BIOL 311 Human Genetics
Fall 2006
Lecture: Model Organisms
Source: Hartwell et al. (2004) From Genes to Genomes, second edition. Reference A-E.
Lecture Outline:
1. Yeast
2. C. elegans
3. D. melanogaster
4. Mouse (Mus musculus)
Lecture:
Genome projects of model organisms have been important for identifying human
genes.
1. Yeast
 Baker's yeast: Saccharomyces cerevisiae
 Single celled eukaryote, alternates between haploid and diploid stages of life
cycle.
 Genome: 16 linear chromosomes
 Encodes 6000-6500 genes. Completion of yeast genome caused us to revise
down predicted number of genes in human genome.
 Most genes (96%) lack introns.
 Possible to do "gene therapy" in yeast--most genes recombine at homologous
sites, unlike humans and mice. Introduction of yeast genes with targeted deletion
leads to creation of "null mutants" by homologous recombination with the
existing gene.
Yeast two-hybrid system:
 Enables any two interacting proteins from any species to be identified.
 Rely on interactions of proteins in activating transcription.
General scenario:
Protein X is attached to a DNA binding domain (region of transcription factor that binds
DNA). Protein Y is attached to an activation domain (region of transcription factor that
activates transcription by RNA polymerase.
If proteins X and Y interact, you get transcriptional activation. If the function of protein
X was not previously known, its association with protein Y of known function helps
clarify protein X's role.
2. C. elegans (Caenorhabditis elegans)
 Nematode worm, model for some parasitic worms that cause disease
 Feeds on soil bacteria; in lab, can feed on E. coli.
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Useful model of development. Lineage of its 959 somatic cells is known.
97 megabase genome
6 chromosomes
have unique dispersed centromere--doesn't map to a single location
about 19,000 genes
introns in genes are generally small
unique aspects of gene expression
have operon structure like bacteria
produce polycistronic mRNAs
trans-splicing of 5'leaders onto mRNAs
Easy to manipulate C. elegans gnes
Introduce DNA by microinjection
Feed bacteria dsRNA to carry out RNA interference (RNAi)
RNAi was discovered in C. elegans--can be applied to most eukaryotic organisms
and cultured cells.
Important organism for identifying genes important for programmed cell death
and cell signaling pathways.
3. Drosophila melanogaster (fruit fly)
 4 chromosomes
 ~13,600 genes
 giant polytene chromosomes enabled the first type of physical map before
recombinant DNA methods
 170,000 bp of DNA
 21% of genome is highly repetitive
 genes can be introduced into Drosophila by transformation with a mobile genetic
element called a "P element"
 important genetic organism for traditional linkage analysis
 important developmental organism
 Drosophila genome project: dry run for human genome project done by Celera,
Craig Venter's company
 61% of human disease genes have homologs in fly
 Drosophila have fewer duplicated genes than mammals
 Goal of Drosophila genome project to disrupt each of the genes to help learn their
function.
 RNAi technology important for "knocking down" gene function.
 Discovery of regulatory proteins of homeodomain family via homeotic mutants
such as Antennapedia and Bithorax. The "homeobox" is a 180 bp DNA sequence
encoding a 60 amino acid DNA binding domain.
4. Mouse (Mus musculus)
 important model for human diseases
 19 autosomes, 2 sex chromosomes
 often whole sets of genes are linked in comparing mouse vs. human (synteny)
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mouse life span is 2 years vs. human life span 78 years
mouse transgenics: add a supplementary gene
mouse knockouts: disrupt gene and determine phenotype as means to learn gene
function
mouse models for cystic fibrosis, muscular dystrophy, cancer genes
mouse genome project has been completed
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