HUMAN GENOME PROJECT

INTRODUCTION

The human genome is the complete set of nucleic acid sequence for humans (Homo sapiens),
encoded as DNA within the 23 chromosome pairs in cell nuclei and in a small DNA molecule
found within individual mitochondria. Human genomes include both protein-coding DNA genes
and non-coding DNA. Haploid human genomes, which are contained in germ cells (the egg and
sperm gamete cells created in the meiosis phase of sexual reproduction before fertilization
creates a zygote) consist of three billion DNA base pairs, while diploid genomes (found in
somatic cells) have twice the DNA content. While there are significant differences among the
genomes of human individuals (on the order of 0.1%), these are considerably smaller than the
differences between humans and their closest living relatives, the chimpanzees (approximately
4%) and bonobos.

The Human Genome Project produced the first complete sequences of individual human
genomes, with the first draft sequence and initial analysis being published on February 12, 2001.
The human genome was the first of all vertebrates to be completely sequenced. As of 2012,
thousands of human genomes have been completely sequenced, and many more have been
mapped at lower levels of resolution. The resulting data are used worldwide in biomedical
science, anthropology, forensics and other branches of science. There is a widely held
expectation that genomic studies will lead to advances in the diagnosis and treatment of diseases,
and to new insights in many fields of biology, including human evolution.

The Human Genome Project (HGP) was an international scientific research project with the goal
of determining the sequence of nucleotide base pairs that make up human DNA, and of
identifying and mapping all of the genes of the human genome from both a physical and a
functional standpoint. It remains the world's largest collaborative biological project.[2] 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 National Institutes of Health (NIH) as well as numerous other groups
from around the world. A parallel project was conducted outside of government by the Celera
Corporation, or Celera Genomics, which was formally launched in 1998. Most of the
government-sponsored sequencing was performed in twenty universities and research centers in
the United States, the United Kingdom, Japan, France, Germany, Canada, and China.

A BRIEF HISTORY OF THE HUMAN GENOME PROJECT

In February 2001, the Human Genome Project (HGP) published its results to that date: a 90
percent complete sequence of all three billion base pairs in the human genome. (The HGP
consortium published its data in the February 15, 2001, issue of the journal Nature.

The project had its ideological origins in the mid-1980s, but its intellectual roots stretch back
further. Alfred Sturtevant created the first Drosophila gene map in 1911.

The crucial first step in molecular genome analysis, and in much of the molecular biological
research of the last half-century, was the discovery of the double helical structure of the DNA
molecule in 1953 by Francis Crick and James Watson. The two researchers shared the 1962
Nobel Prize (along with Maurice Wilkins) in the category of "physiology or medicine."

In the mid-1970s, Frederick Sanger developed techniques to sequence DNA, for which he
received his second Nobel Prize in chemistry in 1980. (His first, in 1958, was for studies of
protein structure). With the automation of DNA sequencing in the 1980s, the idea of analyzing
the entire human genome was first proposed by a few academic biologists.

The United States Department of Energy, seeking data on protecting the genome from the
mutagenic (gene-mutating) effects of radiation, became involved in 1986, and established an
early genome project in 1987.

In 1988, Congress funded both the NIH and the DOE to embark on further exploration of this
concept, and the two government agencies formalized an agreement by signing a Memorandum
of Understanding to "coordinate research and technical activities related to the human genome."

James Watson was appointed to lead the NIH component, which was dubbed the Office of
Human Genome Research. The following year, the Office of Human Genome Research evolved
into the National Center for Human Genome Research (NCHGR).

In 1990, the initial planning stage was completed with the publication of a joint research plan,
"Understanding Our Genetic Inheritance: The Human Genome Project, The First Five Years, FY
1991-1995." This initial research plan set out specific goals for the first five years of what was
then projected to be a 15-year research effort.

In 1992, Watson resigned, and Michael Gottesman was appointed acting director of the center.
The following year, Francis S. Collins was named director.

The advent and employment of improved research techniques, including the use of restriction
fragment-length polymorphisms, the polymerase chain reaction, bacterial and yeast artificial
chromosomes and pulsed-field gel electrophoresis, enabled rapid early progress. Therefore, the
1990 plan was updated with a new five-year plan announced in 1993 in the journal Science (262:
43-46; 1993).

Indeed, a large part of the early work of the HGP was devoted to the development of improved
technologies for accelerating the elucidation of the genome. In a 2001 article in the journal
Genome Research, Collins wrote, "Building detailed genetic and physical maps, developing
better, cheaper and faster technologies for handling DNA, and mapping and sequencing the more
modest-sized genomes of model organisms were all critical stepping stones on the path to
initiating the large-scale sequencing of the human genome."

Also in 1993, the NCHGR established a Division of Intramural Research (DIR), in which
genome technology is developed and used to study specific diseases. By 1996, eight NIH
institutes and centers had also collaborated to create the Center for Inherited Disease Research
(CIDR), for study of the genetics of complex diseases.

