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1.Human DNA Sequencing

Providing a complete, high-quality sequence of human genomic DNA to
the research community as a publicly available resource continues to
be the HGP's highest priority goal. The enormous value of the human
genome sequence to scientists, and the considerable savings in
research costs its widespread availability will allow, are compelling
arguments for advancing the timetable for completion. Recent
technological developments and experience with large-scale sequencing
provide increasing confidence that it will be possible to complete an
accurate, high-quality sequence of the human genome by the end of
2003, 2 years sooner than previously predicted. NIH and DOE expect to
contribute 60 to 70% of this sequence, with the remainder coming from
the effort at the Sanger Center and other international partners.
This is a highly ambitious goal, given that only about 6% of the human
genome sequence has been completed thus far. Sequence completion by
the end of 2003 is a major challenge, but within reach and well worth
the risks and effort. Realizing the goal will require an intense and
dedicated effort and a continuation and expansion of the collaborative
spirit of the international sequencing community. Only sequence of
high accuracy and long-range contiguity will allow a full
interpretation of all the information encoded in the human genome.
Availability of the human sequence will not end the need for
large-scale sequencing. Full interpretation of that sequence will
require much more sequence information from many other organisms, as
well as information about sequence variation in humans. Thus, the
development of sustainable, long-term sequencing capacity is a
critical objective of the HGP. Achieving the goals below will require
a capacity of at least 500 megabases (Mb) of finished sequence per
year by the end of 2003.

a) Finish the complete human genome sequence by the end of 2003.
To best meet the needs of the scientific community, the finished human
DNA sequence must be a faithful representation of the genome, with
high base-pair accuracy and long-range contiguity. Specific quality
standards that balance cost and utility have already been established.
These quality standards should be reexamined periodically; as
experience in using sequence data is gained, the appropriate standards
for sequence quality may change. One of the most important uses for
the human sequence will be comparison with other human and nonhuman
sequences. The sequence differences identified in such comparisons
should, in nearly all cases, reflect real biological differences
rather than errors or incomplete sequence. Consequently, the current
standard for accuracy--an error rate of no more than 1 base in
10,000--remains appropriate.
The current public sequencing strategy is based on mapped clones and
occurs in two phases. The first, or "shotgun" phase, involves random
determination of most of the sequence from a mapped clone of interest.
Methods for doing this are now highly automated and efficient. Mapped
shotgun data are assembled into a product ("working draft" sequence)
that covers most of the region of interest but may still contain gaps
and ambiguities. In the second, finishing phase, the gaps are filled
and discrepancies resolved. At present, the finishing phase is more
labor intensive than the shotgun phase. Already, partially finished,
working-draft sequence is accumulating in public databases at about
twice the rate of finished sequence.

b) Make the sequence totally and freely accessible.
The HGP was initiated because its proponents believed the human
sequence is such a precious scientific resource that it must be made
totally and publicly available to all who want to use it. Only the
wide availability of this unique resource will maximally stimulate the
research that will eventually improve human health.

2.Sequencing Technology

Create a long-term, sustainable sequencing capacity by improving
current technology and developing highly efficient novel technologies.
Achieving this HGP goal will require current sequencing capacity to be
expanded 2-3 times, demanding further incremental advances in standard
sequencing technologies and improvements in efficiency and cost. For
future sequencing applications, planners emphasize the importance of
supporting novel technologies that may be 5-10 years in development.

3.Sequence Variation

Develop technologies for rapid identification of DNA sequence
variants. A new priority for the HGP is examining regions of natural
variation that occur among genomes (except those of identical twins).
Goals specify development of methods to detect different types of
variation, particularly the most common type called single nucleotide
polymorphisms (SNPs) that occur about once every 1000 bases.
Scientists believe SNP maps will help them identify genes associated
with complex diseases such as cancer, diabetes, vascular disease, and
some forms of mental illness. These associations are difficult to make
using conventional gene hunting methods because any individual gene
may make only a small contribution to disease risk. DNA sequence
variations also underlie many individual differences in responses to
the environment and treatments.

4.Functional Genomics

Expand support for current approaches and innovative technologies.
Efficient interpretation of the functions of human genes and other DNA
sequences requires developing the resources and strategies to enable
large-scale investigations across whole genomes. A technically
challenging first priority is to generate complete sets of full-length
cDNA clones and sequences for human and model organism genes. Other
functional genomics goals include studies into gene expression and
control, creation of mutations that cause loss or alteration of
function in nonhuman organisms, and development of experimental and
computational methods for protein analyses.

5.Comparative Genomics

Obtain complete genomic sequences for C. elegans (1998), Drosophila
(2002), and mouse (2008). A first clue toward identifying and
understanding the functions of human genes or other DNA regions is
often obtained by studying their parallels in nonhuman genomes. To
enable efficient comparisons, complete genomic sequences already have
been obtained for the bacterium E. coli and the yeast S. cerevisiae,
and work continues on sequencing the genomes of the roundworm, fruit
fly, and mouse. Planners note that other genomes will need to be
sequenced to realize the full promise of comparative genomics,
stressing the need to build a sustainable sequencing capacity.

6.Ethical, Legal, and Social Implications (ELSI)

• Analyze and address implications of identifying DNA sequence
information for individuals, families, and communities.
• Facilitate safe and effective integration of genetic technologies.
• Facilitate education about genomics in nonclinical and research settings.

Rapid advances in genetics and applications present new and complex
ethical and policy issues for individuals and society. ELSI programs
that identify and address these implications have been an integral
part of the US HGP since its inception. These programs have resulted
in a body of work that promotes education and helps guide the conduct
of genetic research and the development of related health professional
and public policies. Continuing and new challenges include
safeguarding the privacy of individuals and groups who contribute
samples for large-scale sequence variation studies; anticipating how
resulting data may affect concepts of race and ethnicity; identifying
how genetic data could potentially be used in workplaces, schools, and
courts; commercial uses; and the impact of genetic advances on
concepts of humanity and personal responsibility.

7.Bioinformatics and Computational Biology

Improve current databases and develop new databases and better tools
for data generation and capture and comprehensive functional studies.
Continued investment in current and new databases and analytical tools
is critical to the success of the Human Genome Project and to the
future usefulness of the data. Databases must be structured to adapt
to the evolving needs of the scientific community and allow queries to
be answered easily. Planners suggest developing a human genome
database analogous to model organism databases with links to
phenotypic information. Also needed are databases and analytical tools
for the expanding body of gene expression and function data, for
modeling complex biological networks and interactions, and for
collecting and analyzing sequence variation data.

8.Training

Nurture the training of genomic scientists and establish career paths.
Increase the number of scholars knowledgeable in genomics and ethics,
law, or the social sciences. Planners note that future genomics
scientists will require training in interdisciplinary areas that
include biology, computer science, engineering, mathematics, physics,
and chemistry. Additionally, scientists with management skills will be
needed for leading large data-production efforts.