Draft Sequence Of Human Genome Research Articles

Where is the boundary of the human pseudoautosomal region?

A recent publication describing the assembly of the Y chromosomes of 43 males was remarkable not only for its ambitious technical scope but also for the startling suggestion that the boundary of the pseudoautosomal region 1 (PAR1), where the human X and Y chromosomes engage in crossing-over during male meiosis, lies 500 kb distal to its previously reported location. Where is the boundary of the human PAR1? We first review the evidence that mapped the PAR boundary, or PAB, before the human genome draft sequence was produced, then examine post-genomic datasets for evidence of crossing-over between the X and Y, and lastly re-examine contiguous sequence assemblies of the PAR-NPY boundary to see whether they support a more distal PAB. We find ample evidence of X-Y crossovers throughout the 500 kb in question, some as close as 246bp to the previously reported PAB. Our new analyses, combined with previous studies over the past 40 years, provide overwhelming evidence to support the original position and narrow the probable location of the PAB to a 201-bp window.

Polygenic score: An anchor holding the whole life course.

Polygenic score: An anchor holding the whole life course.

A Japanese history of the Human Genome Project.

The Human Genome Project (HGP) is one of the most important international achievements in life sciences, to which Japanese scientists made remarkable contributions. In the early 1980s, Akiyoshi Wada pioneered the first project for the automation of DNA sequencing technology. Ken-ichi Matsubara exhibited exceptional leadership to launch the comprehensive human genome program in Japan. Hideki Kambara made a major contribution by developing a key device for high-speed DNA sequencers, which enabled scientists to construct human genome draft sequences. The RIKEN team led by Yoshiyuki Sakaki (the author) played remarkable roles in the draft sequencing and completion of chromosomes 21, 18, and 11. Additionally, the Keio University team led by Nobuyoshi Shimizu made noteworthy contributions to the completion of chromosomes 22, 21, and 8. In April 2003, the Japanese team joined the international consortium in declaring the completion of the human genome sequence. Consistent with the HGP mandate, Japan has successfully developed a wide range of ambitious genomic sciences.

Last-gen nostalgia: a lighthearted rant and reflection on genome sequencing culture

I sometimes see them in my dreams. The colorful peaks and troughs, the sharp, crisp waves spread across my computer screen, the rolling nitrogenous mountains, each with its own nucleotide sitting solidly on the summit. I'm talking about electropherograms, of course. Remember them? Those beautiful but oh so “old-gen” bioinformatics data generated from automated Sanger sequencing machines, such as the Applied Biosystems 370—the geriatric of genome sequencers. Don't laugh. It was these capillary-based electrophoretic technologies that gave us the draft human genome sequence (Lander et al., 2001) and the genome maps of many other model organisms, from the bacterium Haemophilus influenza to the yeast Saccharomyces cerevisiae to the multicellular green alga Volvox carteri (Fleischmann et al., 1995; Goffeau et al., 1996; Prochnik et al., 2010).

Genomic Medicine, Health Information Technology, and Patient Care

Celebrating the tenth anniversary of completing the draft human genome sequence in 2011, authors from the National Human Genome Research Institute of the US National Institutes of Health outlined the influence of genomic understanding across 5 domains: structure, the biology of the genome, the biology of disease, medicine, and improvements in health care.

Changes in chemistry and biochemistry education: Creative responses to medical college admissions test revisions in the age of the genome

Approximately two million students matriculate into American colleges and universities per year. Almost 20% of these students begin taking a series of courses specified by advisers of health preprofessionals. The single most important influence on health profession advisers and on course selection for this huge population of learners is the Medical College Admissions Test (MCAT), which was last revised in 1991, 10 years before publication of the first draft human genome sequence. In preparation for the 2015 MCAT, there is a broad discussion among stakeholders of how best to revise undergraduate and medical education in the molecular sciences to prepare researchers and doctors to acquire, analyze and use individual genomic and metabolomic data in the coming decades. Getting these changes right is among the most important educational problems of our era.