In 1997, the NCHGR received full institute status at NIH, becoming the National Human
Genome Research Institute in 1997, with Collins remaining as the director for the new institute.
A third five-year plan was announced in 1998, again in Science, (282: 682-689; 1998).

In June 2000 came the announcement that the majority of the human genome had in fact been
sequenced, which was followed by the publication of 90 percent of the sequence of the genome's
three billion base-pairs in the journal Nature, in February 2001.

Surprises accompanying the sequence publication included: the relatively small number of
human genes, perhaps as few as 30,000; the complex architecture of human proteins compared to
their homologs - similar genes with the same functions - in, for example, roundworms and fruit
flies; and the lessons to be taught by repeat sequences of DNA.

GOAL AND FINDINGS

The main goals of the Human Genome Project were to provide a complete and accurate sequence
of the 3 billion DNA base pairs that make up the human genome and to find all of the estimated
20,000 to 25,000 human genes. The Project also aimed to sequence the genomes of several other
organisms that are important to medical research, such as the mouse and the fruit fly.

In addition to sequencing DNA, the Human Genome Project sought to develop new tools to
obtain and analyze the data and to make this information widely available. Also, because
advances in genetics have consequences for individuals and society, the Human Genome Project
committed to exploring the consequences of genomic research through its Ethical, Legal, and
Social Implications (ELSI) program.

FINDINGS:

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

There are approximately 22,300 protein-coding genes in human beings, the same range as
in other mammals.

The human genome has significantly more segmental duplications (nearly identical,
repeated sections of DNA) than had been previously suspected.

At the time when the draft sequence was published fewer than 7% of protein families
appeared to be vertebrate specific.

APPLICATIONS AND BENEFITS

Scientists estimate that chromosomes in the human population differ at about 0.1%.
Understanding these differences could lead to discovery of heritable diseases, as well as diseases
and other traits that are common to man. Information gained from the HGP has already fueled
many positive discoveries in health care. Well-publicized successes include the cloning of genes
responsible for Duchenne muscular dystrophy, retinoblastoma, cystic fibrosis, and
neurofibromatosis. Increasingly detailed genomic maps have also aided researchers seeking
genes associated with fragile X syndrome, types of inherited colon cancer, Alzheimer's disease,
and familial breast cancer.

If other disease-related genes are isolated, scientists can begin to understand the structure and
pathology of other disorders such as heart disease, cancer, and diabetes. This knowledge would
lead to better medical management of these diseases and pharmaceutical discovery.

Current and potential applications of genome research will address national needs in molecular
medicine, waste control and environmental cleanup, biotechnology, energy sources, and risk
assessment.

Molecular Medicine

Through genetic research, medicine will look more into the fundamental causes of diseases
rather than concentrating on treating symptoms. Genetic screening will enable rapid and specific
diagnostic tests making it possible to treat countless maladies. DNA-based tests clarify diagnosis
quickly and enable geneticists to detect carriers within families. Genomic information can
indicate the future likelihood of some diseases. As an example, if the gene responsible for
Huntington's disease is present, it may be certain that symptoms will eventually occur, although
predicting the exact time may not be possible. Other diseases where susceptibility may be
determined include heart disease, cancer, and diabetes.

Medical researchers will be able to create therapeutic products based on new classes of drugs,
immunotherapy techniques, and possible augmentation or replacement of defective genes
through gene therapy.

Waste Control and Environmental Cleanup

In 1994, through advances gained by the HGP, the DOE formulated the Microbial Genome
Initiative to sequence the genomes of bacteria useful in the areas of energy production,
environmental remediation, toxic waste reduction, and industrial processing. Resulting from that
project, six microbes that live under extreme temperature and pressure conditions have been
sequenced. By learning the unique protein structure of these microbes, researchers may be able
to use the organisms and their enzymes for such practical purposes as waste control and
environmental cleanup.

Biotechnology

The potential for commercial development presents U.S. industry with a wealth of opportunities.
Sales of biotechnology products are projected to exceed $20 billion by the year 2000. The HGP
has stimulated significant investment by large corporations and promoted the development of
new biotechnology companies hoping to capitalize on the implications of HGP research.

Energy Sources

Biotechnology, strengthened by the HGP, will be important in improving the use of fossil-based
resources. Increased energy demands require strategies to circumvent the many problems with
today's dominant energy technologies. Biotechnology will help address these needs by providing
a cleaner means for the bioconversion of raw materials to refined products. Additionally, there is
the possibility of developing entirely new biomass-based energy sources. Having the genomic
sequence of the methane-producing microorganism Methanococcus jannaschii, for example, will
allow researchers to explore the process of methanogenesis in more detail and could lead to
cheaper production of fuel-grade methane.

