KNOW THY MOUSE “All mice are equal…. They have fur, four legs, a front end with teeth and a back end with… aren’t they?” Brian Lam JC 7 th March 2007 Brian Lam JC 7 th March 2007

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?  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! BLACK! AGOUTI! …..BLACK! Do I look gorgeous?! AGOUTI! I look yellowish! You look weird, mate!!

I’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 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?  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 Strain In-bred strains are developed by continual sibling mating This forces homozygosity and loss of genetic variability At the same time homozygosity of detrimental alleles develops --> inbreeding depression --> R.I.P. 20 generations --> surviving line has ~98.7% homozygous in all loci --> regarded as 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?

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

Know 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