• THE HUMAN GENOME PROJECT

    Race to Sequence

    HGP: An Animation

    Animated Tutorial of HGP
    Cracking the Code

    The Human Genome Project (HGP) was an international project with the goal of determining the sequence of nucleotide that make up human , and of identifying and mapping all of the of the from both a physical and a functional standpoint. It remains the world’s largest collaborative biological project. After the idea was picked up in 1984 by the US government when the planning started, the project formally launched in 1990 and was declared complete in 2003. Funding came from the US government through the (NIH) as well as numerous other groups from around the world. A parallel project was conducted outside of government by the , or Celera Genomics, which was formally launched in 1998. Most of the government-sponsored sequencing was performed in twenty and research centers in the United States, the United Kingdom, Japan, France, Germany, Canada, and China.

    The Human Genome Project originally aimed to map the contained in a human (more than three billion). The “genome” of any given individual is unique; mapping the “human genome” involved sequencing a small number of individuals and then assembling these together to get a complete sequence for each chromosome. The finished human genome is thus a mosaic, not representing any one individual.

    History

    The $3-billion project was formally founded in 1990 by the US Department of Energy and the National Institutes of Health, and was expected to take 15 years. In addition to the United States, the international comprised in the United Kingdom, France, Australia, China and myriad other spontaneous relationships.

    Due to widespread international cooperation and advances in the field of (especially in ), as well as major advances in computing technology, a ‘rough draft’ of the genome was finished in 2000 (announced jointly by U.S. President and the British on June 26, 2000). This first available rough draft of the genome was completed by the Genome Bioinformatics Group at the , primarily led by then graduate student . Ongoing led to the announcement of the essentially complete on April 14, 2003, two years earlier than planned. In May 2006, another milestone was passed on the way to completion of the project, when the sequence of the was published in .

    State of completion

    The Human Genome Project was declared complete in April 2003. An initial rough draft of the human genome was available in June 2000 and by February 2001 a working draft had been completed and published followed by the final sequencing mapping of the human genome on April 14, 2003. Although this was reported to cover 99% of the euchromatic human genome with 99.99% accuracy, a major quality assessment of the human genome sequence was published on May 27, 2004 indicating over 92% of sampling exceeded 99.99% accuracy which was within the intended goal. Further analyses and papers on the HGP continue to occur.

    Applications and proposed benefits

    The sequencing of the human genome holds benefits for many fields, from to . The Human Genome Project, through its sequencing of the DNA, can help us understand diseases including: of specific to direct appropriate treatment; identification of linked to different forms of ; the design of medication and more accurate prediction of their effects; advancement in applied sciences; and other energy applications; , , ; ; , and . Another proposed benefit is the commercial development of research related to DNA based products, a multibillion-dollar industry.

    The sequence of the DNA is stored in available to anyone on the . The U.S. (and sister organizations in Europe and Japan) house the gene sequence in a database known as , along with sequences of known and hypothetical genes and proteins. Other organizations, such as the at the University of California, Santa Cruz, and present additional data and annotation and powerful tools for visualizing and searching it. have been developed to analyze the data, because the data itself is difficult to interpret without such programs. Generally speaking, advances in genome sequencing technology have followed Moore’s Law, a concept from computer science which states that integrated circuits can increase in complexity at an exponential rate. This means that the speeds at which whole genomes can be sequenced can increase at a similar rate, as was seen during the development of the above-mentioned Human Genome Project.

