The research develops the knowledge and scientific principles necessary to identify understand, and anticipate the long-term health consequences of energy-related radiation and chemicals. Our continuing emphasis is to decrease the uncertainty of health risk estimates from existing and developing energy-related technologies through an increased of understanding of how radiation and chemicals cause biological damage. The sequence of this report of PNL research reflects the OHER programmatic structure. The first section, on human health research, concerns epidemiological and statistical studiesmore » for assessing health risks. The next section contains reports of biological research in laboratory animals and in vitro cell systems, including research with radionuclides and chemicals. The general life sciences research section reports research conducted for the OHER human genome research program.« less

Whole-genome analyses of DS-1-like human G2P[4] and G8P[4] rotavirus strains from Eastern, Western and Southern Africa

PubMed Central

Nyaga, Martin M.; Stucker, Karla M.; Esona, Mathew D.; Jere, Khuzwayo C.; Mwinyi, Bakari; Shonhai, Annie; Tsolenyanu, Enyonam; Mulindwa, Augustine; Chibumbya, Julia N.; Adolfine, Hokororo; Halpin, Rebecca A.; Roy, Sunando; Stockwell, Timothy B.; Berejena, Chipo; Seheri, Mapaseka L.; Mwenda, Jason M.; Steele, A. Duncan; Wentworth, David E.

2018-01-01

Group A rotaviruses (RVAs) with distinct G and P genotype combinations have been reported globally. We report the genome composition and possible origin of seven G8P[4] and five G2P[4] human RVA strains based on the genetic evolution of all 11 genome segments at the nucleotide level. Twelve RVA ELISA positive stool samples collected in the representative countries of Eastern, Southern and West Africa during the 2007–2012 surveillance seasons were subjected to sequencing using the Ion Torrent PGM and Illumina MiSeq platforms. A reference-based assembly was performed using CLC Bio’s clc_ref_assemble_long program, and full-genome consensus sequences were obtained. With the exception of the neutralising antigen, VP7, all study strains exhibited the DS-1-like genome constellation (P[4]-I2-R2-C2-M2-A2-N2-T2-E2-H2) and clustered phylogenetically with reference strains having a DS-1-like genetic backbone. Comparison of the nucleotide and amino acid sequences with selected global cognate genome segments revealed nucleotide and amino acid sequence identities of 81.7–100 % and 90.6–100 %, respectively, with NSP4 gene segment showing the most diversity among the strains. Bayesian analyses of all gene sequences to estimate the time of divergence of the lineage indicated that divergence times ranged from 16 to 44 years, except for the NSP4 gene where the lineage seemed to arise in the more distant past at an estimated 203 years ago. However, the long-term effects of changes found within the NSP4 genome segment should be further explored, and thus we recommend continued whole-genome analyses from larger sample sets to determine the evolutionary mechanisms of the DS-1-like strains collected in Africa. PMID:24952422

A sequence of 'factishes': the media-metaphorical knowledge dynamics structuring the German press coverage of the human genome.

PubMed

Doring, Martin

2005-12-01

This article deals with the cultural framing of the near sequencing of the human genome and its impact on the media coverage in Germany. It investigates in particular the way in which the weekly journal Die Zeit and the daily newspaper Frankfurter Rundschau reported this media event and its aftermath between June 2000 and June 2001. Both newspapers are quality papers that played an essential role in framing the human genome debate--alongside the Frankfurter Allgemeine Zeitung--which became the most prominent genomic forum. The decoding of the human genome prompted a huge controversy concerning the ethics of human engineering, research on stem cells and Preimplantation Genetic Diagnosis. The main aim of this article is to show how this controversy was structured by metaphor. The media coverage of the genome generated DNA-factishes--a neologism designating the ambivalence of something as fact (fait) and as a fetish (fetiche)--that mostly propagated images of a new DNA-scienticism or biological determinism. Mediated by cultural experiences, the human genome became a highly artificial and social construct of a 'NatureCulture'.

The Human Genome Project: big science transforms biology and medicine.

PubMed

Hood, Leroy; Rowen, Lee

2013-01-01

The Human Genome Project has transformed biology through its integrated big science approach to deciphering a reference human genome sequence along with the complete sequences of key model organisms. The project exemplifies the power, necessity and success of large, integrated, cross-disciplinary efforts - so-called 'big science' - directed towards complex major objectives. In this article, we discuss the ways in which this ambitious endeavor led to the development of novel technologies and analytical tools, and how it brought the expertise of engineers, computer scientists and mathematicians together with biologists. It established an open approach to data sharing and open-source software, thereby making the data resulting from the project accessible to all. The genome sequences of microbes, plants and animals have revolutionized many fields of science, including microbiology, virology, infectious disease and plant biology. Moreover, deeper knowledge of human sequence variation has begun to alter the practice of medicine. The Human Genome Project has inspired subsequent large-scale data acquisition initiatives such as the International HapMap Project, 1000 Genomes, and The Cancer Genome Atlas, as well as the recently announced Human Brain Project and the emerging Human Proteome Project.

The Human Genome Project: big science transforms biology and medicine

PubMed Central

2013-01-01

The Human Genome Project has transformed biology through its integrated big science approach to deciphering a reference human genome sequence along with the complete sequences of key model organisms. The project exemplifies the power, necessity and success of large, integrated, cross-disciplinary efforts - so-called ‘big science’ - directed towards complex major objectives. In this article, we discuss the ways in which this ambitious endeavor led to the development of novel technologies and analytical tools, and how it brought the expertise of engineers, computer scientists and mathematicians together with biologists. It established an open approach to data sharing and open-source software, thereby making the data resulting from the project accessible to all. The genome sequences of microbes, plants and animals have revolutionized many fields of science, including microbiology, virology, infectious disease and plant biology. Moreover, deeper knowledge of human sequence variation has begun to alter the practice of medicine. The Human Genome Project has inspired subsequent large-scale data acquisition initiatives such as the International HapMap Project, 1000 Genomes, and The Cancer Genome Atlas, as well as the recently announced Human Brain Project and the emerging Human Proteome Project. PMID:24040834

A decade of human genome project conclusion: Scientific diffusion about our genome knowledge.

PubMed

Moraes, Fernanda; Góes, Andréa

2016-05-06

The Human Genome Project (HGP) was initiated in 1990 and completed in 2003. It aimed to sequence the whole human genome. Although it represented an advance in understanding the human genome and its complexity, many questions remained unanswered. Other projects were launched in order to unravel the mysteries of our genome, including the ENCyclopedia of DNA Elements (ENCODE). This review aims to analyze the evolution of scientific knowledge related to both the HGP and ENCODE projects. Data were retrieved from scientific articles published in 1990-2014, a period comprising the development and the 10 years following the HGP completion. The fact that only 20,000 genes are protein and RNA-coding is one of the most striking HGP results. A new concept about the organization of genome arose. The ENCODE project was initiated in 2003 and targeted to map the functional elements of the human genome. This project revealed that the human genome is pervasively transcribed. Therefore, it was determined that a large part of the non-protein coding regions are functional. Finally, a more sophisticated view of chromatin structure emerged. The mechanistic functioning of the genome has been redrafted, revealing a much more complex picture. Besides, a gene-centric conception of the organism has to be reviewed. A number of criticisms have emerged against the ENCODE project approaches, raising the question of whether non-conserved but biochemically active regions are truly functional. Thus, HGP and ENCODE projects accomplished a great map of the human genome, but the data generated still requires further in depth analysis. © 2016 by The International Union of Biochemistry and Molecular Biology, 44:215-223, 2016. © 2016 The International Union of Biochemistry and Molecular Biology.

Discovery of common sequences absent in the human reference genome using pooled samples from next generation sequencing.

PubMed

Liu, Yu; Koyutürk, Mehmet; Maxwell, Sean; Xiang, Min; Veigl, Martina; Cooper, Richard S; Tayo, Bamidele O; Li, Li; LaFramboise, Thomas; Wang, Zhenghe; Zhu, Xiaofeng; Chance, Mark R

2014-08-16

Sequences up to several megabases in length have been found to be present in individual genomes but absent in the human reference genome. These sequences may be common in populations, and their absence in the reference genome may indicate rare variants in the genomes of individuals who served as donors for the human genome project. As the reference genome is used in probe design for microarray technology and mapping short reads in next generation sequencing (NGS), this missing sequence could be a source of bias in functional genomic studies and variant analysis. One End Anchor (OEA) and/or orphan reads from paired-end sequencing have been used to identify novel sequences that are absent in reference genome. However, there is no study to investigate the distribution, evolution and functionality of those sequences in human populations. To systematically identify and study the missing common sequences (micSeqs), we extended the previous method by pooling OEA reads from large number of individuals and applying strict filtering methods to remove false sequences. The pipeline was applied to data from phase 1 of the 1000 Genomes Project. We identified 309 micSeqs that are present in at least 1% of the human population, but absent in the reference genome. We confirmed 76% of these 309 micSeqs by comparison to other primate genomes, individual human genomes, and gene expression data. Furthermore, we randomly selected fifteen micSeqs and confirmed their presence using PCR validation in 38 additional individuals. Functional analysis using published RNA-seq and ChIP-seq data showed that eleven micSeqs are highly expressed in human brain and three micSeqs contain transcription factor (TF) binding regions, suggesting they are functional elements. In addition, the identified micSeqs are absent in non-primates and show dynamic acquisition during primate evolution culminating with most micSeqs being present in Africans, suggesting some micSeqs may be important sources of human diversity. 76% of micSeqs were confirmed by a comparative genomics approach. Fourteen micSeqs are expressed in human brain or contain TF binding regions. Some micSeqs are primate-specific, conserved and may play a role in the evolution of primates.

Implementation of genomics research in Africa: challenges and recommendations

PubMed Central

Adebamowo, Sally N.; Francis, Veronica; Tambo, Ernest; Diallo, Seybou H.; Landouré, Guida; Nembaware, Victoria; Dareng, Eileen; Muhamed, Babu; Odutola, Michael; Akeredolu, Teniola; Nerima, Barbara; Ozumba, Petronilla J.; Mbhele, Slee; Ghanash, Anita; Wachinou, Ablo P.; Ngomi, Nicholas

2018-01-01

ABSTRACT Background: There is exponential growth in the interest and implementation of genomics research in Africa. This growth has been facilitated by the Human Hereditary and Health in Africa (H3Africa) initiative, which aims to promote a contemporary research approach to the study of genomics and environmental determinants of common diseases in African populations. Objective: The purpose of this article is to describe important challenges affecting genomics research implementation in Africa. Methods: The observations, challenges and recommendations presented in this article were obtained through discussions by African scientists at teleconferences and face-to-face meetings, seminars at consortium conferences and in-depth individual discussions. Results: Challenges affecting genomics research implementation in Africa, which are related to limited resources include ill-equipped facilities, poor accessibility to research centers, lack of expertise and an enabling environment for research activities in local hospitals. Challenges related to the research study include delayed funding, extensive procedures and interventions requiring multiple visits, delays setting up research teams and insufficient staff training, language barriers and an underappreciation of cultural norms. While many African countries are struggling to initiate genomics projects, others have set up genomics research facilities that meet international standards. Conclusions: The lessons learned in implementing successful genomics projects in Africa are recommended as strategies to overcome these challenges. These recommendations may guide the development and application of new research programs in low-resource settings. PMID:29336236

Implementation of genomics research in Africa: challenges and recommendations.

PubMed

Adebamowo, Sally N; Francis, Veronica; Tambo, Ernest; Diallo, Seybou H; Landouré, Guida; Nembaware, Victoria; Dareng, Eileen; Muhamed, Babu; Odutola, Michael; Akeredolu, Teniola; Nerima, Barbara; Ozumba, Petronilla J; Mbhele, Slee; Ghanash, Anita; Wachinou, Ablo P; Ngomi, Nicholas

2018-01-01

There is exponential growth in the interest and implementation of genomics research in Africa. This growth has been facilitated by the Human Hereditary and Health in Africa (H3Africa) initiative, which aims to promote a contemporary research approach to the study of genomics and environmental determinants of common diseases in African populations. The purpose of this article is to describe important challenges affecting genomics research implementation in Africa. The observations, challenges and recommendations presented in this article were obtained through discussions by African scientists at teleconferences and face-to-face meetings, seminars at consortium conferences and in-depth individual discussions. Challenges affecting genomics research implementation in Africa, which are related to limited resources include ill-equipped facilities, poor accessibility to research centers, lack of expertise and an enabling environment for research activities in local hospitals. Challenges related to the research study include delayed funding, extensive procedures and interventions requiring multiple visits, delays setting up research teams and insufficient staff training, language barriers and an underappreciation of cultural norms. While many African countries are struggling to initiate genomics projects, others have set up genomics research facilities that meet international standards. The lessons learned in implementing successful genomics projects in Africa are recommended as strategies to overcome these challenges. These recommendations may guide the development and application of new research programs in low-resource settings.

Genomic Approach to Understand the Association of DNA Repair with Longevity and Healthy Aging Using Genomic Databases of Oldest-Old Population

PubMed Central

Kim, Hyun Soo

2018-01-01

Aged population is increasing worldwide due to the aging process that is inevitable. Accordingly, longevity and healthy aging have been spotlighted to promote social contribution of aged population. Many studies in the past few decades have reported the process of aging and longevity, emphasizing the importance of maintaining genomic stability in exceptionally long-lived population. Underlying reason of longevity remains unclear due to its complexity involving multiple factors. With advances in sequencing technology and human genome-associated approaches, studies based on population-based genomic studies are increasing. In this review, we summarize recent longevity and healthy aging studies of human population focusing on DNA repair as a major factor in maintaining genome integrity. To keep pace with recent growth in genomic research, aging- and longevity-associated genomic databases are also briefly introduced. To suggest novel approaches to investigate longevity-associated genetic variants related to DNA repair using genomic databases, gene set analysis was conducted, focusing on DNA repair- and longevity-associated genes. Their biological networks were additionally analyzed to grasp major factors containing genetic variants of human longevity and healthy aging in DNA repair mechanisms. In summary, this review emphasizes DNA repair activity in human longevity and suggests approach to conduct DNA repair-associated genomic study on human healthy aging.

A statistical framework to predict functional non-coding regions in the human genome through integrated analysis of annotation data.

PubMed

Lu, Qiongshi; Hu, Yiming; Sun, Jiehuan; Cheng, Yuwei; Cheung, Kei-Hoi; Zhao, Hongyu

2015-05-27

Identifying functional regions in the human genome is a major goal in human genetics. Great efforts have been made to functionally annotate the human genome either through computational predictions, such as genomic conservation, or high-throughput experiments, such as the ENCODE project. These efforts have resulted in a rich collection of functional annotation data of diverse types that need to be jointly analyzed for integrated interpretation and annotation. Here we present GenoCanyon, a whole-genome annotation method that performs unsupervised statistical learning using 22 computational and experimental annotations thereby inferring the functional potential of each position in the human genome. With GenoCanyon, we are able to predict many of the known functional regions. The ability of predicting functional regions as well as its generalizable statistical framework makes GenoCanyon a unique and powerful tool for whole-genome annotation. The GenoCanyon web server is available at http://genocanyon.med.yale.edu.

Chromosomal Inversions between Human and Chimpanzee Lineages Caused by Retrotransposons

PubMed Central

Lee, Jungnam; Han, Kyudong; Meyer, Thomas J.; Kim, Heui-Soo; Batzer, Mark A.

2008-01-01

The long interspersed element-1 (LINE-1 or L1) and Alu elements are the most abundant mobile elements comprising 21% and 11% of the human genome, respectively. Since the divergence of human and chimpanzee lineages, these elements have vigorously created chromosomal rearrangements causing genomic difference between humans and chimpanzees by either increasing or decreasing the size of genome. Here, we report an exotic mechanism, retrotransposon recombination-mediated inversion (RRMI), that usually does not alter the amount of genomic material present. Through the comparison of the human and chimpanzee draft genome sequences, we identified 252 inversions whose respective inversion junctions can clearly be characterized. Our results suggest that L1 and Alu elements cause chromosomal inversions by either forming a secondary structure or providing a fragile site for double-strand breaks. The detailed analysis of the inversion breakpoints showed that L1 and Alu elements are responsible for at least 44% of the 252 inversion loci between human and chimpanzee lineages, including 49 RRMI loci. Among them, three RRMI loci inverted exonic regions in known genes, which implicates this mechanism in generating the genomic and phenotypic differences between human and chimpanzee lineages. This study is the first comprehensive analysis of mobile element bases inversion breakpoints between human and chimpanzee lineages, and highlights their role in primate genome evolution. PMID:19112500

The ‘Morbid Anatomy’ of the Human Genome: Tracing the Observational and Representational Approaches of Postwar Genetics and Biomedicine The William Bynum Prize Essay

PubMed Central

Hogan, Andrew J.

2014-01-01

This paper explores evolving conceptions and depictions of the human genome among human and medical geneticists during the postwar period. Historians of science and medicine have shown significant interest in the use of informational approaches in postwar genetics, which treat the genome as an expansive digital data set composed of three billion DNA nucleotides. Since the 1950s, however, geneticists have largely interacted with the human genome at the microscopically visible level of chromosomes. Mindful of this, I examine the observational and representational approaches of postwar human and medical genetics. During the 1970s and 1980s, the genome increasingly came to be understood as, at once, a discrete part of the human anatomy and a standardised scientific object. This paper explores the role of influential medical geneticists in recasting the human genome as being a visible, tangible, and legible entity, which was highly relevant to traditional medical thinking and practice. I demonstrate how the human genome was established as an object amenable to laboratory and clinical research, and argue that the observational and representational approaches of postwar medical genetics reflect, more broadly, the interdisciplinary efforts underlying the development of contemporary biomedicine. PMID:25045177

The Genetics Revolution: Programs and Issues for the Community College. A Monograph Highlighting the Winners of the Exxon Education Foundation Innovation Awards.

ERIC Educational Resources Information Center

Mays, Marilyn Elaine, Ed.

Presented at a 1996 conference on the implications of the Human Genome Project for community and technical colleges, the 30 papers included in this monograph describe methods for incorporating genetics studies into the two-year college curriculum. Among the papers provided are: (1) "Facing the Unknown: The Ethical Challenges of…

The MICROBE Project, A Report from the Interagency Working Group on Microbial Genomics

DTIC Science & Technology

2001-01-01

including targeting of genes related to pathogenesis, possibilities for acquired pathogen resistance, industrial and food -grade enzymes, and probiotics ...safety, food security, biotechnology, value-added products , human nutrition and functional foods , plant and animal protection and furthering fundamental...supports a number of microbial studies, which are integral components of the USDA national programs in animal health, food animal production , food

Human genome-microbiome interaction: metagenomics frontiers for the aetiopathology of autoimmune diseases.

PubMed

Gundogdu, Aycan; Nalbantoglu, Ufuk

2017-04-01

A short while ago, the human genome and microbiome were analysed simultaneously for the first time as a multi-omic approach. The analyses of heterogeneous population cohorts showed that microbiome components were associated with human genome variations. In-depth analysis of these results reveals that the majority of those relationships are between immune pathways and autoimmune disease-associated microbiome components. Thus, it can be hypothesized that autoimmunity may be associated with homeostatic disequilibrium of the human-microbiome interactome. Further analysis of human genome-human microbiome relationships in disease contexts with tailored systems biology approaches may yield insights into disease pathogenesis and prognosis.

77 FR 58913 - Genomic Medicine Program Advisory Committee, Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-24

... DEPARTMENT OF VETERANS AFFAIRS Genomic Medicine Program Advisory Committee, Notice of Meeting The Department of Veterans Affairs (VA) gives notice under Public Law 92-463 (Federal Advisory Committee Act) that the Genomic Medicine Program Advisory Committee will meet on October 16, 2012, at the American...

76 FR 24573 - Genomic Medicine Program Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-02

... DEPARTMENT OF VETERANS AFFAIRS Genomic Medicine Program Advisory Committee; Notice of Meeting The Department of Veterans Affairs (VA) gives notice under Public Law 92-463 (Federal Advisory Committee Act) that the Genomic Medicine Program Advisory Committee will meet on May 20, 2011, at the St. Regis Hotel...

78 FR 58612 - Genomic Medicine Program Advisory Committee, Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-24

... DEPARTMENT OF VETERANS AFFAIRS Genomic Medicine Program Advisory Committee, Notice of Meeting The Department of Veterans Affairs (VA) gives notice under the Federal Advisory Committee Act, 5 U.S.C. App. 2, that the Genomic Medicine Program Advisory Committee will meet on October 16, 2013, at the Sheraton...

75 FR 61861 - Genomic Medicine Program Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-06

... DEPARTMENT OF VETERANS AFFAIRS Genomic Medicine Program Advisory Committee; Notice of Meeting The Department of Veterans Affairs (VA) gives notice under Public Law 92-463 (Federal Advisory Committee Act) that the Genomic Medicine Program Advisory Committee will meet on October 22, 2010, at the Embassy...

77 FR 16898 - Genomic Medicine Program Advisory Committee, Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-22

... DEPARTMENT OF VETERANS AFFAIRS Genomic Medicine Program Advisory Committee, Notice of Meeting The Department of Veterans Affairs (VA) gives notice under Public Law 92-463 (Federal Advisory Committee Act) that the Genomic Medicine Program Advisory Committee will meet on April 17, 2012, at the Sheraton...

77 FR 27471 - National Human Genome Research Institute Amended Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-10

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Human Genome Research Institute Amended Notice of Meeting Notice is hereby given of a change in the meeting of the National Advisory Council for Human Genome Research, May 21, 2012, 8:30 a.m. to May 22, 2012, 5:00 p.m...

Whole Genome Amplification and Reduced-Representation Genome Sequencing of Schistosoma japonicum Miracidia.

PubMed

Shortt, Jonathan A; Card, Daren C; Schield, Drew R; Liu, Yang; Zhong, Bo; Castoe, Todd A; Carlton, Elizabeth J; Pollock, David D

2017-01-01

In areas where schistosomiasis control programs have been implemented, morbidity and prevalence have been greatly reduced. However, to sustain these reductions and move towards interruption of transmission, new tools for disease surveillance are needed. Genomic methods have the potential to help trace the sources of new infections, and allow us to monitor drug resistance. Large-scale genotyping efforts for schistosome species have been hindered by cost, limited numbers of established target loci, and the small amount of DNA obtained from miracidia, the life stage most readily acquired from humans. Here, we present a method using next generation sequencing to provide high-resolution genomic data from S. japonicum for population-based studies. We applied whole genome amplification followed by double digest restriction site associated DNA sequencing (ddRADseq) to individual S. japonicum miracidia preserved on Whatman FTA cards. We found that we could effectively and consistently survey hundreds of thousands of variants from 10,000 to 30,000 loci from archived miracidia as old as six years. An analysis of variation from eight miracidia obtained from three hosts in two villages in Sichuan showed clear population structuring by village and host even within this limited sample. This high-resolution sequencing approach yields three orders of magnitude more information than microsatellite genotyping methods that have been employed over the last decade, creating the potential to answer detailed questions about the sources of human infections and to monitor drug resistance. Costs per sample range from $50-$200, depending on the amount of sequence information desired, and we expect these costs can be reduced further given continued reductions in sequencing costs, improvement of protocols, and parallelization. This approach provides new promise for using modern genome-scale sampling to S. japonicum surveillance, and could be applied to other schistosome species and other parasitic helminthes.

ELF-MF exposure affects the robustness of epigenetic programming during granulopoiesis

NASA Astrophysics Data System (ADS)

Manser, Melissa; Sater, Mohamad R. Abdul; Schmid, Christoph D.; Noreen, Faiza; Murbach, Manuel; Kuster, Niels; Schuermann, David; Schär, Primo

2017-03-01

Extremely-low-frequency magnetic fields (ELF-MF) have been classified as “possibly carcinogenic” to humans on the grounds of an epidemiological association of ELF-MF exposure with an increased risk of childhood leukaemia. Yet, underlying mechanisms have remained obscure. Genome instability seems an unlikely reason as the energy transmitted by ELF-MF is too low to damage DNA and induce cancer-promoting mutations. ELF-MF, however, may perturb the epigenetic code of genomes, which is well-known to be sensitive to environmental conditions and generally deranged in cancers, including leukaemia. We examined the potential of ELF-MF to influence key epigenetic modifications in leukaemic Jurkat cells and in human CD34+ haematopoietic stem cells undergoing in vitro differentiation into the neutrophilic lineage. During granulopoiesis, sensitive genome-wide profiling of multiple replicate experiments did not reveal any statistically significant, ELF-MF-dependent alterations in the patterns of active (H3K4me2) and repressive (H3K27me3) histone marks nor in DNA methylation. However, ELF-MF exposure showed consistent effects on the reproducibility of these histone and DNA modification profiles (replicate variability), which appear to be of a stochastic nature but show preferences for the genomic context. The data indicate that ELF-MF exposure stabilizes active chromatin, particularly during the transition from a repressive to an active state during cell differentiation.

Mobile Interspersed Repeats Are Major Structural Variants in the Human Genome

PubMed Central

Huang, Cheng Ran Lisa; Schneider, Anna M.; Lu, Yunqi; Niranjan, Tejasvi; Shen, Peilin; Robinson, Matoya A.; Steranka, Jared P.; Valle, David; Civin, Curt I.; Wang, Tao; Wheelan, Sarah J.; Ji, Hongkai; Boeke, Jef D.; Burns, Kathleen H.

2010-01-01

Summary Characterizing structural variants in the human genome is of great importance, but a genome wide analysis to detect interspersed repeats has not been done. Thus, the degree to which mobile DNAs contribute to genetic diversity, heritable disease, and oncogenesis remains speculative. We perform transposon insertion profiling by microarray (TIP-chip) to map human L1(Ta) retrotransposons (LINE-1 s) genome-wide. This identified numerous novel human L1(Ta) insertional polymorphisms with highly variant allelic frequencies. We also explored TIP-chip's usefulness to identify candidate alleles associated with different phenotypes in clinical cohorts. Our data suggest that the occurrence of new insertions is twice as high as previously estimated, and that these repeats are under-recognized as sources of human genomic and phenotypic diversity. We have just begun to probe the universe of human L1(Ta) polymorphisms, and as TIP-chip is applied to other insertions such as Alu SINEs, it will expand the catalog of genomic variants even further. PMID:20602999

Mapping and Sequencing the Human Genome

DOE R&D Accomplishments Database

1988-01-01

Numerous meetings have been held and a debate has developed in the biological community over the merits of mapping and sequencing the human genome. In response a committee to examine the desirability and feasibility of mapping and sequencing the human genome was formed to suggest options for implementing the project. The committee asked many questions. Should the analysis of the human genome be left entirely to the traditionally uncoordinated, but highly successful, support systems that fund the vast majority of biomedical research. Or should a more focused and coordinated additional support system be developed that is limited to encouraging and facilitating the mapping and eventual sequencing of the human genome. If so, how can this be done without distorting the broader goals of biological research that are crucial for any understanding of the data generated in such a human genome project. As the committee became better informed on the many relevant issues, the opinions of its members coalesced, producing a shared consensus of what should be done. This report reflects that consensus.

The bonobo genome compared with the chimpanzee and human genomes

PubMed Central

Prüfer, Kay; Munch, Kasper; Hellmann, Ines; Akagi, Keiko; Miller, Jason R.; Walenz, Brian; Koren, Sergey; Sutton, Granger; Kodira, Chinnappa; Winer, Roger; Knight, James R.; Mullikin, James C.; Meader, Stephen J.; Ponting, Chris P.; Lunter, Gerton; Higashino, Saneyuki; Hobolth, Asger; Dutheil, Julien; Karakoç, Emre; Alkan, Can; Sajjadian, Saba; Catacchio, Claudia Rita; Ventura, Mario; Marques-Bonet, Tomas; Eichler, Evan E.; André, Claudine; Atencia, Rebeca; Mugisha, Lawrence; Junhold, Jörg; Patterson, Nick; Siebauer, Michael; Good, Jeffrey M.; Fischer, Anne; Ptak, Susan E.; Lachmann, Michael; Symer, David E.; Mailund, Thomas; Schierup, Mikkel H.; Andrés, Aida M.; Kelso, Janet; Pääbo, Svante

2012-01-01

Two African apes are the closest living relatives of humans: the chimpanzee (Pan troglodytes) and the bonobo (Pan paniscus). Although they are similar in many respects, bonobos and chimpanzees differ strikingly in key social and sexual behaviours1–4, and for some of these traits they show more similarity with humans than with each other. Here we report the sequencing and assembly of the bonobo genome to study its evolutionary relationship with the chimpanzee and human genomes. We find that more than three per cent of the human genome is more closely related to either the bonobo or the chimpanzee genome than these are to each other. These regions allow various aspects of the ancestry of the two ape species to be reconstructed. In addition, many of the regions that overlap genes may eventually help us understand the genetic basis of phenotypes that humans share with one of the two apes to the exclusion of the other. PMID:22722832

Nuclear calcium is required for human T cell activation

PubMed Central

Samstag, Yvonne

2016-01-01

Calcium signals in stimulated T cells are generally considered single entities that merely trigger immune responses, whereas costimulatory events specify the type of reaction. Here we show that the “T cell calcium signal” is a composite signal harboring two distinct components that antagonistically control genomic programs underlying the immune response. Using human T cells from healthy individuals, we establish nuclear calcium as a key signal in human T cell adaptogenomics that drives T cell activation and is required for signaling to cyclic adenosine monophosphate response element–binding protein and the induction of CD25, CD69, interleukin-2, and γ-interferon. In the absence of nuclear calcium signaling, cytosolic calcium activating nuclear factor of activated T cells translocation directed the genomic response toward enhanced expression of genes that negatively modulate T cell activation and are associated with a hyporesponsive state. Thus, nuclear calcium controls the T cell fate decision between a proliferative immune response and tolerance. Modulators of nuclear calcium–driven transcription may be used to develop a new type of pro-tolerance immunosuppressive therapy. PMID:27810914

The ATM signaling network in development and disease.