Patient‐Specific Modelling in Drug Design, Development and Selection Including its Role in Clinical Decision‐Making

Genomics has made enormous progress in the twelve years since the publication of the first draft human genome sequence, but it has not yet been translated into the clinic. Despite spiralling development costs, the number of new drug registrations is not increasing. One reason for this lies in the genetic complexity of disease. Most diseases involve dysregulation in pathways that involve many genes, and many (including most cancers) are themselves genetically heterogeneous. Systems biology involves the multi-level simulation of physiology, cell biology and biochemistry using complex computational techniques. We show here using case studies in cancer and HIV how such computational models, and particularly models based on individual patient data, can be used for drug design and development, and in the selection of the appropriate treatment for a given patient in the face of resistance mutations. If these techniques are to be adopted in routine clinical practice, clinicians will need better training in modern approaches to the integrated analysis of large-scale heterogeneous data and multi-scale models, while developers will need to provide much more usable tools. Investment in computational infrastructure is needed so that results can be returned on clinically relevant timescales and data warehouses designed with data protection as well as accessibility in mind.

The Human Gut Microbiome: The Ghost in the Machine

The Human Gut Microbiome: The Ghost in the Machine

Interrogating of cancer genomes: towards more profile-based therapeutics

Although death rates due to common diseases such as heart disease, stroke and infectious diseases have declined over the last half-century, there has been only a small change in cancer mortality rates. The availability of the draft human genome sequence and a number of technological advances now provide us with the opportunity to explore the genomic landscape of cancer in an unprecedented way. Here, we will describe the application of multiple genomic technologies toward the interrogation of a number of cancer genomes, in order to discover molecular determinants of cancer that might be associated with clinical outcome and those that might be candidates for targeted therapy. It is our hope that these data would one day be translated into clinical practice to improve therapeutic decision-making for more knowledge-based clinical management.

Cancer Genome Sequencing and Functional Genomics: From Translational to Clinical Medicine

Dulbecco noted that ‘‘If we wish to learn more about cancer, we must now concentrate on the cellular genome’’, and he advocated sequencing ‘‘the whole genome of a selected animal species’’, specifically, the human genome [2]. The Human Genome Project (HGP) began in 1989 with the goal to identify and map the human genes and understand human biology. In 2000, President Bill Clinton announced the completion of the two first drafts of human genome sequence [3,4] and in a White House press statement articulated that genomics would “lead to a new era of molecular medicine, an era that will bring new ways to prevent, diagnose, treat and cure disease” [5]. Now, a decade later, we know that despite the major advances in genomics research, neither the revolution in genomic medicine for improving health [6], nor genome heterogeneitybased personalized clinical decisions on prevention or treatment of cancer have yet arrived. Does genomic medicine remain a first priority to understanding cancer biology and discovering novel therapeutics? In a paper on global cancer statistics published in 2011 [7], the increase in cancer incidence and mortality is particularly growing in the developing world. A small decrease in cancer death rates in the economically developed parts of the world is mostly attributable to early detection, for example, of the most common type of breast cancer and improved treatment with tamoxifen or aromatase inhibitors and tobacco control for reducing lung cancer incidence. But modest progress has been achieved in improving overall survival rates of patients with advanced stages of disease for which a cure still remains elusive.

Alu pair exclusions in the human genome

BackgroundThe human genome contains approximately one million Alu elements which comprise more than 10% of human DNA by mass. Alu elements possess direction, and are distributed almost equally in positive and negative strand orientations throughout the genome. Previously, it has been shown that closely spaced Alu pairs in opposing orientation (inverted pairs) are found less frequently than Alu pairs having the same orientation (direct pairs). However, this imbalance has only been investigated for Alu pairs separated by 650 or fewer base pairs (bp) in a study conducted prior to the completion of the draft human genome sequence.ResultsWe performed a comprehensive analysis of all (> 800,000) full-length Alu elements in the human genome. This large sample size permits detection of small differences in the ratio between inverted and direct Alu pairs (I:D). We have discovered a significant depression in the full-length Alu pair I:D ratio that extends to repeat pairs separated by ≤ 350,000 bp. Within this imbalance bubble (those Alu pairs separated by ≤ 350,000 bp), direct pairs outnumber inverted pairs. Using PCR, we experimentally verified several examples of inverted Alu pair exclusions that were caused by deletions.ConclusionsOver 50 million full-length Alu pairs reside within the I:D imbalance bubble. Their collective impact may represent one source of Alu element-related human genomic instability that has not been previously characterized.

