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March 14, 2013.docx

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Human Biology
Richard Brown

March 14 2013 MODELS, MOUSE GENETICS AND APPLICATIONS Number of issues with primate models – no large group sizes, not very reproductive, disease susceptibility (close to humans, complicating care and housing), VERY expensive, public sensitivity to studies involving primates Rodents – have been used in research for long time; small, reproduce quickly; genetics known and applicable due to quick reproduction; preferred Chicken – advantage is embryo Zebrafish – many offspring; embryo develop externally; transparent; Invertebrates – drosophila, c elegans – Conservation between mouse and human Long non-coding RNAs recognized – even though not conserved at sequence level – when sequencing mammalian genomes, able to decipher that some long non-coding RNA have secondary structure characteristics Many mouse strains sequenced – typically inbred strains – Human and mouse chromosomes While related by evolution, chromosomes X chromosome – pieces have flipped around on the X Large amount of movement of genomes between species and mouse chromosomes generally acrocentric (no centromere) Origins of lab mice Chromosome two has large linkage region on distal arm (organe); human orthologous region in green Some overlaps – 56 loci PROBLEM OF INBRED MICE?????????? Loci do not all match perfectly well If enough mapping projects done, able to align them Streght is speed and ability to get large pedigrees Studying mouse traits and disease Source of trait – variety of things Some mice generated because mutations have occurred spontaneously Backcross Common mouse breeding strategies Backcross – heterozygote x homozygote In cross – to maintain a line Intercross – gives most variety of types of genotypes – breeding heterozygotes Outcross – if want to get optimal different – if have two lines, and they are very different in phenotype, can cross-breed them and get heterozygote – this is first step of example to get into – from then design strategy – Specialized strains and derivatives Mice and humans are different – tried to generate a Tay Sachs mice model – buildup of gangliocides in the brain caused the severe phenotype in humans, but in mice, there is another side metabolic pathway that slowly degraded the gangliocytes, so given the absence of __________ (an enzyme), symptoms due to this is apparent but did not see the ost sever phenotype in the mice Want to compare with minimal background difference – Generation of congenic strains – Graph - Top is mutant strain; bottom is background strain Cross the two – first offspring is 50/50 Recombinant Studying human disease models First disease models – actually models found spontaneously – looking at mouse’s behaviour, features – resemblance to human genes Some of the examples – muscular dystrophy – Mutants generated from drugs – treat with toxic mutagens – breed for large numbers – genera
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