PubMed

Stracker, Travis H; Roig, Ignasi; Knobel, Philip A; Marjanović, Marko

2013-01-01

The DNA damage response (DDR) rapidly recognizes DNA lesions and initiates the appropriate cellular programs to maintain genome integrity. This includes the coordination of cell cycle checkpoints, transcription, translation, DNA repair, metabolism, and cell fate decisions, such as apoptosis or senescence (Jackson and Bartek, 2009). DNA double-strand breaks (DSBs) represent one of the most cytotoxic DNA lesions and defects in their metabolism underlie many human hereditary diseases characterized by genomic instability (Stracker and Petrini, 2011; McKinnon, 2012). Patients with hereditary defects in the DDR display defects in development, particularly affecting the central nervous system, the immune system and the germline, as well as aberrant metabolic regulation and cancer predisposition. Central to the DDR to DSBs is the ataxia-telangiectasia mutated (ATM) kinase, a master controller of signal transduction. Understanding how ATM signaling regulates various aspects of the DDR and its roles in vivo is critical for our understanding of human disease, its diagnosis and its treatment. This review will describe the general roles of ATM signaling and highlight some recent advances that have shed light on the diverse roles of ATM and related proteins in human disease.

The ATM signaling network in development and disease

PubMed Central

Stracker, Travis H.; Roig, Ignasi; Knobel, Philip A.; Marjanović, Marko

2013-01-01

The DNA damage response (DDR) rapidly recognizes DNA lesions and initiates the appropriate cellular programs to maintain genome integrity. This includes the coordination of cell cycle checkpoints, transcription, translation, DNA repair, metabolism, and cell fate decisions, such as apoptosis or senescence (Jackson and Bartek, 2009). DNA double-strand breaks (DSBs) represent one of the most cytotoxic DNA lesions and defects in their metabolism underlie many human hereditary diseases characterized by genomic instability (Stracker and Petrini, 2011; McKinnon, 2012). Patients with hereditary defects in the DDR display defects in development, particularly affecting the central nervous system, the immune system and the germline, as well as aberrant metabolic regulation and cancer predisposition. Central to the DDR to DSBs is the ataxia-telangiectasia mutated (ATM) kinase, a master controller of signal transduction. Understanding how ATM signaling regulates various aspects of the DDR and its roles in vivo is critical for our understanding of human disease, its diagnosis and its treatment. This review will describe the general roles of ATM signaling and highlight some recent advances that have shed light on the diverse roles of ATM and related proteins in human disease. PMID:23532176

PopHuman: the human population genomics browser

PubMed Central

Mulet, Roger; Villegas-Mirón, Pablo; Hervas, Sergi; Sanz, Esteve; Velasco, Daniel; Bertranpetit, Jaume; Laayouni, Hafid

2018-01-01

Abstract The 1000 Genomes Project (1000GP) represents the most comprehensive world-wide nucleotide variation data set so far in humans, providing the sequencing and analysis of 2504 genomes from 26 populations and reporting >84 million variants. The availability of this sequence data provides the human lineage with an invaluable resource for population genomics studies, allowing the testing of molecular population genetics hypotheses and eventually the understanding of the evolutionary dynamics of genetic variation in human populations. Here we present PopHuman, a new population genomics-oriented genome browser based on JBrowse that allows the interactive visualization and retrieval of an extensive inventory of population genetics metrics. Efficient and reliable parameter estimates have been computed using a novel pipeline that faces the unique features and limitations of the 1000GP data, and include a battery of nucleotide variation measures, divergence and linkage disequilibrium parameters, as well as different tests of neutrality, estimated in non-overlapping windows along the chromosomes and in annotated genes for all 26 populations of the 1000GP. PopHuman is open and freely available at http://pophuman.uab.cat. PMID:29059408

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics.

PubMed

Liu, Jianfang; Lichtenberg, Tara; Hoadley, Katherine A; Poisson, Laila M; Lazar, Alexander J; Cherniack, Andrew D; Kovatich, Albert J; Benz, Christopher C; Levine, Douglas A; Lee, Adrian V; Omberg, Larsson; Wolf, Denise M; Shriver, Craig D; Thorsson, Vesteinn; Hu, Hai

2018-04-05

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Copyright © 2018 Elsevier Inc. All rights reserved.

Processes Underlying Rabies Virus Incursions across US-Canada Border as Revealed by Whole-Genome Phylogeography.

PubMed

Trewby, Hannah; Nadin-Davis, Susan A; Real, Leslie A; Biek, Roman

2017-09-01

Disease control programs aim to constrain and reduce the spread of infection. Human disease interventions such as wildlife vaccination play a major role in determining the limits of a pathogen's spatial distribution. Over the past few decades, a raccoon-specific variant of rabies virus (RRV) has invaded large areas of eastern North America. Although expansion into Canada has been largely prevented through vaccination along the US border, several outbreaks have occurred in Canada. Applying phylogeographic approaches to 289 RRV whole-genome sequences derived from isolates collected in Canada and adjacent US states, we examined the processes underlying these outbreaks. RRV incursions were attributable predominantly to systematic virus leakage of local strains across areas along the border where vaccination has been conducted but also to single stochastic events such as long-distance translocations. These results demonstrate the utility of phylogeographic analysis of pathogen genomes for understanding transboundary outbreaks.

Meta genome-wide network from functional linkages of genes in human gut microbial ecosystems.

PubMed

Ji, Yan; Shi, Yixiang; Wang, Chuan; Dai, Jianliang; Li, Yixue

2013-03-01

The human gut microbial ecosystem (HGME) exerts an important influence on the human health. In recent researches, meta-genomics provided deep insights into the HGME in terms of gene contents, metabolic processes and genome constitutions of meta-genome. Here we present a novel methodology to investigate the HGME on the basis of a set of functionally coupled genes regardless of their genome origins when considering the co-evolution properties of genes. By analyzing these coupled genes, we showed some basic properties of HGME significantly associated with each other, and further constructed a protein interaction map of human gut meta-genome to discover some functional modules that may relate with essential metabolic processes. Compared with other studies, our method provides a new idea to extract basic function elements from meta-genome systems and investigate complex microbial environment by associating its biological traits with co-evolutionary fingerprints encoded in it.

The genome sequence of avian pathogenic Escherichia coli strain O1:K1:H7 shares strong similarities with human extraintestinal pathogenic E. coli genomes.

PubMed

Johnson, Timothy J; Kariyawasam, Subhashinie; Wannemuehler, Yvonne; Mangiamele, Paul; Johnson, Sara J; Doetkott, Curt; Skyberg, Jerod A; Lynne, Aaron M; Johnson, James R; Nolan, Lisa K

2007-04-01

Escherichia coli strains that cause disease outside the intestine are known as extraintestinal pathogenic E. coli (ExPEC) and include human uropathogenic E. coli (UPEC) and avian pathogenic E. coli (APEC). Regardless of host of origin, ExPEC strains share many traits. It has been suggested that these commonalities may enable APEC to cause disease in humans. Here, we begin to test the hypothesis that certain APEC strains possess potential to cause human urinary tract infection through virulence genotyping of 1,000 APEC and UPEC strains, generation of the first complete genomic sequence of an APEC (APEC O1:K1:H7) strain, and comparison of this genome to all available human ExPEC genomic sequences. The genomes of APEC O1 and three human UPEC strains were found to be remarkably similar, with only 4.5% of APEC O1's genome not found in other sequenced ExPEC genomes. Also, use of multilocus sequence typing showed that some of the sequenced human ExPEC strains were more like APEC O1 than other human ExPEC strains. This work provides evidence that at least some human and avian ExPEC strains are highly similar to one another, and it supports the possibility that a food-borne link between some APEC and UPEC strains exists. Future studies are necessary to assess the ability of APEC to overcome the hurdles necessary for such a food-borne transmission, and epidemiological studies are required to confirm that such a phenomenon actually occurs.

StereoGene: rapid estimation of genome-wide correlation of continuous or interval feature data.

PubMed

Stavrovskaya, Elena D; Niranjan, Tejasvi; Fertig, Elana J; Wheelan, Sarah J; Favorov, Alexander V; Mironov, Andrey A

2017-10-15

Genomics features with similar genome-wide distributions are generally hypothesized to be functionally related, for example, colocalization of histones and transcription start sites indicate chromatin regulation of transcription factor activity. Therefore, statistical algorithms to perform spatial, genome-wide correlation among genomic features are required. Here, we propose a method, StereoGene, that rapidly estimates genome-wide correlation among pairs of genomic features. These features may represent high-throughput data mapped to reference genome or sets of genomic annotations in that reference genome. StereoGene enables correlation of continuous data directly, avoiding the data binarization and subsequent data loss. Correlations are computed among neighboring genomic positions using kernel correlation. Representing the correlation as a function of the genome position, StereoGene outputs the local correlation track as part of the analysis. StereoGene also accounts for confounders such as input DNA by partial correlation. We apply our method to numerous comparisons of ChIP-Seq datasets from the Human Epigenome Atlas and FANTOM CAGE to demonstrate its wide applicability. We observe the changes in the correlation between epigenomic features across developmental trajectories of several tissue types consistent with known biology and find a novel spatial correlation of CAGE clusters with donor splice sites and with poly(A) sites. These analyses provide examples for the broad applicability of StereoGene for regulatory genomics. The StereoGene C ++ source code, program documentation, Galaxy integration scripts and examples are available from the project homepage http://stereogene.bioinf.fbb.msu.ru/. favorov@sensi.org. Supplementary data are available at Bioinformatics online. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Conservation of synteny between the genome of the pufferfish (Fugu rubripes) and the region on human chromosome 14 (14q24.3) associated with familial Alzheimer disease (AD3 locus)

PubMed

Trower, M K; Orton, S M; Purvis, I J; Sanseau, P; Riley, J; Christodoulou, C; Burt, D; See, C G; Elgar, G; Sherrington, R; Rogaev, E I; St George-Hyslop, P; Brenner, S; Dykes, C W

1996-02-20

The genome of the pufferfish (Fugu rubripes) (400 Mb) is approximately 7.5 times smaller than the human genome, but it has a similar gene repertoire to that of man. If regions of the two genomes exhibited conservation of gene order (i.e., were syntenic), it should be possible to reduce dramatically the effort required for identification of candidate genes in human disease loci by sequencing syntenic regions of the compact Fugu genome. We have demonstrated that three genes (dihydrolipoamide succinyltransferase, S31iii125, and S20i15), which are linked to FOS in the familial Alzheimer disease focus (AD3) on human chromosome 14, have homologues in the Fugu genome adjacent to Fugu cFOS. The relative gene order of cFOS, S31iii125, and S20i15 was the same in both genomes, but in Fugu these three genes lay within a 12.4-kb region, compared to >600 kb in the human AD3 locus. These results demonstrate the conservation of synteny between the genomes of Fugu and man and highlight the utility of this approach for sequence-based identification of genes in human disease loci.

The ethics of creating genetically modified children using genome editing.

PubMed

Ishii, Tetsuya

2017-12-01

To review the recent ethical, legal, and social issues surrounding human reproduction involving germline genome editing. Genome editing techniques, such as CRISPR/Cas9, have facilitated genetic modification in human embryos. The most likely purpose of germline genome editing is the prevention of serious genetic disease in offspring. However, complex issues still remain, including irremediable risks to fetuses and future generations, the role of women, the availability of alternatives, long-term follow-up, health insurance coverage, misuse for human enhancement, and the potential effects on adoption. Further discussions, a broad consensus, and appropriate regulations are required before human germline genome editing is introduced into the global society. Before germline genome editing is used for disease prevention, a broad consensus must be formed by carefully discussing its ethical, legal, and social issues.

Transposable Elements in Human Cancer: Causes and Consequences of Deregulation.

PubMed

Anwar, Sumadi Lukman; Wulaningsih, Wahyu; Lehmann, Ulrich

2017-05-04

Transposable elements (TEs) comprise nearly half of the human genome and play an essential role in the maintenance of genomic stability, chromosomal architecture, and transcriptional regulation. TEs are repetitive sequences consisting of RNA transposons, DNA transposons, and endogenous retroviruses that can invade the human genome with a substantial contribution in human evolution and genomic diversity. TEs are therefore firmly regulated from early embryonic development and during the entire course of human life by epigenetic mechanisms, in particular DNA methylation and histone modifications. The deregulation of TEs has been reported in some developmental diseases, as well as for different types of human cancers. To date, the role of TEs, the mechanisms underlying TE reactivation, and the interplay with DNA methylation in human cancers remain largely unexplained. We reviewed the loss of epigenetic regulation and subsequent genomic instability, chromosomal aberrations, transcriptional deregulation, oncogenic activation, and aberrations of non-coding RNAs as the potential mechanisms underlying TE deregulation in human cancers.

Transposable Elements in Human Cancer: Causes and Consequences of Deregulation

PubMed Central

Anwar, Sumadi Lukman; Wulaningsih, Wahyu; Lehmann, Ulrich

2017-01-01

Transposable elements (TEs) comprise nearly half of the human genome and play an essential role in the maintenance of genomic stability, chromosomal architecture, and transcriptional regulation. TEs are repetitive sequences consisting of RNA transposons, DNA transposons, and endogenous retroviruses that can invade the human genome with a substantial contribution in human evolution and genomic diversity. TEs are therefore firmly regulated from early embryonic development and during the entire course of human life by epigenetic mechanisms, in particular DNA methylation and histone modifications. The deregulation of TEs has been reported in some developmental diseases, as well as for different types of human cancers. To date, the role of TEs, the mechanisms underlying TE reactivation, and the interplay with DNA methylation in human cancers remain largely unexplained. We reviewed the loss of epigenetic regulation and subsequent genomic instability, chromosomal aberrations, transcriptional deregulation, oncogenic activation, and aberrations of non-coding RNAs as the potential mechanisms underlying TE deregulation in human cancers. PMID:28471386

Future potential of the Human Epigenome Project.

PubMed

Eckhardt, Florian; Beck, Stephan; Gut, Ivo G; Berlin, Kurt

2004-09-01

Deciphering the information encoded in the human genome is key for the further understanding of human biology, physiology and evolution. With the draft sequence of the human genome completed, elucidation of the epigenetic information layer of the human genome becomes accessible. Epigenetic mechanisms are mediated by either chemical modifications of the DNA itself or by modifications of proteins that are closely associated with DNA. Defects of the epigenetic regulation involved in processes such as imprinting, X chromosome inactivation, transcriptional control of genes, as well as mutations affecting DNA methylation enzymes, contribute fundamentally to the etiology of many human diseases. Headed by the Human Epigenome Consortium, the Human Epigenome Project is a joint effort by an international collaboration that aims to identify, catalog and interpret genome-wide DNA methylation patterns of all human genes in all major tissues. Methylation variable positions are thought to reflect gene activity, tissue type and disease state, and are useful epigenetic markers revealing the dynamic state of the genome. Like single nucleotide polymorphisms, methylation variable positions will greatly advance our ability to elucidate and diagnose the molecular basis of human diseases.

Human memory CD8 T cell effector potential is epigenetically preserved during in vivo homeostasis.

PubMed

Abdelsamed, Hossam A; Moustaki, Ardiana; Fan, Yiping; Dogra, Pranay; Ghoneim, Hazem E; Zebley, Caitlin C; Triplett, Brandon M; Sekaly, Rafick-Pierre; Youngblood, Ben

2017-06-05

Antigen-independent homeostasis of memory CD8 T cells is vital for sustaining long-lived T cell-mediated immunity. In this study, we report that maintenance of human memory CD8 T cell effector potential during in vitro and in vivo homeostatic proliferation is coupled to preservation of acquired DNA methylation programs. Whole-genome bisulfite sequencing of primary human naive, short-lived effector memory (T EM ), and longer-lived central memory (T CM ) and stem cell memory (T SCM ) CD8 T cells identified effector molecules with demethylated promoters and poised for expression. Effector-loci demethylation was heritably preserved during IL-7- and IL-15-mediated in vitro cell proliferation. Conversely, cytokine-driven proliferation of T CM and T SCM memory cells resulted in phenotypic conversion into T EM cells and was coupled to increased methylation of the CCR7 and Tcf7 loci. Furthermore, haploidentical donor memory CD8 T cells undergoing in vivo proliferation in lymphodepleted recipients also maintained their effector-associated demethylated status but acquired T EM -associated programs. These data demonstrate that effector-associated epigenetic programs are preserved during cytokine-driven subset interconversion of human memory CD8 T cells. © 2017 Abdelsamed et al.

Early-life adversity-induced long-term epigenetic programming associated with early onset of chronic physical aggression: Studies in humans and animals.

PubMed

Chistiakov, Dimitry A; Chekhonin, Vladimir P

2017-06-05

To examine whether chronic physical aggression (CPA) in adulthood can be epigenetically programmed early in life due to exposure to early-life adversity. Literature search of public databases such as PubMed/MEDLINE and Scopus. Children/adolescents susceptible for CPA and exposed to early-life abuse fail to efficiently cope with stress that in turn results in the development of CPA later in life. This phenomenon was observed in humans and animal models of aggression. The susceptibility to aggression is a complex trait that is regulated by the interaction between environmental and genetic factors. Epigenetic mechanisms mediate this interaction. Subjects exposed to stress early in life exhibited long-term epigenetic programming that can influence their behaviour in adulthood. This programming affects expression of many genes not only in the brain but also in other systems such as neuroendocrine and immune. The propensity to adult CPA behaviour in subjects experienced to early-life adversity is mediated by epigenetic programming that involves long-term systemic epigenetic alterations in a whole genome.

Navigating the evidentiary turn in public health: Sensemaking strategies to integrate genomics into state-level chronic disease prevention programs.

PubMed

Senier, Laura; Smollin, Leandra; Lee, Rachael; Nicoll, Lauren; Shields, Michael; Tan, Catherine

2018-06-23

In the past decade, healthcare delivery has faced two major disruptions: the mapping of the human genome and the rise of evidence-based practice. Sociologists have documented the paradigmatic shift towards evidence-based practice in medicine, but have yet to examine its effect on other health professions or the broader healthcare arena. This article shows how evidence-based practice is transforming public health in the United States. We present an in-depth qualitative analysis of interview, ethnographic, and archival data to show how Michigan's state public health agency has navigated the turn to evidence-based practice, as they have integrated scientific advances in genomics into their chronic disease prevention programming. Drawing on organizational theory, we demonstrate how they managed ambiguity through a combination of sensegiving and sensemaking activities. Specifically, they linked novel developments in genomics to a long-accepted public health planning model, the Core Public Health Functions. This made cutting edge advances in genomics more familiar to their peers in the state health agency. They also marshaled state-specific surveillance data to illustrate the public health burden of hereditary cancers in Michigan, and to make expert panel recommendations for genetic screening more locally relevant. Finally, they mobilized expertise to help their internal colleagues and external partners modernize conventional public health activities in chronic disease prevention. Our findings show that tools and concepts from organizational sociology can help medical sociologists understand how evidence-based practice is shaping institutions and interprofessional relations in the healthcare arena. Copyright © 2018 Elsevier Ltd. All rights reserved.

ILP-based maximum likelihood genome scaffolding

PubMed Central

2014-01-01

Background Interest in de novo genome assembly has been renewed in the past decade due to rapid advances in high-throughput sequencing (HTS) technologies which generate relatively short reads resulting in highly fragmented assemblies consisting of contigs. Additional long-range linkage information is typically used to orient, order, and link contigs into larger structures referred to as scaffolds. Due to library preparation artifacts and erroneous mapping of reads originating from repeats, scaffolding remains a challenging problem. In this paper, we provide a scalable scaffolding algorithm (SILP2) employing a maximum likelihood model capturing read mapping uncertainty and/or non-uniformity of contig coverage which is solved using integer linear programming. A Non-Serial Dynamic Programming (NSDP) paradigm is applied to render our algorithm useful in the processing of larger mammalian genomes. To compare scaffolding tools, we employ novel quantitative metrics in addition to the extant metrics in the field. We have also expanded the set of experiments to include scaffolding of low-complexity metagenomic samples. Results SILP2 achieves better scalability throughg a more efficient NSDP algorithm than previous release of SILP. The results show that SILP2 compares favorably to previous methods OPERA and MIP in both scalability and accuracy for scaffolding single genomes of up to human size, and significantly outperforms them on scaffolding low-complexity metagenomic samples. Conclusions Equipped with NSDP, SILP2 is able to scaffold large mammalian genomes, resulting in the longest and most accurate scaffolds. The ILP formulation for the maximum likelihood model is shown to be flexible enough to handle metagenomic samples. PMID:25253180

Implementing genomics and pharmacogenomics in the clinic: The National Human Genome Research Institute’s genomic medicine portfolio

PubMed Central

Manolio, Teri A.

2016-01-01

Increasing knowledge about the influence of genetic variation on human health and growing availability of reliable, cost-effective genetic testing have spurred the implementation of genomic medicine in the clinic. As defined by the National Human Genome Research Institute (NHGRI), genomic medicine uses an individual’s genetic information in his or her clinical care, and has begun to be applied effectively in areas such as cancer genomics, pharmacogenomics, and rare and undiagnosed diseases. In 2011 NHGRI published its strategic vision for the future of genomic research, including an ambitious research agenda to facilitate and promote the implementation of genomic medicine. To realize this agenda, NHGRI is consulting and facilitating collaborations with the external research community through a series of “Genomic Medicine Meetings,” under the guidance and leadership of the National Advisory Council on Human Genome Research. These meetings have identified and begun to address significant obstacles to implementation, such as lack of evidence of efficacy, limited availability of genomics expertise and testing, lack of standards, and diffficulties in integrating genomic results into electronic medical records. The six research and dissemination initiatives comprising NHGRI’s genomic research portfolio are designed to speed the evaluation and incorporation, where appropriate, of genomic technologies and findings into routine clinical care. Actual adoption of successful approaches in clinical care will depend upon the willingness, interest, and energy of professional societies, practitioners, patients, and payers to promote their responsible use and share their experiences in doing so. PMID:27612677

Implementing genomics and pharmacogenomics in the clinic: The National Human Genome Research Institute's genomic medicine portfolio.

PubMed

Manolio, Teri A

2016-10-01

Increasing knowledge about the influence of genetic variation on human health and growing availability of reliable, cost-effective genetic testing have spurred the implementation of genomic medicine in the clinic. As defined by the National Human Genome Research Institute (NHGRI), genomic medicine uses an individual's genetic information in his or her clinical care, and has begun to be applied effectively in areas such as cancer genomics, pharmacogenomics, and rare and undiagnosed diseases. In 2011 NHGRI published its strategic vision for the future of genomic research, including an ambitious research agenda to facilitate and promote the implementation of genomic medicine. To realize this agenda, NHGRI is consulting and facilitating collaborations with the external research community through a series of "Genomic Medicine Meetings," under the guidance and leadership of the National Advisory Council on Human Genome Research. These meetings have identified and begun to address significant obstacles to implementation, such as lack of evidence of efficacy, limited availability of genomics expertise and testing, lack of standards, and difficulties in integrating genomic results into electronic medical records. The six research and dissemination initiatives comprising NHGRI's genomic research portfolio are designed to speed the evaluation and incorporation, where appropriate, of genomic technologies and findings into routine clinical care. Actual adoption of successful approaches in clinical care will depend upon the willingness, interest, and energy of professional societies, practitioners, patients, and payers to promote their responsible use and share their experiences in doing so. Published by Elsevier Ireland Ltd.

The whole genome sequences and experimentally phased haplotypes of over 100 personal genomes.

PubMed

Mao, Qing; Ciotlos, Serban; Zhang, Rebecca Yu; Ball, Madeleine P; Chin, Robert; Carnevali, Paolo; Barua, Nina; Nguyen, Staci; Agarwal, Misha R; Clegg, Tom; Connelly, Abram; Vandewege, Ward; Zaranek, Alexander Wait; Estep, Preston W; Church, George M; Drmanac, Radoje; Peters, Brock A

2016-10-11

Since the completion of the Human Genome Project in 2003, it is estimated that more than 200,000 individual whole human genomes have been sequenced. A stunning accomplishment in such a short period of time. However, most of these were sequenced without experimental haplotype data and are therefore missing an important aspect of genome biology. In addition, much of the genomic data is not available to the public and lacks phenotypic information. As part of the Personal Genome Project, blood samples from 184 participants were collected and processed using Complete Genomics' Long Fragment Read technology. Here, we present the experimental whole genome haplotyping and sequencing of these samples to an average read coverage depth of 100X. This is approximately three-fold higher than the read coverage applied to most whole human genome assemblies and ensures the highest quality results. Currently, 114 genomes from this dataset are freely available in the GigaDB repository and are associated with rich phenotypic data; the remaining 70 should be added in the near future as they are approved through the PGP data release process. For reproducibility analyses, 20 genomes were sequenced at least twice using independent LFR barcoded libraries. Seven genomes were also sequenced using Complete Genomics' standard non-barcoded library process. In addition, we report 2.6 million high-quality, rare variants not previously identified in the Single Nucleotide Polymorphisms database or the 1000 Genomes Project Phase 3 data. These genomes represent a unique source of haplotype and phenotype data for the scientific community and should help to expand our understanding of human genome evolution and function.

Comparative primate genomics: emerging patterns of genome content and dynamics.

PubMed

Rogers, Jeffrey; Gibbs, Richard A

2014-05-01

Advances in genome sequencing technologies have created new opportunities for comparative primate genomics. Genome assemblies have been published for various primate species, and analyses of several others are underway. Whole-genome assemblies for the great apes provide remarkable new information about the evolutionary origins of the human genome and the processes involved. Genomic data for macaques and other non-human primates offer valuable insights into genetic similarities and differences among species that are used as models for disease-related research. This Review summarizes current knowledge regarding primate genome content and dynamics, and proposes a series of goals for the near future.

78 FR 55752 - National Human Genome Research Institute; Notice of Closed Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-11

... applications. Place: National Human Genome Research Institute, 4th Floor Library, 5635 Fishers Lane, Rockville... Research Institute; Notice of Closed Meetings Pursuant to section 10(d) of the Federal Advisory Committee... clearly unwarranted invasion of personal privacy. Name of Committee: National Human Genome Research...

Characterization of canine osteosarcoma by array comparative genomic hybridization and RT-qPCR: signatures of genomic imbalance in canine osteosarcoma parallel the human counterpart.

PubMed

Angstadt, Andrea Y; Motsinger-Reif, Alison; Thomas, Rachael; Kisseberth, William C; Guillermo Couto, C; Duval, Dawn L; Nielsen, Dahlia M; Modiano, Jaime F; Breen, Matthew

2011-11-01

Osteosarcoma (OS) is the most commonly diagnosed malignant bone tumor in humans and dogs, characterized in both species by extremely complex karyotypes exhibiting high frequencies of genomic imbalance. Evaluation of genomic signatures in human OS using array comparative genomic hybridization (aCGH) has assisted in uncovering genetic mechanisms that result in disease phenotype. Previous low-resolution (10-20 Mb) aCGH analysis of canine OS identified a wide range of recurrent DNA copy number aberrations, indicating extensive genomic instability. In this study, we profiled 123 canine OS tumors by 1 Mb-resolution aCGH to generate a dataset for direct comparison with current data for human OS, concluding that several high frequency aberrations in canine and human OS are orthologous. To ensure complete coverage of gene annotation, we identified the human refseq genes that map to these orthologous aberrant dog regions and found several candidate genes warranting evaluation for OS involvement. Specifically, subsequenct FISH and qRT-PCR analysis of RUNX2, TUSC3, and PTEN indicated that expression levels correlated with genomic copy number status, showcasing RUNX2 as an OS associated gene and TUSC3 as a possible tumor suppressor candidate. Together these data demonstrate the ability of genomic comparative oncology to identify genetic abberations which may be important for OS progression. Large scale screening of genomic imbalance in canine OS further validates the use of the dog as a suitable model for human cancers, supporting the idea that dysregulation discovered in canine cancers will provide an avenue for complementary study in human counterparts. Copyright © 2011 Wiley-Liss, Inc.

New bioinformatic tool for quick identification of functionally relevant endogenous retroviral inserts in human genome.

PubMed

Garazha, Andrew; Ivanova, Alena; Suntsova, Maria; Malakhova, Galina; Roumiantsev, Sergey; Zhavoronkov, Alex; Buzdin, Anton

2015-01-01

Endogenous retroviruses (ERVs) and LTR retrotransposons (LRs) occupy ∼8% of human genome. Deep sequencing technologies provide clues to understanding of functional relevance of individual ERVs/LRs by enabling direct identification of transcription factor binding sites (TFBS) and other landmarks of functional genomic elements. Here, we performed the genome-wide identification of human ERVs/LRs containing TFBS according to the ENCODE project. We created the first interactive ERV/LRs database that groups the individual inserts according to their familial nomenclature, number of mapped TFBS and divergence from their consensus sequence. Information on any particular element can be easily extracted by the user. We also created a genome browser tool, which enables quick mapping of any ERV/LR insert according to genomic coordinates, known human genes and TFBS. These tools can be used to easily explore functionally relevant individual ERV/LRs, and for studying their impact on the regulation of human genes. Overall, we identified ∼110,000 ERV/LR genomic elements having TFBS. We propose a hypothesis of "domestication" of ERV/LR TFBS by the genome milieu including subsequent stages of initial epigenetic repression, partial functional release, and further mutation-driven reshaping of TFBS in tight coevolution with the enclosing genomic loci.

Genome Editing: A New Approach to Human Therapeutics.

PubMed

Porteus, Matthew

2016-01-01

The ability to manipulate the genome with precise spatial and nucleotide resolution (genome editing) has been a powerful research tool. In the past decade, the tools and expertise for using genome editing in human somatic cells and pluripotent cells have increased to such an extent that the approach is now being developed widely as a strategy to treat human disease. The fundamental process depends on creating a site-specific DNA double-strand break (DSB) in the genome and then allowing the cell's endogenous DSB repair machinery to fix the break such that precise nucleotide changes are made to the DNA sequence. With the development and discovery of several different nuclease platforms and increasing knowledge of the parameters affecting different genome editing outcomes, genome editing frequencies now reach therapeutic relevance for a wide variety of diseases. Moreover, there is a series of complementary approaches to assessing the safety and toxicity of any genome editing process, irrespective of the underlying nuclease used. Finally, the development of genome editing has raised the issue of whether it should be used to engineer the human germline. Although such an approach could clearly prevent the birth of people with devastating and destructive genetic diseases, questions remain about whether human society is morally responsible enough to use this tool.