    Techniques and analysis

    The process of identifying the boundaries between genes and other features in a raw DNA sequence is called and is in the domain of . While expert biologists make the best annotators, their work proceeds slowly, and computer programs are increasingly used to meet the high-throughput demands of genome sequencing projects. Beginning in 2008, a new technology known as was introduced that allowed scientists to directly sequence the messenger RNA in cells. This replaced previous methods of annotation, which relied on inherent properties of the DNA sequence, with direct measurement, which was much more accurate. Today, annotation of the human genome and other genomes relies primarily on deep sequencing of the transcripts in every human tissue using RNA-seq. These experiments have revealed that over 90% of genes contain at least one and usually several alternative splice variants, in which the are combined in different ways to produce 2 or more gene products from the same locus.[]

    The genome published by the HGP does not represent the sequence of every individual’s genome. It is the combined mosaic of a small number of anonymous donors, all of European origin. The HGP genome is a scaffold for future work in identifying differences among individuals. Subsequent projects sequenced the genomes of multiple distinct ethnic groups, though as of today there is still only one “reference genome.”[]

    Findings

    Key findings of the draft (2001) and complete (2004) genome sequences include:

    1. There are approximately 22,300 protein-coding genes in human beings, the same range as in other mammals.
    2. The human genome has significantly more (nearly identical, repeated sections of DNA) than had been previously suspected.
    3. At the time when the draft sequence was published fewer than 7% of appeared to be vertebrate specific.

     Public versus private approaches

    In 1998, a similar, privately funded quest was launched by the American researcher , and his firm Celera Genomics. Venter was a scientist at the NIH during the early 1990s when the project was initiated. The $300,000,000 Celera effort was intended to proceed at a faster pace and at a fraction of the cost of the roughly $3 billion . The Celera approach was able to proceed at a much more rapid rate, and at a lower cost than the public project because it relied upon data made available by the publicly funded project.

    Celera used a technique called , employing , which had been used to sequence bacterial genomes of up to six million base pairs in length, but not for anything nearly as large as the three billion base pair human genome.

    Celera initially announced that it would seek patent protection on “only 200–300” genes, but later amended this to seeking “intellectual property protection” on “fully-characterized important structures” amounting to 100–300 targets. The firm eventually filed preliminary (“place-holder”) patent applications on 6,500 whole or partial genes. Celera also promised to publish their findings in accordance with the terms of the 1996 ““, by releasing new data annually (the HGP released its new data daily), although, unlike the publicly funded project, they would not permit free redistribution or scientific use of the data. The publicly funded competitors were compelled to release the first draft of the human genome before Celera for this reason. On July 7, 2000, the UCSC Genome Bioinformatics Group released a first working draft on the web. The scientific community downloaded about 500 GB of information from the UCSC genome server in the first 24 hours of free and unrestricted access.

    In March 2000, announced that the could not be patented, and should be made freely available to all researchers. The statement sent Celera’s stock plummeting and dragged down the -heavy . The biotechnology sector lost about $50 billion in in two days.

    Although the working draft was announced in June 2000, it was not until February 2001 that Celera and the HGP scientists published details of their drafts. Special issues of (which published the publicly funded project’s ) and (which published Celera’s paper) described the methods used to produce the draft sequence and offered analysis of the sequence. These drafts covered about 83% of the genome (90% of the euchromatic regions with 150,000 gaps and the order and orientation of many segments not yet established). In February 2001, at the time of the joint publications, announced that the project had been completed by both groups. Improved drafts were announced in 2003 and 2005, filling in to approximately 92% of the sequence currently.

    Genome donors

    In the IHGSC international Human Genome Project (HGP), researchers collected blood (female) or sperm (male) samples from a large number of donors. Only a few of many collected samples were processed as DNA resources. Thus the donor identities were protected so neither donors nor scientists could know whose DNA was sequenced. DNA clones from many different were used in the overall project, with most of those libraries being created by . Much of the sequence (>70%) of the produced by the public HGP came from a single anonymous male donor from ( RP11).

    HGP scientists used from the blood of two male and two female donors (randomly selected from 20 of each) – each donor yielding a separate DNA library. One of these libraries (RP11) was used considerably more than others, due to quality considerations. One minor technical issue is that male samples contain just over half as much DNA from the sex chromosomes (one and one ) compared to female samples (which contain two ). The other 22 chromosomes (the autosomes) are the same for both sexes.

