KNOW THY MOUSEKNOW THY MOUSE“All mice are equal…. They have fur, four legs, a front end with teeth and a back end with… aren’t they?”

“All mice are equal…. They have fur, four legs, a front end with teeth and a back end with… aren’t they?”

Brian LamJC 7th March 2007

Brian LamJC 7th March 2007

A mouse’s tale:The origin of the laboratory mouse

A mouse’s tale:The origin of the laboratory mouse

The humble house mouse:

Came all the way from Asia -> Mediterranean -> Europe

Adopted human for more than 10K years as a human commensal (or pest if you like to call it)!

It gains a superstardom in world’s modern science, known as Mus musculus (NOT Rattus norvegicus)

The humble house mouse:

Came all the way from Asia -> Mediterranean -> Europe

Adopted human for more than 10K years as a human commensal (or pest if you like to call it)!

It gains a superstardom in world’s modern science, known as Mus musculus (NOT Rattus norvegicus)

I’m a superstar!?

The Fancy Mice?The Fancy Mice?

In 1900, a retired school teacher Abbie Lathrop begins breeding "fancy" mice at her farm in Granby, Massachusetts, as pets, because of various coat colours

Initially sought as pets though, the Granby mice became increasing important in scientific research

In 1900, a retired school teacher Abbie Lathrop begins breeding "fancy" mice at her farm in Granby, Massachusetts, as pets, because of various coat colours

Initially sought as pets though, the Granby mice became increasing important in scientific research

I’m black

ALBINO X AGOUTI!

AGOUTI!

AGOUTI!

BLACK!

AGOUTI!

…..BLACK!

Do I look gorgeous?!

AGOUTI!

I look yellowish!

You look weird, mate!!

I’m from Cage # 57I’m from Cage # 57

In 1909, mouse geneticist Clarence Cook Little (later found the Jackson Lab in 1929) developed DBA (Dilute-Brown-non-Agouti)

In 1921, Little bred 2x black mice (from cage 57?) at Granby farm and developed the C57BL & C57BR strain

C57BL/6J (“Black Six”) then became the world’s most essential inbred strain.

In 1909, mouse geneticist Clarence Cook Little (later found the Jackson Lab in 1929) developed DBA (Dilute-Brown-non-Agouti)

In 1921, Little bred 2x black mice (from cage 57?) at Granby farm and developed the C57BL & C57BR strain

C57BL/6J (“Black Six”) then became the world’s most essential inbred strain.

Hey, what are you going

to do with me?

Not decided yet.

Mouse in Scientific ResearchMouse in Scientific Research Mice are being used as animal models for various diseases and conditions

Genetically manipulated mice (transgenics, knock-out’s, knock-in’s) widely available

Whole mouse genome sequenced (C57BL/6)

Mice are being used as animal models for various diseases and conditions

Genetically manipulated mice (transgenics, knock-out’s, knock-in’s) widely available

Whole mouse genome sequenced (C57BL/6)

Why In-bred?Why In-bred? Ethically un-acceptable in

human though, in-bred are developed by mating between brothers and sisters

Very low genetic variability --> almost clonal in the sense that most mice have almost identical genetic make up.

Thus providing a homogeneous background and high reproducibility for scientific studies

Ethically un-acceptable in human though, in-bred are developed by mating between brothers and sisters

Very low genetic variability --> almost clonal in the sense that most mice have almost identical genetic make up.

Thus providing a homogeneous background and high reproducibility for scientific studies

Oh REALLY? I’m not as stupid as you?!

We are the same,, do you know?

The Generation of an In-bred StrainThe Generation of an In-bred Strain

In-bred strains are In-bred strains are developed by continual developed by continual sibling matingsibling mating

This forces homozygosity and This forces homozygosity and loss of genetic variabilityloss of genetic variability

At the same time At the same time homozygosity of detrimental homozygosity of detrimental alleles develops --> alleles develops --> inbreeding depression --> inbreeding depression --> R.I.P. R.I.P.

20 generations --> surviving 20 generations --> surviving line has ~98.7% homozygous line has ~98.7% homozygous in all loci --> regarded as in all loci --> regarded as in-bredin-bred

Genetic Variations in In-bred?Genetic Variations in In-bred? Genetic contamination

HUMAN ERROR?! Effect --> variable But preventable through management & QC

Genetic drift Nothing can escape Darwinian principles -> genetic change (MUTATIONS!) does happen even in in-bred strains over time

Not easily noticeable --> may result in dramatic and irreversible change in phenotype

Genetic contamination HUMAN ERROR?! Effect --> variable But preventable through management & QC

Genetic drift Nothing can escape Darwinian principles -> genetic change (MUTATIONS!) does happen even in in-bred strains over time

Not easily noticeable --> may result in dramatic and irreversible change in phenotype

Genetic Drift….when and how?

Genetic Drift….when and how?

How to Control Genetic Drift?How to Control Genetic Drift? It can’t be stopped

But can be slowed down by freezing down stocks of embryo (cryopreservation), and used them to replace the foundation stocks after a few generations..

It can’t be stopped

But can be slowed down by freezing down stocks of embryo (cryopreservation), and used them to replace the foundation stocks after a few generations..

The Genetic Stability Program at the Jackson Lab

The Genetic Stability Program at the Jackson Lab

Know thy mouseKnow thy mouse

Even though every mouse has fur, four legs, a front end with teeth and a back end with…

They are a result of a summation of more than one billion years of evolution --> not as simple as they seem to be.

It is crucial to be aware of the the effect of genetic drift & contamination --> largely endanger our scientific endeavor in terms of uniformity and data reproducibility

Even though every mouse has fur, four legs, a front end with teeth and a back end with…

They are a result of a summation of more than one billion years of evolution --> not as simple as they seem to be.

It is crucial to be aware of the the effect of genetic drift & contamination --> largely endanger our scientific endeavor in terms of uniformity and data reproducibility

Failure to do so will lead to UNINTERPRETABLE RESULTS, LOSS OF VALUABLE TIME and perhaps even LOSS OF REPUTATION…

Therefore, KNOW THY MOUSE

Failure to do so will lead to UNINTERPRETABLE RESULTS, LOSS OF VALUABLE TIME and perhaps even LOSS OF REPUTATION…

Therefore, KNOW THY MOUSE