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MOUSE GENOME PROJECTBIOINFORMATICS 407

“ T he ab i l i t y t o man ipu la t e t he mouse genome coup led w i t h t he ava i l ab i l i t y o f genome sequence make t he mouse a

un ique resea rch t oo l ”

G E NO ME P RO JECT ? 2O CHRO MO S O ME PAI RS 2 . 5 B I L L I O N BAS E PAI RS 30 , 000 G E NE S

Comparative Genomics Analysis and comparison of genomes from different species.

Functional Genomics Conducted using model organisms. Close Relation Of Mouse And Human

Mus musculus (mouse) Homo sapien (human) 40 Chromosomes 46 Chromosomes 2.6 billion Base pairs 3.2 billion Base pairs 25,000 Gene numbers 25,000 Gene numbers

Knock Out Mouse Transgenic mice. Target specific genes. Determination of gene function. Testing new drugs and devising novel

therapies.

History By the 1700s, many varieties of mice domesticated. Mice were used to test the new theories of inheritance. Mating programs established to create inbred strains.HUMAN MOUSE GENOME HUMOLOGY Mouse and Human shared common ancestor. 99% genes are homologous. Homology between genes at numerous chromosomal positions.

Genetic mapping of the mouse: “Graphic representation of the arrangement of genes or DNA

sequences on a chromosome” Haldane’s report in 1915led to genetic mapping in mouse. Genetic linkage map of the mouse, consisting entirely of genetic

markers. Provide thousands of anchor points that could be used to tie

clones or DNA sequences to specific locations in the mouse genome.

OVER THE PAST CENTURY:•As mammalian model system for genet ic research. •I t has genet ic and physio logical s imi lar i t ies to humans.•I f immunodeficient mice. Current researches: •Mice prone to different d iseases.•Immunodeficient mice .•Researchers produced a process known as chemical mutagenesis .

Background of Mouse as a Model Organism

Many technologies are produced:•Transgenic mice.•Knock out genes.•Knock in genes.

Some reproductive technologies produced as follows:•Cryopreservat ion of embryos,•  In v itro   fert i l izat ion• Ovary transplantat ion.

Recent decades researches

I t is nat ional repository for mouse .Establ ished in 1929.The famous "Black 6" or C57BL/6J mouse stra in was developed in the ear ly 1920s by The Jackson Laboratory.

Recent researchers at The Jackson Laboratory Includes cancer, development and aging, immune system and blood disorders , neurological and sensory disorders , and metabol ic diseases.

The Jackson Laboratory

•Down Syndrome •Cystic Fibrosis •Cancer•Glaucoma•Type 1 Diabetes •Epilepsy•Heart Disease •Muscular Dystrophy •Ovarian Tumors

Listed below is a sampling of mouse models developed by The Jackson

Laboratory:

Comparison of human & mouse genome

The mouse genome has about 2.5 billion base pairs

The human genome has about 2.9 billion base pairs

 Synteny and conserved syntenty between the

mouse and human genomes

   

Repeat sequences in mouse and human genome

Repeat sequences are mainly either active or inactive elements are called Transposons or Transposable elements that move around the genome.

Three different mechanisms for transposition:

Conservative transposition Replicative transposition Retrotransposition

There are two sorts of repeat sequence:

Ancestral repeatsLineage specific repeats

• 23,000 predicted genes and 200,000 exons.• 22,000 predicted genes and 191,000 exons.• Pseudogenesi. An error can occur during

transcription.ii. Unprocessed pseudogenes

Comparison of mouse and human coding genes

Comparison of Mouse and Human gene sets

99% of mouse genes have homologues in man.

80% of mouse genes that have a match on the same syntenic region in man are also the best match for that human gene.

The less than 1% mouse genes (118) with no homologues in humans do have homologues in other species.

 

Gene families

A number of genes in the same families is different between mouse and human

About 20% of mouse olfactory receptor homologues are pseudogenes

25 mouse-specific gene clusters were identified where multiple duplications had occurred to the ancestral gene.

I. reproduction. II. host defense and immunityTwo categories of gene family (Ly49 in mouse and KIR

in human) are unrelated.  

Mouse Genome Databases

Mouse Genome Database (MGD)The Cancer Genome Anatomy ProjectMouse Genome Informatics (MGI) Gene Expression Database (GXD) ProjectMouse Tumor Biology (MTB) Database

Project

Transgenic organismWhose genetic material has been altered.First transgenic mice was created by Rudolf Jaenisch in

1974.To study gene function & how and why a specific gene is

"turned on" in some tissues and "turned off" in others.

Production of Transgenic Animals:Randomly Inserted Transgenes:

microinjection of DNA into the pronucleus of zygotesTargeted Gene Mutations:

injection of embryonic stem cells into blastocysts. Complete microinjection set-containing of a microscope,

micromanipulators, microinjectors and micropipettes.

Mario R. Capecchi, Ph.D., of the University of Utah, has won the 2007

Nobel Prize in Physiology or Medicine.

work on "knockout mouse" technology,To "knockout" the OhNo gene, replace it with a

mutated copy that doesn't work. Here's how:

A 17-month project culminates in a physical map of the mouse using 300,000 BACs.

305,768 clones present in the physical map, 289,506 of which are contained within the 7,582 contigs.

first breaking the genome into 150,000 base pair pieces called BACs, assembling

Shotgun sequencing: long stretch of DNA is physically broken into small, approximately 2,000

base-pair. Craig Venter developed the technique in 1996. The NIEHS, National Academy of Sciences Institute of Laboratory Animal

Resources (ILAR), and Oak Ridge National Laboratory Human Genome Group have combined efforts to establish a database that catalogs information on transgenic animals.

Genome Sequence a Physical Map of the Mouse Genome:

Ethical consideration

The genetic modification or cloning of companion animals.

Experiments intended to reduce the sentience of any species are not allowed.

A presumption against the genetic modification and cloning animals should only be allowed if it will contribute to the relief of serious human sufferings.

the applicant wishing to undertake genetic modification of animals to demonstrate that other approaches could not achieve broadly similar goals.

Advantages:

First, it is among the smallest mammals known with adult weights in the range of 25-40 g, 2,000-3,000-fold lighter than the average human adult.

Second, it has a short generation time — on the order of 10 weeks from being born to giving birth.

Third, females breed prolifically in the lab with an average of 5-10 pups per litter.

Fourth, an often forgotten advantage is the fact that fathers do not harm their young, and thus breeding pairs can be maintained together after litters are born.

most laboratory-bred strains are relatively docile and easy to handle

Disadvantages:

Most significant differences between mice and humans are not in the number of genes but in the structure of genes and the activities of protein products.

Single nucleotide differences can alter protein function and causes tissue malfunction.

Changes have been linked to hereditary differences in height, brain development, facial structure, pigmentation.

Due to changes, hands can develop structures that look like toes instead of fingers, and a mouse's tail can disappear completely.

Disorders to detect, model and treat

Cystic fibrosis (CF) is the most common severe single gene disorder.

Sufferers usually die in their mid twenties. But CF mice generally die perinatally from severe intestinal obstruction .

Several transgenic mouse models have been created by insertional mutation and display similar molecular changes to CF patients. But the disease progress is extremely different.

Serious lung disease is the cause of death in 95% of human patients but CF mice develop lung disease infrequently and mildly

Lesch Nyhan Syndrome is another single gene disorder, characterized by mental retardation and distressing behavioural abnormalities.

Several mouse models were created with the same genetic defect but the mice did not display abnormal behaviour.

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