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Molecular Genetics and Microbiology
Johanna Rommens

MGY470 – January 22, 2013 Inheritance, X-inactivation, and imprinting Nuclear inheritance (NOT mitochondrial inheritance) Look at a series of families – as long as looking at exactly same trait, phenotype caused by the same gene Ascertainment biases – if pediatric hospital, bias that disease is pediatric because patient population is pediatric Situations when inherited disease will not appear Mendelian – ex. Imprinting Digenic and more complex traits Pedigree symbols Characteristics of mendelian inheritance patterns Parents are carriers of disease – if unaffected but carrying trait X-linked recessive – X inactivation process – so X-linked dominant inheritance – may be lethal in males; may be mildly or variably affected than males Y-linked inheritance – male must have affected father UNLESS NEW MUTATIONS Complications of inheritance patterns – pseudodominance, penetrance, etc. age related penetrance (must be past cetain age before showing disease) New mutations – occur in germline of parent – so mutations not seen in parent, but in offspring If allele that contributes to the disease is common – see trait like – some recessive traits like colour blindness – recessive inheritance – but in pedigree appear like pseudoddominant because alleles are common in population Mendelian traits – Type 1 diabetes – no longer able to produce insulin – able to determine genes – predict genes as well given the pathobiology of the disease Some genes involved – component of pathobiology – immune destruction Evaluate the relative weight of multiple genes – do not yet know variation of these genes cross the population X chromosome – pseudoautosomal regions – X and Y chromsoomes do share genes Y chromosome – acrocentric - largely inert, made up of heterochromatin that is highly repetive – in humans, determines maleness, determined by sex determing region of Y – locus of chromosome – if transfer region of this chromosome to mouse, the mouse becomes male – sex determination in huamns is carried by Y chromosome Female is default the developmental pattern of humans Sex chromosome evolution Ancestral sex chromosomes – must have determined sex locus – if retained on chromosome – suppression of recombination – marked chromosome differentiation – afford to be small – advantage, so no recombination so retain sex determination properly – favoured by evolution X-inactivation Inbalance in copy number of particular gene expression in males vs females Elaborate process to maintain gene expression copy number for most of the genes on X – MOST of genes – via process of X-inactivation Dosage compensation – dealt with in evolution in different ways – do not need compensation of PAR loci or dosage compensation of other genes in chromosome that correspond to homologs in X chromosome – can see formation of BARR body that can eprsis through subsequent cell division – heterochromatic – see as separate entity at all times in cell cycle in contrast to bother chromosomes Dosage compensation – random in all somatic tissues In humans – timing of inactivation is different – features different as well In trophoblasts, no preffered paternal X inactivation – RANDOM Because of this process, females are mosaics- females are hemizygous Translocations – evident from population studies – X-inactivation is completely random but Predict 50 50 in females, but may not be true in indivudla s- not perfectly random Another instance of not being perfectly random is in older females – blood lineages – in older females, some skewing of X inactivation – younger, random, due to loss or depletion of some cells, that gave the equivalence of matching; older, depletion of line carrying X inactivation, see skewing Autosome X translocation – depending on what loci is there – a trend of what starts X inactivation – as long as have X inactivation centre – retain portion number 13 Inactivation starts and moves into translocated portion – so cannot spread like on X chromosome – distinct features of X chromosome that contribute to activation Requirement for translocated chromosome for gene to stay active – friction between gene staying on and X-inactivaiton that can prevent X-inactivation from happening How many chromsomes are there – if there is an X missing Initiation – occurs at X inactivation centre Propagation along chromosome Maintenance through somatic cell division Recognize counting in addition to 45 X – there is – rare occasions of unusual number of chromsomes Inactivation pattern must be maintained – gets erased with each generation At X inactivation centre – gene called XIST – non-coding RNA – large RNA – multiple introns, exons – function to serve as RNA – it codes the X that is inactivated, gives – help activate XIST gene – opposite gene is complementary RNA that is expressed TSIX – these two genes come together, if TSIX expressed on opposite strand, then XIST exists – do not know which is first – TSIX is expressed most times out all the XIST early – Genes are complementary to each other – times when both transcripts are present at low level – contributing – to get X inactivation must have r
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