FOXM1 upregulation is an early event in human squamous cell carcinoma and it is enhanced by nicotine during malignant transformation.

PubMed

Gemenetzidis, Emilios; Bose, Amrita; Riaz, Adeel M; Chaplin, Tracy; Young, Bryan D; Ali, Muhammad; Sugden, David; Thurlow, Johanna K; Cheong, Sok-Ching; Teo, Soo-Hwang; Wan, Hong; Waseem, Ahmad; Parkinson, Eric K; Fortune, Farida; Teh, Muy-Teck

2009-01-01

Cancer associated with smoking and drinking remains a serious health problem worldwide. The survival of patients is very poor due to the lack of effective early biomarkers. FOXM1 overexpression is linked to the majority of human cancers but its mechanism remains unclear in head and neck squamous cell carcinoma (HNSCC). FOXM1 mRNA and protein expressions were investigated in four independent cohorts (total 75 patients) consisting of normal, premalignant and HNSCC tissues and cells using quantitative PCR (qPCR), expression microarray, immunohistochemistry and immunocytochemistry. Effect of putative oral carcinogens on FOXM1 transcriptional activity was dose-dependently assayed and confirmed using a FOXM1-specific luciferase reporter system, qPCR, immunoblotting and short-hairpin RNA interference. Genome-wide single nucleotide polymorphism (SNP) array was used to 'trace' the genomic instability signature pattern in 8 clonal lines of FOXM1-induced malignant human oral keratinocytes. Furthermore, acute FOXM1 upregulation in primary oral keratinocytes directly induced genomic instability. We have shown for the first time that overexpression of FOXM1 precedes HNSCC malignancy. Screening putative carcinogens in human oral keratinocytes surprisingly showed that nicotine, which is not perceived to be a human carcinogen, directly induced FOXM1 mRNA, protein stabilisation and transcriptional activity at concentrations relevant to tobacco chewers. Importantly, nicotine also augmented FOXM1-induced transformation of human oral keratinocytes. A centrosomal protein CEP55 and a DNA helicase/putative stem cell marker HELLS, both located within a consensus loci (10q23), were found to be novel targets of FOXM1 and their expression correlated tightly with HNSCC progression. This study cautions the potential co-carcinogenic effect of nicotine in tobacco replacement therapies. We hypothesise that aberrant upregulation of FOXM1 may be inducing genomic instability through a program of malignant transformation involving the activation of CEP55 and HELLS which may facilitate aberrant mitosis and epigenetic modifications. Our finding that FOXM1 is upregulated early during oral cancer progression renders FOXM1 an attractive diagnostic biomarker for early cancer detection and its candidate mechanistic targets, CEP55 and HELLS, as indicators of malignant conversion and progression.

Strategies and tools for whole genome alignments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Couronne, Olivier; Poliakov, Alexander; Bray, Nicolas

2002-11-25

The availability of the assembled mouse genome makespossible, for the first time, an alignment and comparison of two largevertebrate genomes. We have investigated different strategies ofalignment for the subsequent analysis of conservation of genomes that areeffective for different quality assemblies. These strategies were appliedto the comparison of the working draft of the human genome with the MouseGenome Sequencing Consortium assembly, as well as other intermediatemouse assemblies. Our methods are fast and the resulting alignmentsexhibit a high degree of sensitivity, covering more than 90 percent ofknown coding exons in the human genome. We have obtained such coveragewhile preserving specificity. With amore » view towards the end user, we havedeveloped a suite of tools and websites for automatically aligning, andsubsequently browsing and working with whole genome comparisons. Wedescribe the use of these tools to identify conserved non-coding regionsbetween the human and mouse genomes, some of which have not beenidentified by other methods.« less

The first genome sequences of human bocaviruses from Vietnam

PubMed Central

Thanh, Tran Tan; Van, Hoang Minh Tu; Hong, Nguyen Thi Thu; Nhu, Le Nguyen Truc; Anh, Nguyen To; Tuan, Ha Manh; Hien, Ho Van; Tuong, Nguyen Manh; Kien, Trinh Trung; Khanh, Truong Huu; Nhan, Le Nguyen Thanh; Hung, Nguyen Thanh; Chau, Nguyen Van Vinh; Thwaites, Guy; van Doorn, H. Rogier; Tan, Le Van

2017-01-01

As part of an ongoing effort to generate complete genome sequences of hand, foot and mouth disease-causing enteroviruses directly from clinical specimens, two complete coding sequences and two partial genomic sequences of human bocavirus 1 (n=3) and 2 (n=1) were co-amplified and sequenced, representing the first genome sequences of human bocaviruses from Vietnam. The sequences may aid future study aiming at understanding the evolution of the virus. PMID:28090592

Ancestry of a human endogenous retrovirus family.

PubMed Central

Mariani-Costantini, R; Horn, T M; Callahan, R

1989-01-01

The human endogenous retrovirus type II (HERVII) family of HERV genomes has been found by Southern blot analysis to be characteristic of humans, apes, and Old World monkeys. New World monkeys and prosimians lack HERVII proviral genomes. Cellular DNAs of humans, common chimpanzees, gorillas, and orangutans, but not lesser ape lar gibbons, appear to contain the HERVII-related HLM-2 proviral genome integrated at the same site (HLM-2 maps to human chromosome 1). This suggests that the ancestral HERVII retrovirus(es) entered the genomes of Old World anthropoids by infection after the divergence of New World monkeys (platyrrhines) but before the evolutionary radiation of large hominoids. Images PMID:2507793

PSE-HMM: genome-wide CNV detection from NGS data using an HMM with Position-Specific Emission probabilities.

PubMed

Malekpour, Seyed Amir; Pezeshk, Hamid; Sadeghi, Mehdi

2016-11-03

Copy Number Variation (CNV) is envisaged to be a major source of large structural variations in the human genome. In recent years, many studies apply Next Generation Sequencing (NGS) data for the CNV detection. However, still there is a necessity to invent more accurate computational tools. In this study, mate pair NGS data are used for the CNV detection in a Hidden Markov Model (HMM). The proposed HMM has position specific emission probabilities, i.e. a Gaussian mixture distribution. Each component in the Gaussian mixture distribution captures a different type of aberration that is observed in the mate pairs, after being mapped to the reference genome. These aberrations may include any increase (decrease) in the insertion size or change in the direction of mate pairs that are mapped to the reference genome. This HMM with Position-Specific Emission probabilities (PSE-HMM) is utilized for the genome-wide detection of deletions and tandem duplications. The performance of PSE-HMM is evaluated on a simulated dataset and also on a real data of a Yoruban HapMap individual, NA18507. PSE-HMM is effective in taking observation dependencies into account and reaches a high accuracy in detecting genome-wide CNVs. MATLAB programs are available at http://bs.ipm.ir/softwares/PSE-HMM/ .

The Human Microbiome: Our Second Genome*

PubMed Central

Grice, Elizabeth A.; Segre, Julia A.

2012-01-01

The human genome has been referred to as the blueprint of human biology. In this review we consider an essential but largely ignored overlay to that blueprint, the human microbiome, which is composed of those microbes that live in and on our bodies. The human microbiome is a source of genetic diversity, a modifier of disease, an essential component of immunity, and a functional entity that influences metabolism and modulates drug interactions. Characterization and analysis of the human microbiome have been greatly catalyzed by advances in genomic technologies. We discuss how these technologies have shaped this emerging field of study and advanced our understanding of the human microbiome. We also identify future challenges, many of which are common to human genetic studies, and predict that in the future, analyzing genetic variation and risk of human disease will sometimes necessitate the integration of human and microbial genomic data sets. PMID:22703178

Recent advances in understanding the role of nutrition in human genome evolution.

PubMed

Ye, Kaixiong; Gu, Zhenglong

2011-11-01

Dietary transitions in human history have been suggested to play important roles in the evolution of mankind. Genetic variations caused by adaptation to diet during human evolution could have important health consequences in current society. The advance of sequencing technologies and the rapid accumulation of genome information provide an unprecedented opportunity to comprehensively characterize genetic variations in human populations and unravel the genetic basis of human evolution. Series of selection detection methods, based on various theoretical models and exploiting different aspects of selection signatures, have been developed. Their applications at the species and population levels have respectively led to the identification of human specific selection events that distinguish human from nonhuman primates and local adaptation events that contribute to human diversity. Scrutiny of candidate genes has revealed paradigms of adaptations to specific nutritional components and genome-wide selection scans have verified the prevalence of diet-related selection events and provided many more candidates awaiting further investigation. Understanding the role of diet in human evolution is fundamental for the development of evidence-based, genome-informed nutritional practices in the era of personal genomics.

Integrative analysis of 111 reference human epigenomes

PubMed Central

Kundaje, Anshul; Meuleman, Wouter; Ernst, Jason; Bilenky, Misha; Yen, Angela; Kheradpour, Pouya; Zhang, Zhizhuo; Heravi-Moussavi, Alireza; Liu, Yaping; Amin, Viren; Ziller, Michael J; Whitaker, John W; Schultz, Matthew D; Sandstrom, Richard S; Eaton, Matthew L; Wu, Yi-Chieh; Wang, Jianrong; Ward, Lucas D; Sarkar, Abhishek; Quon, Gerald; Pfenning, Andreas; Wang, Xinchen; Claussnitzer, Melina; Coarfa, Cristian; Harris, R Alan; Shoresh, Noam; Epstein, Charles B; Gjoneska, Elizabeta; Leung, Danny; Xie, Wei; Hawkins, R David; Lister, Ryan; Hong, Chibo; Gascard, Philippe; Mungall, Andrew J; Moore, Richard; Chuah, Eric; Tam, Angela; Canfield, Theresa K; Hansen, R Scott; Kaul, Rajinder; Sabo, Peter J; Bansal, Mukul S; Carles, Annaick; Dixon, Jesse R; Farh, Kai-How; Feizi, Soheil; Karlic, Rosa; Kim, Ah-Ram; Kulkarni, Ashwinikumar; Li, Daofeng; Lowdon, Rebecca; Mercer, Tim R; Neph, Shane J; Onuchic, Vitor; Polak, Paz; Rajagopal, Nisha; Ray, Pradipta; Sallari, Richard C; Siebenthall, Kyle T; Sinnott-Armstrong, Nicholas; Stevens, Michael; Thurman, Robert E; Wu, Jie; Zhang, Bo; Zhou, Xin; Beaudet, Arthur E; Boyer, Laurie A; De Jager, Philip; Farnham, Peggy J; Fisher, Susan J; Haussler, David; Jones, Steven; Li, Wei; Marra, Marco; McManus, Michael T; Sunyaev, Shamil; Thomson, James A; Tlsty, Thea D; Tsai, Li-Huei; Wang, Wei; Waterland, Robert A; Zhang, Michael; Chadwick, Lisa H; Bernstein, Bradley E; Costello, Joseph F; Ecker, Joseph R; Hirst, Martin; Meissner, Alexander; Milosavljevic, Aleksandar; Ren, Bing; Stamatoyannopoulos, John A; Wang, Ting; Kellis, Manolis

2015-01-01

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but a similar reference has lacked for epigenomic studies. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection to-date of human epigenomes for primary cells and tissues. Here, we describe the integrative analysis of 111 reference human epigenomes generated as part of the program, profiled for histone modification patterns, DNA accessibility, DNA methylation, and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically-relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation, and human disease. PMID:25693563

Population genetic inference from personal genome data: impact of ancestry and admixture on human genomic variation.

PubMed

Kidd, Jeffrey M; Gravel, Simon; Byrnes, Jake; Moreno-Estrada, Andres; Musharoff, Shaila; Bryc, Katarzyna; Degenhardt, Jeremiah D; Brisbin, Abra; Sheth, Vrunda; Chen, Rong; McLaughlin, Stephen F; Peckham, Heather E; Omberg, Larsson; Bormann Chung, Christina A; Stanley, Sarah; Pearlstein, Kevin; Levandowsky, Elizabeth; Acevedo-Acevedo, Suehelay; Auton, Adam; Keinan, Alon; Acuña-Alonzo, Victor; Barquera-Lozano, Rodrigo; Canizales-Quinteros, Samuel; Eng, Celeste; Burchard, Esteban G; Russell, Archie; Reynolds, Andy; Clark, Andrew G; Reese, Martin G; Lincoln, Stephen E; Butte, Atul J; De La Vega, Francisco M; Bustamante, Carlos D

2012-10-05

Full sequencing of individual human genomes has greatly expanded our understanding of human genetic variation and population history. Here, we present a systematic analysis of 50 human genomes from 11 diverse global populations sequenced at high coverage. Our sample includes 12 individuals who have admixed ancestry and who have varying degrees of recent (within the last 500 years) African, Native American, and European ancestry. We found over 21 million single-nucleotide variants that contribute to a 1.75-fold range in nucleotide heterozygosity across diverse human genomes. This heterozygosity ranged from a high of one heterozygous site per kilobase in west African genomes to a low of 0.57 heterozygous sites per kilobase in segments inferred to have diploid Native American ancestry from the genomes of Mexican and Puerto Rican individuals. We show evidence of all three continental ancestries in the genomes of Mexican, Puerto Rican, and African American populations, and the genome-wide statistics are highly consistent across individuals from a population once ancestry proportions have been accounted for. Using a generalized linear model, we identified subtle variations across populations in the proportion of neutral versus deleterious variation and found that genome-wide statistics vary in admixed populations even once ancestry proportions have been factored in. We further infer that multiple periods of gene flow shaped the diversity of admixed populations in the Americas-70% of the European ancestry in today's African Americans dates back to European gene flow happening only 7-8 generations ago. Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

A 1000 Arab genome project to study the Emirati population.

PubMed

Al-Ali, Mariam; Osman, Wael; Tay, Guan K; AlSafar, Habiba S

2018-04-01

Discoveries from the human genome, HapMap, and 1000 genome projects have collectively contributed toward the creation of a catalog of human genetic variations that has improved our understanding of human diversity. Despite the collegial nature of many of these genome study consortiums, which has led to the cataloging of genetic variations of different ethnic groups from around the world, genome data on the Arab population remains overwhelmingly underrepresented. The National Arab Genome project in the United Arab Emirates (UAE) aims to address this deficiency by using Next Generation Sequencing (NGS) technology to provide data to improve our understanding of the Arab genome and catalog variants that are unique to the Arab population of the UAE. The project was conceived to shed light on the similarities and differences between the Arab genome and those of the other ethnic groups.

The collaborative African genomics network training program: A trainee perspective on training the next generation of African scientists

USDA-ARS?s Scientific Manuscript database

The Collaborative African Genomics Network (CAfGEN) aims to establish sustainable genomics research programs in Botswana and Uganda through long-term training of PhD students from these countries at Baylor College of Medicine. Here, we present an overview of the CAfGEN PhD training program alongside...

76 FR 65563 - Genomic Medicine Program Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-21

... DEPARTMENT OF VETERANS AFFAIRS Genomic Medicine Program Advisory Committee; Notice of Meeting The Department of Veterans Affairs (VA) gives notice under Public Law 92-463 (Federal Advisory Committee Act) that the Genomic Medicine Program Advisory Committee will meet on November 2, 2011, at the Hamilton Crowne Plaza, 14th and K Streets, NW.,...

Cancer Genomic Resources and Present Needs in the Latin American Region.

PubMed

Torres, Ángela; Oliver, Javier; Frecha, Cecilia; Montealegre, Ana Lorena; Quezada-Urbán, Rosalía; Díaz-Velásquez, Clara Estela; Vaca-Paniagua, Felipe; Perdomo, Sandra

2017-01-01

In Latin America (LA), cancer is the second leading cause of death, and little is known about the capacities and needs for the development of research in the field of cancer genomics. In order to evaluate the current capacity for and development of cancer genomics in LA, we collected the available information on genomics, including the number of next-generation sequencing (NGS) platforms, the number of cancer research institutions and research groups, publications in the last 10 years, educational programs, and related national cancer control policies. Currently, there are 221 NGS platforms and 118 research groups in LA developing cancer genomics projects. A total of 272 articles in the field of cancer genetics/genomics were published by authors affiliated to Latin American institutions. Educational programs in genomics are scarce, almost exclusive of graduate programs, and only few are concerning cancer. Only 14 countries have national cancer control plans, but all of them consider secondary prevention strategies for early diagnosis, opportune treatment, and decreasing mortality, where genomic analyses could be implemented. Despite recent advances in introducing knowledge about cancer genomics and its application to LA, the region lacks development of integrated genomic research projects, improved use of NGS platforms, implementation of associated educational programs, and health policies that could have an impact on cancer care. © 2017 S. Karger AG, Basel.

The Evolution and Functional Impact of Human Deletion Variants Shared with Archaic Hominin Genomes

PubMed Central

Lin, Yen-Lung; Pavlidis, Pavlos; Karakoc, Emre; Ajay, Jerry; Gokcumen, Omer

2015-01-01

Allele sharing between modern and archaic hominin genomes has been variously interpreted to have originated from ancestral genetic structure or through non-African introgression from archaic hominins. However, evolution of polymorphic human deletions that are shared with archaic hominin genomes has yet to be studied. We identified 427 polymorphic human deletions that are shared with archaic hominin genomes, approximately 87% of which originated before the Human–Neandertal divergence (ancient) and only approximately 9% of which have been introgressed from Neandertals (introgressed). Recurrence, incomplete lineage sorting between human and chimp lineages, and hominid-specific insertions constitute the remaining approximately 4% of allele sharing between humans and archaic hominins. We observed that ancient deletions correspond to more than 13% of all common (>5% allele frequency) deletion variation among modern humans. Our analyses indicate that the genomic landscapes of both ancient and introgressed deletion variants were primarily shaped by purifying selection, eliminating large and exonic variants. We found 17 exonic deletions that are shared with archaic hominin genomes, including those leading to three fusion transcripts. The affected genes are involved in metabolism of external and internal compounds, growth and sperm formation, as well as susceptibility to psoriasis and Crohn’s disease. Our analyses suggest that these “exonic” deletion variants have evolved through different adaptive forces, including balancing and population-specific positive selection. Our findings reveal that genomic structural variants that are shared between humans and archaic hominin genomes are common among modern humans and can influence biomedically and evolutionarily important phenotypes. PMID:25556237

Sequence Analysis and Characterization of Active Human Alu Subfamilies Based on the 1000 Genomes Pilot Project.

PubMed

Konkel, Miriam K; Walker, Jerilyn A; Hotard, Ashley B; Ranck, Megan C; Fontenot, Catherine C; Storer, Jessica; Stewart, Chip; Marth, Gabor T; Batzer, Mark A

2015-08-29

The goal of the 1000 Genomes Consortium is to characterize human genome structural variation (SV), including forms of copy number variations such as deletions, duplications, and insertions. Mobile element insertions, particularly Alu elements, are major contributors to genomic SV among humans. During the pilot phase of the project we experimentally validated 645 (611 intergenic and 34 exon targeted) polymorphic "young" Alu insertion events, absent from the human reference genome. Here, we report high resolution sequencing of 343 (322 unique) recent Alu insertion events, along with their respective target site duplications, precise genomic breakpoint coordinates, subfamily assignment, percent divergence, and estimated A-rich tail lengths. All the sequenced Alu loci were derived from the AluY lineage with no evidence of retrotransposition activity involving older Alu families (e.g., AluJ and AluS). AluYa5 is currently the most active Alu subfamily in the human lineage, followed by AluYb8, and many others including three newly identified subfamilies we have termed AluYb7a3, AluYb8b1, and AluYa4a1. This report provides the structural details of 322 unique Alu variants from individual human genomes collectively adding about 100 kb of genomic variation. Many Alu subfamilies are currently active in human populations, including a surprising level of AluY retrotransposition. Human Alu subfamilies exhibit continuous evolution with potential drivers sprouting new Alu lineages. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Characterization and distribution of repetitive elements in association with genes in the human genome.

PubMed

Liang, Kai-Chiang; Tseng, Joseph T; Tsai, Shaw-Jenq; Sun, H Sunny

2015-08-01

Repetitive elements constitute more than 50% of the human genome. Recent studies implied that the complexity of living organisms is not just a direct outcome of a number of coding sequences; the repetitive elements, which do not encode proteins, may also play a significant role. Though scattered studies showed that repetitive elements in the regulatory regions of a gene control gene expression, no systematic survey has been done to report the characterization and distribution of various types of these repetitive elements in the human genome. Sequences from 5' and 3' untranslated regions and upstream and downstream of a gene were downloaded from the Ensembl database. The repetitive elements in the neighboring of each gene were identified and classified using cross-matching implemented in the RepeatMasker. The annotation and distribution of distinct classes of repetitive elements associated with individual gene were collected to characterize genes in association with different types of repetitive elements using systems biology program. We identified a total of 1,068,400 repetitive elements which belong to 37-class families and 1235 subclasses that are associated with 33,761 genes and 57,365 transcripts. In addition, we found that the tandem repeats preferentially locate proximal to the transcription start site (TSS) of genes and the major function of these genes are involved in developmental processes. On the other hand, interspersed repetitive elements showed a tendency to be accumulated at distal region from the TSS and the function of interspersed repeat-containing genes took part in the catabolic/metabolic processes. Results from the distribution analysis were collected and used to construct a gene-based repetitive element database (GBRED; http://www.binfo.ncku.edu.tw/GBRED/index.html). A user-friendly web interface was designed to provide the information of repetitive elements associated with any particular gene(s). This is the first study focusing on the gene-associated repetitive elements in the human genome. Our data showed distinct genes associated with different kinds of repetitive element and implied such combination may shape the function of these genes. Aside from the conventional view of these elements in genome evolution, results from this study offer a systemic review to facilitate exploitation of these elements in genome function. Copyright © 2015 Elsevier Ltd. All rights reserved.

The collaborative African genomics network training program: a trainee perspective on training the next generation of African scientists.

PubMed

Mlotshwa, Busisiwe C; Mwesigwa, Savannah; Mboowa, Gerald; Williams, Lesedi; Retshabile, Gaone; Kekitiinwa, Adeodata; Wayengera, Misaki; Kyobe, Samuel; Brown, Chester W; Hanchard, Neil A; Mardon, Graeme; Joloba, Moses; Anabwani, Gabriel; Mpoloka, Sununguko W

2017-07-01

The Collaborative African Genomics Network (CAfGEN) aims to establish sustainable genomics research programs in Botswana and Uganda through long-term training of PhD students from these countries at Baylor College of Medicine. Here, we present an overview of the CAfGEN PhD training program alongside trainees' perspectives on their involvement. Historically, collaborations between high-income countries (HICs) and low- and middle-income countries (LMICs), or North-South collaborations, have been criticized for the lack of a mutually beneficial distribution of resources and research findings, often undermining LMICs. CAfGEN plans to address this imbalance in the genomics field through a program of technology and expertise transfer to the participating LMICs. An overview of the training program is presented. Trainees from the CAfGEN project summarized their experiences, looking specifically at the training model, benefits of the program, challenges encountered relating to the cultural transition, and program outcomes after the first 2 years. Collaborative training programs like CAfGEN will not only help establish sustainable long-term research initiatives in LMICs but also foster stronger North-South and South-South networks. The CAfGEN model offers a framework for the development of training programs aimed at genomics education for those for whom genomics is not their "first language." Genet Med advance online publication 06 April 2017.

The collaborative African genomics network training program: a trainee perspective on training the next generation of African scientists

PubMed Central

Mlotshwa, Busisiwe C.; Mwesigwa, Savannah; Mboowa, Gerald; Williams, Lesedi; Retshabile, Gaone; Kekitiinwa, Adeodata; Wayengera, Misaki; Kyobe, Samuel; Brown, Chester W.; Hanchard, Neil A.; Mardon, Graeme; Joloba, Moses; Anabwani, Gabriel; Mpoloka, Sununguko W.

2017-01-01

Purpose: The Collaborative African Genomics Network (CAfGEN) aims to establish sustainable genomics research programs in Botswana and Uganda through long-term training of PhD students from these countries at Baylor College of Medicine. Here, we present an overview of the CAfGEN PhD training program alongside trainees’ perspectives on their involvement. Background: Historically, collaborations between high-income countries (HICs) and low- and middle-income countries (LMICs), or North–South collaborations, have been criticized for the lack of a mutually beneficial distribution of resources and research findings, often undermining LMICs. CAfGEN plans to address this imbalance in the genomics field through a program of technology and expertise transfer to the participating LMICs. Methods: An overview of the training program is presented. Trainees from the CAfGEN project summarized their experiences, looking specifically at the training model, benefits of the program, challenges encountered relating to the cultural transition, and program outcomes after the first 2 years. Conclusion: Collaborative training programs like CAfGEN will not only help establish sustainable long-term research initiatives in LMICs but also foster stronger North–South and South–South networks. The CAfGEN model offers a framework for the development of training programs aimed at genomics education for those for whom genomics is not their “first language.” Genet Med advance online publication 06 April 2017 PMID:28383545

Epistasis analysis using artificial intelligence.

PubMed

Moore, Jason H; Hill, Doug P

2015-01-01

Here we introduce artificial intelligence (AI) methodology for detecting and characterizing epistasis in genetic association studies. The ultimate goal of our AI strategy is to analyze genome-wide genetics data as a human would using sources of expert knowledge as a guide. The methodology presented here is based on computational evolution, which is a type of genetic programming. The ability to generate interesting solutions while at the same time learning how to solve the problem at hand distinguishes computational evolution from other genetic programming approaches. We provide a general overview of this approach and then present a few examples of its application to real data.

Ensembl core software resources: storage and programmatic access for DNA sequence and genome annotation.

PubMed

Ruffier, Magali; Kähäri, Andreas; Komorowska, Monika; Keenan, Stephen; Laird, Matthew; Longden, Ian; Proctor, Glenn; Searle, Steve; Staines, Daniel; Taylor, Kieron; Vullo, Alessandro; Yates, Andrew; Zerbino, Daniel; Flicek, Paul

2017-01-01

The Ensembl software resources are a stable infrastructure to store, access and manipulate genome assemblies and their functional annotations. The Ensembl 'Core' database and Application Programming Interface (API) was our first major piece of software infrastructure and remains at the centre of all of our genome resources. Since its initial design more than fifteen years ago, the number of publicly available genomic, transcriptomic and proteomic datasets has grown enormously, accelerated by continuous advances in DNA-sequencing technology. Initially intended to provide annotation for the reference human genome, we have extended our framework to support the genomes of all species as well as richer assembly models. Cross-referenced links to other informatics resources facilitate searching our database with a variety of popular identifiers such as UniProt and RefSeq. Our comprehensive and robust framework storing a large diversity of genome annotations in one location serves as a platform for other groups to generate and maintain their own tailored annotation. We welcome reuse and contributions: our databases and APIs are publicly available, all of our source code is released with a permissive Apache v2.0 licence at http://github.com/Ensembl and we have an active developer mailing list ( http://www.ensembl.org/info/about/contact/index.html ). http://www.ensembl.org. © The Author(s) 2017. Published by Oxford University Press.

Discovery of human inversion polymorphisms by comparative analysis of human and chimpanzee DNA sequence assemblies.

PubMed

Feuk, Lars; MacDonald, Jeffrey R; Tang, Terence; Carson, Andrew R; Li, Martin; Rao, Girish; Khaja, Razi; Scherer, Stephen W

2005-10-01

With a draft genome-sequence assembly for the chimpanzee available, it is now possible to perform genome-wide analyses to identify, at a submicroscopic level, structural rearrangements that have occurred between chimpanzees and humans. The goal of this study was to investigate chromosomal regions that are inverted between the chimpanzee and human genomes. Using the net alignments for the builds of the human and chimpanzee genome assemblies, we identified a total of 1,576 putative regions of inverted orientation, covering more than 154 mega-bases of DNA. The DNA segments are distributed throughout the genome and range from 23 base pairs to 62 mega-bases in length. For the 66 inversions more than 25 kilobases (kb) in length, 75% were flanked on one or both sides by (often unrelated) segmental duplications. Using PCR and fluorescence in situ hybridization we experimentally validated 23 of 27 (85%) semi-randomly chosen regions; the largest novel inversion confirmed was 4.3 mega-bases at human Chromosome 7p14. Gorilla was used as an out-group to assign ancestral status to the variants. All experimentally validated inversion regions were then assayed against a panel of human samples and three of the 23 (13%) regions were found to be polymorphic in the human genome. These polymorphic inversions include 730 kb (at 7p22), 13 kb (at 7q11), and 1 kb (at 16q24) fragments with a 5%, 30%, and 48% minor allele frequency, respectively. Our results suggest that inversions are an important source of variation in primate genome evolution. The finding of at least three novel inversion polymorphisms in humans indicates this type of structural variation may be a more common feature of our genome than previously realized.

Genomic Flexibility of Human Endogenous Retrovirus Type K

PubMed Central

Dube, Derek; Contreras-Galindo, Rafael; He, Shirley; King, Steven R.; Gonzalez-Hernandez, Marta J.; Gitlin, Scott D.; Kaplan, Mark H.

