the ac-ds system - university of arizona · 2004. 10. 5. · a robertsonian translocation is...

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 Goals1.) Identify the ~30,000 genes in human DNA2.) Determine the sequences of the 3 billion bases of

the human genome3.) Develop databases to store and access this

information4.) Improve tools for data analysis5.) Transfer related technologies to the private sector6.) Address the ethical, legal and social issues that

would arise from the project

The Human Genome ProjectThe 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 ProjectBy 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 SequencingDNA sequencing involves:1) Isolation and purification

of DNA from individuals2) 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 DNAFor 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. Gene number, exact locations, and functions 2. Gene regulation 3. DNA sequence organization 4. Chromosomal structure and organization5. Noncoding DNA types, amount, distribution, information

content, and functions 6. Coordination of gene expression, protein synthesis, and

post-translational events 7. Interaction of proteins in complex molecular machines 8. Predicted vs experimentally determined gene function

Research Challenges9. 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.

DefinitionsEuploidEuploid:: An organism or cell with the correct

number of chromosomes.

AneuploidAneuploid:: An organism that has lost or gained an individual chromosome, but not an entire set.

MonosomyMonosomy:: The loss of a single chromosome from an otherwise diploid genome.

TrisomyTrisomy:: The gain of a single chromosome from an otherwise diploid genome.

DefinitionsPolyploidPolyploid:: An organism with more than two entire

sets of chromosomes.Triploid:Triploid: An organism with three sets of

chromosomes.

TetraploidTetraploid:: An organism with four sets of chromosomes.Note: polyploidy can be the normal condition in

plants.

Notes on Chromosome AbnormalitiesMost 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-DisjunctionNon-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-DisjunctionKlinefelter 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

MonosomyTurner 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 MonosomyCri-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.

TrisomyTrisomy 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 RearrangementsThese are variations in the structure and arrangement of chromosomesNote 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

DeletionMay 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 SyndromeA 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

PericentricPericentric: The centromere IS part of the inversion. (To help you remember: Pariicentric IS)

ParacentricParacentric: The centromere is NOT part of the inversion.

Consequences of InversionsIf 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 SyndromeSite along X-chromosome that is prone to breakage.

Occur in fetuses of women who are deficient for the B-vitamin folic acidfolic acid.

Associated with a particular form of mental retardation and/or attention deficit disorder.

Fragile Sites and CancerA 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.