The Human Genome Project
An international research effort
to sequence and map all the genes together known as the genome was completed in
Complete genetic blueprint
Genomes of various organisms
commonly used in biomedical model organisms
Mice, fruit flies, and roundworms
Involved NIH, NHGRI, DOE , universities and research facilities in
US, UK, France, Germany, Japan, & China
HGP researchers deciphered the
Determining the sequence
Making maps that show the locations of genes for major sections of
Produced linkage maps which inherited traits (genetic disease) can
be tracked over generations
DNA from all organisms is made
up of the same chemical and physical components. The DNA sequence is the
particular side-by-side arrangement of bases along the DNA strand (e.g.,
ATTCCGGA). This order spells out the exact instructions required to create a
particular organism with its own unique traits.
The genome is an organism’s
complete set of DNA including its gene. Human and mouse genomes both have 3
billion. Except for mature red blood cells, all human cells contain a complete
Genes are specific sequences of
bases that encode instructions on how to make proteins.
Genes comprise only about 2% of the human genome
Remainder consists of noncoding regions
Functions include providing chromosomal structural integrity and
regulating where, when, and in what quantity proteins are made.
Human genome is estimated to contain 30,000 to 40,000 genes
Genomes are expressed by the set
of direction embedded in the DNA sequence.
Protein is responsible for:
Mediate information within the cells
Cells divide into two daughter
cell and the full genome is duplicated in the nucleus.
RNA is produced by
Substitutes the sugar ribose for deoxyribose and the base uracil
MRNA conveys the DNA information for protein synthesis to the cell
What we’ve learned so far
The human genome contains 3164.7
million chemical nucleotide bases (Adenine, Cytosine, Thymine, and Guanine).
The average gene consists of
3000 bases, but varies in size
Almost all (99.9%) nucleotide
bases are exactly the same in all people.
The functions are unknown for
over 50% of discovered genes.
Less than 2% of the genome codes
Repeated sequences that do not
code for proteins ("junk DNA") make up at least 50% of the human genome.
Repetitive sequences are thought
to have no direct functions, but they shed light on chromosome structure and
dynamics. Over time, these repeats reshape the genome by rearranging it,
creating entirely new genes, and modifying and reshuffling existing genes.
During the past 50 million
years, a dramatic decrease seems to have occurred in the rate of accumulation of
repeats in the human genome.
Humans compared to other
Humans have on average three
times as many kinds of proteins as the fly or worm because of mRNA transcripts
and chemical modifications to the proteins.
Humans share most of the same
protein families with worms, flies and plants, but the number of gene family
members has expanded in humans.
The human genome has a much
greater portion (50%) of repeat sequences than the mustard weed (11%), the worm
(7%), and the fly (3%).
Although humans appear to have
stopped accumulating repeated DNA over 50 million years ago, there seems to be
no such decline in rodents. This may account for some of the fundamental
differences between hominids and rodents, although gene estimates are similar in
Variations and Mutations
Scientists have identified about
1.4 million locations where single-base DNA differences (SNPs) occur in humans.
This information changes the processes of finding chromosomal locations for a
Gene tests (also called
DNA-based tests), used to test for genetic disorders, involve direct examination
of the DNA molecule itself.
Genetic tests are used for
several reasons, including:
preimplantation genetic diagnosis
presymptomatic testing for predicting adult-onset disorders
presymptomatic testing for estimating the risk of developing
adult-onset cancers and Alzheimer's disease
confirmational diagnosis of a symptomatic individual
prenatal diagnostic testing
How Does it Work
Scan a patient's DNA sample for a mutated sequences
DNA sample can be obtained from any tissue
Design short pieces of DNA called probes
sequences are complementary to the mutated sequences.
Probes will seek their complement among the three billion base
pairs of an individual's genome.
Mutated sequence is present in the patient's genome, the probe
will bind to it and flag the mutation.
Isolation of single gene
Confirm that a disease is transmitted from parent to child
Tells which chromosome contains the gene and where it is in the
Cystic fibrosis and muscular dystrophy
Correcting defective genes
responsible for disease development
An abnormal gene could be
swapped for a normal gene through homologous recombination.
The abnormal gene could be
repaired through selective reverse mutation, which returns the gene to normal.
A normal gene may be inserted
into a nonspecific location within the genome to replace a nonfunctional gene.