2014-01-01

ABSTRACT Human endogenous retrovirus type K (HERV-K) proviruses are scattered throughout the human genome, but as no infectious HERV-K virus has been detected to date, the mechanism by which these viruses replicated and populated the genome remains unresolved. Here, we provide evidence that, in addition to the RNA genomes that canonical retroviruses package, modern HERV-K viruses can contain reverse-transcribed DNA (RT-DNA) genomes. Indeed, reverse transcription of genomic HERV-K RNA into the DNA form is able to occur in three distinct times and locations: (i) in the virus-producing cell prior to viral release, yielding a DNA-containing extracellular virus particle similar to the spumaviruses; (ii) within the extracellular virus particle itself, transitioning from an RNA-containing particle to a DNA-containing particle; and (iii) after entry of the RNA-containing virus into the target cell, similar to canonical retroviruses, such as murine leukemia virus and HIV. Moreover, using a resuscitated HERV-K virus construct, we show that both viruses with RNA genomes and viruses with DNA genomes are capable of infecting target cells. This high level of genomic flexibility historically could have permitted these viruses to replicate in various host cell environments, potentially assisting in their many integration events and resulting in their high prevalence in the human genome. Moreover, the ability of modern HERV-K viruses to proceed through reverse transcription and package RT-DNA genomes suggests a higher level of replication competency than was previously understood, and it may be relevant in HERV-K-associated human diseases. IMPORTANCE Retroviral elements comprise at least 8% of the human genome. Of all the endogenous retroviruses, HERV-K viruses are the most intact and biologically active. While a modern infectious HERV-K has yet to be found, HERV-K activation has been associated with cancers, autoimmune diseases, and HIV-1 infection. Thus, determining how this virus family became such a prevalent member of our genome and what it is capable of in its current form are of the utmost importance. Here, we provide evidence that HERV-K viruses currently found in the human genome are able to proceed through reverse transcription and historically utilized a life cycle with a surprising degree of genomic flexibility in which both RNA- and DNA-containing viruses were capable of mediating infection. PMID:24920813

NIH Health Disparities Strategic Plan, Fiscal Years 2004-2008

ERIC Educational Resources Information Center

National Human Genome Research Institute, 2008

2008-01-01

The National Human Genome Research Institute (NHGRI) led the National Institutes of Health's (NIH) contribution to the International Human Genome Project, whose primary goal was the sequencing of the human genome. This project was successfully completed in April 2003. Now, the NHGRI's mission is focused on a broad range of studies aimed at…

Microsatellite Interruptions Stabilize Primate Genomes and Exist as Population-Specific Single Nucleotide Polymorphisms within Individual Human Genomes

PubMed Central

Ananda, Guruprasad; Hile, Suzanne E.; Breski, Amanda; Wang, Yanli; Kelkar, Yogeshwar; Makova, Kateryna D.; Eckert, Kristin A.

2014-01-01

Interruptions of microsatellite sequences impact genome evolution and can alter disease manifestation. However, human polymorphism levels at interrupted microsatellites (iMSs) are not known at a genome-wide scale, and the pathways for gaining interruptions are poorly understood. Using the 1000 Genomes Phase-1 variant call set, we interrogated mono-, di-, tri-, and tetranucleotide repeats up to 10 units in length. We detected ∼26,000–40,000 iMSs within each of four human population groups (African, European, East Asian, and American). We identified population-specific iMSs within exonic regions, and discovered that known disease-associated iMSs contain alleles present at differing frequencies among the populations. By analyzing longer microsatellites in primate genomes, we demonstrate that single interruptions result in a genome-wide average two- to six-fold reduction in microsatellite mutability, as compared with perfect microsatellites. Centrally located interruptions lowered mutability dramatically, by two to three orders of magnitude. Using a biochemical approach, we tested directly whether the mutability of a specific iMS is lower because of decreased DNA polymerase strand slippage errors. Modeling the adenomatous polyposis coli tumor suppressor gene sequence, we observed that a single base substitution interruption reduced strand slippage error rates five- to 50-fold, relative to a perfect repeat, during synthesis by DNA polymerases α, β, or η. Computationally, we demonstrate that iMSs arise primarily by base substitution mutations within individual human genomes. Our biochemical survey of human DNA polymerase α, β, δ, κ, and η error rates within certain microsatellites suggests that interruptions are created most frequently by low fidelity polymerases. Our combined computational and biochemical results demonstrate that iMSs are abundant in human genomes and are sources of population-specific genetic variation that may affect genome stability. The genome-wide identification of iMSs in human populations presented here has important implications for current models describing the impact of microsatellite polymorphisms on gene expression. PMID:25033203

[Genetic system for maintaining the mitochondrial human genome in yeast Yarrowia lipolytica].

PubMed

Isakova, E P; Deryabina, Yu I; Velyakova, A V; Biryukova, J K; Teplova, V V; Shevelev, A B

2016-01-01

For the first time, the possibility of maintaining an intact human mitochondrial genome in a heterologous system in the mitochondria of yeast Yarrowia lipolytica is shown. A method for introducing directional changes into the structure of the mitochondrial human genome replicating in Y. lipolytica by an artificially induced ability of yeast mitochondria for homologous recombination is proposed. A method of introducing and using phenotypic selection markers for the presence or absence of defects in genes tRNA-Lys and tRNA-Leu of the mitochondrial genome is developed. The proposed system can be used to correct harmful mutations of the human mitochondrial genome associated with mitochondrial diseases and for preparative amplification of intact mitochondrial DNA with an adjusted sequence in yeast cells. The applicability of the new system for the correction of mutations in the genes of Lys- and Leu-specific tRNAs of the human mitochondrial genome associated with serious and widespread human mitochondrial diseases such as myoclonic epilepsy with lactic acidosis (MELAS) and myoclonic epilepsy with ragged-red fibers (MERRF) is shown.

17th Chromosome-Centric Human Proteome Project Symposium in Tehran.

PubMed

Meyfour, Anna; Pahlavan, Sara; Sobhanian, Hamid; Salekdeh, Ghasem Hosseini

2018-04-01

This report describes the 17th Chromosome-Centric Human Proteome Project which was held in Tehran, Iran, April 27 and 28, 2017. A brief summary of the symposium's talks including new technical and computational approaches for the identification of novel proteins from non-coding genomic regions, physicochemical and biological causes of missing proteins, and the close interactions between Chromosome- and Biology/Disease-driven Human Proteome Project are presented. A synopsis of decisions made on the prospective programs to maintain collaborative works, share resources and information, and establishment of a newly organized working group, the task force for missing protein analysis are discussed. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PopHuman: the human population genomics browser.

PubMed

Casillas, Sònia; Mulet, Roger; Villegas-Mirón, Pablo; Hervas, Sergi; Sanz, Esteve; Velasco, Daniel; Bertranpetit, Jaume; Laayouni, Hafid; Barbadilla, Antonio

2018-01-04

The 1000 Genomes Project (1000GP) represents the most comprehensive world-wide nucleotide variation data set so far in humans, providing the sequencing and analysis of 2504 genomes from 26 populations and reporting >84 million variants. The availability of this sequence data provides the human lineage with an invaluable resource for population genomics studies, allowing the testing of molecular population genetics hypotheses and eventually the understanding of the evolutionary dynamics of genetic variation in human populations. Here we present PopHuman, a new population genomics-oriented genome browser based on JBrowse that allows the interactive visualization and retrieval of an extensive inventory of population genetics metrics. Efficient and reliable parameter estimates have been computed using a novel pipeline that faces the unique features and limitations of the 1000GP data, and include a battery of nucleotide variation measures, divergence and linkage disequilibrium parameters, as well as different tests of neutrality, estimated in non-overlapping windows along the chromosomes and in annotated genes for all 26 populations of the 1000GP. PopHuman is open and freely available at http://pophuman.uab.cat. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

A Draft Sequence of the Neandertal Genome

PubMed Central

Green, Richard E.; Li, Heng; Zhai, Weiwei; Fritz, Markus Hsi-Yang; Hansen, Nancy F.; Durand, Eric Y.; Malaspinas, Anna-Sapfo; Jensen, Jeffrey D.; Marques-Bonet, Tomas; Alkan, Can; Prüfer, Kay; Meyer, Matthias; Burbano, Hernán A.; Good, Jeffrey M.; Schultz, Rigo; Aximu-Petri, Ayinuer; Butthof, Anne; Höber, Barbara; Höffner, Barbara; Siegemund, Madlen; Weihmann, Antje; Nusbaum, Chad; Lander, Eric S.; Russ, Carsten; Novod, Nathaniel; Affourtit, Jason; Egholm, Michael; Verna, Christine; Rudan, Pavao; Brajkovic, Dejana; Kucan, Željko; Gušic, Ivan; Doronichev, Vladimir B.; Golovanova, Liubov V.; Lalueza-Fox, Carles; de la Rasilla, Marco; Fortea, Javier; Rosas, Antonio; Schmitz, Ralf W.; Johnson, Philip L. F.; Eichler, Evan E.; Falush, Daniel; Birney, Ewan; Mullikin, James C.; Slatkin, Montgomery; Nielsen, Rasmus; Kelso, Janet; Lachmann, Michael; Reich, David; Pääbo, Svante

2016-01-01

Neandertals, the closest evolutionary relatives of present-day humans, lived in large parts of Europe and western Asia before disappearing 30,000 years ago. We present a draft sequence of the Neandertal genome composed of more than 4 billion nucleotides from three individuals. Comparisons of the Neandertal genome to the genomes of five present-day humans from different parts of the world identify a number of genomic regions that may have been affected by positive selection in ancestral modern humans, including genes involved in metabolism and in cognitive and skeletal development. We show that Neandertals shared more genetic variants with present-day humans in Eurasia than with present-day humans in sub-Saharan Africa, suggesting that gene flow from Neandertals into the ancestors of non-Africans occurred before the divergence of Eurasian groups from each other. PMID:20448178

DOE Joint Genome Institute 2008 Progress Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gilbert, David

2009-03-12

While initially a virtual institute, the driving force behind the creation of the DOE Joint Genome Institute in Walnut Creek, California in the Fall of 1999 was the Department of Energy's commitment to sequencing the human genome. With the publication in 2004 of a trio of manuscripts describing the finished 'DOE Human Chromosomes', the Institute successfully completed its human genome mission. In the time between the creation of the Department of Energy Joint Genome Institute (DOE JGI) and completion of the Human Genome Project, sequencing and its role in biology spread to fields extending far beyond what could be imaginedmore » when the Human Genome Project first began. Accordingly, the targets of the DOE JGI's sequencing activities changed, moving from a single human genome to the genomes of large numbers of microbes, plants, and other organisms, and the community of users of DOE JGI data similarly expanded and diversified. Transitioning into operating as a user facility, the DOE JGI modeled itself after other DOE user facilities, such as synchrotron light sources and supercomputer facilities, empowering the science of large numbers of investigators working in areas of relevance to energy and the environment. The JGI's approach to being a user facility is based on the concept that by focusing state-of-the-art sequencing and analysis capabilities on the best peer-reviewed ideas drawn from a broad community of scientists, the DOE JGI will effectively encourage creative approaches to DOE mission areas and produce important science. This clearly has occurred, only partially reflected in the fact that the DOE JGI has played a major role in more than 45 papers published in just the past three years alone in Nature and Science. The involvement of a large and engaged community of users working on important problems has helped maximize the impact of JGI science. A seismic technological change is presently underway at the JGI. The Sanger capillary-based sequencing process that dominated how sequencing was done in the last decade is being replaced by a variety of new processes and sequencing instruments. The JGI, with an increasing number of next-generation sequencers, whose throughput is 100- to 1,000-fold greater than the Sanger capillary-based sequencers, is increasingly focused in new directions on projects of scale and complexity not previously attempted. These new directions for the JGI come, in part, from the 2008 National Research Council report on the goals of the National Plant Genome Initiative as well as the 2007 National Research Council report on the New Science of Metagenomics. Both reports outline a crucial need for systematic large-scale surveys of the plant and microbial components of the biosphere as well as an increasing need for large-scale analysis capabilities to meet the challenge of converting sequence data into knowledge. The JGI is extensively discussed in both reports as vital to progress in these fields of major national interest. JGI's future plan for plants and microbes includes a systematic approach for investigation of these organisms at a scale requiring the special capabilities of the JGI to generate, manage, and analyze the datasets. JGI will generate and provide not only community access to these plant and microbial datasets, but also the tools for analyzing them. These activities will produce essential knowledge that will be needed if we are to be able to respond to the world's energy and environmental challenges. As the JGI Plant and Microbial programs advance, the JGI as a user facility is also evolving. The Institute has been highly successful in bending its technical and analytical skills to help users solve large complex problems of major importance, and that effort will continue unabated. The JGI will increasingly move from a central focus on 'one-off' user projects coming from small user communities to much larger scale projects driven by systematic and problem-focused approaches to selection of sequencing targets. Entire communities of scientists working in a particular field, such as feedstock improvement or biomass degradation, will be users of this information. Despite this new emphasis, an investigator-initiated user program will remain. This program in the future will replace small projects that increasingly can be accomplished without the involvement of JGI, with imaginative large-scale 'Grand Challenge' projects of foundational relevance to energy and the environment that require a new scale of sequencing and analysis capabilities. Close interactions with the DOE Bioenergy Research Centers, and with other DOE institutions that may follow, will also play a major role in shaping aspects of how the JGI operates as a user facility. Based on increased availability of high-throughput sequencing, the JGI will increasingly provide to users, in addition to DNA sequencing, an array of both pre- and post-sequencing value-added capabilities to accelerate their science.« less

Genome-to-genome analysis highlights the effect of the human innate and adaptive immune systems on the hepatitis C virus.

PubMed

Ansari, M Azim; Pedergnana, Vincent; L C Ip, Camilla; Magri, Andrea; Von Delft, Annette; Bonsall, David; Chaturvedi, Nimisha; Bartha, Istvan; Smith, David; Nicholson, George; McVean, Gilean; Trebes, Amy; Piazza, Paolo; Fellay, Jacques; Cooke, Graham; Foster, Graham R; Hudson, Emma; McLauchlan, John; Simmonds, Peter; Bowden, Rory; Klenerman, Paul; Barnes, Eleanor; Spencer, Chris C A

2017-05-01

Outcomes of hepatitis C virus (HCV) infection and treatment depend on viral and host genetic factors. Here we use human genome-wide genotyping arrays and new whole-genome HCV viral sequencing technologies to perform a systematic genome-to-genome study of 542 individuals who were chronically infected with HCV, predominantly genotype 3. We show that both alleles of genes encoding human leukocyte antigen molecules and genes encoding components of the interferon lambda innate immune system drive viral polymorphism. Additionally, we show that IFNL4 genotypes determine HCV viral load through a mechanism dependent on a specific amino acid residue in the HCV NS5A protein. These findings highlight the interplay between the innate immune system and the viral genome in HCV control.

[Efficient genome editing in human pluripotent stem cells through CRISPR/Cas9].

PubMed

Liu, Gai-gai; Li, Shuang; Wei, Yu-da; Zhang, Yong-xian; Ding, Qiu-rong

2015-11-01

The RNA-guided CRISPR (clustered regularly interspaced short palindromic repeat)-associated Cas9 nuclease has offered a new platform for genome editing with high efficiency. Here, we report the use of CRISPR/Cas9 technology to target a specific genomic region in human pluripotent stem cells. We show that CRISPR/Cas9 can be used to disrupt a gene by introducing frameshift mutations to gene coding region; to knock in specific sequences (e.g. FLAG tag DNA sequence) to targeted genomic locus via homology directed repair; to induce large genomic deletion through dual-guide multiplex. Our results demonstrate the versatile application of CRISPR/Cas9 in stem cell genome editing, which can be widely utilized for functional studies of genes or genome loci in human pluripotent stem cells.

Deorphanizing the human transmembrane genome: A landscape of uncharacterized membrane proteins.

PubMed

Babcock, Joseph J; Li, Min

2014-01-01

The sequencing of the human genome has fueled the last decade of work to functionally characterize genome content. An important subset of genes encodes membrane proteins, which are the targets of many drugs. They reside in lipid bilayers, restricting their endogenous activity to a relatively specialized biochemical environment. Without a reference phenotype, the application of systematic screens to profile candidate membrane proteins is not immediately possible. Bioinformatics has begun to show its effectiveness in focusing the functional characterization of orphan proteins of a particular functional class, such as channels or receptors. Here we discuss integration of experimental and bioinformatics approaches for characterizing the orphan membrane proteome. By analyzing the human genome, a landscape reference for the human transmembrane genome is provided.

Human genome project: revolutionizing biology through leveraging technology

NASA Astrophysics Data System (ADS)

Dahl, Carol A.; Strausberg, Robert L.

1996-04-01

The Human Genome Project (HGP) is an international project to develop genetic, physical, and sequence-based maps of the human genome. Since the inception of the HGP it has been clear that substantially improved technology would be required to meet the scientific goals, particularly in order to acquire the complete sequence of the human genome, and that these technologies coupled with the information forthcoming from the project would have a dramatic effect on the way biomedical research is performed in the future. In this paper, we discuss the state-of-the-art for genomic DNA sequencing, technological challenges that remain, and the potential technological paths that could yield substantially improved genomic sequencing technology. The impact of the technology developed from the HGP is broad-reaching and a discussion of other research and medical applications that are leveraging HGP-derived DNA analysis technologies is included. The multidisciplinary approach to the development of new technologies that has been successful for the HGP provides a paradigm for facilitating new genomic approaches toward understanding the biological role of functional elements and systems within the cell, including those encoded within genomic DNA and their molecular products.

Engineered LINE-1 retrotransposition in nondividing human neurons

PubMed Central

Macia, Angela; Widmann, Thomas J.; Heras, Sara R.; Ayllon, Veronica; Sanchez, Laura; Benkaddour-Boumzaouad, Meriem; Muñoz-Lopez, Martin; Rubio, Alejandro; Amador-Cubero, Suyapa; Blanco-Jimenez, Eva; Garcia-Castro, Javier; Menendez, Pablo; Ng, Philip; Muotri, Alysson R.; Goodier, John L.; Garcia-Perez, Jose L.

2017-01-01

Half the human genome is made of transposable elements (TEs), whose ongoing activity continues to impact our genome. LINE-1 (or L1) is an autonomous non-LTR retrotransposon in the human genome, comprising 17% of its genomic mass and containing an average of 80–100 active L1s per average genome that provide a source of inter-individual variation. New LINE-1 insertions are thought to accumulate mostly during human embryogenesis. Surprisingly, the activity of L1s can further impact the somatic human brain genome. However, it is currently unknown whether L1 can retrotranspose in other somatic healthy tissues or if L1 mobilization is restricted to neuronal precursor cells (NPCs) in the human brain. Here, we took advantage of an engineered L1 retrotransposition assay to analyze L1 mobilization rates in human mesenchymal (MSCs) and hematopoietic (HSCs) somatic stem cells. Notably, we have observed that L1 expression and engineered retrotransposition is much lower in both MSCs and HSCs when compared to NPCs. Remarkably, we have further demonstrated for the first time that engineered L1s can retrotranspose efficiently in mature nondividing neuronal cells. Thus, these findings suggest that the degree of somatic mosaicism and the impact of L1 retrotransposition in the human brain is likely much higher than previously thought. PMID:27965292

Trial and error: how the unclonable human mitochondrial genome was cloned in yeast.

PubMed

Bigger, Brian W; Liao, Ai-Yin; Sergijenko, Ana; Coutelle, Charles

2011-11-01

Development of a human mitochondrial gene delivery vector is a critical step in the ability to treat diseases arising from mutations in mitochondrial DNA. Although we have previously cloned the mouse mitochondrial genome in its entirety and developed it as a mitochondrial gene therapy vector, the human mitochondrial genome has been dubbed unclonable in E. coli, due to regions of instability in the D-loop and tRNA(Thr) gene. We tested multi- and single-copy vector systems for cloning human mitochondrial DNA in E. coli and Saccharomyces cerevisiae, including transformation-associated recombination. Human mitochondrial DNA is unclonable in E. coli and cannot be retained in multi- or single-copy vectors under any conditions. It was, however, possible to clone and stably maintain the entire human mitochondrial genome in yeast as long as a single-copy centromeric plasmid was used. D-loop and tRNA(Thr) were both stable and unmutated. This is the first report of cloning the entire human mitochondrial genome and the first step in developing a gene delivery vehicle for human mitochondrial gene therapy.

Replication domains are self-interacting structural chromatin units of human chromosomes

NASA Astrophysics Data System (ADS)

Arneodo, Alain

2011-03-01

In higher eukaryotes, the absence of specific sequence motifs marking the origins of replication has been a serious hindrance to the understanding of the mechanisms that regulate the initiation and the maintenance of the replication program in different cell types. In silico analysis of nucleotide compositional skew has predicted the existence, in the germline, of replication N-domains bordered by putative replication origins and where the skew decreases rather linearly as the signature of a progressive inversion of the average fork polarity. Here, from the demonstration that the average fork polarity can be directly extracted from the derivative of replication timing profiles, we develop a wavelet-based pattern recognition methodology to delineate replication U-domains where the replication timing profile is shaped as a U and its derivative as a N. Replication U-domains are robustly found in seven cell lines as covering a significant portion (40-50%) of the human genome where the replication timing data actually displays some plasticity between cell lines. The early replication initiation zones at U-domains borders are found to be hypersensitive to DNase I cleavage, to be associated with transcriptional activity and to present a significant enrichment in insular-binding proteins CTCF, the hallmark of an open chromatin structure. A comparative analysis of genome-wide chromatin interaction (HiC) data shows that replication-U domains correspond to self-interacting structural high order chromatin units of megabase characteristic size. Taken together, these findings provide evidence that the epigenetic compartmentalization of the human genome into autonomous replication U-domains comes along with an extensive remodelling of the threedimensional chromosome architecture during development or in specific diseases. The observed cell specific conservation of the replication timing between the human and mouse genomes strongly suggests that this chromosome organization into self-interacting structural and functional units is a general feature of mammalian organisms.

Population-Based in Vitro Hazard and Concentration–Response Assessment of Chemicals: The 1000 Genomes High-Throughput Screening Study

PubMed Central

Abdo, Nour; Xia, Menghang; Brown, Chad C.; Kosyk, Oksana; Huang, Ruili; Sakamuru, Srilatha; Zhou, Yi-Hui; Jack, John R.; Gallins, Paul; Xia, Kai; Li, Yun; Chiu, Weihsueh A.; Motsinger-Reif, Alison A.; Austin, Christopher P.; Tice, Raymond R.

2015-01-01

Background: Understanding of human variation in toxicity to environmental chemicals remains limited, so human health risk assessments still largely rely on a generic 10-fold factor (10½ each for toxicokinetics and toxicodynamics) to account for sensitive individuals or subpopulations. Objectives: We tested a hypothesis that population-wide in vitro cytotoxicity screening can rapidly inform both the magnitude of and molecular causes for interindividual toxicodynamic variability. Methods: We used 1,086 lymphoblastoid cell lines from the 1000 Genomes Project, representing nine populations from five continents, to assess variation in cytotoxic response to 179 chemicals. Analysis included assessments of population variation and heritability, and genome-wide association mapping, with attention to phenotypic relevance to human exposures. Results: For about half the tested compounds, cytotoxic response in the 1% most “sensitive” individual occurred at concentrations within a factor of 10½ (i.e., approximately 3) of that in the median individual; however, for some compounds, this factor was > 10. Genetic mapping suggested important roles for variation in membrane and transmembrane genes, with a number of chemicals showing association with SNP rs13120371 in the solute carrier SLC7A11, previously implicated in chemoresistance. Conclusions: This experimental approach fills critical gaps unaddressed by recent large-scale toxicity testing programs, providing quantitative, experimentally based estimates of human toxicodynamic variability, and also testable hypotheses about mechanisms contributing to interindividual variation. Citation: Abdo N, Xia M, Brown CC, Kosyk O, Huang R, Sakamuru S, Zhou YH, Jack JR, Gallins P, Xia K, Li Y, Chiu WA, Motsinger-Reif AA, Austin CP, Tice RR, Rusyn I, Wright FA. 2015. Population-based in vitro hazard and concentration–response assessment of chemicals: the 1000 Genomes high-throughput screening study. Environ Health Perspect 123:458–466; http://dx.doi.org/10.1289/ehp.1408775 PMID:25622337

DNA methylation at hepatitis B viral integrants is associated with methylation at flanking human genomic sequences

PubMed Central

Watanabe, Yoshiyuki; Yamamoto, Hiroyuki; Oikawa, Ritsuko; Toyota, Minoru; Yamamoto, Masakazu; Kokudo, Norihiro; Tanaka, Shinji; Arii, Shigeki; Yotsuyanagi, Hiroshi; Koike, Kazuhiko; Itoh, Fumio

2015-01-01

Integration of DNA viruses into the human genome plays an important role in various types of tumors, including hepatitis B virus (HBV)–related hepatocellular carcinoma. However, the molecular details and clinical impact of HBV integration on either human or HBV epigenomes are unknown. Here, we show that methylation of the integrated HBV DNA is related to the methylation status of the flanking human genome. We developed a next-generation sequencing-based method for structural methylation analysis of integrated viral genomes (denoted G-NaVI). This method is a novel approach that enables enrichment of viral fragments for sequencing using unique baits based on the sequence of the HBV genome. We detected integrated HBV sequences in the genome of the PLC/PRF/5 cell line and found variable levels of methylation within the integrated HBV genomes. Allele-specific methylation analysis revealed that the HBV genome often became significantly methylated when integrated into highly methylated host sites. After integration into unmethylated human genome regions such as promoters, however, the HBV DNA remains unmethylated and may eventually play an important role in tumorigenesis. The observed dynamic changes in DNA methylation of the host and viral genomes may functionally affect the biological behavior of HBV. These findings may impact public health given that millions of people worldwide are carriers of HBV. We also believe our assay will be a powerful tool to increase our understanding of the various types of DNA virus-associated tumorigenesis. PMID:25653310

Towards the delineation of the ancestral eutherian genome organization: comparative genome maps of human and the African elephant (Loxodonta africana) generated by chromosome painting.

PubMed Central

Frönicke, Lutz; Wienberg, Johannes; Stone, Gary; Adams, Lisa; Stanyon, Roscoe

2003-01-01

This study presents a whole-genome comparison of human and a representative of the Afrotherian clade, the African elephant, generated by reciprocal Zoo-FISH. An analysis of Afrotheria genomes is of special interest, because recent DNA sequence comparisons identify them as the oldest placental mammalian clade. Complete sets of whole-chromosome specific painting probes for the African elephant and human were constructed by degenerate oligonucleotide-primed PCR amplification of flow-sorted chromosomes. Comparative genome maps are presented based on their hybridization patterns. These maps show that the elephant has a moderately rearranged chromosome complement when compared to humans. The human paint probes identified 53 evolutionary conserved segments on the 27 autosomal elephant chromosomes and the X chromosome. Reciprocal experiments with elephant probes delineated 68 conserved segments in the human genome. The comparison with a recent aardvark and elephant Zoo-FISH study delineates new chromosomal traits which link the two Afrotherian species phylogenetically. In the absence of any morphological evidence the chromosome painting data offer the first non-DNA sequence support for an Afrotherian clade. The comparative human and elephant genome maps provide new insights into the karyotype organization of the proto-afrotherian, the ancestor of extant placental mammals, which most probably consisted of 2n=46 chromosomes. PMID:12965023

A Secure Alignment Algorithm for Mapping Short Reads to Human Genome.

PubMed

Zhao, Yongan; Wang, Xiaofeng; Tang, Haixu

2018-05-09

The elastic and inexpensive computing resources such as clouds have been recognized as a useful solution to analyzing massive human genomic data (e.g., acquired by using next-generation sequencers) in biomedical researches. However, outsourcing human genome computation to public or commercial clouds was hindered due to privacy concerns: even a small number of human genome sequences contain sufficient information for identifying the donor of the genomic data. This issue cannot be directly addressed by existing security and cryptographic techniques (such as homomorphic encryption), because they are too heavyweight to carry out practical genome computation tasks on massive data. In this article, we present a secure algorithm to accomplish the read mapping, one of the most basic tasks in human genomic data analysis based on a hybrid cloud computing model. Comparing with the existing approaches, our algorithm delegates most computation to the public cloud, while only performing encryption and decryption on the private cloud, and thus makes the maximum use of the computing resource of the public cloud. Furthermore, our algorithm reports similar results as the nonsecure read mapping algorithms, including the alignment between reads and the reference genome, which can be directly used in the downstream analysis such as the inference of genomic variations. We implemented the algorithm in C++ and Python on a hybrid cloud system, in which the public cloud uses an Apache Spark system.

Analysis of the full genome of human group C rotaviruses reveals lineage diversification and reassortment.

PubMed

Medici, Maria Cristina; Tummolo, Fabio; Martella, Vito; Arcangeletti, Maria Cristina; De Conto, Flora; Chezzi, Carlo; Fehér, Enikő; Marton, Szilvia; Calderaro, Adriana; Bányai, Krisztián

2016-08-01

Group C rotaviruses (RVC) are enteric pathogens of humans and animals. Whole-genome sequences are available only for few RVCs, leaving gaps in our knowledge about their genetic diversity. We determined the full-length genome sequence of two human RVCs (PR2593/2004 and PR713/2012), detected in Italy from hospital-based surveillance for rotavirus infection in 2004 and 2012. In the 11 RNA genomic segments, the two Italian RVCs segregated within separate intra-genotypic lineages showed variation ranging from 1.9 % (VP6) to 15.9 % (VP3) at the nucleotide level. Comprehensive analysis of human RVC sequences available in the databases allowed us to reveal the existence of at least two major genome configurations, defined as type I and type II. Human RVCs of type I were all associated with the M3 VP3 genotype, including the Italian strain PR2593/2004. Conversely, human RVCs of type II were all associated with the M2 VP3 genotype, including the Italian strain PR713/2012. Reassortant RVC strains between these major genome configurations were identified. Although only a few full-genome sequences of human RVCs, mostly of Asian origin, are available, the analysis of human RVC sequences retrieved from the databases indicates that at least two intra-genotypic RVC lineages circulate in European countries. Gathering more sequence data is necessary to develop a standardized genotype and intra-genotypic lineage classification system useful for epidemiological investigations and avoiding confusion in the literature.

Genome-wide analysis of alternative splicing during dendritic cell response to a bacterial challenge.

PubMed

Rodrigues, Raquel; Grosso, Ana Rita; Moita, Luís

2013-01-01

The immune system relies on the plasticity of its components to produce appropriate responses to frequent environmental challenges. Dendritic cells (DCs) are critical initiators of innate immunity and orchestrate the later and more specific adaptive immunity. The generation of diversity in transcriptional programs is central for effective immune responses. Alternative splicing is widely considered a key generator of transcriptional and proteomic complexity, but its role has been rarely addressed systematically in immune cells. Here we used splicing-sensitive arrays to assess genome-wide gene- and exon-level expression profiles in human DCs in response to a bacterial challenge. We find widespread alternative splicing events and splicing factor transcriptional signatures induced by an E. coli challenge to human DCs. Alternative splicing acts in concert with transcriptional modulation, but these two mechanisms of gene regulation affect primarily distinct functional gene groups. Alternative splicing is likely to have an important role in DC immunobiology because it affects genes known to be involved in DC development, endocytosis, antigen presentation and cell cycle arrest.

