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• The Human Genome Project (HGP) is an international research effort to
determine the DNA sequence of the entire human genome.
• Contributors to the HGP include the National Human Genome Research
Institute (NHGRI) of the National Institutes of Health (NIH), which
initiated its funding of the HGP in 1988; the U.S. Department of Energy
• The discussions of the HGP began as early as 1984; numerous universities
and laboratories throughout the United States; and international partners
in the United Kingdom, France, Germany, Japan and China.
• The HGP already has revealed that there are probably somewhere around
30,000 human genes. Sanger method used for DNA sequencing purposes.
• The existing and ultimate products of the HGP will give the world a
resource of detailed information about the structure, organization and
function of the complete set of human genes and other functional
elements found in DNA.
• This information can be thought of as the basic set of inheritable
"instructions" for the development and function of a human being.
• The International Human Genome Sequencing Consortium published the first draft of
the human genome in the journal Nature in February 2001 with the sequence of the
entire genome's three billion base pairs some 90 percent covered at an accuracy of
• A startling finding of this first draft is that the number of human genes appears to be
significantly fewer than previous estimates, which ranged from 50,000 genes to as
many as 140,000.
• We can compare the landscape of the human genome with that of older species and
identify evolutionarily conserved regions of DNA.
• This will allow us to identify sections of DNA that are functionally very important
because they haven't changed over millions of years of evolution.
• The publication of the first sequence of the human genome is
regarded as one of the major landmarks in modern biological
• In the US, the National Institutes of Health have funded three
projects examining the use of NGS as part of established newborn
screening programs and in the UK, a major publicly funded initiative
aims to sequence the genomes of 100,000 patients with a view to
learning new medical insights and bring benefits to patients.
Advancement in Clinics
• Screening is the systematic, proactive offer of a test to
members of a certain group of individuals.
• This differs distinctly from clinical genetics in that the
application of the screening test is not initially pre-specified
on the basis of a person’s family or medical history.
• The goal of screening is disease detection at an early or
precursor phase, where intervention may alter natural
• New strategies for identifying sub-groups of patients with
monogenic versions of common serious disorders are being
evaluated, blurring the boundary between diagnostic investigation
and targeted screening.
• For example, while it is currently not feasible to test all breast
cancer patients for genetic susceptibility, specific tumor phenotypes
(e.g. receptor status) may provide a clue to genetic etiology, and
prompt germ line mutation testing in the patient.
• The result would also alert clinicians to the importance of offering
at-risk relatives genetic counseling and mutation testing.
• If appropriate, newborn screening for serious genetic disorders
family-based cascade screening of first and second degree relatives
of individuals diagnosed with genetic conditions and carrier
screening of targeted population groups to inform reproductive
planning or early disease detection are common applications.
• The focus of traditional clinical genetics has been on identifying
monogenic disorders, often pre-specified on the basis of a person’s family
history, ethnicity or medical history.
• These variants mutations are usually of high penetrance, i.e. carrying the
mutation is associated with a high likelihood of developing the disorder in
• The family history may point to dominant, recessive, X-linked, or some
other form of single gene (monogenic), Mendelian inheritance.
• In terms of service organization and culture, medical genetics
departments are generally specialist units, often located in tertiary
care facilities, sometimes linked with dedicated testing laboratories,
and staffed by medical genetics specialists and formally trained
• Patients are usually referred on the basis of an unusual family
history, birth of a child with a serious congenital anomaly, or
diagnosis of a suspected genetic condition.
• Genetic assessment is a painstaking process, of which comprehensive family history
collection is a central activity.
• In contrast, personalized medicine is conceived as more broadly applicable across health
care. It includes the strategy of genetic profiling to offer individual risk information for multi
factorial disorders (e.g. cardiovascular disease, cancers, and type 2 diabetes), where disease
risk results from interaction between several genes (polygenic) as well as non-genomic
• Thus, the scope of personalized medicine may range from targeted testing of one or several
mutations associated with rare monogenic, high penetrance disorders at one extreme to at
the other sequencing a patient’s exome or genome without targeting specific variants.
• Personalized screening involves the offer of a test to a target population,
for the purpose of disease (or pre-disease) detection at a sufficiently early
stage for interventions to reduce mortality and/or morbidity.
• The principle of risk stratification is already universally embedded in
population screening approaches, in the form of age-based eligibility
• For example, the risk threshold used by the UK National Breast Screening
program is a 10 year absolute risk of >2.5%, this translates to age eligibility
of 47–73 years.
• However, even honing down on a population group exceeding an age-
based risk threshold, it is inevitable that all population-based screening
programs experience an unavoidable rate of false positive and false
negative screen results.
• However, when combined with age, genetic panels may offer more
accurate risk stratification and indicate more tailored approaches to the
timing or intensity of screening tests.
• For example, for individuals in a highest risk society, surveillance might
begin at a younger age or screening frequency shortened; while
individuals in lower risk society might benefit from a reduction in
HapMap & SNPs
• Linkage disequilibrium was a classical concept, but its genome-wide structure had never
been characterized in any organism. Humans turned out to have a surprisingly simple
structure, reflecting recent expansion from a small founding population.
• Tight correlations seen in a few dozen regions implied that a limited set of around
500,000–1,000,000 SNPs could capture and around 90% of the genetic variation in the
• The International Haplotype Map (HapMap) project soon defined these patterns across
the entire genome, by genotyping nearly 3 million SNPs.
• The second advance was the development of genotyping arrays (often called SNP
chips), which can now assay up to 2 million variants simultaneously.
• Since the early 1980s, humans were known to carry a heterozygous site roughly every
1,300 bases. Genetic maps containing a few thousand markers, adequate for
rudimentary linkage mapping of Mendelian diseases, were constructed in the late
1980s and early 1990s.
• Systematic methods to discover and catalogue single nucleotide polymorphisms (SNPs)
were developed in the late 1990s and resulted in the report of 1.42 million genetic
variants in a companion to the HGP paper.
• Still, the list was far from complete. Moreover, there was no way to actually assay the
genotypes of the SNPs in human samples. Today, the vast majority of human variants
with frequency >5% have been discovered and 95% of heterozygous SNPs in an
individual are represented in current databases.
• The HGP is revolutionizing the way biology and medicine will be explored
in the next century and beyond.
• The availability of entire genome sequences is enabling a new approach to
biology often called functional genomics the interpretation of the function
of DNA sequence on a genomic scale.
• Already, the availability of the sequence of entire organisms has
demonstrated that many genes and other functional elements of the
genome are discovered only when the full DNA sequence is known. Such
discoveries will accelerate as sequence data accumulate.
• These exciting successes confirm the view that acquisition of a comprehensive high-
quality human genome sequence will have unprecedented impact and long lasting
value for basic biology, biomedical research, biotechnology and health care.
• The transition to sequence-based biology will spur continued progress in understanding
gene-environment interactions and in development of highly accurate DNA-based
medical diagnostics and therapeutics.
• In the future, de novo sequencing of additional genomes, comparative sequencing of
closely related genomes, and sequencing to assess variation within genomes will
become increasingly indispensable tools for biological and medical research. Much
more efficient sequencing technology will be needed than is currently available.