The Genome Project: What Will It Do as a Teenager?

The 10th anniversary of the completion of the draft human genome sequence has been a time for celebration—and also for sober stock-taking. Eric Green, director of the U.S. National Human Genome Research Institute, discussed the institute's 10-year map with Science in an interview.

First decade of post-genomic era. Hopes, disappointments, new answers

The first decade after the announcement of the draft sequence of human genome has brought spectacular advances in basic science, however, the fact that human health did not benefit that much caused disappointment, as well. In order to explore the causes of the absence of revolution in medicine, beside the extension of research strategy new conception about the role of genetics in health and disease should also be considered. In order to resolve the disappointments, the author recommends a new perspective to view the role of genetics in health and diseases. When the contribution of recent research results is evaluated not only in the original transgenerational aspect but also in developmental aspect of genetics, some questions about the genomic medicine might be clearer. This review discusses the advantage of this concept in (1) clinical interpretation of the findings of molecular technologies, (2) understanding the novel concept of gene-environment relationship, and (3) organizing the health service delivery through reasonable professional competences. The developmental aspect of genetics is suggested to consider in future research strategy, interpretation of the results, understanding the role of genes and environment in health and disease, and construction of health service delivery system in genomic medicine.

Individual genomes and personalized medicine: life diversity and complexity.

Patients and tumors are unique. The conceptual design is great. Identifying the genetic variants underlying phenotype can lead to personalized medicine. Tailoring the best medical intervention to the right individual or patient can dramatically improve health. A decade after the first draft of human genome sequence [1,2] and the promises of a health revolution, what progress has been made in both genomics and personalized medical practice and what are the challenges and perspectives to deal with for the next decade? The use of personalized medicine to improve both the prevention and cure of disease is potentially achievable through: predicting both the disease risk among healthly individuals in the general population and the therapeutic response among patients. Genomic information from individuals or patients can substantially contribute to biomarker-based guided personalized prevention and treatment. The first strategy to use personalized medicine, in the prevention setting, involves identifying high-risk individuals that may develop major common diseases, such as cardiovascular disorder, diabetes and cancer, and then selecting the most appropriate preventive intervention to protect them from these diseases. This strategy can substantially reduce disease incidence and it is particularly important for hard-to-treat disorders, such as cancer. However, despite current research efforts, the development of robust biomarkers based on primary prevention has only modestly improved. In the second strategy, in the treatment setting, efforts by academia and industry have been focused on how to improve diagnostics and prognosis of diseases and how, through the development of predictors of drug response and adverse effects, to improve the safety and efficacy of drugs. Indeed, not only is the therapeutic response rate for several complex diseases low, but general toxicity rates of currently used agents are also still alarmingly high. Several research strategies and scientific fields have been developed towards personalized medicine. Pharmacogenetics, studying the genetic associations with drug efficacy and toxicity has led to the identification of several dugmetabolizing enzymes, with the most important belonging to the cytochrome P450 family [3]. The aim is to predict adverse effects to guide individualized treatment. Despite overlap with pharmacogenetics, the term pharmacogenomics is distinct because it evaluates the application of genomics to drug discovery. Pharmacogenomics involves the mechanism of the action of drugs on cells as revealed by gene-expression patterns. Pharmacoproteomics provides a more functional representation of patient-to-patient variation than that which is provided by genotyping, and therfore also contributes to personalized medicine. A ‘pharmacometabonomic’ approach involves the study of metabolites and how these can contribute to personalizing drug treatment.