Replication landscape of the human genome

PubMed Central

Petryk, Nataliya; Kahli, Malik; d'Aubenton-Carafa, Yves; Jaszczyszyn, Yan; Shen, Yimin; Silvain, Maud; Thermes, Claude; Chen, Chun-Long; Hyrien, Olivier

2016-01-01

Despite intense investigation, human replication origins and termini remain elusive. Existing data have shown strong discrepancies. Here we sequenced highly purified Okazaki fragments from two cell types and, for the first time, quantitated replication fork directionality and delineated initiation and termination zones genome-wide. Replication initiates stochastically, primarily within non-transcribed, broad (up to 150 kb) zones that often abut transcribed genes, and terminates dispersively between them. Replication fork progression is significantly co-oriented with the transcription. Initiation and termination zones are frequently contiguous, sometimes separated by regions of unidirectional replication. Initiation zones are enriched in open chromatin and enhancer marks, even when not flanked by genes, and often border ‘topologically associating domains' (TADs). Initiation zones are enriched in origin recognition complex (ORC)-binding sites and better align to origins previously mapped using bubble-trap than λ-exonuclease. This novel panorama of replication reveals how chromatin and transcription modulate the initiation process to create cell-type-specific replication programs. PMID:26751768

Characterization of a New HIV-1 CRF01_AE/ CRF07_BC recombinant virus in Tianjin, China.

PubMed

Zhou, Zhehua; Ma, Ping; Feng, Yi; Ou, Weidong; Qian, Jing; Gao, Liying; Zhang, Defa; Shao, Yiming; Wei, Min

2018-05-04

Human immunodeficiency virus (HIV) is notorious for its rapid evolving since its transmissions from money to human. Currently, HIV contains multiple subtypes, circulating recombinant forms (CRFs) and unique recombinant forms (URFs). Here, from an HIV-positive mother and her child in Tianjin, China, we identified a novel HIV-1 second-generation recombinant virus (TJ20170316 and TJ20170317) between CRF01_AE and CRF07_BC. Near full-length genomes were obtained from both samples, and they shared very close sequences, except some point mutations. Phylogenetic analyses of the near full-length genomes showed that they consist of CRF01_AE backbone and part CRF07_BC sequences. Recombinant Identification Program (RIP) and Simplot software identified four breakpoints in gag, pol, vif, tat genes in TJ20170316, totally different from other reported CRFs and URFs. The emergence of such URF in Tianjin, China, highlights the complexity of HIV-1 epidemic and more measures should be taken to prevent HIV transmissions.

Genome-Wide Prediction and Analysis of 3D-Domain Swapped Proteins in the Human Genome from Sequence Information.

PubMed

Upadhyay, Atul Kumar; Sowdhamini, Ramanathan

2016-01-01

3D-domain swapping is one of the mechanisms of protein oligomerization and the proteins exhibiting this phenomenon have many biological functions. These proteins, which undergo domain swapping, have acquired much attention owing to their involvement in human diseases, such as conformational diseases, amyloidosis, serpinopathies, proteionopathies etc. Early realisation of proteins in the whole human genome that retain tendency to domain swap will enable many aspects of disease control management. Predictive models were developed by using machine learning approaches with an average accuracy of 78% (85.6% of sensitivity, 87.5% of specificity and an MCC value of 0.72) to predict putative domain swapping in protein sequences. These models were applied to many complete genomes with special emphasis on the human genome. Nearly 44% of the protein sequences in the human genome were predicted positive for domain swapping. Enrichment analysis was performed on the positively predicted sequences from human genome for their domain distribution, disease association and functional importance based on Gene Ontology (GO). Enrichment analysis was also performed to infer a better understanding of the functional importance of these sequences. Finally, we developed hinge region prediction, in the given putative domain swapped sequence, by using important physicochemical properties of amino acids.

Child Development and Structural Variation in the Human Genome

ERIC Educational Resources Information Center

Zhang, Ying; Haraksingh, Rajini; Grubert, Fabian; Abyzov, Alexej; Gerstein, Mark; Weissman, Sherman; Urban, Alexander E.

2013-01-01

Structural variation of the human genome sequence is the insertion, deletion, or rearrangement of stretches of DNA sequence sized from around 1,000 to millions of base pairs. Over the past few years, structural variation has been shown to be far more common in human genomes than previously thought. Very little is currently known about the effects…

Understanding the Human Genome Project: Using Stations to Provide a Comprehensive Overview

ERIC Educational Resources Information Center

Soto, Julio G.

2005-01-01

A lesson was designed for lower division general education, non-major biology lecture-only course that included the historical and scientific context, some of the skills used to study the human genome, results, conclusions and ethical consideration. Students learn to examine and compare the published Human Genome maps, and employ the strategies…

A BAC clone fingerprinting approach to the detection of human genome rearrangements

PubMed Central

Krzywinski, Martin; Bosdet, Ian; Mathewson, Carrie; Wye, Natasja; Brebner, Jay; Chiu, Readman; Corbett, Richard; Field, Matthew; Lee, Darlene; Pugh, Trevor; Volik, Stas; Siddiqui, Asim; Jones, Steven; Schein, Jacquie; Collins, Collin; Marra, Marco

2007-01-01

We present a method, called fingerprint profiling (FPP), that uses restriction digest fingerprints of bacterial artificial chromosome clones to detect and classify rearrangements in the human genome. The approach uses alignment of experimental fingerprint patterns to in silico digests of the sequence assembly and is capable of detecting micro-deletions (1-5 kb) and balanced rearrangements. Our method has compelling potential for use as a whole-genome method for the identification and characterization of human genome rearrangements. PMID:17953769

Genomic selection needs to be carefully assessed to meet specific requirements in livestock breeding programs

PubMed Central

Jonas, Elisabeth; de Koning, Dirk-Jan

2015-01-01

Genomic selection is a promising development in agriculture, aiming improved production by exploiting molecular genetic markers to design novel breeding programs and to develop new markers-based models for genetic evaluation. It opens opportunities for research, as novel algorithms and lab methodologies are developed. Genomic selection can be applied in many breeds and species. Further research on the implementation of genomic selection (GS) in breeding programs is highly desirable not only for the common good, but also the private sector (breeding companies). It has been projected that this approach will improve selection routines, especially in species with long reproduction cycles, late or sex-limited or expensive trait recording and for complex traits. The task of integrating GS into existing breeding programs is, however, not straightforward. Despite successful integration into breeding programs for dairy cattle, it has yet to be shown how much emphasis can be given to the genomic information and how much additional phenotypic information is needed from new selection candidates. Genomic selection is already part of future planning in many breeding companies of pigs and beef cattle among others, but further research is needed to fully estimate how effective the use of genomic information will be for the prediction of the performance of future breeding stock. Genomic prediction of production in crossbreeding and across-breed schemes, costs and choice of individuals for genotyping are reasons for a reluctance to fully rely on genomic information for selection decisions. Breeding objectives are highly dependent on the industry and the additional gain when using genomic information has to be considered carefully. This review synthesizes some of the suggested approaches in selected livestock species including cattle, pig, chicken, and fish. It outlines tasks to help understanding possible consequences when applying genomic information in breeding scenarios. PMID:25750652

Genomic selection needs to be carefully assessed to meet specific requirements in livestock breeding programs.

PubMed

Jonas, Elisabeth; de Koning, Dirk-Jan

2015-01-01

Genomic selection is a promising development in agriculture, aiming improved production by exploiting molecular genetic markers to design novel breeding programs and to develop new markers-based models for genetic evaluation. It opens opportunities for research, as novel algorithms and lab methodologies are developed. Genomic selection can be applied in many breeds and species. Further research on the implementation of genomic selection (GS) in breeding programs is highly desirable not only for the common good, but also the private sector (breeding companies). It has been projected that this approach will improve selection routines, especially in species with long reproduction cycles, late or sex-limited or expensive trait recording and for complex traits. The task of integrating GS into existing breeding programs is, however, not straightforward. Despite successful integration into breeding programs for dairy cattle, it has yet to be shown how much emphasis can be given to the genomic information and how much additional phenotypic information is needed from new selection candidates. Genomic selection is already part of future planning in many breeding companies of pigs and beef cattle among others, but further research is needed to fully estimate how effective the use of genomic information will be for the prediction of the performance of future breeding stock. Genomic prediction of production in crossbreeding and across-breed schemes, costs and choice of individuals for genotyping are reasons for a reluctance to fully rely on genomic information for selection decisions. Breeding objectives are highly dependent on the industry and the additional gain when using genomic information has to be considered carefully. This review synthesizes some of the suggested approaches in selected livestock species including cattle, pig, chicken, and fish. It outlines tasks to help understanding possible consequences when applying genomic information in breeding scenarios.

Yeast for virus research

PubMed Central

Zhao, Richard Yuqi

2017-01-01

Budding yeast (Saccharomyces cerevisiae) and fission yeast (Schizosaccharomyces pombe) are two popular model organisms for virus research. They are natural hosts for viruses as they carry their own indigenous viruses. Both yeasts have been used for studies of plant, animal and human viruses. Many positive sense (+) RNA viruses and some DNA viruses replicate with various levels in yeasts, thus allowing study of those viral activities during viral life cycle. Yeasts are single cell eukaryotic organisms. Hence, many of the fundamental cellular functions such as cell cycle regulation or programed cell death are highly conserved from yeasts to higher eukaryotes. Therefore, they are particularly suited to study the impact of those viral activities on related cellular activities during virus-host interactions. Yeasts present many unique advantages in virus research over high eukaryotes. Yeast cells are easy to maintain in the laboratory with relative short doubling time. They are non-biohazardous, genetically amendable with small genomes that permit genome-wide analysis of virologic and cellular functions. In this review, similarities and differences of these two yeasts are described. Studies of virologic activities such as viral translation, viral replication and genome-wide study of virus-cell interactions in yeasts are highlighted. Impacts of viral proteins on basic cellular functions such as cell cycle regulation and programed cell death are discussed. Potential applications of using yeasts as hosts to carry out functional analysis of small viral genome and to develop high throughput drug screening platform for the discovery of antiviral drugs are presented. PMID:29082230

Genome stability of programmed stem cell products.

PubMed

Martin, Ulrich

2017-10-01

Inherited and acquired genomic abnormalities are known to cause genetic diseases and contribute to cancer formation. Recent studies demonstrated a substantial mutational load in mouse and human embryonic and induced pluripotent stem cells (ESCs and iPSCs). Single nucleotide variants, copy number variations, and larger chromosomal abnormalities may influence the differentiation capacity of pluripotent stem cells and the functionality of their derivatives in disease modeling and drug screening, and are considered a serious risk for cellular therapies based on ESC or iPSC derivatives. This review discusses the types and origins of different genetic abnormalities in pluripotent stem cells, methods for their detection, and the mechanisms of development and enrichment during reprogramming and culture expansion. Copyright © 2017 Elsevier B.V. All rights reserved.

Identification of human papillomavirus (HPV) 16 DNA integration and the ensuing patterns of methylation in HPV-associated head and neck squamous cell carcinoma cell lines.

PubMed

Hatano, Takashi; Sano, Daisuke; Takahashi, Hideaki; Hyakusoku, Hiroshi; Isono, Yasuhiro; Shimada, Shoko; Sawakuma, Kae; Takada, Kentaro; Oikawa, Ritsuko; Watanabe, Yoshiyuki; Yamamoto, Hiroyuki; Itoh, Fumio; Myers, Jeffrey N; Oridate, Nobuhiko

2017-04-01

Recent studies showed that human papillomavirus (HPV) integration contributes to the genomic instability seen in HPV-associated head and neck squamous cell carcinoma (HPV-HNSCC). However, the epigenetic alterations induced after HPV integration remains unclear. To identify the molecular details of HPV16 DNA integration and the ensuing patterns of methylation in HNSCC, we performed next-generation sequencing using a target-enrichment method for the effective identification of HPV16 integration breakpoints as well as the characterization of genomic sequences adjacent to HPV16 integration breakpoints with three HPV16-related HNSCC cell lines. The DNA methylation levels of the integrated HPV16 genome and that of the adjacent human genome were also analyzed by bisulfite pyrosequencing. We found various integration loci, including novel integration sites. Integration loci were located predominantly in the intergenic region, with a significant enrichment of the microhomologous sequences between the human and HPV16 genomes at the integration breakpoints. Furthermore, various levels of methylation within both the human genome and the integrated HPV genome at the integration breakpoints in each integrant were observed. Allele-specific methylation analysis suggested that the HPV16 integrants remained hypomethylated when the flanking host genome was hypomethylated. After integration into highly methylated human genome regions, however, the HPV16 DNA became methylated. In conclusion, we found novel integration sites and methylation patterns in HPV-HNSCC using our unique method. These findings may provide insights into understanding of viral integration mechanism and virus-associated carcinogenesis of HPV-HNSCC. © 2016 UICC.

Therapeutic Genome Editing and its Potential Enhancement through CRISPR Guide RNA and Cas9 Modifications.

PubMed

Batzir, Nurit Assia; Tovin, Adi; Hendel, Ayal

2017-06-01

Genome editing with engineered nucleases is a rapidly growing field thanks to transformative technologies that allow researchers to precisely alter genomes for numerous applications including basic research, biotechnology, and human gene therapy. The genome editing process relies on creating a site-specific DNA double-strand break (DSB) by engineered nucleases and then allowing the cell's repair machinery to repair the break such that precise changes are made to the DNA sequence. The recent development of CRISPR-Cas systems as easily accessible and programmable tools for genome editing accelerates the progress towards using genome editing as a new approach to human therapeutics. Here we review how genome editing using engineered nucleases works and how using different genome editing outcomes can be used as a tool set for treating human diseases. We then review the major challenges of therapeutic genome editing and we discuss how its potential enhancement through CRISPR guide RNA and Cas9 protein modifications could resolve some of these challenges. Copyright© of YS Medical Media ltd.

Productive Lifecycle of Human Papillomaviruses that Depends Upon Squamous Epithelial Differentiation

PubMed Central

Kajitani, Naoko; Satsuka, Ayano; Kawate, Akifumi; Sakai, Hiroyuki

2012-01-01

Human papillomaviruses (HPVs) target the stratified epidermis, and can causes diseases ranging from benign condylomas to malignant tumors. Infections of HPVs in the genital tract are among the most common sexually transmitted diseases, and a major risk factor for cervical cancer. The virus targets epithelial cells in the basal layer of the epithelium, while progeny virions egress from terminally differentiated cells in the cornified layer, the surface layer of the epithelium. In infected basal cells, the virus maintains its genomic DNA at low-copy numbers, at which the viral productive lifecycle cannot proceed. Progression of the productive lifecycle requires differentiation of the host cell, indicating that there is tight crosstalk between viral replication and host differentiation programs. In this review, we discuss the regulation of the HPV lifecycle controlled by the differentiation program of the host cells. PMID:22536200

Molluscan Evolutionary Genomics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Simison, W. Brian; Boore, Jeffrey L.

2005-12-01

In the last 20 years there have been dramatic advances in techniques of high-throughput DNA sequencing, most recently accelerated by the Human Genome Project, a program that has determined the three billion base pair code on which we are based. Now this tremendous capability is being directed at other genome targets that are being sampled across the broad range of life. This opens up opportunities as never before for evolutionary and organismal biologists to address questions of both processes and patterns of organismal change. We stand at the dawn of a new 'modern synthesis' period, paralleling that of the earlymore » 20th century when the fledgling field of genetics first identified the underlying basis for Darwin's theory. We must now unite the efforts of systematists, paleontologists, mathematicians, computer programmers, molecular biologists, developmental biologists, and others in the pursuit of discovering what genomics can teach us about the diversity of life. Genome-level sampling for mollusks to date has mostly been limited to mitochondrial genomes and it is likely that these will continue to provide the best targets for broad phylogenetic sampling in the near future. However, we are just beginning to see an inroad into complete nuclear genome sequencing, with several mollusks and other eutrochozoans having been selected for work about to begin. Here, we provide an overview of the state of molluscan mitochondrial genomics, highlight a few of the discoveries from this research, outline the promise of broadening this dataset, describe upcoming projects to sequence whole mollusk nuclear genomes, and challenge the community to prepare for making the best use of these data.« less

The Ensembl genome database project.

PubMed

Hubbard, T; Barker, D; Birney, E; Cameron, G; Chen, Y; Clark, L; Cox, T; Cuff, J; Curwen, V; Down, T; Durbin, R; Eyras, E; Gilbert, J; Hammond, M; Huminiecki, L; Kasprzyk, A; Lehvaslaiho, H; Lijnzaad, P; Melsopp, C; Mongin, E; Pettett, R; Pocock, M; Potter, S; Rust, A; Schmidt, E; Searle, S; Slater, G; Smith, J; Spooner, W; Stabenau, A; Stalker, J; Stupka, E; Ureta-Vidal, A; Vastrik, I; Clamp, M

2002-01-01

The Ensembl (http://www.ensembl.org/) database project provides a bioinformatics framework to organise biology around the sequences of large genomes. It is a comprehensive source of stable automatic annotation of the human genome sequence, with confirmed gene predictions that have been integrated with external data sources, and is available as either an interactive web site or as flat files. It is also an open source software engineering project to develop a portable system able to handle very large genomes and associated requirements from sequence analysis to data storage and visualisation. The Ensembl site is one of the leading sources of human genome sequence annotation and provided much of the analysis for publication by the international human genome project of the draft genome. The Ensembl system is being installed around the world in both companies and academic sites on machines ranging from supercomputers to laptops.

The expanding universe of cohesin functions: a new genome stability caretaker involved in human disease and cancer.

PubMed

Mannini, Linda; Menga, Stefania; Musio, Antonio

2010-06-01

Cohesin is responsible for sister chromatid cohesion, ensuring the correct chromosome segregation. Beyond this role, cohesin and regulatory cohesin genes seem to play a role in preserving genome stability and gene transcription regulation. DNA damage is thought to be a major culprit for many human diseases, including cancer. Our present knowledge of the molecular basis underlying genome instability is extremely limited. Mutations in cohesin genes cause human diseases such as Cornelia de Lange syndrome and Roberts syndrome/SC phocomelia, and all the cell lines derived from affected patients show genome instability. Cohesin mutations have also been identified in colorectal cancer. Here, we will discuss the human disorders caused by alterations of cohesin function, with emphasis on the emerging role of cohesin as a genome stability caretaker.

Identification of functional elements and regulatory circuits by Drosophila modENCODE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roy, Sushmita; Ernst, Jason; Kharchenko, Peter V.

2010-12-22

To gain insight into how genomic information is translated into cellular and developmental programs, the Drosophila model organism Encyclopedia of DNA Elements (modENCODE) project is comprehensively mapping transcripts, histone modifications, chromosomal proteins, transcription factors, replication proteins and intermediates, and nucleosome properties across a developmental time course and in multiple cell lines. We have generated more than 700 data sets and discovered protein-coding, noncoding, RNA regulatory, replication, and chromatin elements, more than tripling the annotated portion of the Drosophila genome. Correlated activity patterns of these elements reveal a functional regulatory network, which predicts putative new functions for genes, reveals stage- andmore » tissue-specific regulators, and enables gene-expression prediction. Our results provide a foundation for directed experimental and computational studies in Drosophila and related species and also a model for systematic data integration toward comprehensive genomic and functional annotation. Several years after the complete genetic sequencing of many species, it is still unclear how to translate genomic information into a functional map of cellular and developmental programs. The Encyclopedia of DNA Elements (ENCODE) (1) and model organism ENCODE (modENCODE) (2) projects use diverse genomic assays to comprehensively annotate the Homo sapiens (human), Drosophila melanogaster (fruit fly), and Caenorhabditis elegans (worm) genomes, through systematic generation and computational integration of functional genomic data sets. Previous genomic studies in flies have made seminal contributions to our understanding of basic biological mechanisms and genome functions, facilitated by genetic, experimental, computational, and manual annotation of the euchromatic and heterochromatic genome (3), small genome size, short life cycle, and a deep knowledge of development, gene function, and chromosome biology. The functions of {approx}40% of the protein and nonprotein-coding genes [FlyBase 5.12 (4)] have been determined from cDNA collections (5, 6), manual curation of gene models (7), gene mutations and comprehensive genome-wide RNA interference screens (8-10), and comparative genomic analyses (11, 12). The Drosophila modENCODE project has generated more than 700 data sets that profile transcripts, histone modifications and physical nucleosome properties, general and specific transcription factors (TFs), and replication programs in cell lines, isolated tissues, and whole organisms across several developmental stages (Fig. 1). Here, we computationally integrate these data sets and report (i) improved and additional genome annotations, including full-length proteincoding genes and peptides as short as 21 amino acids; (ii) noncoding transcripts, including 132 candidate structural RNAs and 1608 nonstructural transcripts; (iii) additional Argonaute (Ago)-associated small RNA genes and pathways, including new microRNAs (miRNAs) encoded within protein-coding exons and endogenous small interfering RNAs (siRNAs) from 3-inch untranslated regions; (iv) chromatin 'states' defined by combinatorial patterns of 18 chromatin marks that are associated with distinct functions and properties; (v) regions of high TF occupancy and replication activity with likely epigenetic regulation; (vi)mixed TF and miRNA regulatory networks with hierarchical structure and enriched feed-forward loops; (vii) coexpression- and co-regulation-based functional annotations for nearly 3000 genes; (viii) stage- and tissue-specific regulators; and (ix) predictive models of gene expression levels and regulator function.« less

Explaining human uniqueness: genome interactions with environment, behaviour and culture.

PubMed

Varki, Ajit; Geschwind, Daniel H; Eichler, Evan E

2008-10-01

What makes us human? Specialists in each discipline respond through the lens of their own expertise. In fact, 'anthropogeny' (explaining the origin of humans) requires a transdisciplinary approach that eschews such barriers. Here we take a genomic and genetic perspective towards molecular variation, explore systems analysis of gene expression and discuss an organ-systems approach. Rejecting any 'genes versus environment' dichotomy, we then consider genome interactions with environment, behaviour and culture, finally speculating that aspects of human uniqueness arose because of a primate evolutionary trend towards increasing and irreversible dependence on learned behaviours and culture - perhaps relaxing allowable thresholds for large-scale genomic diversity.

Explaining human uniqueness: genome interactions with environment, behaviour and culture

PubMed Central

Varki, Ajit; Geschwind, Daniel H.; Eichler, Evan E.

2009-01-01

What makes us human? Specialists in each discipline respond through the lens of their own expertise. In fact, ‘anthropogeny’ (explaining the origin of humans) requires a transdisciplinary approach that eschews such barriers. Here we take a genomic and genetic perspective towards molecular variation, explore systems analysis of gene expression and discuss an organ-systems approach. Rejecting any ‘genes versus environment’ dichotomy, we then consider genome interactions with environment, behaviour and culture, finally speculating that aspects of human uniqueness arose because of a primate evolutionary trend towards increasing and irreversible dependence on learned behaviours and culture — perhaps relaxing allowable thresholds for large-scale genomic diversity. PMID:18802414

Confidentiality and data sharing: vulnerabilities of the Mexican Genomics Sovereignty Act.

PubMed

Rojas-Martínez, Augusto

2015-07-01

A law known as "Genomic Sovereignty Act", instituted in 2011, regulates research on the human genome in Mexico. This law establishes Government regulations for the exportation of DNA samples from Mexican nationals for population genetics studies. The Genomic Sovereignty Act protects fundamental human values, as confidentiality and non-discrimination based on personal genetic information. It also supports the development of the genome-based medical biotechnology and the bio-economy. Current laws for the protection of the genomic confidentiality, however, are inexplicit and insufficient, and the legal and technological instruments are primitive and insufficient to safeguard this bioethical principle. In addition, this law may undermine efforts of the national and international scientific communities to cooperate with big-data analysis for the development of the genome-based biomedical sciences. The argument of this article is that deficiencies in the protection of the confidentiality of genomic information and limitations in data sharing severely weaken the objectives and scope of the Genomic Sovereignty Act. In addition, the Act may compromise the national biomedical development and the international cooperation for research and development in the field of human genomics.

The Warburg effect version 2.0

PubMed Central

Menendez, Javier A.; Joven, Jorge; Cufí, Sílvia; Corominas-Faja, Bruna; Oliveras-Ferraros, Cristina; Cuyàs, Elisabet; Martin-Castillo, Begoña; López-Bonet, Eugeni; Alarcón, Tomás; Vazquez-Martin, Alejandro

2013-01-01

When fighting cancer, knowledge on metabolism has always been important. Today, it matters more than ever. The restricted cataloging of cancer genomes is quite unlikely to achieve the task of curing cancer, unless it is integrated into metabolic networks that respond to and influence the constantly evolving cancer stem cell (CSC) cellular states. Once the genomic era of carcinogenesis had pushed the 1920s Otto Warburg’s metabolic cancer hypothesis into obscurity for decades, the most recent studies begin to support a new developing paradigm, in which the molecular logic behind the conversion of non-CSCs into CSCs can be better understood in terms of the “metabolic facilitators” and “metabolic impediments” that operate as proximate openings and roadblocks, respectively, for the transcriptional events and signal transduction programs that ultimately orchestrate the intrinsic and/or microenvironmental paths to CSC cellular states. Here we propose that a profound understanding of how human carcinomas install a proper “Warburg effect version 2.0” allowing them to “run” the CSCs’ “software” programs should guide a new era of metabolo-genomic-personalized cancer medicine. By viewing metabolic reprogramming of CSCs as an essential characteristic that allows dynamic, multidimensional and evolving cancer populations to compete successfully for their expansion on the organism, we now argue that CSCs bioenergetics might be another cancer hallmark. A definitive understanding of metabolic reprogramming in CSCs may complement or to some extent replace, the 30-y-old paradigm of targeting oncogenes to treat human carcinomas, because it can be possible to metabolically create non-permissive or “hostile” metabotypes to prevent the occurrence of CSC cellular states with tumor- and metastasis-initiating capacity. PMID:23549172

Beyond 'knock-out' mice: new perspectives for the programmed modification of the mammalian genome.

PubMed

Cohen-Tannoudji, M; Babinet, C

1998-10-01

The emergence of gene inactivation by homologous recombination methodology in embryonic stem cells has revolutionized the field of mouse genetics. Indeed, the availability of a rapidly growing number of mouse null mutants has represented an invaluable source of knowledge on mammalian development, cellular biology and physiology and has provided many models for human inherited diseases. In recent years, improvements of the original 'knock-out' strategy, as well as the exploitation of exogenous enzymatic systems that are active in the recombination process, have considerably extended the range of genetic manipulations that can be produced. For example, it is now possible to create a mouse bearing a targeted point mutation as the unique change in its entire genome therefore allowing very fine dissection of gene function in vivo. Chromosome alterations such as large deletions, inversions or translocations can also be designed and will facilitate the global functional analysis of the mouse genome. This will extend the possibilities of creating models of human pathologies that frequently originate from various chromosomal disorders. Finally, the advent of methods allowing conditional gene targeting will open the way for the analysis of the consequence of a particular mutation in a defined organ and at a specific time during the life of a mouse.

The human genome as public: Justifications and implications.

PubMed

Bayefsky, Michelle J

2017-03-01

Since the human genome was decoded, great emphasis has been placed on the unique, personal nature of the genome, along with the benefits that personalized medicine can bring to individuals and the importance of safeguarding genetic privacy. As a result, an equally important aspect of the human genome - its common nature - has been underappreciated and underrepresented in the ethics literature and policy dialogue surrounding genetics and genomics. This article will argue that, just as the personal nature of the genome has been used to reinforce individual rights and justify important privacy protections, so too the common nature of the genome can be employed to support protections of the genome at a population level and policies designed to promote the public's wellbeing. In order for public health officials to have the authority to develop genetics policies for the sake of the public good, the genome must have not only a common, but also a public, dimension. This article contends that DNA carries a public dimension through the use of two conceptual frameworks: the common heritage (CH) framework and the common resource (CR) framework. Both frameworks establish a public interest in the human genome, but the CH framework can be used to justify policies aimed at preserving and protecting the genome, while the CR framework can be employed to justify policies for utilizing the genome for the public benefit. A variety of possible policy implications are discussed, with special attention paid to the use of large-scale genomics databases for public health research. © Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Human evolution: a tale from ancient genomes

PubMed Central

2017-01-01

The field of human ancient DNA (aDNA) has moved from mitochondrial sequencing that suffered from contamination and provided limited biological insights, to become a fully genomic discipline that is changing our conception of human history. Recent successes include the sequencing of extinct hominins, and true population genomic studies of Bronze Age populations. Among the emerging areas of aDNA research, the analysis of past epigenomes is set to provide more new insights into human adaptation and disease susceptibility through time. Starting as a mere curiosity, ancient human genetics has become a major player in the understanding of our evolutionary history. This article is part of the themed issue ‘Evo-devo in the genomics era, and the origins of morphological diversity’. PMID:27994125

The human genome project: an historical perspective for social workers.

PubMed

Saunders, Marlene

2011-01-01

Having mapped the human genome, the Human Genome Project maintains that certain genes can be linked to specific diseases and certain forms of human behavior. This breakthrough, it is hoped, will lead to the effective treatment, even the elimination of serious, debilitating illnesses for all groups of people. However, because the project conjures up memories of eugenics, the project raises concerns about its potential for identifying and linking diseases and social conditions (e.g., criminal behavior) to certain groups. This article places the Human Genome Project in historical context in terms of its resemblance to the eugenics movement in America and a period in social work history when the profession embraced eugenics and was guided by the movement's premises in its response to poor people.