Risk Assessment

Understanding the human genome will have an enormous impact on the ability to assess risks
posed to individuals by environmental exposure to toxic agents. Scientists know that genetic
differences cause some people to be more susceptible than others to such agents. More work
must be done to determine the genetic basis of such variability, but this knowledge will directly
address the DOE's long-term mission to understand the effects of low-level exposures to
radiation and other energy-related agents, especially in terms of cancer risk. Additional positive
spin-offs from this research include a better understanding of biology, increased taxonomic
understanding, increased development of pest-resistant and productive crops and livestock, and
other commercially useful microorganisms.
Another proposed benefit is the commercial development of genomics research related to DNA
based products, a multibillion-dollar industry.

TECHNIQUES AND ANALYSIS

The process of identifying the boundaries between genes and other features in a raw DNA
sequence is called genome annotation and is in the domain of bioinformatics. 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 RNA-seq 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 exons 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.

ETHICAL, LEGAL AND SOCIAL IMPLICATIONS

Early planners of the HGP realized that human genomic mapping and sequencing would have
profound implications for individuals, families and our society. Although this information can
potentially and dramatically improve human health, it would raise a number of ethical, legal and
social issues (ELSI) such as how this information would be interpreted and used, who would
have access to it, and how can society prevent harm from improper use of genetic information.
To address these issues, the ELSI Program was established as a part of the HGP. ELSI was
created so that potential problem areas could be identified and solutions created before genetic
information is integrated into modern health care practices. This is a unique aspect because the
HGP is the first large scientific endeavor to address social issues that may arise from the project.
The DOE and NIH genome programs each set aside 3-5% of their annual budgets for the study
of ELSI.

There are four major priorities being addressed by ELSI. The first is the issue of privacy and
fairness in the use and interpretation of genetic information. As genetic information is being
discovered, the risk of genetic discrimination increases as new disease genes are identified. The
issue of privacy and confidentiality, including questions of ownership and control of genetic
information becomes critical. Fair use of this information for insurance, employment, criminal
justice, education, adoption, and the military is necessary. Also, the impact of genetic
information on psychological responses to family relationships and individual stigmatizations
becomes an issue.

The second priority for ELSI is the clinical integration of new genetic technologies. It has been
questioned if health professionals are adequately educated about genetics, genetic technologies
and the implications of their use. Important issues include individual and family counseling and
testing, informed consent for individual considering genetic testing, and the use of such genetic
test for the use of reproductive risk assessment and making reproductive decisions.

The issues that surround genetic research are the third priority of ELSI. Such issues include the
commercialization of the products from human genetic research. Examples are questions of the
ownership of tissue and tissue derived products, patents, copyrights, and accessibility of data and
materials.

The fourth priority is the education of the general public and health care providers. ELSI funded
surveys have revealed that most of the public and health professionals are not knowledgeable
about genetics, genetic technologies and the implications of having genetic information. It is
essential that the public understands the meaning of genetic information and that the nation's
health professionals have the knowledge, skills, and resources to integrate this new knowledge
and technologies into diagnosis, prevention, and treatment of diseases.
ACCOMPLISHMENT MADE
The Human Genome Project was started in 1990 with the goal of sequencing and identifying all
three billion chemical units in the human genetic instruction set, finding the genetic roots of
disease and then developing treatments. It is considered a Mega Project because the human
genome has approximately 3.3 billion base-pairs. With the sequence in hand, the next step was to
identify the genetic variants that increase the risk for common diseases like cancer and diabetes.

It was far too expensive at that time to think of sequencing patients whole genomes. So the
National Institutes of Health embraced the idea for a "shortcut", which was to look just at sites
on the genome where many people have a variant DNA unit. The theory behind the shortcut was
that, since the major diseases are common, so too would be the genetic variants that caused
them. Natural selection keeps the human genome free of variants that damage health before
children are grown, the theory held, but fails against variants that strike later in life, allowing
them to become quite common. (In 2002 the National Institutes of Health started a $138 million
dollar project called the HapMap to catalog the common variants in European, East Asian and
African genomes.)

The genome was broken into smaller pieces; approximately 150,000 base pairs in length. These
pieces were then ligated into a type of vector known as "bacterial artificial chromosomes", or
BACs, which are derived from bacterial chromosomes which have been genetically engineered.
The vectors containing the genes can be inserted into bacteria where they are copied by the
bacterial DNA replication machinery. Each of these pieces was then sequenced separately as a
small "shotgun" project and then assembled. The larger, 150,000 base pairs go together to create
chromosomes. This is known as the "hierarchical shotgun" approach, because the genome is first
broken into relatively large chunks, which are then mapped to chromosomes before being
selected for sequencing.

Funding came from the US government through the National Institutes of Health in the United
States, and a UK charity organization, the Wellcome Trust, as well as numerous other groups
from around the world. The funding supported a number of large sequencing centers including
those at Whitehead Institute, the Sanger Centre, Washington University in St. Louis, and Baylor
College of Medicine.
The United Nations Educational, Scientific and Cultural Organization (UNESCO) served as an
important channel for the involvement of developing countries in the Human Genome Project.[38]
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