Personalized Medicine Flashcards
clinical application of NGS
rare undiagnosed diseases
pathogen variants __ with phenotype, ___ do not.
pathogenic variants segregate with phenotype, benign variants do not.
Is variant polymorphic in “normal” population?
requires accurate DBs with large control populations
Is variant de novo in the proband, or inherited from a phenotypically normal parent?
presumes variant is fully penetrant.
how do we focus on the variants that are clinically significant?
penetrance assumption
inheritance hypotheses
candidate genes/context
effect/functional/evolutionary predictions.
databases: caveat emptor
databases are incomplete
the upstream literature is incomplete.
numerous errors in databases.
true or false: loss of function indicates a disease
false
false-positive and false-negative variant calles increase with the
size of the sequenced target (gene > exome > genome)
Takahashi’s experiment
he took skin cells from adult mice and infected them with a virus to introduce 24 genes. The cells transformed, and looked and behaved like pluripotent embryonic stem cells.
What the cells (ES like cells, or pluripotent stem cells) from Takahashi’s experiment were called
induced pluripotent stem cells, or iPS cells.
iPS cells are important for
modelling and investigating human diseases, as well as for screening drugs.
A prolbem with iPS cells is
consistency - some people have done something remarkable with one cell line, and it turns out nobody else can do it.
genes responsible for reprogramming adult cells into iPS cells
oct3/4
sox2
Klf4
c-myc.
scientists discovered that iPS cells retain an
epigenetic memory: a pattern of chemical marks on their DNA that reflects their original cell type. Such changes should not affect the cells’ use in therapies.
The reslt of implanting retinal pigment epithelium from iPS cells in a patient with macular degeneration was
a halt in the patient’s macular degeneration.
most iPS reprogramming teachiques are
inefficient: only a small fraction of cells end up fully reprogrammed. iPS cells vary from one strain to another. That has made it hard to establish controls in experiments.
CRISPR-Cas9 gene editing tool, has enabled researchers to
introduce disease associated mutations into a sample of iPS cells and then comparethem with the original, unedited cell lines.
because iPS cells resemble embryonic cells, they are not always ideal for
studying late-onset diseases such as dementia.
iPS cells have also been used with some success in
drug discovery: they provide a plentiful source of patient derived cells to screen or test experimental drugs.