An overview of human genetic privacy

PubMed Central

Shi, Xinghua; Wu, Xintao

2016-01-01

The study of human genomics is becoming a Big Data science, owing to recent biotechnological advances leading to availability of millions of personal genome sequences, which can be combined with biometric measurements from mobile apps and fitness trackers, and of human behavior data monitored from mobile devices and social media. With increasing research opportunities for integrative genomic studies through data sharing, genetic privacy emerges as a legitimate yet challenging concern that needs to be carefully addressed, not only for individuals but also for their families. In this paper, we present potential genetic privacy risks and relevant ethics and regulations for sharing and protecting human genomics data. We also describe the techniques for protecting human genetic privacy from three broad perspectives: controlled access, differential privacy, and cryptographic solutions. PMID:27626905

Introduction to Metagenomics at DOE JGI: Program Overview and Program Informatics (Metagenomics Informatics Challenges Workshop: 10K Genomes at a Time)

ScienceCinema

Tringe, Susannah

2018-01-15

Susannah Tringe of the DOE Joint Genome Institute talks about the Program Overview and Program Informatics at the Metagenomics Informatics Challenges Workshop held at the DOE JGI on October 12-13, 2011.

Population Genetic Inference from Personal Genome Data: Impact of Ancestry and Admixture on Human Genomic Variation

PubMed Central

Kidd, Jeffrey M.; Gravel, Simon; Byrnes, Jake; Moreno-Estrada, Andres; Musharoff, Shaila; Bryc, Katarzyna; Degenhardt, Jeremiah D.; Brisbin, Abra; Sheth, Vrunda; Chen, Rong; McLaughlin, Stephen F.; Peckham, Heather E.; Omberg, Larsson; Bormann Chung, Christina A.; Stanley, Sarah; Pearlstein, Kevin; Levandowsky, Elizabeth; Acevedo-Acevedo, Suehelay; Auton, Adam; Keinan, Alon; Acuña-Alonzo, Victor; Barquera-Lozano, Rodrigo; Canizales-Quinteros, Samuel; Eng, Celeste; Burchard, Esteban G.; Russell, Archie; Reynolds, Andy; Clark, Andrew G.; Reese, Martin G.; Lincoln, Stephen E.; Butte, Atul J.; De La Vega, Francisco M.; Bustamante, Carlos D.

2012-01-01

Full sequencing of individual human genomes has greatly expanded our understanding of human genetic variation and population history. Here, we present a systematic analysis of 50 human genomes from 11 diverse global populations sequenced at high coverage. Our sample includes 12 individuals who have admixed ancestry and who have varying degrees of recent (within the last 500 years) African, Native American, and European ancestry. We found over 21 million single-nucleotide variants that contribute to a 1.75-fold range in nucleotide heterozygosity across diverse human genomes. This heterozygosity ranged from a high of one heterozygous site per kilobase in west African genomes to a low of 0.57 heterozygous sites per kilobase in segments inferred to have diploid Native American ancestry from the genomes of Mexican and Puerto Rican individuals. We show evidence of all three continental ancestries in the genomes of Mexican, Puerto Rican, and African American populations, and the genome-wide statistics are highly consistent across individuals from a population once ancestry proportions have been accounted for. Using a generalized linear model, we identified subtle variations across populations in the proportion of neutral versus deleterious variation and found that genome-wide statistics vary in admixed populations even once ancestry proportions have been factored in. We further infer that multiple periods of gene flow shaped the diversity of admixed populations in the Americas—70% of the European ancestry in today’s African Americans dates back to European gene flow happening only 7–8 generations ago. PMID:23040495

Neolithic and medieval virus genomes reveal complex evolution of hepatitis B

PubMed Central

Key, Felix M; Kühnert, Denise; Bosse, Esther; Immel, Alexander; Rinne, Christoph; Kornell, Sabin-Christin; Yepes, Diego; Franzenburg, Sören; Heyne, Henrike O; Meier, Thomas; Lösch, Sandra; Meller, Harald; Friederich, Susanne; Nicklisch, Nicole; Alt, Kurt W; Schreiber, Stefan; Tholey, Andreas; Herbig, Alexander; Nebel, Almut

2018-01-01

The hepatitis B virus (HBV) is one of the most widespread human pathogens known today, yet its origin and evolutionary history are still unclear and controversial. Here, we report the analysis of three ancient HBV genomes recovered from human skeletons found at three different archaeological sites in Germany. We reconstructed two Neolithic and one medieval HBV genome by de novo assembly from shotgun DNA sequencing data. Additionally, we observed HBV-specific peptides using paleo-proteomics. Our results demonstrated that HBV has circulated in the European population for at least 7000 years. The Neolithic HBV genomes show a high genomic similarity to each other. In a phylogenetic network, they do not group with any human-associated HBV genome and are most closely related to those infecting African non-human primates. The ancient viruses appear to represent distinct lineages that have no close relatives today and possibly went extinct. Our results reveal the great potential of ancient DNA from human skeletons in order to study the long-time evolution of blood borne viruses. PMID:29745896

Recurrent DNA inversion rearrangements in the human genome

PubMed Central

Flores, Margarita; Morales, Lucía; Gonzaga-Jauregui, Claudia; Domínguez-Vidaña, Rocío; Zepeda, Cinthya; Yañez, Omar; Gutiérrez, María; Lemus, Tzitziki; Valle, David; Avila, Ma. Carmen; Blanco, Daniel; Medina-Ruiz, Sofía; Meza, Karla; Ayala, Erandi; García, Delfino; Bustos, Patricia; González, Víctor; Girard, Lourdes; Tusie-Luna, Teresa; Dávila, Guillermo; Palacios, Rafael

2007-01-01

Several lines of evidence suggest that reiterated sequences in the human genome are targets for nonallelic homologous recombination (NAHR), which facilitates genomic rearrangements. We have used a PCR-based approach to identify breakpoint regions of rearranged structures in the human genome. In particular, we have identified intrachromosomal identical repeats that are located in reverse orientation, which may lead to chromosomal inversions. A bioinformatic workflow pathway to select appropriate regions for analysis was developed. Three such regions overlapping with known human genes, located on chromosomes 3, 15, and 19, were analyzed. The relative proportion of wild-type to rearranged structures was determined in DNA samples from blood obtained from different, unrelated individuals. The results obtained indicate that recurrent genomic rearrangements occur at relatively high frequency in somatic cells. Interestingly, the rearrangements studied were significantly more abundant in adults than in newborn individuals, suggesting that such DNA rearrangements might start to appear during embryogenesis or fetal life and continue to accumulate after birth. The relevance of our results in regard to human genomic variation is discussed. PMID:17389356

Neolithic and Medieval virus genomes reveal complex evolution of Hepatitis B.

PubMed

Krause-Kyora, Ben; Susat, Julian; Key, Felix M; Kühnert, Denise; Bosse, Esther; Immel, Alexander; Rinne, Christoph; Kornell, Sabin-Christin; Yepes, Diego; Franzenburg, Sören; Heyne, Henrike O; Meier, Thomas; Lösch, Sandra; Meller, Harald; Friederich, Susanne; Nicklisch, Nicole; Alt, Kurt W; Schreiber, Stefan; Tholey, Andreas; Herbig, Alexander; Nebel, Almut; Krause, Johannes

2018-05-10

The hepatitis B virus (HBV) is one of the most widespread human pathogens known today, yet its origin and evolutionary history are still unclear and controversial. Here, we report the analysis of three ancient HBV genomes recovered from human skeletons found at three different archaeological sites in Germany. We reconstructed two Neolithic and one medieval HBV genomes by de novo assembly from shotgun DNA sequencing data. Additionally, we observed HBV-specific peptides using paleo-proteomics. Our results show that HBV circulates in the European population for at least 7000 years. The Neolithic HBV genomes show a high genomic similarity to each other. In a phylogenetic network, they do not group with any human-associated HBV genome and are most closely related to those infecting African non-human primates. These ancient virus forms appear to represent distinct lineages that have no close relatives today and possibly went extinct. Our results reveal the great potential of ancient DNA from human skeletons in order to study the long-time evolution of blood borne viruses. © 2018, Krause-Kyora et al.

Engineered LINE-1 retrotransposition in nondividing human neurons.

PubMed

Macia, Angela; Widmann, Thomas J; Heras, Sara R; Ayllon, Veronica; Sanchez, Laura; Benkaddour-Boumzaouad, Meriem; Muñoz-Lopez, Martin; Rubio, Alejandro; Amador-Cubero, Suyapa; Blanco-Jimenez, Eva; Garcia-Castro, Javier; Menendez, Pablo; Ng, Philip; Muotri, Alysson R; Goodier, John L; Garcia-Perez, Jose L

2017-03-01

Half the human genome is made of transposable elements (TEs), whose ongoing activity continues to impact our genome. LINE-1 (or L1) is an autonomous non-LTR retrotransposon in the human genome, comprising 17% of its genomic mass and containing an average of 80-100 active L1s per average genome that provide a source of inter-individual variation. New LINE-1 insertions are thought to accumulate mostly during human embryogenesis. Surprisingly, the activity of L1s can further impact the somatic human brain genome. However, it is currently unknown whether L1 can retrotranspose in other somatic healthy tissues or if L1 mobilization is restricted to neuronal precursor cells (NPCs) in the human brain. Here, we took advantage of an engineered L1 retrotransposition assay to analyze L1 mobilization rates in human mesenchymal (MSCs) and hematopoietic (HSCs) somatic stem cells. Notably, we have observed that L1 expression and engineered retrotransposition is much lower in both MSCs and HSCs when compared to NPCs. Remarkably, we have further demonstrated for the first time that engineered L1s can retrotranspose efficiently in mature nondividing neuronal cells. Thus, these findings suggest that the degree of somatic mosaicism and the impact of L1 retrotransposition in the human brain is likely much higher than previously thought. © 2017 Macia et al.; Published by Cold Spring Harbor Laboratory Press.

A new polymorphic and multicopy MHC gene family related to nonmammalian class I

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leelayuwat, C.; Degli-Esposti, M.A.; Abraham, L.J.

1994-12-31

The authors have used genomic analysis to characterize a region of the central major histocompatibility complex (MHC) spanning {approximately} 300 kilobases (kb) between TNF and HLA-B. This region has been suggested to carry genetic factors relevant to the development of autoimmune diseases such as myasthenia gravis (MG) and insulin dependent diabetes mellitus (IDDM). Genomic sequence was analyzed for coding potential, using two neural network programs, GRAIL and GeneParser. A genomic probe, JAB, containing putative coding sequences (PERB11) located 60 kb centromeric of HLA-B, was used for northern analysis of human tissues. Multiple transcripts were detected. Southern analysis of genomic DNAmore » and overlapping YAC clones, covering the region from BAT1 to HLA-F, indicated that there are at least five copies of PERB11, four of which are located within this region of the MHC. The partial cDNA sequence of PERB11 was obtained from poly-A RNA derived from skeletal muscle. The putative amino acid sequence of PERB11 shares {approximately} 30% identity to MHC class I molecules from various species, including reptiles, chickens, and frogs, as well as to other MHC class I-like molecules, such as the IgG FcR of the mouse and rat and the human Zn-{alpha}2-glycoprotein. From direct comparison of amino acid sequences, it is concluded that PERB11 is a distinct molecule more closely related to nonmammalian than known mammalian MHC class I molecules. Genomic sequence analysis of PERB11 from five MHC ancestral haplotypes (AH) indicated that the gene is polymorphic at both DNA and protein level. The results suggest that the authors have identified a novel polymorphic gene family with multiple copies within the MHC. 48 refs., 10 figs., 2 tabs.« less

Segmenting the human genome based on states of neutral genetic divergence.

PubMed

Kuruppumullage Don, Prabhani; Ananda, Guruprasad; Chiaromonte, Francesca; Makova, Kateryna D

2013-09-03

Many studies have demonstrated that divergence levels generated by different mutation types vary and covary across the human genome. To improve our still-incomplete understanding of the mechanistic basis of this phenomenon, we analyze several mutation types simultaneously, anchoring their variation to specific regions of the genome. Using hidden Markov models on insertion, deletion, nucleotide substitution, and microsatellite divergence estimates inferred from human-orangutan alignments of neutrally evolving genomic sequences, we segment the human genome into regions corresponding to different divergence states--each uniquely characterized by specific combinations of divergence levels. We then parsed the mutagenic contributions of various biochemical processes associating divergence states with a broad range of genomic landscape features. We find that high divergence states inhabit guanine- and cytosine (GC)-rich, highly recombining subtelomeric regions; low divergence states cover inner parts of autosomes; chromosome X forms its own state with lowest divergence; and a state of elevated microsatellite mutability is interspersed across the genome. These general trends are mirrored in human diversity data from the 1000 Genomes Project, and departures from them highlight the evolutionary history of primate chromosomes. We also find that genes and noncoding functional marks [annotations from the Encyclopedia of DNA Elements (ENCODE)] are concentrated in high divergence states. Our results provide a powerful tool for biomedical data analysis: segmentations can be used to screen personal genome variants--including those associated with cancer and other diseases--and to improve computational predictions of noncoding functional elements.

Functional Assays to Screen and Dissect Genomic Hits: Doubling Down on the National Investment in Genomic Research.

PubMed

Musunuru, Kiran; Bernstein, Daniel; Cole, F Sessions; Khokha, Mustafa K; Lee, Frank S; Lin, Shin; McDonald, Thomas V; Moskowitz, Ivan P; Quertermous, Thomas; Sankaran, Vijay G; Schwartz, David A; Silverman, Edwin K; Zhou, Xiaobo; Hasan, Ahmed A K; Luo, Xiao-Zhong James

2018-04-01

The National Institutes of Health have made substantial investments in genomic studies and technologies to identify DNA sequence variants associated with human disease phenotypes. The National Heart, Lung, and Blood Institute has been at the forefront of these commitments to ascertain genetic variation associated with heart, lung, blood, and sleep diseases and related clinical traits. Genome-wide association studies, exome- and genome-sequencing studies, and exome-genotyping studies of the National Heart, Lung, and Blood Institute-funded epidemiological and clinical case-control studies are identifying large numbers of genetic variants associated with heart, lung, blood, and sleep phenotypes. However, investigators face challenges in identification of genomic variants that are functionally disruptive among the myriad of computationally implicated variants. Studies to define mechanisms of genetic disruption encoded by computationally identified genomic variants require reproducible, adaptable, and inexpensive methods to screen candidate variant and gene function. High-throughput strategies will permit a tiered variant discovery and genetic mechanism approach that begins with rapid functional screening of a large number of computationally implicated variants and genes for discovery of those that merit mechanistic investigation. As such, improved variant-to-gene and gene-to-function screens-and adequate support for such studies-are critical to accelerating the translation of genomic findings. In this White Paper, we outline the variety of novel technologies, assays, and model systems that are making such screens faster, cheaper, and more accurate, referencing published work and ongoing work supported by the National Heart, Lung, and Blood Institute's R21/R33 Functional Assays to Screen Genomic Hits program. We discuss priorities that can accelerate the impressive but incomplete progress represented by big data genomic research. © 2018 American Heart Association, Inc.

Season of conception in rural gambia affects DNA methylation at putative human metastable epialleles.

PubMed

Waterland, Robert A; Kellermayer, Richard; Laritsky, Eleonora; Rayco-Solon, Pura; Harris, R Alan; Travisano, Michael; Zhang, Wenjuan; Torskaya, Maria S; Zhang, Jiexin; Shen, Lanlan; Manary, Mark J; Prentice, Andrew M

2010-12-23

Throughout most of the mammalian genome, genetically regulated developmental programming establishes diverse yet predictable epigenetic states across differentiated cells and tissues. At metastable epialleles (MEs), conversely, epigenotype is established stochastically in the early embryo then maintained in differentiated lineages, resulting in dramatic and systemic interindividual variation in epigenetic regulation. In the mouse, maternal nutrition affects this process, with permanent phenotypic consequences for the offspring. MEs have not previously been identified in humans. Here, using an innovative 2-tissue parallel epigenomic screen, we identified putative MEs in the human genome. In autopsy samples, we showed that DNA methylation at these loci is highly correlated across tissues representing all 3 embryonic germ layer lineages. Monozygotic twin pairs exhibited substantial discordance in DNA methylation at these loci, suggesting that their epigenetic state is established stochastically. We then tested for persistent epigenetic effects of periconceptional nutrition in rural Gambians, who experience dramatic seasonal fluctuations in nutritional status. DNA methylation at MEs was elevated in individuals conceived during the nutritionally challenged rainy season, providing the first evidence of a permanent, systemic effect of periconceptional environment on human epigenotype. At MEs, epigenetic regulation in internal organs and tissues varies among individuals and can be deduced from peripheral blood DNA. MEs should therefore facilitate an improved understanding of the role of interindividual epigenetic variation in human disease.

A Single Multiplex crRNA Array for FnCpf1-Mediated Human Genome Editing.

PubMed

Sun, Huihui; Li, Fanfan; Liu, Jie; Yang, Fayu; Zeng, Zhenhai; Lv, Xiujuan; Tu, Mengjun; Liu, Yeqing; Ge, Xianglian; Liu, Changbao; Zhao, Junzhao; Zhang, Zongduan; Qu, Jia; Song, Zongming; Gu, Feng

2018-06-15

Cpf1 has been harnessed as a tool for genome manipulation in various species because of its simplicity and high efficiency. Our recent study demonstrated that FnCpf1 could be utilized for human genome editing with notable advantages for target sequence selection due to the flexibility of the protospacer adjacent motif (PAM) sequence. Multiplex genome editing provides a powerful tool for targeting members of multigene families, dissecting gene networks, modeling multigenic disorders in vivo, and applying gene therapy. However, there are no reports at present that show FnCpf1-mediated multiplex genome editing via a single customized CRISPR RNA (crRNA) array. In the present study, we utilize a single customized crRNA array to simultaneously target multiple genes in human cells. In addition, we also demonstrate that a single customized crRNA array to target multiple sites in one gene could be achieved. Collectively, FnCpf1, a powerful genome-editing tool for multiple genomic targets, can be harnessed for effective manipulation of the human genome. Copyright © 2018 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Is mammalian chromosomal evolution driven by regions of genome fragility?

PubMed Central

Ruiz-Herrera, Aurora; Castresana, Jose; Robinson, Terence J

2006-01-01

Background A fundamental question in comparative genomics concerns the identification of mechanisms that underpin chromosomal change. In an attempt to shed light on the dynamics of mammalian genome evolution, we analyzed the distribution of syntenic blocks, evolutionary breakpoint regions, and evolutionary breakpoints taken from public databases available for seven eutherian species (mouse, rat, cattle, dog, pig, cat, and horse) and the chicken, and examined these for correspondence with human fragile sites and tandem repeats. Results Our results confirm previous investigations that showed the presence of chromosomal regions in the human genome that have been repeatedly used as illustrated by a high breakpoint accumulation in certain chromosomes and chromosomal bands. We show, however, that there is a striking correspondence between fragile site location, the positions of evolutionary breakpoints, and the distribution of tandem repeats throughout the human genome, which similarly reflect a non-uniform pattern of occurrence. Conclusion These observations provide further evidence that certain chromosomal regions in the human genome have been repeatedly used in the evolutionary process. As a consequence, the genome is a composite of fragile regions prone to reorganization that have been conserved in different lineages, and genomic tracts that do not exhibit the same levels of evolutionary plasticity. PMID:17156441

Defining functional DNA elements in the human genome

PubMed Central

Kellis, Manolis; Wold, Barbara; Snyder, Michael P.; Bernstein, Bradley E.; Kundaje, Anshul; Marinov, Georgi K.; Ward, Lucas D.; Birney, Ewan; Crawford, Gregory E.; Dekker, Job; Dunham, Ian; Elnitski, Laura L.; Farnham, Peggy J.; Feingold, Elise A.; Gerstein, Mark; Giddings, Morgan C.; Gilbert, David M.; Gingeras, Thomas R.; Green, Eric D.; Guigo, Roderic; Hubbard, Tim; Kent, Jim; Lieb, Jason D.; Myers, Richard M.; Pazin, Michael J.; Ren, Bing; Stamatoyannopoulos, John A.; Weng, Zhiping; White, Kevin P.; Hardison, Ross C.

2014-01-01

With the completion of the human genome sequence, attention turned to identifying and annotating its functional DNA elements. As a complement to genetic and comparative genomics approaches, the Encyclopedia of DNA Elements Project was launched to contribute maps of RNA transcripts, transcriptional regulator binding sites, and chromatin states in many cell types. The resulting genome-wide data reveal sites of biochemical activity with high positional resolution and cell type specificity that facilitate studies of gene regulation and interpretation of noncoding variants associated with human disease. However, the biochemically active regions cover a much larger fraction of the genome than do evolutionarily conserved regions, raising the question of whether nonconserved but biochemically active regions are truly functional. Here, we review the strengths and limitations of biochemical, evolutionary, and genetic approaches for defining functional DNA segments, potential sources for the observed differences in estimated genomic coverage, and the biological implications of these discrepancies. We also analyze the relationship between signal intensity, genomic coverage, and evolutionary conservation. Our results reinforce the principle that each approach provides complementary information and that we need to use combinations of all three to elucidate genome function in human biology and disease. PMID:24753594

Gene discovery in the hamster: a comparative genomics approach for gene annotation by sequencing of hamster testis cDNAs

PubMed Central

Oduru, Sreedhar; Campbell, Janee L; Karri, SriTulasi; Hendry, William J; Khan, Shafiq A; Williams, Simon C

2003-01-01

Background Complete genome annotation will likely be achieved through a combination of computer-based analysis of available genome sequences combined with direct experimental characterization of expressed regions of individual genomes. We have utilized a comparative genomics approach involving the sequencing of randomly selected hamster testis cDNAs to begin to identify genes not previously annotated on the human, mouse, rat and Fugu (pufferfish) genomes. Results 735 distinct sequences were analyzed for their relatedness to known sequences in public databases. Eight of these sequences were derived from previously unidentified genes and expression of these genes in testis was confirmed by Northern blotting. The genomic locations of each sequence were mapped in human, mouse, rat and pufferfish, where applicable, and the structure of their cognate genes was derived using computer-based predictions, genomic comparisons and analysis of uncharacterized cDNA sequences from human and macaque. Conclusion The use of a comparative genomics approach resulted in the identification of eight cDNAs that correspond to previously uncharacterized genes in the human genome. The proteins encoded by these genes included a new member of the kinesin superfamily, a SET/MYND-domain protein, and six proteins for which no specific function could be predicted. Each gene was expressed primarily in testis, suggesting that they may play roles in the development and/or function of testicular cells. PMID:12783626

GENOMICS: CHALLENGES AND OPPORTUNITIES FOR THE U.S. ENVIRONMENTAL PROTECTION AGENCY

EPA Science Inventory

Genomics information has great potential to enhance assessment of risks to human health and the environment, and consequently, will have significant implications for EPA. Although understanding genomic responses with respect to adverse ecological and/or human health outcomes is n...

77 FR 64816 - National Human Genome Research Institute; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-23

... sign language interpretation or other reasonable accommodations, should notify the Contact Person... relevance. Place: National Human Genome Research Institute, 5635 Fishers Lane, Terrace Level Conference Room... Genome Research Institute, 5635 Fishers Lane, Terrace Level Conference Room, Rockville, MD 20892. Contact...

Genome image programs: visualization and interpretation of Escherichia coli microarray experiments.

PubMed

Zimmer, Daniel P; Paliy, Oleg; Thomas, Brian; Gyaneshwar, Prasad; Kustu, Sydney

2004-08-01

We have developed programs to facilitate analysis of microarray data in Escherichia coli. They fall into two categories: manipulation of microarray images and identification of known biological relationships among lists of genes. A program in the first category arranges spots from glass-slide DNA microarrays according to their position in the E. coli genome and displays them compactly in genome order. The resulting genome image is presented in a web browser with an image map that allows the user to identify genes in the reordered image. Another program in the first category aligns genome images from two or more experiments. These images assist in visualizing regions of the genome with common transcriptional control. Such regions include multigene operons and clusters of operons, which are easily identified as strings of adjacent, similarly colored spots. The images are also useful for assessing the overall quality of experiments. The second category of programs includes a database and a number of tools for displaying biological information about many E. coli genes simultaneously rather than one gene at a time, which facilitates identifying relationships among them. These programs have accelerated and enhanced our interpretation of results from E. coli DNA microarray experiments. Examples are given. Copyright 2004 Genetics Society of America

dbWGFP: a database and web server of human whole-genome single nucleotide variants and their functional predictions.

PubMed

Wu, Jiaxin; Wu, Mengmeng; Li, Lianshuo; Liu, Zhuo; Zeng, Wanwen; Jiang, Rui

2016-01-01

The recent advancement of the next generation sequencing technology has enabled the fast and low-cost detection of all genetic variants spreading across the entire human genome, making the application of whole-genome sequencing a tendency in the study of disease-causing genetic variants. Nevertheless, there still lacks a repository that collects predictions of functionally damaging effects of human genetic variants, though it has been well recognized that such predictions play a central role in the analysis of whole-genome sequencing data. To fill this gap, we developed a database named dbWGFP (a database and web server of human whole-genome single nucleotide variants and their functional predictions) that contains functional predictions and annotations of nearly 8.58 billion possible human whole-genome single nucleotide variants. Specifically, this database integrates 48 functional predictions calculated by 17 popular computational methods and 44 valuable annotations obtained from various data sources. Standalone software, user-friendly query services and free downloads of this database are available at http://bioinfo.au.tsinghua.edu.cn/dbwgfp. dbWGFP provides a valuable resource for the analysis of whole-genome sequencing, exome sequencing and SNP array data, thereby complementing existing data sources and computational resources in deciphering genetic bases of human inherited diseases. © The Author(s) 2016. Published by Oxford University Press.

Comparative (Meta)genomic Analysis and Ecological Profiling of Human Gut-Specific Bacteriophage φB124-14

PubMed Central

Ogilvie, Lesley A.; Caplin, Jonathan; Dedi, Cinzia; Diston, David; Cheek, Elizabeth; Bowler, Lucas; Taylor, Huw; Ebdon, James; Jones, Brian V.

2012-01-01

Bacteriophage associated with the human gut microbiome are likely to have an important impact on community structure and function, and provide a wealth of biotechnological opportunities. Despite this, knowledge of the ecology and composition of bacteriophage in the gut bacterial community remains poor, with few well characterized gut-associated phage genomes currently available. Here we describe the identification and in-depth (meta)genomic, proteomic, and ecological analysis of a human gut-specific bacteriophage (designated φB124-14). In doing so we illuminate a fraction of the biological dark matter extant in this ecosystem and its surrounding eco-genomic landscape, identifying a novel and uncharted bacteriophage gene-space in this community. φB124-14 infects only a subset of closely related gut-associated Bacteroides fragilis strains, and the circular genome encodes functions previously found to be rare in viral genomes and human gut viral metagenome sequences, including those which potentially confer advantages upon phage and/or host bacteria. Comparative genomic analyses revealed φB124-14 is most closely related to φB40-8, the only other publically available Bacteroides sp. phage genome, whilst comparative metagenomic analysis of both phage failed to identify any homologous sequences in 136 non-human gut metagenomic datasets searched, supporting the human gut-specific nature of this phage. Moreover, a potential geographic variation in the carriage of these and related phage was revealed by analysis of their distribution and prevalence within 151 human gut microbiomes and viromes from Europe, America and Japan. Finally, ecological profiling of φB124-14 and φB40-8, using both gene-centric alignment-driven phylogenetic analyses, as well as alignment-free gene-independent approaches was undertaken. This not only verified the human gut-specific nature of both phage, but also indicated that these phage populate a distinct and unexplored ecological landscape within the human gut microbiome. PMID:22558115

The dog genome map and its use in mammalian comparative genomics.

PubMed

Switonski, Marek; Szczerbal, Izabela; Nowacka, Joanna

2004-01-01

The dog genome organization was extensively studied in the last ten years. The most important achievements are the well-developed marker genome maps, including over 3200 marker loci, and a survey of the DNA genome sequence. This knowledge, along with the most advanced map of the human genome, turned out to be very useful in comparative genomic studies. On the one hand, it has promoted the development of marker genome maps of other species of the family Canidae (red fox, arctic fox, Chinese raccoon dog) as well as studies on the evolution of their karyotype. But the most important approach is the comparative analysis of human and canine hereditary diseases. At present, causative gene mutations are known for 30 canine hereditary diseases. A majority of them have human counterparts with similar clinical and molecular features. Studies on identification of genes having a major impact on some multifactorial diseases (hip dysplasia, epilepsy) and cancers (multifocal renal cystadenocarcinoma and nodular dermatofibrosis) are advanced. Very promising are the results of gene therapy for certain canine monogenic diseases (haemophilia, hereditary retinal dystrophy, mucopolysaccharidosis), which have human equivalents. The above-mentioned examples prove a very important model role of the dog in studies of human genetic diseases. On the other hand, the identification of gene mutations responsible for hereditary diseases has a substantial impact on breeding strategy in the dog.

Orthology for comparative genomics in the mouse genome database.

PubMed

Dolan, Mary E; Baldarelli, Richard M; Bello, Susan M; Ni, Li; McAndrews, Monica S; Bult, Carol J; Kadin, James A; Richardson, Joel E; Ringwald, Martin; Eppig, Janan T; Blake, Judith A

2015-08-01

The mouse genome database (MGD) is the model organism database component of the mouse genome informatics system at The Jackson Laboratory. MGD is the international data resource for the laboratory mouse and facilitates the use of mice in the study of human health and disease. Since its beginnings, MGD has included comparative genomics data with a particular focus on human-mouse orthology, an essential component of the use of mouse as a model organism. Over the past 25 years, novel algorithms and addition of orthologs from other model organisms have enriched comparative genomics in MGD data, extending the use of orthology data to support the laboratory mouse as a model of human biology. Here, we describe current comparative data in MGD and review the history and refinement of orthology representation in this resource.

