06 - January 24, 2013.docx

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Molecular Genetics and Microbiology
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Johanna Rommens

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06 – January 24, 2013 Strategies to identify genes in inherited diseases Disease gene identification Mendelian trait – specific inheritance pattern – relatively easy to follow – Major limitation - ___________ Categorize disease gene finding – two or three categories – Functional cloning – do nt use genome to find gene; use particular aspect of trait property Position dependent and indepentnt candidate ene approaches – candidate gene approach used in most gene disease searches – power of newer technology of next generation sequencing – used frequently to unravel what gene is involve d- combination of position dependent and parallel sequencing Cluster patients into groups – different things can look like what is thinking like the trait – concern – most genetic methods fail if not on top of issue – looking at cluster of same trait or related? Essential to disease gene identification – If right gene identified, WT gene in recessive traits or altered level of expression of mutated gene may resort to normal phenotype in cells studied – would predict could restore to normal by altering expression – wild-type gene loss of function, usually occurs for recessive trait – not always though Cystic fibrosis – affected gene is cloric channel – how does this mutation lead to failed lung function and proneness to infections? Nature of work involved – for each given disease, A functional cloning Rescue cells deficient – hypothesize something might be true and look for it Method used to identify genes involved in Fanconi anemia (blood disease, high sucesceptibility to cancers) – cells have problem with DNA repair – gives system to score whether the disease is present or not in the cell – mitomycin C – add al the genes back one by one – at some point, have right gene should rescue the right phenotype – No assay to distinguish between wild type and disease gene Wilson disease – disease of copper metabolism – unusual disease with immune effect – antibodies of patient generated towards self in some way – be able to use antibodies and ask question of expression library – library that expresse all the proteins – able to identify what the antibodies are against – to understand what the disease I Candidate gene approaches Humans cannot generate vitamin B – diet Similar gene on chromosome 1 after finding the one on 14 – related – thought overlapping function – Functional pathway – upstream or downstream gene – may lead to phenotype that lead to disease – gene product – culprits – causing disease – receptor or ligand because instigating same signalling pathway – either could be mutated or altered to lead to disease Positional candidate gene approaches Positional candidate gene – idea of location in genome that get from genetic studies To locate a gene – marker denser – physically mapping them so know which markers take along chromsomes – identify location with five families – All the genes in the region are candidates based on position – hence the term positional candidates Some diseases due to alternate splicing – particular disease Location of disease gene position Have a little bit more evidence – frequency of observation Some aberrations appear to be aberrations but have NO clinical consequence Once location is indicated Go to physical map – assay each gene – is this a candidate? Sequence them all for mutations – expecting to find mutations in these genes – do not randomly sequence each gene – if studying gene that causes disease in liver – skip over gene candidates expressed in brain – prioritize the ones expressed in liver Translocation – also other anomalies detected that help guide to particular region in chromosomes Use probes to hone in to where the break is Once location is indicated On chromosome 7 – break points not occurring in the same place – may be genes away yet turned out ultimately – one gene involved and this found to be mutated in this conditions, SHH Rergulatory elements megabases away that control this gene – SHH target of this regu
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