Gene Therapy Vectors
Double stranded DNA copies RNA
Integrated into the chromosomes of host cell
Double stranded DNA genomes that cause respiratory, intestinal,
and eye infections in humans
Single stranded DNA viruses that can insert their genetic material
at a specific site on chromosome 19
Herpes Simplex viruses
Double stranded DNA viruses that infect a particular cell type
Non Viral Options for Gene
Direct introduction of therapeutic DNA into target cell
Creation of an artificial lipid sphere with an aqueous core
Chemically linking the DNA to a molecule that will bind to special
Factors that have kept gene therapy from becoming effective
Short lived nature of gene therapy
Problem with viral vectors
Potential Benefits of Human
Anthropology, Evolution, and Human Migration
Agriculture, Livestock Breeding, and Bioprocessing
Revolutionary ways to diagnose, treat, and prevent thousands of
Fairness in the use of genetic information by insurers, employers,
courts, schools, adoption agencies, and the military, among others.
Who should have access to personal genetic information, and how
will it be used?
Privacy and confidentiality of genetic information.
Who owns and controls genetic information?
Reproductive issues including adequate informed consent for
complex and potentially controversial procedures, use of genetic information in
reproductive decision making, and reproductive rights.
Do healthcare personnel properly counsel parents about the risks
and limitations of genetic technology?
How reliable and useful is fetal genetic testing?
Psychological impact and stigmatization due to an individual's
How does personal genetic information affect an individual and
society's perceptions of that individual?
How does genomic information affect members of minority
Commercialization of products including property rights (patents,
copyrights, and trade secrets) and accessibility of data and materials.
Who owns genes and other pieces of DNA?
Will patenting DNA sequences limit their accessibility and
development into useful products?
Where is this going?
Study an individual’s genotype
Risk for complex condition
Ex. Dental Caries, Cleft lip/ cleft palate, oral cancer
Molecular basis of a disease
An accurate molecular based
diagnosis helps clinicians to delineate conditions with a similar phenotype.
Congenitally missing teeth
Premature loss of teeth
Determining the molecular basis is helpful in confirming the
Provide counseling for recurrence risk
Congenitally Missing Teeth
Most common hereditary dental condition
Simple dental trait
MSX1 homeobox gene
Can be part of a syndrome
Premature Loss of Teeth
Chediak Higashi Syndrome
Dentinogenesis Type I
Occurs with osteogenesis imperfecta
Primary teeth more severe
Permanent teeth central incisors and 1st molars
Scalloped DEJ, normal mantle dentin
Bulbous crowns and short roots
Dentinogenesis Imperfecta II
Hereditary Opalescent dentin
Primary and permanent equally affected
Irregular or tubular pattern
Periapical radiolucencies, alveolar abscess
Similar to DI-I
Dentinogenesis Imperfecta III
Bell shaped crowns, opalescent hue
Shell teeth with short roots and enlarged pulp chambers; only
mantle dentin formed
Outer layer of primary dentin, less mineralized
Multiple pulpal exposure
Different expression for the same DI-II gene
Ex. Amelogenesis Imperfecta
Genetic studies allow for accurate diagnosis
X linked AI forms are caused by mutation in the amelogenin gene
Smooth hypoplastic AI – mutation in the enamelin gene
Hypoplastic (Type I)
Hypomaturation (Type II)
Hypocalcified (Type III)
Problem with the enamel could
Elaboration of the organic matrix
Mineralization of the matrix
Maturation of the enamel
14 different hereditary subtypes
Numerous patterns of inheritance
Wide variety of clinical manifestation
Deciduous and permanent
Treatment varies depending on
What to look forward to as
the Human Genome Project advances
Better prediction of disease
Early preventive therapies or
Advances in tissue engineering
and tissue regeneration
New and effective
The Next Step
To generate a 3-D structures of one or more proteins from each
protein family, which will offer clues to function and biological targets for
Reveals what happens in the cell than gene expression studies.
Will help with drug design.
Analysis of messenger RNAs transcribed from active genes to follow
when, where and what conditions are expressed.
Integration of molecular biology and computer science to help
analyze and interpret the information derived from the genome and related
Analyzing DNA sequencing pattern of humans and well studied model
organisms side by side.
Experimental method for understanding functions DNA sequencing.