Whole genome sequencing of the fish pathogen Francisella noatunensis subsp. orientalis Toba04 gives novel insights into Francisella evolution and pathogenecity

PubMed Central

2012-01-01

Background Francisella is a genus of gram-negative bacterium highly virulent in fishes and human where F. tularensis is causing the serious disease tularaemia in human. Recently Francisella species have been reported to cause mortality in aquaculture species like Atlantic cod and tilapia. We have completed the sequencing and draft assembly of the Francisella noatunensis subsp. orientalisToba04 strain isolated from farmed Tilapia. Compared to other available Francisella genomes, it is most similar to the genome of Francisella philomiragia subsp. philomiragia, a free-living bacterium not virulent to human. Results The genome is rearranged compared to the available Francisella genomes even though we found no IS-elements in the genome. Nearly 16% percent of the predicted ORFs are pseudogenes. Computational pathway analysis indicates that a number of the metabolic pathways are disrupted due to pseudogenes. Comparing the novel genome with other available Francisella genomes, we found around 2.5% of unique genes present in Francisella noatunensis subsp. orientalis Toba04 and a list of genes uniquely present in the human-pathogenic Francisella subspecies. Most of these genes might have transferred from bacterial species through horizontal gene transfer. Comparative analysis between human and fish pathogen also provide insights into genes responsible for pathogenecity. Our analysis of pseudogenes indicates that the evolution of Francisella subspecies’s pseudogenes from Tilapia is old with large number of pseudogenes having more than one inactivating mutation. Conclusions The fish pathogen has lost non-essential genes some time ago. Evolutionary analysis of the Francisella genomes, strongly suggests that human and fish pathogenic Francisella species have evolved independently from free-living metabolically competent Francisella species. These findings will contribute to understanding the evolution of Francisella species and pathogenesis. PMID:23131096

Segmental Duplications and Copy-Number Variation in the Human Genome

PubMed Central

Sharp, Andrew J. ; Locke, Devin P. ; McGrath, Sean D. ; Cheng, Ze ; Bailey, Jeffrey A. ; Vallente, Rhea U. ; Pertz, Lisa M. ; Clark, Royden A. ; Schwartz, Stuart ; Segraves, Rick ; Oseroff, Vanessa V. ; Albertson, Donna G. ; Pinkel, Daniel ; Eichler, Evan E. 

2005-01-01

The human genome contains numerous blocks of highly homologous duplicated sequence. This higher-order architecture provides a substrate for recombination and recurrent chromosomal rearrangement associated with genomic disease. However, an assessment of the role of segmental duplications in normal variation has not yet been made. On the basis of the duplication architecture of the human genome, we defined a set of 130 potential rearrangement hotspots and constructed a targeted bacterial artificial chromosome (BAC) microarray (with 2,194 BACs) to assess copy-number variation in these regions by array comparative genomic hybridization. Using our segmental duplication BAC microarray, we screened a panel of 47 normal individuals, who represented populations from four continents, and we identified 119 regions of copy-number polymorphism (CNP), 73 of which were previously unreported. We observed an equal frequency of duplications and deletions, as well as a 4-fold enrichment of CNPs within hotspot regions, compared with control BACs (P < .000001), which suggests that segmental duplications are a major catalyst of large-scale variation in the human genome. Importantly, segmental duplications themselves were also significantly enriched >4-fold within regions of CNP. Almost without exception, CNPs were not confined to a single population, suggesting that these either are recurrent events, having occurred independently in multiple founders, or were present in early human populations. Our study demonstrates that segmental duplications define hotspots of chromosomal rearrangement, likely acting as mediators of normal variation as well as genomic disease, and it suggests that the consideration of genomic architecture can significantly improve the ascertainment of large-scale rearrangements. Our specialized segmental duplication BAC microarray and associated database of structural polymorphisms will provide an important resource for the future characterization of human genomic disorders. PMID:15918152

Sequencing of a new target genome: the Pediculus humanus humanus (Phthiraptera: Pediculidae) genome project.

PubMed

Pittendrigh, B R; Clark, J M; Johnston, J S; Lee, S H; Romero-Severson, J; Dasch, G A

2006-11-01

The human body louse, Pediculus humanus humanus (L.), and the human head louse, Pediculus humanus capitis, belong to the hemimetabolous order Phthiraptera. The body louse is the primary vector that transmits the bacterial agents of louse-borne relapsing fever, trench fever, and epidemic typhus. The genomes of the bacterial causative agents of several of these aforementioned diseases have been sequenced. Thus, determining the body louse genome will enhance studies of host-vector-pathogen interactions. Although not important as a major disease vector, head lice are of major social concern. Resistance to traditional pesticides used to control head and body lice have developed. It is imperative that new molecular targets be discovered for the development of novel compounds to control these insects. No complete genome sequence exists for a hemimetabolous insect species primarily because hemimetabolous insects often have large (2000 Mb) to very large (up to 16,300 Mb) genomes. Fortuitously, we determined that the human body louse has one of the smallest genome sizes known in insects, suggesting it may be a suitable choice as a minimal hemimetabolous genome in which many genes have been eliminated during its adaptation to human parasitism. Because many louse species infest birds and mammals, the body louse genome-sequencing project will facilitate studies of their comparative genomics. A 6-8X coverage of the body louse genome, plus sequenced expressed sequence tags, should provide the entomological, evolutionary biology, medical, and public health communities with useful genetic information.

Human genome education model project. Ethical, legal, and social implications of the human genome project: Education of interdisciplinary professionals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weiss, J.O.; Lapham, E.V.

1996-12-31

This meeting was held June 10, 1996 at Georgetown University. The purpose of this meeting was to provide a multidisciplinary forum for exchange of state-of-the-art information on the human genome education model. Topics of discussion include the following: psychosocial issues; ethical issues for professionals; legislative issues and update; and education issues.

LncRNA/DNA binding analysis reveals losses and gains and lineage specificity of genomic imprinting in mammals.

PubMed

Liu, Haihua; Shang, Xiaoxiao; Zhu, Hao

2017-05-15

Genomic imprinting is regulated by lncRNAs and is important for embryogenesis, physiology and behaviour in mammals. Aberrant imprinting causes diseases and disorders. Experimental studies have examined genomic imprinting primarily in humans and mice, thus leaving some fundamental issues poorly addressed. The cost of experimentally examining imprinted genes in many tissues in diverse species makes computational analysis of lncRNAs' DNA binding sites valuable. We performed lncRNA/DNA binding analysis in imprinting clusters from multiple mammalian clades and discovered the following: (i) lncRNAs and imprinting sites show significant losses and gains and distinct lineage-specificity; (ii) binding of lncRNAs to promoters of imprinted genes may occur widely throughout the genome; (iii) a considerable number of imprinting sites occur in only evolutionarily more derived species; and (iv) multiple lncRNAs may bind to the same imprinting sites, and some lncRNAs have multiple DNA binding motifs. These results suggest that the occurrence of abundant lncRNAs in mammalian genomes makes genomic imprinting a mechanism of adaptive evolution at the epigenome level. The data and program are available at the database LongMan at lncRNA.smu.edu.cn. zhuhao@smu.edu.cn. Supplementary data are available at Bioinformatics online. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

The life cycle of a genome project: perspectives and guidelines inspired by insect genome projects

PubMed Central

Papanicolaou, Alexie

2016-01-01

Many research programs on non-model species biology have been empowered by genomics. In turn, genomics is underpinned by a reference sequence and ancillary information created by so-called “genome projects”. The most reliable genome projects are the ones created as part of an active research program and designed to address specific questions but their life extends past publication. In this opinion paper I outline four key insights that have facilitated maintaining genomic communities: the key role of computational capability, the iterative process of building genomic resources, the value of community participation and the importance of manual curation. Taken together, these ideas can and do ensure the longevity of genome projects and the growing non-model species community can use them to focus a discussion with regards to its future genomic infrastructure. PMID:27006757

JGI Fungal Genomics Program

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grigoriev, Igor V.

2011-03-14

Genomes of energy and environment fungi are in focus of the Fungal Genomic Program at the US Department of Energy Joint Genome Institute (JGI). Its key project, the Genomics Encyclopedia of Fungi, targets fungi related to plant health (symbionts, pathogens, and biocontrol agents) and biorefinery processes (cellulose degradation, sugar fermentation, industrial hosts), and explores fungal diversity by means of genome sequencing and analysis. Over 50 fungal genomes have been sequenced by JGI to date and released through MycoCosm (www.jgi.doe.gov/fungi), a fungal web-portal, which integrates sequence and functional data with genome analysis tools for user community. Sequence analysis supported by functionalmore » genomics leads to developing parts list for complex systems ranging from ecosystems of biofuel crops to biorefineries. Recent examples of such 'parts' suggested by comparative genomics and functional analysis in these areas are presented here« less

The life cycle of a genome project: perspectives and guidelines inspired by insect genome projects.

PubMed

Papanicolaou, Alexie

2016-01-01

Many research programs on non-model species biology have been empowered by genomics. In turn, genomics is underpinned by a reference sequence and ancillary information created by so-called "genome projects". The most reliable genome projects are the ones created as part of an active research program and designed to address specific questions but their life extends past publication. In this opinion paper I outline four key insights that have facilitated maintaining genomic communities: the key role of computational capability, the iterative process of building genomic resources, the value of community participation and the importance of manual curation. Taken together, these ideas can and do ensure the longevity of genome projects and the growing non-model species community can use them to focus a discussion with regards to its future genomic infrastructure.

Genome editing: a robust technology for human stem cells.

PubMed

Chandrasekaran, Arun Pandian; Song, Minjung; Ramakrishna, Suresh

2017-09-01

Human pluripotent stem cells comprise induced pluripotent and embryonic stem cells, which have tremendous potential for biological and therapeutic applications. The development of efficient technologies for the targeted genome alteration of stem cells in disease models is a prerequisite for utilizing stem cells to their full potential. Genome editing of stem cells is possible with the help of synthetic nucleases that facilitate site-specific modification of a gene of interest. Recent advances in genome editing techniques have improved the efficiency and speed of the development of stem cells for human disease models. Zinc finger nucleases, transcription activator-like effector nucleases, and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated system are powerful tools for editing DNA at specific loci. Here, we discuss recent technological advances in genome editing with site-specific nucleases in human stem cells.

Genetic Transformation and Genomic Resources for Next-Generation Precise Genome Engineering in Vegetable Crops

PubMed Central

Cardi, Teodoro; D’Agostino, Nunzio; Tripodi, Pasquale

2017-01-01

In the frame of modern agriculture facing the predicted increase of population and general environmental changes, the securement of high quality food remains a major challenge to deal with. Vegetable crops include a large number of species, characterized by multiple geographical origins, large genetic variability and diverse reproductive features. Due to their nutritional value, they have an important place in human diet. In recent years, many crop genomes have been sequenced permitting the identification of genes and superior alleles associated with desirable traits. Furthermore, innovative biotechnological approaches allow to take a step forward towards the development of new improved cultivars harboring precise genome modifications. Sequence-based knowledge coupled with advanced biotechnologies is supporting the widespread application of new plant breeding techniques to enhance the success in modification and transfer of useful alleles into target varieties. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 system, zinc-finger nucleases, and transcription activator-like effector nucleases represent the main methods available for plant genome engineering through targeted modifications. Such technologies, however, require efficient transformation protocols as well as extensive genomic resources and accurate knowledge before they can be efficiently exploited in practical breeding programs. In this review, we revise the state of the art in relation to availability of such scientific and technological resources in various groups of vegetables, describe genome editing results obtained so far and discuss the implications for future applications. PMID:28275380

Modeling the functional genomics of autism using human neurons.

PubMed

Konopka, G; Wexler, E; Rosen, E; Mukamel, Z; Osborn, G E; Chen, L; Lu, D; Gao, F; Gao, K; Lowe, J K; Geschwind, D H

2012-02-01

Human neural progenitors from a variety of sources present new opportunities to model aspects of human neuropsychiatric disease in vitro. Such in vitro models provide the advantages of a human genetic background combined with rapid and easy manipulation, making them highly useful adjuncts to animal models. Here, we examined whether a human neuronal culture system could be utilized to assess the transcriptional program involved in human neural differentiation and to model some of the molecular features of a neurodevelopmental disorder, such as autism. Primary normal human neuronal progenitors (NHNPs) were differentiated into a post-mitotic neuronal state through addition of specific growth factors and whole-genome gene expression was examined throughout a time course of neuronal differentiation. After 4 weeks of differentiation, a significant number of genes associated with autism spectrum disorders (ASDs) are either induced or repressed. This includes the ASD susceptibility gene neurexin 1, which showed a distinct pattern from neurexin 3 in vitro, and which we validated in vivo in fetal human brain. Using weighted gene co-expression network analysis, we visualized the network structure of transcriptional regulation, demonstrating via this unbiased analysis that a significant number of ASD candidate genes are coordinately regulated during the differentiation process. As NHNPs are genetically tractable and manipulable, they can be used to study both the effects of mutations in multiple ASD candidate genes on neuronal differentiation and gene expression in combination with the effects of potential therapeutic molecules. These data also provide a step towards better understanding of the signaling pathways disrupted in ASD.

Mating programs including genomic relationships

USDA-ARS?s Scientific Manuscript database

Computer mating programs have helped breeders minimize pedigree inbreeding and avoid recessive defects by mating animals with parents that have fewer common ancestors. With genomic selection, breed associations, AI organizations, and on-farm software providers could use new programs to minimize geno...

Early Developmental and Evolutionary Origins of Gene Body DNA Methylation Patterns in Mammalian Placentas

PubMed Central

Schroeder, Diane I.; Jayashankar, Kartika; Douglas, Kory C.; Thirkill, Twanda L.; York, Daniel; Dickinson, Pete J.; Williams, Lawrence E.; Samollow, Paul B.; Ross, Pablo J.; Bannasch, Danika L.; Douglas, Gordon C.; LaSalle, Janine M.

2015-01-01

Over the last 20-80 million years the mammalian placenta has taken on a variety of morphologies through both divergent and convergent evolution. Recently we have shown that the human placenta genome has a unique epigenetic pattern of large partially methylated domains (PMDs) and highly methylated domains (HMDs) with gene body DNA methylation positively correlating with level of gene expression. In order to determine the evolutionary conservation of DNA methylation patterns and transcriptional regulatory programs in the placenta, we performed a genome-wide methylome (MethylC-seq) analysis of human, rhesus macaque, squirrel monkey, mouse, dog, horse, and cow placentas as well as opossum extraembryonic membrane. We found that, similar to human placenta, mammalian placentas and opossum extraembryonic membrane have globally lower levels of methylation compared to somatic tissues. Higher relative gene body methylation was the conserved feature across all mammalian placentas, despite differences in PMD/HMDs and absolute methylation levels. Specifically, higher methylation over the bodies of genes involved in mitosis, vesicle-mediated transport, protein phosphorylation, and chromatin modification was observed compared with the rest of the genome. As in human placenta, higher methylation is associated with higher gene expression and is predictive of genic location across species. Analysis of DNA methylation in oocytes and preimplantation embryos shows a conserved pattern of gene body methylation similar to the placenta. Intriguingly, mouse and cow oocytes and mouse early embryos have PMD/HMDs but their placentas do not, suggesting that PMD/HMDs are a feature of early preimplantation methylation patterns that become lost during placental development in some species and following implantation of the embryo. PMID:26241857

Intricacies in arrangement of SNP haplotypes suggest "Great Admixture" that created modern humans.

PubMed

Dutta, Rajib; Mainsah, Joseph; Yatskiv, Yuriy; Chakrabortty, Sharmistha; Brennan, Patrick; Khuder, Basil; Qiu, Shuhao; Fedorova, Larisa; Fedorov, Alexei

2017-06-05

Inferring history from genomic sequences is challenging and problematic because chromosomes are mosaics of thousands of small Identicalby-descent (IBD) fragments, each of them having their own unique story. However, the main events in recent evolution might be deciphered from comparative analysis of numerous loci. A paradox of why humans, whose effective population size is only 10 4 , have nearly three million frequent SNPs is formulated and examined. We studied 5398 loci evenly covering all human autosomes. Common haplotypes built from frequent SNPs that are present in people from various populations have been examined. We demonstrated highly non-random arrangement of alleles in common haplotypes. Abundance of mutually exclusive pairs of common haplotypes that have different alleles at every polymorphic position (so-called Yin/Yang haplotypes) was found in 56% of loci. A novel widely spread category of common haplotypes named Mosaic has been described. Mosaic consists of numerous pieces of Yin/Yang haplotypes and represents an ancestral stage of one of them. Scenarios of possible appearance of large number of frequent human SNPs and their habitual arrangement in Yin/Yang common haplotypes have been evaluated with an advanced genomic simulation algorithm. Computer modeling demonstrated that the observed arrangement of 2.9 million frequent SNPs could not originate from a sole stand-alone population. A "Great Admixture" event has been proposed that can explain peculiarities with frequent SNP distributions. This Great Admixture presumably occurred 100-300 thousand years ago between two ancestral populations that had been separated from each other about a million years ago. Our programs and algorithms can be applied to other species to perform evolutionary and comparative genomics.

In the Beginning was the Genome: Genomics and the Bi-textuality of Human Existence.

PubMed

Zwart, H A E Hub

2018-04-01

This paper addresses the cultural impact of genomics and the Human Genome Project (HGP) on human self-understanding. Notably, it addresses the claim made by Francis Collins (director of the HGP) that the genome is the language of God and the claim made by Max Delbrück (founding father of molecular life sciences research) that Aristotle must be credited with having predicted DNA as the soul that organises bio-matter. From a continental philosophical perspective I will argue that human existence results from a dialectical interaction between two types of texts: the language of molecular biology and the language of civilisation; the language of the genome and the language of our socio-cultural, symbolic ambiance. Whereas the former ultimately builds on the alphabets of genes and nucleotides, the latter is informed by primordial texts such as the Bible and the Quran. In applied bioethics deliberations on genomics, science is easily framed as liberating and progressive, religious world-views as conservative and restrictive (Zwart 1993). This paper focusses on the broader cultural ambiance of the debate to discern how the bi-textuality of human existence is currently undergoing a transition, as not only the physiological, but also the normative dimension is being reframed in biomolecular and terabyte terms.

Genetic recombination pathways and their application for genome modification of human embryonic stem cells.

PubMed

Nieminen, Mikko; Tuuri, Timo; Savilahti, Harri

2010-10-01

Human embryonic stem cells are pluripotent cells derived from early human embryo and retain a potential to differentiate into all adult cell types. They provide vast opportunities in cell replacement therapies and are expected to become significant tools in drug discovery as well as in the studies of cellular and developmental functions of human genes. The progress in applying different types of DNA recombination reactions for genome modification in a variety of eukaryotic cell types has provided means to utilize recombination-based strategies also in human embryonic stem cells. Homologous recombination-based methods, particularly those utilizing extended homologous regions and those employing zinc finger nucleases to boost genomic integration, have shown their usefulness in efficient genome modification. Site-specific recombination systems are potent genome modifiers, and they can be used to integrate DNA into loci that contain an appropriate recombination signal sequence, either naturally occurring or suitably pre-engineered. Non-homologous recombination can be used to generate random integrations in genomes relatively effortlessly, albeit with a moderate efficiency and precision. DNA transposition-based strategies offer substantially more efficient random strategies and provide means to generate single-copy insertions, thus potentiating the generation of genome-wide insertion libraries applicable in genetic screens. 2010 Elsevier Inc. All rights reserved.

The Human Genome Project: An Imperative for International Collaboration.

ERIC Educational Resources Information Center

Allende, J. E.

1989-01-01

Discussed is the Human Genome Project which aims to decipher the totality of the human genetic information. The historical background, the objectives, international cooperation, ethical discussion, and the role of UNESCO are included. (KR)

Production of Purified CasRNPs for Efficacious Genome Editing.

PubMed

Lingeman, Emily; Jeans, Chris; Corn, Jacob E

2017-10-02

CRISPR-Cas systems have been harnessed as modular genome editing reagents for functional genomics and show promise to cure genetic diseases. Directed by a guide RNA, a Cas effector introduces a double stranded break in DNA and host cell DNA repair leads to the introduction of errors (e.g., to knockout a gene) or a programmed change. Introduction of a Cas effector and guide RNA as a purified Cas ribonucleoprotein complex (CasRNP) has recently emerged as a powerful approach to alter cell types and organisms. Not only does CasRNP editing exhibit increased efficacy and specificity, it avoids optimization and iteration of species-specific factors such as codon usage, promoters, and terminators. CasRNP editing has been rapidly adopted for research use in many contexts and is quickly becoming a popular method to edit primary cells for therapeutic application. This article describes how to make a Cas9 RNP and outlines its use for gene editing in human cells. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

GenPlay Multi-Genome, a tool to compare and analyze multiple human genomes in a graphical interface.

PubMed

Lajugie, Julien; Fourel, Nicolas; Bouhassira, Eric E

2015-01-01

Parallel visualization of multiple individual human genomes is a complex endeavor that is rapidly gaining importance with the increasing number of personal, phased and cancer genomes that are being generated. It requires the display of variants such as SNPs, indels and structural variants that are unique to specific genomes and the introduction of multiple overlapping gaps in the reference sequence. Here, we describe GenPlay Multi-Genome, an application specifically written to visualize and analyze multiple human genomes in parallel. GenPlay Multi-Genome is ideally suited for the comparison of allele-specific expression and functional genomic data obtained from multiple phased genomes in a graphical interface with access to multiple-track operation. It also allows the analysis of data that have been aligned to custom genomes rather than to a standard reference and can be used as a variant calling format file browser and as a tool to compare different genome assembly, such as hg19 and hg38. GenPlay is available under the GNU public license (GPL-3) from http://genplay.einstein.yu.edu. The source code is available at https://github.com/JulienLajugie/GenPlay. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Human genome project and sickle cell disease.

PubMed

Norman, Brenda J; Miller, Sheila D

2011-01-01

Sickle cell disease is one of the most common genetic blood disorders in the United States that affects 1 in every 375 African Americans. Sickle cell disease is an inherited condition caused by abnormal hemoglobin in the red blood cells. The Human Genome Project has provided valuable insight and extensive research advances in the understanding of the human genome and sickle cell disease. Significant progress in genetic knowledge has led to an increase in the ability for researchers to map and sequence genes for diagnosis, treatment, and prevention of sickle cell disease and other chronic illnesses. This article explores some of the recent knowledge and advances about sickle cell disease and the Human Genome Project.

Development and application of Human Genome Epidemiology

NASA Astrophysics Data System (ADS)

Xu, Jingwen

2017-12-01

Epidemiology is a science that studies distribution of diseases and health in population and its influencing factors, it also studies how to prevent and cure disease and promote health strategies and measures. Epidemiology has developed rapidly in recent years and it is an intercross subject with various other disciplines to form a series of branch disciplines such as Genetic epidemiology, molecular epidemiology, drug epidemiology and tumor epidemiology. With the implementation and completion of Human Genome Project (HGP), Human Genome Epidemiology (HuGE) has emerged at this historic moment. In this review, the development of Human Genome Epidemiology, research content, the construction and structure of relevant network, research standards, as well as the existing results and problems are briefly outlined.

First moves of the USSR Human Genome Project

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bayev, A.A.

1991-01-01

The USSR Human Genome Project is an intrinsic part of genetic research that still has to recover from the hard ordeal of the past. The imperious influence of Trofim Lysenko and his concepts inhibited the progress of genetics, which had been developing quite successfully before him, and suppressed and often physically destroyed many of our outstanding scientists. Human genome studies were discussed for the first time at a general meeting of the USSR Academy of Sciences in 1988. As early as December 1988, the USSR Council of Ministers adopted a resolution on the creation of a Human Genome Project, whichmore » since 1989 exists in the USSR as one of the national projects.« less

Genomics Community Resources | Informatics Technology for Cancer Research (ITCR)

Cancer.gov

To facilitate genomic research and the dissemination of its products, National Human Genome Research Institute (NHGRI) supports genomic resources that are crucial for basic research, disease studies, model organism studies, and other biomedical research.  Awards under this FOA will support the development and distribution of genomic resources that will be valuable for the broad research community, using cost-effective approaches.  Such resources include (but are not limited to) databases and informatics resources (such as human and model organism databases, ontologies, and analysi

An overview of human genetic privacy.

PubMed

Shi, Xinghua; Wu, Xintao

2017-01-01

The study of human genomics is becoming a Big Data science, owing to recent biotechnological advances leading to availability of millions of personal genome sequences, which can be combined with biometric measurements from mobile apps and fitness trackers, and of human behavior data monitored from mobile devices and social media. With increasing research opportunities for integrative genomic studies through data sharing, genetic privacy emerges as a legitimate yet challenging concern that needs to be carefully addressed, not only for individuals but also for their families. In this paper, we present potential genetic privacy risks and relevant ethics and regulations for sharing and protecting human genomics data. We also describe the techniques for protecting human genetic privacy from three broad perspectives: controlled access, differential privacy, and cryptographic solutions. © 2016 New York Academy of Sciences.

From hacking the human genome to editing organs.

PubMed

Tobita, Takamasa; Guzman-Lepe, Jorge; Collin de l'Hortet, Alexandra

2015-01-01

In the recent decades, human genome engineering has been one of the major interesting research subjects, essentially because it raises new possibilities for personalized medicine and biotechnologies. With the development of engineered nucleases such as the Zinc Finger Nucleases (ZFNs), the Transcription activator-like effector nucleases (TALENs) and more recently the Clustered Regularly Interspaced short Palindromic Repeats (CRISPR), the field of human genome edition has evolved very rapidly. Every new genetic tool is broadening the scope of applications on human tissues, even before we can completely master each of these tools. In this review, we will present the recent advances regarding human genome edition tools, we will discuss the numerous implications they have in research and medicine, and we will mention the limits and concerns about such technologies.

From hacking the human genome to editing organs

PubMed Central

Tobita, Takamasa; Guzman-Lepe, Jorge; Collin de l'Hortet, Alexandra

2015-01-01

ABSTRACT In the recent decades, human genome engineering has been one of the major interesting research subjects, essentially because it raises new possibilities for personalized medicine and biotechnologies. With the development of engineered nucleases such as the Zinc Finger Nucleases (ZFNs), the Transcription activator-like effector nucleases (TALENs) and more recently the Clustered Regularly Interspaced short Palindromic Repeats (CRISPR), the field of human genome edition has evolved very rapidly. Every new genetic tool is broadening the scope of applications on human tissues, even before we can completely master each of these tools. In this review, we will present the recent advances regarding human genome edition tools, we will discuss the numerous implications they have in research and medicine, and we will mention the limits and concerns about such technologies PMID:26588350

GenomeGraphs: integrated genomic data visualization with R.

PubMed

Durinck, Steffen; Bullard, James; Spellman, Paul T; Dudoit, Sandrine

2009-01-06

Biological studies involve a growing number of distinct high-throughput experiments to characterize samples of interest. There is a lack of methods to visualize these different genomic datasets in a versatile manner. In addition, genomic data analysis requires integrated visualization of experimental data along with constantly changing genomic annotation and statistical analyses. We developed GenomeGraphs, as an add-on software package for the statistical programming environment R, to facilitate integrated visualization of genomic datasets. GenomeGraphs uses the biomaRt package to perform on-line annotation queries to Ensembl and translates these to gene/transcript structures in viewports of the grid graphics package. This allows genomic annotation to be plotted together with experimental data. GenomeGraphs can also be used to plot custom annotation tracks in combination with different experimental data types together in one plot using the same genomic coordinate system. GenomeGraphs is a flexible and extensible software package which can be used to visualize a multitude of genomic datasets within the statistical programming environment R.

Discovering functional DNA elements using population genomic information: a proof of concept using human mtDNA.

PubMed

Schrider, Daniel R; Kern, Andrew D

2014-06-09

Identifying the complete set of functional elements within the human genome would be a windfall for multiple areas of biological research including medicine, molecular biology, and evolution. Complete knowledge of function would aid in the prioritization of loci when searching for the genetic bases of disease or adaptive phenotypes. Because mutations that disrupt function are disfavored by natural selection, purifying selection leaves a detectable signature within functional elements; accordingly, this signal has been exploited for over a decade through the use of genomic comparisons of distantly related species. While this is so, the functional complement of the genome changes extensively across time and between lineages; therefore, evidence of the current action of purifying selection in humans is essential. Because the removal of deleterious mutations by natural selection also reduces within-species genetic diversity within functional loci, dense population genetic data have the potential to reveal genomic elements that are currently functional. Here, we assess the potential of this approach by examining an ultradeep sample of human mitochondrial genomes (n = 16,411). We show that the high density of polymorphism in this data set precisely delineates regions experiencing purifying selection. Furthermore, we show that the number of segregating alleles at a site is strongly correlated with its divergence across species after accounting for known mutational biases in human mitochondrial DNA (ρ = 0.51; P < 2.2 × 10(-16)). These two measures track one another at a remarkably fine scale across many loci-a correlation that is purely the result of natural selection. Our results demonstrate that genetic variation has the potential to reveal with surprising precision which regions in the genome are currently performing important functions and likely to have deleterious fitness effects when mutated. As more complete human genomes are sequenced, similar power to reveal purifying selection may be achievable in the human nuclear genome. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

LaGomiCs—Lagomorph Genomics Consortium: An International Collaborative Effort for Sequencing the Genomes of an Entire Mammalian Order

PubMed Central

Di Palma, Federica; Flicek, Paul; Smith, Andrew T.; Thulin, Carl-Gustaf

2016-01-01

The order Lagomorpha comprises about 90 living species, divided in 2 families: the pikas (Family Ochotonidae), and the rabbits, hares, and jackrabbits (Family Leporidae). Lagomorphs are important economically and scientifically as major human food resources, valued game species, pests of agricultural significance, model laboratory animals, and key elements in food webs. A quarter of the lagomorph species are listed as threatened. They are native to all continents except Antarctica, and occur up to 5000 m above sea level, from the equator to the Arctic, spanning a wide range of environmental conditions. The order has notable taxonomic problems presenting significant difficulties for defining a species due to broad phenotypic variation, overlap of morphological characteristics, and relatively recent speciation events. At present, only the genomes of 2 species, the European rabbit (Oryctolagus cuniculus) and American pika (Ochotona princeps) have been sequenced and assembled. Starting from a paucity of genome information, the main scientific aim of the Lagomorph Genomics Consortium (LaGomiCs), born from a cooperative initiative of the European COST Action “A Collaborative European Network on Rabbit Genome Biology—RGB-Net” and the World Lagomorph Society (WLS), is to provide an international framework for the sequencing of the genome of all extant and selected extinct lagomorphs. Sequencing the genomes of an entire order will provide a large amount of information to address biological problems not only related to lagomorphs but also to all mammals. We present current and planned sequencing programs and outline the final objective of LaGomiCs possible through broad international collaboration. PMID:26921276

The Nature and Evolution of Genomic Diversity in the Mycobacterium tuberculosis Complex.

