The Ac-Ds System
Genome Projects
The Human Genome Project
In 1990, the Department of Energy proposed the
importance of understanding the biological effects
of radiation, and spearheaded a massive,
international project to sequence every base in the
3.1 billion base pair human genome.
The plan was to accomplish this goal in 15 years.
The Human Genome Project Goals
1.) Identify the ~30,000 genes in human DNA
2.) Determine the sequences of the 3 billion bases of
the human genome
3.) Develop databases to store and access this
information
4.) Improve tools for data analysis
5.) Transfer related technologies to the private sector
6.) Address the ethical, legal and social issues that
would arise from the project
The Human Genome Project
The project officially ended in 2003, two years ahead
of schedule, with the entire genome sequenced. A
working draft had been completed in 2000.
The cost: $3.8 billion over 13 years, including
associated research projects in addition to direct
sequencing.
The Human Genome Project
By licensing technologies to the private sector and
awarding grants for innovative research, the
project not only moved forward more rapidly, but
also catalyzed the multibillion-dollar US
biotechnology industry, fostered the development
of new medical, industrial, environmental and
agricultural applications.
International Cooperation
At least 18 countries have established genome
research programs. Some of the larger programs
are in Australia, Brazil, Canada, China,
Denmark, European Union, France, Germany,
Israel, Italy, Japan, Korea, Mexico, Netherlands,
Russia, Sweden, United Kingdom, and the
United States.
DNA Sequencing
DNA sequencing involves:
1)
Isolation and purification
of DNA from individuals
2)
Chemical sequencing to
establish the order of
nucleotides
3)
Arranging the DNA
sequences into the proper
order
Reducing Costs and Speeding Up
Sequencing
Technological developments dramatically decreased
DNA sequencing's cost while increasing its speed and
efficiency. For example, it took 4 years for the
international Human Genome Project to produce the
first billion base pairs of sequence and less than 4
months to produce the second billion base pairs. In the
month of January 2003, the DOE team sequenced 1.5
billion bases. The cost of sequencing has dropped
dramatically since the project began and is still
dropping rapidly.
Reducing Costs and Speeding Up
Sequencing
Source DNA
For the publicly funded HGP, human DNA was
isolated from blood (female) and sperm (male)
collected from a large number of donors.
For the work privately funded by Celera Genomics,
DNA resources used for these studies came from
anonymous donors of European, African,
American (North, Central, South), and Asian
ancestry.
Research Challenges
1.
2.
3.
4.
5.
6.
7.
8.
Gene number, exact locations, and functions
Gene regulation
DNA sequence organization
Chromosomal structure and organization
Noncoding DNA types, amount, distribution, information
content, and functions
Coordination of gene expression, protein synthesis, and
post-translational events
Interaction of proteins in complex molecular machines
Predicted vs experimentally determined gene function
Research Challenges
9. Conservation among organisms
10. Proteomes (total protein content and function) in
organisms
11. Correlation of SNPs (single-base DNA variations among
individuals) with health and disease
12. Disease-susceptibility prediction based on gene sequence
variation
13. Genes involved in complex traits and multigene diseases
14. Complex systems biology including microbes useful for
environmental restoration
15. Developmental genetics, genomics
Other Genome Projects Underway or
Completed
Agriculturally important species: chicken, cow (Bos
taurus with Bos indicus planned), honeybee
Related organisms: mouse, rat, dog, chimpanzee,
macaque, laboratory opossum, duckbilled platypus
Lower animals: Fruit fly, roundworm, sea squirt, sea
urchin, planarian, puffer fish, red flour beetle
Single-celled species: E coli and other bacteria,
multiple fungi species.
Chromosome Aberrations
Chromosome Aberrations
Variations in the number and/or arrangement.
Chromosome abnormalities are passed on to
offspring in a predictable manner, resulting
in unique genetic outcomes.
Definitions
Euploid: An organism or cell with the correct
number of chromosomes.
Aneuploid: An organism that has lost or gained an
individual chromosome, but not an entire set.
Monosomy: The loss of a single chromosome from
an otherwise diploid genome.
Trisomy: The gain of a single chromosome from an
otherwise diploid genome.
Definitions
Polyploid: An organism with more than two entire
sets of chromosomes.
Triploid: An organism with three sets of
chromosomes.