    Although the main sequencing phase of the HGP has been completed, studies of DNA variation continue in the , whose goal is to identify patterns of (SNP) groups (called , or “haps”). The DNA samples for the HapMap came from a total of 270 individuals: in , ; in ; in ; and the French (CEPH) resource, which consisted of residents of the United States having ancestry from Western and .

    In the Celera Genomics project, DNA from five different individuals were used for sequencing. The lead scientist of Celera Genomics at that time, Craig Venter, later acknowledged (in a public letter to the journal ) that his DNA was one of 21 samples in the pool, five of which were selected for use.

    In 2007, a team led by published ‘s entire genome, unveiling the six-billion-nucleotide genome of a single individual for the first time.

    Developments

    The work on interpretation and analysis of genome data is still in its initial stages. It is anticipated that detailed knowledge of the human genome will provide new avenues for advances in and . Clear practical results of the project emerged even before the work was finished. For example, a number of companies, such as , started offering easy ways to administer genetic tests that can show predisposition to a variety of illnesses, including , , , diseases and many others. Also, the for , and other areas of clinical interest are considered likely to benefit from genome information and possibly may lead in the long term to significant advances in their management.

    There are also many tangible benefits for biologists. For example, a researcher investigating a certain form of may have narrowed down his/her search to a particular gene. By visiting the human genome database on the , this researcher can examine what other scientists have written about this gene, including (potentially) the three-dimensional structure of its product, its function(s), its evolutionary relationships to other human genes, or to genes in mice or yeast or fruit flies, possible detrimental mutations, interactions with other genes, body tissues in which this gene is activated, and diseases associated with this gene or other datatypes. Further, deeper understanding of the disease processes at the level of molecular biology may determine new therapeutic procedures. Given the established importance of DNA in molecular biology and its central role in determining the fundamental operation of , it is likely that expanded knowledge in this area will facilitate medical advances in numerous areas of clinical interest that may not have been possible without them.

    The analysis of similarities between DNA sequences from different organisms is also opening new avenues in the study of . In many cases, evolutionary questions can now be framed in terms of ; indeed, many major evolutionary milestones (the emergence of the and , the development of with body plans, the ) can be related to the molecular level. Many questions about the similarities and differences between humans and our closest relatives (the , and indeed the other ) are expected to be illuminated by the data in this project.

    The project inspired and paved the way for genomic work in other fields, such as agriculture. For example, by studying the genetic composition of Tritium aestivum, the world’s most commonly used bread wheat, great insight has been gained into the ways that domestication has impacted the evolution of the plant. Which loci are most susceptible to manipulation, and how does this play out in evolutionary terms? Genetic sequencing has allowed these questions to be addressed for the first time, as specific loci can be compared in wild and domesticated strains of the plant. This will allow for advances in genetic modification in the future which could yield healthier, more disease-resistant wheat crops.

    Ethical, legal and social issues

    At the onset of the Human Genome Project several ethical, legal, and social concerns were raised in regards to how increased knowledge of the human genome could be used to discriminate against people. One of the main concerns of most individuals was the fear that both employers and health insurance companies would refuse to hire individuals or refuse to provide insurance to people because of a health concern indicated by someone’s genes. In 1996 the United States passed the (HIPAA) which protects against the unauthorized and non-consensual release of individually identifiable health information to any entity not actively engaged in the provision of healthcare services to a patient.

    Along with identifying all of the approximately 20,000–25,000 genes in the human genome, the Human Genome Project also sought to address the ethical, legal, and social issues that were created by the onset of the project. For that the Ethical, Legal, and Social Implications (ELSI) program was founded in 1990. Five percent of the annual budget was allocated to address the ELSI arising from the project. This budget started at approximately $1.57 million in the year 1990, but increased to approximately $18 million in the year 2014.

    Whilst the project may offer significant benefits to medicine and scientific research, some authors have emphasised the need to address the potential social consequences of mapping the human genome. “Molecularising disease and their possible cure will have a profound impact on what patients expect from medical help and the new generation of doctors’ perception of illness.”

     

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