Discovery of human disease genes Flashcards
why do we want to identify disease causing genes
molecular confirmation of clinical diagnosis, accurate carrier testing for individuals or couples, presymptomatic testing for adult onset conditions, prenatal diagnosis for pregnancies, provides insight into pathological mechanisms underlying the disease
What are the properties of autosomal dominant inheritance
vertical transmission, equal no. affected males and females, male to male transmission observed, unaffected individuals have unaffected offspring
What are the properties of autosomal recesssive inheritance
both parents are carriers, generally clinically normal. equal no. affected females and males, cosanguinity may be present
What are the properties of X linked recessive
incidence higher in males than females, no male to male transmission
What is genetic linkage
tendency for DNA regions located close together to be co-inherited
What does the LOD score show and how do you calculate it
detect presence of linkage
LOD=log10 L(linkage)/L(no linkage)
LOD score >3 shows linkage, LOD score
What is done after linkage to chromosomal region is identified
identify the genes located within linkage interval
asses the genes as potential candidates based on their biological function
sequences of genes in affected individuals to try to identify the causative mutation
What can linkage analysis be confounded by
non penetrance, phenocopies, genetic heterogeneity (if linkage analysis performed in multiple pedigrees)
What does sequencing the exome do
catalogue all protein altering variation in individual
if the disease is monogenic, filter through to identify which variant causing disease
How to find true mutation when there are many variants
Compare unrelated people to find which genes in both samples have a novel protein altering heterozygous variant. Add more people (think of venn diagram)
what did sequencing for hajdu cheney syndrome lead to
discovering of 14 independent mutations leading to premature stop codons