Tetraploid: An organism with four sets of
chromosomes.
Note: polyploidy can be the normal condition in
plants.
Notes on Chromosome Abnormalities
Most of the examples will be conditions observed in
humans. Often the abnormalities produce a
negative effect.
In animals, the loss of function usually prevents the
animal from being vigorous such that it does not
become a member of the breeding population, and
the conditions are not preserved. (Selection
pressure)
Non-Disjunction
Non-disjunction occurs when chromosomes do not
assort evenly during meiosis, such that the
resulting gametes have either extra chromosomes
or not enough chromosomes.
Non-disjunction may occur during either meiosis I or
meiosis II.
Non-Disjunction: Anaphase I
Non-Disjunction: Anaphase II
Non-Disjunction
Klinefelter Syndrome: (47:XXY) An extra X
chromosome; males, may be unusually tall (>6 ft),
underdeveloped testes, usually infertile, some
feminization. (↑ to XXX, XXXX, more severe)
Turner Syndrome: (45:X) Loss of one X
chromosome; females characterized by short
stature (<5 ft), subfertile ovaries and inadequate
secondary sex characteristics.
Klinefelter Syndrome
Monosomy
Turner Syndrome is an example of monosomy, or
loss of a chromosome.
Loss of autosomes (non-sex chromosomes) are not
usually tolerated in either humans or animals
(organism dies during development).
As usual, there is something of an
exception.
Partial Monosomy
Cri-du-Chat (“Cry of the cat”) syndrome: (46:-5p)
Due to a partial deletion of chromosome 5; infants
have a high-pitched, mewling cry, due to abnormal
development of the larynx and glottis. Infants are
also characterized by abnormal gastrointestinal
tract, mental and cardiac development.
The longer the deletion, the more severe the
complications.
Trisomy
Trisomy 21: Down Syndrome; impaired mental and
cardiac development. Affected individuals usually
live to the mid30s.
Trisomy 13: Patau Syndrome; affected individuals
are not mentally alert, have a cleft palate, may
exhibit polydactyly (extra digit on hands or feet),
Chromosome Rearrangements
™ These
are variations in the structure and
arrangement of chromosomes
™ Note that rearrangement of chromosomes may
exert a positional effect, such that genes may be
suppressed or expressed by moving from one place
in the genome to another.
Animation Credits
The animation clips were created by Dr. Lester
Newman, Professor of Biology at Portland State
University
http://www.irn.pdx.edu/~newmanl/moviepage.html
Duplication
Deletion
May involve loss of a whole chromosome (Turner
syndrome) or part of one chromosome.
A partial deletion of chromosome 5 is responsible for
the partial monosomy of Cri-du-Chat syndrome.
46:-5P Deletion in Cri-du-Chat
Translocations
Portions of chromosomes trade places.
Deletion
Reciprocal Translocation
Robertsonian Translocations
Familial Down Syndrome
A Robertsonian translocation is responsible for about
5% of Down syndrome incidence.
In these cases, one of the parents will have a
translocation of chromosomes 14 and 21. As a
result, 25% of that person’s gametes will have
three copies of chromosome 21 (two normal, plus
most of another one attached to chromosome 14).
Note that in this case, the affected individual has the
normal complete number of 46, but one of the
copies of 14 possesses the translocation.
Inversions
Portions of a chromosome become reversed.
Inversions may or may not involve the
centromere
Inversions
Pericentric: The centromere IS part of the
inversion. (To help you remember: Paricentric IS)
Paracentric: The centromere is NOT part of the
inversion.
Consequences of Inversions
If only one homologue of a pair experiences an
inversion, normal linear synapsis cannot occur
during meiosis.
Recombination may not occur at all, or if it does,
will produce gametes with duplications and
deletions. Often, gametes with broken
chromosomes will form.
Fragile Sites—Fragile X Syndrome
Site along X-chromosome that is prone to breakage.
Occur in fetuses of women who are deficient for the
B-vitamin folic acid.
Associated with a particular form of mental
retardation and/or attention deficit disorder.
Fragile Sites and Cancer
A number of fragile sites have been associated with
cancer, particularly one site on chromosome 3.
The gene inactivated by the break has been shown to
be involved in cancer development in a number of
tissues.
It is not known if breakage at the fragile site causes
cancer or if activity of cancerous cells induces the
break.