PubMed

Brites, Daniela; Gagneux, Sebastien

2017-01-01

The Mycobacterium tuberculosis Complex (MTBC) consists of a clonal group of several mycobacterial lineages pathogenic to a range of different mammalian hosts. In this chapter, we discuss the origins and the evolutionary forces shaping the genomic diversity of the human-adapted MTBC. Advances in whole-genome sequencing have brought invaluable insights into the macro-evolution of the MTBC, and the biogeographical distribution of the different MTBC lineages, the phylogenetic relationships between these lineages. Moreover, micro-evolutionary processes start to be better understood, including those influencing bacterial mutation rates and those governing the fate of new mutations emerging within patients during treatment. Current genomic and epidemiological evidence reflect the fact that, through ecological specialization, the MTBC affecting humans became an obligate and extremely well-adapted human pathogen. Identifying the adaptive traits of human-adapted MTBC and unraveling the bacterial loci that interact with human genomic variation might help identify new targets for developing better vaccines and designing more effective treatments.

The bornavirus-derived human protein EBLN1 promotes efficient cell cycle transit, microtubule organisation and genome stability.

PubMed

Myers, Katie N; Barone, Giancarlo; Ganesh, Anil; Staples, Christopher J; Howard, Anna E; Beveridge, Ryan D; Maslen, Sarah; Skehel, J Mark; Collis, Spencer J

2016-10-14

It was recently discovered that vertebrate genomes contain multiple endogenised nucleotide sequences derived from the non-retroviral RNA bornavirus. Strikingly, some of these elements have been evolutionary maintained as open reading frames in host genomes for over 40 million years, suggesting that some endogenised bornavirus-derived elements (EBL) might encode functional proteins. EBLN1 is one such element established through endogenisation of the bornavirus N gene (BDV N). Here, we functionally characterise human EBLN1 as a novel regulator of genome stability. Cells depleted of human EBLN1 accumulate DNA damage both under non-stressed conditions and following exogenously induced DNA damage. EBLN1-depleted cells also exhibit cell cycle abnormalities and defects in microtubule organisation as well as premature centrosome splitting, which we attribute in part, to improper localisation of the nuclear envelope protein TPR. Our data therefore reveal that human EBLN1 possesses important cellular functions within human cells, and suggest that other EBLs present within vertebrate genomes may also possess important cellular functions.

Substantial variation in the extent of mitochondrial genome fragmentation among blood-sucking lice of mammals.

PubMed

Jiang, Haowei; Barker, Stephen C; Shao, Renfu

2013-01-01

Blood-sucking lice of humans have extensively fragmented mitochondrial (mt) genomes. Human head louse and body louse have their 37 mt genes on 20 minichromosomes. In human pubic louse, the 34 mt genes known are on 14 minichromosomes. To understand the process of mt genome fragmentation in the blood-sucking lice of mammals, we sequenced the mt genomes of the domestic pig louse, Haematopinus suis, and the wild pig louse, H. apri, which diverged from human lice approximately 65 Ma. The 37 mt genes of the pig lice are on nine circular minichromosomes; each minichromosome is 3-4 kb in size. The pig lice have four genes per minichromosome on average, in contrast to two genes per minichromosome in the human lice. One minichromosome of the pig lice has eight genes and is the most gene-rich minichromosome found in the sucking lice. Our results indicate substantial variation in the rate and extent of mt genome fragmentation among different lineages of the sucking lice.

Substantial Variation in the Extent of Mitochondrial Genome Fragmentation among Blood-Sucking Lice of Mammals

PubMed Central

Jiang, Haowei; Barker, Stephen C.; Shao, Renfu

2013-01-01

Blood-sucking lice of humans have extensively fragmented mitochondrial (mt) genomes. Human head louse and body louse have their 37 mt genes on 20 minichromosomes. In human pubic louse, the 34 mt genes known are on 14 minichromosomes. To understand the process of mt genome fragmentation in the blood-sucking lice of mammals, we sequenced the mt genomes of the domestic pig louse, Haematopinus suis, and the wild pig louse, H. apri, which diverged from human lice approximately 65 Ma. The 37 mt genes of the pig lice are on nine circular minichromosomes; each minichromosome is 3–4 kb in size. The pig lice have four genes per minichromosome on average, in contrast to two genes per minichromosome in the human lice. One minichromosome of the pig lice has eight genes and is the most gene-rich minichromosome found in the sucking lice. Our results indicate substantial variation in the rate and extent of mt genome fragmentation among different lineages of the sucking lice. PMID:23781098

Unexplored therapeutic opportunities in the human genome.

PubMed

Oprea, Tudor I; Bologa, Cristian G; Brunak, Søren; Campbell, Allen; Gan, Gregory N; Gaulton, Anna; Gomez, Shawn M; Guha, Rajarshi; Hersey, Anne; Holmes, Jayme; Jadhav, Ajit; Jensen, Lars Juhl; Johnson, Gary L; Karlson, Anneli; Leach, Andrew R; Ma'ayan, Avi; Malovannaya, Anna; Mani, Subramani; Mathias, Stephen L; McManus, Michael T; Meehan, Terrence F; von Mering, Christian; Muthas, Daniel; Nguyen, Dac-Trung; Overington, John P; Papadatos, George; Qin, Jun; Reich, Christian; Roth, Bryan L; Schürer, Stephan C; Simeonov, Anton; Sklar, Larry A; Southall, Noel; Tomita, Susumu; Tudose, Ilinca; Ursu, Oleg; Vidovic, Dušica; Waller, Anna; Westergaard, David; Yang, Jeremy J; Zahoránszky-Köhalmi, Gergely

2018-05-01

A large proportion of biomedical research and the development of therapeutics is focused on a small fraction of the human genome. In a strategic effort to map the knowledge gaps around proteins encoded by the human genome and to promote the exploration of currently understudied, but potentially druggable, proteins, the US National Institutes of Health launched the Illuminating the Druggable Genome (IDG) initiative in 2014. In this article, we discuss how the systematic collection and processing of a wide array of genomic, proteomic, chemical and disease-related resource data by the IDG Knowledge Management Center have enabled the development of evidence-based criteria for tracking the target development level (TDL) of human proteins, which indicates a substantial knowledge deficit for approximately one out of three proteins in the human proteome. We then present spotlights on the TDL categories as well as key drug target classes, including G protein-coupled receptors, protein kinases and ion channels, which illustrate the nature of the unexplored opportunities for biomedical research and therapeutic development.

Whole Genome Amplification and Reduced-Representation Genome Sequencing of Schistosoma japonicum Miracidia

PubMed Central

Shortt, Jonathan A.; Card, Daren C.; Schield, Drew R.; Liu, Yang; Zhong, Bo; Castoe, Todd A.

2017-01-01

Background In areas where schistosomiasis control programs have been implemented, morbidity and prevalence have been greatly reduced. However, to sustain these reductions and move towards interruption of transmission, new tools for disease surveillance are needed. Genomic methods have the potential to help trace the sources of new infections, and allow us to monitor drug resistance. Large-scale genotyping efforts for schistosome species have been hindered by cost, limited numbers of established target loci, and the small amount of DNA obtained from miracidia, the life stage most readily acquired from humans. Here, we present a method using next generation sequencing to provide high-resolution genomic data from S. japonicum for population-based studies. Methodology/Principal Findings We applied whole genome amplification followed by double digest restriction site associated DNA sequencing (ddRADseq) to individual S. japonicum miracidia preserved on Whatman FTA cards. We found that we could effectively and consistently survey hundreds of thousands of variants from 10,000 to 30,000 loci from archived miracidia as old as six years. An analysis of variation from eight miracidia obtained from three hosts in two villages in Sichuan showed clear population structuring by village and host even within this limited sample. Conclusions/Significance This high-resolution sequencing approach yields three orders of magnitude more information than microsatellite genotyping methods that have been employed over the last decade, creating the potential to answer detailed questions about the sources of human infections and to monitor drug resistance. Costs per sample range from $50-$200, depending on the amount of sequence information desired, and we expect these costs can be reduced further given continued reductions in sequencing costs, improvement of protocols, and parallelization. This approach provides new promise for using modern genome-scale sampling to S. japonicum surveillance, and could be applied to other schistosome species and other parasitic helminthes. PMID:28107347

Single-molecule optical genome mapping of a human HapMap and a colorectal cancer cell line.

PubMed

Teo, Audrey S M; Verzotto, Davide; Yao, Fei; Nagarajan, Niranjan; Hillmer, Axel M

2015-01-01

Next-generation sequencing (NGS) technologies have changed our understanding of the variability of the human genome. However, the identification of genome structural variations based on NGS approaches with read lengths of 35-300 bases remains a challenge. Single-molecule optical mapping technologies allow the analysis of DNA molecules of up to 2 Mb and as such are suitable for the identification of large-scale genome structural variations, and for de novo genome assemblies when combined with short-read NGS data. Here we present optical mapping data for two human genomes: the HapMap cell line GM12878 and the colorectal cancer cell line HCT116. High molecular weight DNA was obtained by embedding GM12878 and HCT116 cells, respectively, in agarose plugs, followed by DNA extraction under mild conditions. Genomic DNA was digested with KpnI and 310,000 and 296,000 DNA molecules (≥ 150 kb and 10 restriction fragments), respectively, were analyzed per cell line using the Argus optical mapping system. Maps were aligned to the human reference by OPTIMA, a new glocal alignment method. Genome coverage of 6.8× and 5.7× was obtained, respectively; 2.9× and 1.7× more than the coverage obtained with previously available software. Optical mapping allows the resolution of large-scale structural variations of the genome, and the scaffold extension of NGS-based de novo assemblies. OPTIMA is an efficient new alignment method; our optical mapping data provide a resource for genome structure analyses of the human HapMap reference cell line GM12878, and the colorectal cancer cell line HCT116.

Genome-Wide Analysis of the Arabidopsis Replication Timing Program1[OPEN

PubMed Central

Brooks, Ashley M.; Wheeler, Emily; LeBlanc, Chantal; Lee, Tae-Jin; Martienssen, Robert A.; Thompson, William F.

2018-01-01

Eukaryotes use a temporally regulated process, known as the replication timing program, to ensure that their genomes are fully and accurately duplicated during S phase. Replication timing programs are predictive of genomic features and activity and are considered to be functional readouts of chromatin organization. Although replication timing programs have been described for yeast and animal systems, much less is known about the temporal regulation of plant DNA replication or its relationship to genome sequence and chromatin structure. We used the thymidine analog, 5-ethynyl-2′-deoxyuridine, in combination with flow sorting and Repli-Seq to describe, at high-resolution, the genome-wide replication timing program for Arabidopsis (Arabidopsis thaliana) Col-0 suspension cells. We identified genomic regions that replicate predominantly during early, mid, and late S phase, and correlated these regions with genomic features and with data for chromatin state, accessibility, and long-distance interaction. Arabidopsis chromosome arms tend to replicate early while pericentromeric regions replicate late. Early and mid-replicating regions are gene-rich and predominantly euchromatic, while late regions are rich in transposable elements and primarily heterochromatic. However, the distribution of chromatin states across the different times is complex, with each replication time corresponding to a mixture of states. Early and mid-replicating sequences interact with each other and not with late sequences, but early regions are more accessible than mid regions. The replication timing program in Arabidopsis reflects a bipartite genomic organization with early/mid-replicating regions and late regions forming separate, noninteracting compartments. The temporal order of DNA replication within the early/mid compartment may be modulated largely by chromatin accessibility. PMID:29301956

Human genome-microbiome interaction: metagenomics frontiers for the aetiopathology of autoimmune diseases

PubMed Central

Nalbantoglu, Ufuk

2017-01-01

A short while ago, the human genome and microbiome were analysed simultaneously for the first time as a multi-omic approach. The analyses of heterogeneous population cohorts showed that microbiome components were associated with human genome variations. In-depth analysis of these results reveals that the majority of those relationships are between immune pathways and autoimmune disease-associated microbiome components. Thus, it can be hypothesized that autoimmunity may be associated with homeostatic disequilibrium of the human-microbiome interactome. Further analysis of human genome–human microbiome relationships in disease contexts with tailored systems biology approaches may yield insights into disease pathogenesis and prognosis. PMID:28785422

The zebrafish reference genome sequence and its relationship to the human genome.

PubMed

Howe, Kerstin; Clark, Matthew D; Torroja, Carlos F; Torrance, James; Berthelot, Camille; Muffato, Matthieu; Collins, John E; Humphray, Sean; McLaren, Karen; Matthews, Lucy; McLaren, Stuart; Sealy, Ian; Caccamo, Mario; Churcher, Carol; Scott, Carol; Barrett, Jeffrey C; Koch, Romke; Rauch, Gerd-Jörg; White, Simon; Chow, William; Kilian, Britt; Quintais, Leonor T; Guerra-Assunção, José A; Zhou, Yi; Gu, Yong; Yen, Jennifer; Vogel, Jan-Hinnerk; Eyre, Tina; Redmond, Seth; Banerjee, Ruby; Chi, Jianxiang; Fu, Beiyuan; Langley, Elizabeth; Maguire, Sean F; Laird, Gavin K; Lloyd, David; Kenyon, Emma; Donaldson, Sarah; Sehra, Harminder; Almeida-King, Jeff; Loveland, Jane; Trevanion, Stephen; Jones, Matt; Quail, Mike; Willey, Dave; Hunt, Adrienne; Burton, John; Sims, Sarah; McLay, Kirsten; Plumb, Bob; Davis, Joy; Clee, Chris; Oliver, Karen; Clark, Richard; Riddle, Clare; Elliot, David; Eliott, David; Threadgold, Glen; Harden, Glenn; Ware, Darren; Begum, Sharmin; Mortimore, Beverley; Mortimer, Beverly; Kerry, Giselle; Heath, Paul; Phillimore, Benjamin; Tracey, Alan; Corby, Nicole; Dunn, Matthew; Johnson, Christopher; Wood, Jonathan; Clark, Susan; Pelan, Sarah; Griffiths, Guy; Smith, Michelle; Glithero, Rebecca; Howden, Philip; Barker, Nicholas; Lloyd, Christine; Stevens, Christopher; Harley, Joanna; Holt, Karen; Panagiotidis, Georgios; Lovell, Jamieson; Beasley, Helen; Henderson, Carl; Gordon, Daria; Auger, Katherine; Wright, Deborah; Collins, Joanna; Raisen, Claire; Dyer, Lauren; Leung, Kenric; Robertson, Lauren; Ambridge, Kirsty; Leongamornlert, Daniel; McGuire, Sarah; Gilderthorp, Ruth; Griffiths, Coline; Manthravadi, Deepa; Nichol, Sarah; Barker, Gary; Whitehead, Siobhan; Kay, Michael; Brown, Jacqueline; Murnane, Clare; Gray, Emma; Humphries, Matthew; Sycamore, Neil; Barker, Darren; Saunders, David; Wallis, Justene; Babbage, Anne; Hammond, Sian; Mashreghi-Mohammadi, Maryam; Barr, Lucy; Martin, Sancha; Wray, Paul; Ellington, Andrew; Matthews, Nicholas; Ellwood, Matthew; Woodmansey, Rebecca; Clark, Graham; Cooper, James D; Cooper, James; Tromans, Anthony; Grafham, Darren; Skuce, Carl; Pandian, Richard; Andrews, Robert; Harrison, Elliot; Kimberley, Andrew; Garnett, Jane; Fosker, Nigel; Hall, Rebekah; Garner, Patrick; Kelly, Daniel; Bird, Christine; Palmer, Sophie; Gehring, Ines; Berger, Andrea; Dooley, Christopher M; Ersan-Ürün, Zübeyde; Eser, Cigdem; Geiger, Horst; Geisler, Maria; Karotki, Lena; Kirn, Anette; Konantz, Judith; Konantz, Martina; Oberländer, Martina; Rudolph-Geiger, Silke; Teucke, Mathias; Lanz, Christa; Raddatz, Günter; Osoegawa, Kazutoyo; Zhu, Baoli; Rapp, Amanda; Widaa, Sara; Langford, Cordelia; Yang, Fengtang; Schuster, Stephan C; Carter, Nigel P; Harrow, Jennifer; Ning, Zemin; Herrero, Javier; Searle, Steve M J; Enright, Anton; Geisler, Robert; Plasterk, Ronald H A; Lee, Charles; Westerfield, Monte; de Jong, Pieter J; Zon, Leonard I; Postlethwait, John H; Nüsslein-Volhard, Christiane; Hubbard, Tim J P; Roest Crollius, Hugues; Rogers, Jane; Stemple, Derek L

2013-04-25

Zebrafish have become a popular organism for the study of vertebrate gene function. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.

The zebrafish reference genome sequence and its relationship to the human genome

PubMed Central

Howe, Kerstin; Clark, Matthew D.; Torroja, Carlos F.; Torrance, James; Berthelot, Camille; Muffato, Matthieu; Collins, John E.; Humphray, Sean; McLaren, Karen; Matthews, Lucy; McLaren, Stuart; Sealy, Ian; Caccamo, Mario; Churcher, Carol; Scott, Carol; Barrett, Jeffrey C.; Koch, Romke; Rauch, Gerd-Jörg; White, Simon; Chow, William; Kilian, Britt; Quintais, Leonor T.; Guerra-Assunção, José A.; Zhou, Yi; Gu, Yong; Yen, Jennifer; Vogel, Jan-Hinnerk; Eyre, Tina; Redmond, Seth; Banerjee, Ruby; Chi, Jianxiang; Fu, Beiyuan; Langley, Elizabeth; Maguire, Sean F.; Laird, Gavin K.; Lloyd, David; Kenyon, Emma; Donaldson, Sarah; Sehra, Harminder; Almeida-King, Jeff; Loveland, Jane; Trevanion, Stephen; Jones, Matt; Quail, Mike; Willey, Dave; Hunt, Adrienne; Burton, John; Sims, Sarah; McLay, Kirsten; Plumb, Bob; Davis, Joy; Clee, Chris; Oliver, Karen; Clark, Richard; Riddle, Clare; Eliott, David; Threadgold, Glen; Harden, Glenn; Ware, Darren; Mortimer, Beverly; Kerry, Giselle; Heath, Paul; Phillimore, Benjamin; Tracey, Alan; Corby, Nicole; Dunn, Matthew; Johnson, Christopher; Wood, Jonathan; Clark, Susan; Pelan, Sarah; Griffiths, Guy; Smith, Michelle; Glithero, Rebecca; Howden, Philip; Barker, Nicholas; Stevens, Christopher; Harley, Joanna; Holt, Karen; Panagiotidis, Georgios; Lovell, Jamieson; Beasley, Helen; Henderson, Carl; Gordon, Daria; Auger, Katherine; Wright, Deborah; Collins, Joanna; Raisen, Claire; Dyer, Lauren; Leung, Kenric; Robertson, Lauren; Ambridge, Kirsty; Leongamornlert, Daniel; McGuire, Sarah; Gilderthorp, Ruth; Griffiths, Coline; Manthravadi, Deepa; Nichol, Sarah; Barker, Gary; Whitehead, Siobhan; Kay, Michael; Brown, Jacqueline; Murnane, Clare; Gray, Emma; Humphries, Matthew; Sycamore, Neil; Barker, Darren; Saunders, David; Wallis, Justene; Babbage, Anne; Hammond, Sian; Mashreghi-Mohammadi, Maryam; Barr, Lucy; Martin, Sancha; Wray, Paul; Ellington, Andrew; Matthews, Nicholas; Ellwood, Matthew; Woodmansey, Rebecca; Clark, Graham; Cooper, James; Tromans, Anthony; Grafham, Darren; Skuce, Carl; Pandian, Richard; Andrews, Robert; Harrison, Elliot; Kimberley, Andrew; Garnett, Jane; Fosker, Nigel; Hall, Rebekah; Garner, Patrick; Kelly, Daniel; Bird, Christine; Palmer, Sophie; Gehring, Ines; Berger, Andrea; Dooley, Christopher M.; Ersan-Ürün, Zübeyde; Eser, Cigdem; Geiger, Horst; Geisler, Maria; Karotki, Lena; Kirn, Anette; Konantz, Judith; Konantz, Martina; Oberländer, Martina; Rudolph-Geiger, Silke; Teucke, Mathias; Osoegawa, Kazutoyo; Zhu, Baoli; Rapp, Amanda; Widaa, Sara; Langford, Cordelia; Yang, Fengtang; Carter, Nigel P.; Harrow, Jennifer; Ning, Zemin; Herrero, Javier; Searle, Steve M. J.; Enright, Anton; Geisler, Robert; Plasterk, Ronald H. A.; Lee, Charles; Westerfield, Monte; de Jong, Pieter J.; Zon, Leonard I.; Postlethwait, John H.; Nüsslein-Volhard, Christiane; Hubbard, Tim J. P.; Crollius, Hugues Roest; Rogers, Jane; Stemple, Derek L.

2013-01-01

Zebrafish have become a popular organism for the study of vertebrate gene function1,2. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease3–5. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes6, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination. PMID:23594743

GDC 2: Compression of large collections of genomes

PubMed Central

Deorowicz, Sebastian; Danek, Agnieszka; Niemiec, Marcin

2015-01-01

The fall of prices of the high-throughput genome sequencing changes the landscape of modern genomics. A number of large scale projects aimed at sequencing many human genomes are in progress. Genome sequencing also becomes an important aid in the personalized medicine. One of the significant side effects of this change is a necessity of storage and transfer of huge amounts of genomic data. In this paper we deal with the problem of compression of large collections of complete genomic sequences. We propose an algorithm that is able to compress the collection of 1092 human diploid genomes about 9,500 times. This result is about 4 times better than what is offered by the other existing compressors. Moreover, our algorithm is very fast as it processes the data with speed 200 MB/s on a modern workstation. In a consequence the proposed algorithm allows storing the complete genomic collections at low cost, e.g., the examined collection of 1092 human genomes needs only about 700 MB when compressed, what can be compared to about 6.7 TB of uncompressed FASTA files. The source code is available at http://sun.aei.polsl.pl/REFRESH/index.php?page=projects&project=gdc&subpage=about. PMID:26108279

GDC 2: Compression of large collections of genomes.

PubMed

Deorowicz, Sebastian; Danek, Agnieszka; Niemiec, Marcin

2015-06-25

The fall of prices of the high-throughput genome sequencing changes the landscape of modern genomics. A number of large scale projects aimed at sequencing many human genomes are in progress. Genome sequencing also becomes an important aid in the personalized medicine. One of the significant side effects of this change is a necessity of storage and transfer of huge amounts of genomic data. In this paper we deal with the problem of compression of large collections of complete genomic sequences. We propose an algorithm that is able to compress the collection of 1092 human diploid genomes about 9,500 times. This result is about 4 times better than what is offered by the other existing compressors. Moreover, our algorithm is very fast as it processes the data with speed 200 MB/s on a modern workstation. In a consequence the proposed algorithm allows storing the complete genomic collections at low cost, e.g., the examined collection of 1092 human genomes needs only about 700 MB when compressed, what can be compared to about 6.7 TB of uncompressed FASTA files. The source code is available at http://sun.aei.polsl.pl/REFRESH/index.php?page=projects&project=gdc&subpage=about.

Genomic signatures of diet-related shifts during human origins

PubMed Central

Babbitt, Courtney C.; Warner, Lisa R.; Fedrigo, Olivier; Wall, Christine E.; Wray, Gregory A.

2011-01-01

There are numerous anthropological analyses concerning the importance of diet during human evolution. Diet is thought to have had a profound influence on the human phenotype, and dietary differences have been hypothesized to contribute to the dramatic morphological changes seen in modern humans as compared with non-human primates. Here, we attempt to integrate the results of new genomic studies within this well-developed anthropological context. We then review the current evidence for adaptation related to diet, both at the level of sequence changes and gene expression. Finally, we propose some ways in which new technologies can help identify specific genomic adaptations that have resulted in metabolic and morphological differences between humans and non-human primates. PMID:21177690

Human cDNA mapping using fluorescence in situ hybridization. Final progress report, April 1, 1994--July 31, 1997

DOE Office of Scientific and Technical Information (OSTI.GOV)

Korenberg, J.R.

The ultimate goal of this research is to generate and apply novel technologies to speed completion and integration of the human genome map and sequence with biomedical problems. To do this, techniques were developed and genome-wide resources generated. This includes a genome-wide Mapped and Integrated BAC/PAC Resource that has been used for gene finding, map completion and anchoring, breakpoint definition and sequencing. In the last period of the grant, the Human Mapped BAC/PAC Resource was also applied to determine regions of human variation and to develop a novel paradigm of primate evolution through to humans. Further, in order to moremore » rapidly evaluate animal models of human disease, a BAC Map of the mouse was generated in collaboration with the MTI Genome Center, Dr. Bruce Birren.« less

SMARCA4/Brg1 coordinates genetic and epigenetic networks underlying Shh-type medulloblastoma development.

PubMed

Shi, X; Wang, Q; Gu, J; Xuan, Z; Wu, J I

2016-11-03

Recent large-scale genomic studies have classified medulloblastoma into four subtypes: Wnt, Shh, Group 3 and Group 4. Each is characterized by specific mutations and distinct epigenetic states. Previously, we showed that a chromatin regulator SMARCA4/Brg1 is required for Gli-mediated transcription activation in Sonic hedgehog (Shh) signaling. We report here that Brg1 controls a transcriptional program that specifically regulates Shh-type medulloblastoma growth. Using a mouse model of Shh-type medulloblastoma, we deleted Brg1 in precancerous progenitors and primary or transplanted tumors. Brg1 deletion significantly inhibited tumor formation and progression. Genome-wide expression analyses and binding experiments indicate that Brg1 specifically coordinates with key transcription factors including Gli1, Atoh1 and REST to regulate the expression of both oncogenes and tumor suppressors that are required for medulloblastoma identity and proliferation. Shh-type medulloblastoma displays distinct H3K27me3 properties. We demonstrate that Brg1 modulates activities of H3K27me3 modifiers to regulate the expression of medulloblastoma genes. Brg1-regulated pathways are conserved in human Shh-type medulloblastoma, and Brg1 is important for the growth of a human medulloblastoma cell line. Thus, Brg1 coordinates a genetic and epigenetic network that regulates the transcriptional program underlying the Shh-type medulloblastoma development.

Repetitive Elements May Comprise Over Two-Thirds of the Human Genome

PubMed Central

de Koning, A. P. Jason; Gu, Wanjun; Castoe, Todd A.; Batzer, Mark A.; Pollock, David D.

2011-01-01

Transposable elements (TEs) are conventionally identified in eukaryotic genomes by alignment to consensus element sequences. Using this approach, about half of the human genome has been previously identified as TEs and low-complexity repeats. We recently developed a highly sensitive alternative de novo strategy, P-clouds, that instead searches for clusters of high-abundance oligonucleotides that are related in sequence space (oligo “clouds”). We show here that P-clouds predicts >840 Mbp of additional repetitive sequences in the human genome, thus suggesting that 66%–69% of the human genome is repetitive or repeat-derived. To investigate this remarkable difference, we conducted detailed analyses of the ability of both P-clouds and a commonly used conventional approach, RepeatMasker (RM), to detect different sized fragments of the highly abundant human Alu and MIR SINEs. RM can have surprisingly low sensitivity for even moderately long fragments, in contrast to P-clouds, which has good sensitivity down to small fragment sizes (∼25 bp). Although short fragments have a high intrinsic probability of being false positives, we performed a probabilistic annotation that reflects this fact. We further developed “element-specific” P-clouds (ESPs) to identify novel Alu and MIR SINE elements, and using it we identified ∼100 Mb of previously unannotated human elements. ESP estimates of new MIR sequences are in good agreement with RM-based predictions of the amount that RM missed. These results highlight the need for combined, probabilistic genome annotation approaches and suggest that the human genome consists of substantially more repetitive sequence than previously believed. PMID:22144907

Tracing the peopling of the world through genomics

PubMed Central

Nielsen, Rasmus; Akey, Joshua M.; Jakobsson, Mattias; Pritchard, Jonathan K.; Tishkoff, Sarah; Willerslev, Eske

2018-01-01

Advances in the sequencing and the analysis of the genomes of both modern and ancient peoples have facilitated a number of breakthroughs in our understanding of human evolutionary history. These include the discovery of interbreeding between anatomically modern humans and extinct hominins; the development of an increasingly detailed description of the complex dispersal of modern humans out of Africa and their population expansion worldwide; and the characterization of many of the genetic adaptions of humans to local environmental conditions. Our interpretation of the evolutionary history and adaptation of humans is being transformed by analyses of these new genomic data. PMID:28102248

Mapping and annotating obesity-related genes in pig and human genomes.

PubMed

Martelli, Pier Luigi; Fontanesi, Luca; Piovesan, Damiano; Fariselli, Piero; Casadio, Rita

2014-01-01

Background. Obesity is a major health problem in both developed and emerging countries. Obesity is a complex disease whose etiology involves genetic factors in strong interplay with environmental determinants and lifestyle. The discovery of genetic factors and biological pathways underlying human obesity is hampered by the difficulty in controlling the genetic background of human cohorts. Animal models are then necessary to further dissect the genetics of obesity. Pig has emerged as one of the most attractive models, because of the similarity with humans in the mechanisms regulating the fat deposition. Results. We collected the genes related to obesity in humans and to fat deposition traits in pig. We localized them on both human and pig genomes, building a map useful to interpret comparative studies on obesity. We characterized the collected genes structurally and functionally with BAR+ and mapped them on KEGG pathways and on STRING protein interaction network. Conclusions. The collected set consists of 361 obesity related genes in human and pig genomes. All genes were mapped on the human genome, and 54 could not be localized on the pig genome (release 2012). Only for 3 human genes there is no counterpart in pig, confirming that this animal is a good model for human obesity studies. Obesity related genes are mostly involved in regulation and signaling processes/pathways and relevant connection emerges between obesity-related genes and diseases such as cancer and infectious diseases.