HUMAN GENOME SEQUENCE MILESTONE

HAPPY BIRTHDAY to the human genome sequence, or at least human knowledge of it. This week marks the 10th anniversary of the completion of the draft human genome sequence by the international Human Genome Project (HGP) and the private company Celera Genomics. That artificial finishing point, announced on June 26, 2000, at the White House, has turned out to be a commencement. Since then, advances in collecting, organizing, and interpreting genetic data and dramatic reductions in the cost of gene sequencing have made it possible for genomics to have a growing influence on human health care. It’s been said that a truly transformational technology will always have its immediate consequences overestimated and its long-term consequences underestimated, noted National Institutes of Health Director Francis S. Collins at a recent meeting. “I think that’s turning out to be true for what we are learning from the human genome. This science is driving a lot of the ...

Human genome at ten: Science after the sequence

The completion of the draft human genome sequence was announced ten years ago. Nature's survey of life scientists reveals that biology will never be the same again. Declan Butler reports.

2020 foresight: Envisioning therapeutic innovations for pain

The explosion in scientific knowledge since the completion of the draft human genome sequence 10 years ago illustrates the quantum leap that is possible when emerging technology is focused on an important scientific question. We are now on the threshold of the next decade that holds the potential for translating our increased understanding of the molecular-genetic processes that form the basis for pain processing and analgesic mechanisms. This article attempts to envision the therapeutic innovations for pain based on translating genomic findings into new approaches to pain management, identifying epigenetic targets for analgesia, and finally moving from a century-old search for a single ‘magic bullet’ among derivatives of opium and will bark to new molecular entities engaging novel targets and multiple pathways that interact with the complex processes that modulate pain and its transition to chronicity.

Separating derived from ancestral features of mouse and human genomes

To take full advantage of the mouse as a model organism, it is essential to distinguish lineage-specific biology from what is shared between human and mouse. Investigations into shared genetic elements common to both have been well served by the draft human and mouse genome sequences. More recently, the virtually complete euchromatic sequences of the two reference genomes have been finished. These reveal a high ( approximately 5%) level of sequence duplications that had previously been recalcitrant to sequencing and assembly. Within these duplications lie large numbers of rodent- or primate-specific genes. In the present paper, we review the sequence properties of the two genomes, dwelling most on the duplications, deletions and insertions that separate each of them from their most recent common ancestor, approx. 90 million years ago. We consider the differences in gene numbers and repertoires between the two species, and speculate on their contributions to lineage-specific biology. Loss of ancient single-copy genes are rare, as are gains of new functional genes through retrotransposition. Instead, most changes to the gene repertoire have occurred in large multicopy families. It has been proposed that numbers of such 'environmental genes' rise and fall, and their sequences change, as adaptive responses to infection and other environmental pressures, including conspecific competition. Nevertheless, many such genes may be under little or no selection.

The drifting human genome

Around the time of the completion of the draft human genome sequence, biologists heatedly debated the number of genes contained in the human genome. In 2003, GeneSweep, an informal gene-count betting pool that began at the 2000 Cold Spring Harbor Laboratory Genome Meeting, announced Lee Rowen of the Institute of Systems Biology in Seattle to be the winner. His bet (25,946) was the lowest and was closest to what many computer programs predicted from the then draft human genome sequence (1). But, in this issue of PNAS, Nozawa, Kawahara, and Nei (2) tell us that asking about the exact number of human genes is meaningless, because different human individuals have different numbers of genes, and it is not uncommon for one person to have 100 more gene copies than another person. They argue that this large variation reflects genomic drift, random changes of gene copy number in evolution.

The drifting human genome

Around the time of the completion of the draft human genome sequence, biologists heatedly debated the number of genes contained in the human genome. In 2003, GeneSweep, an informal gene-count betting pool that began at the 2000 Cold Spring Harbor Laboratory Genome Meeting, announced Lee Rowen of the Institute of Systems Biology in Seattle to be the winner. His bet (25,946) was the lowest and was closest to what many computer programs predicted from the then draft human genome sequence (1). But, in this issue of PNAS, Nozawa, Kawahara, and Nei (2) tell us that asking about the exact number of human genes is meaningless, because different human individuals have different numbers of genes, and it is not uncommon for one person to have 100 more gene copies than another person. They argue that this large variation reflects genomic drift, random changes of gene copy number in evolution.