Personalized Medicine Flashcards
Personzliaed genomics/ personalized medicine
- predict dx predisposition and treatment response
- explain traits and where they come from
- identify relatives
- identify ancestry
- participate in citizen science research
- usually based on genotyping (from saliva or blood) but newer tests based on sequencing available in humans
- great promise but ethical concerns
almost never come across common variants with
large disease effect because they would be weeded out unless its a dx that doesn’t have a big impact on fitness
what type of variants do we test for
high effect because its the most useful (these will usually be rare but will have high effect)
hardest things to identify by genetic means
rare variants of small effect
if find common dx variant will have __ effect
low
Huntington’s
this is a rare dx with large effect, it is autosomal dominant but occurs after age or reproduction; can’t treat it if you know you’re getting it
Alzheimner’s dx
diff genes can make you signigicalty more likely to get alzheimers not too much to do but maybe some mediations you can give to try to slow down progression; do you tell people if they’re prone to it is big ethical question if there isn’t anything you can do
Pharmocogenomics
study of how genetics affects an individuals response to drugs
MDR1
multidrug resistent gene in dogs; 1 copy bad 2 is worse affects ability to metabolize common drugs; pump to pump toxic drugs out of cells is not functioning properly in these dogs which makes doses ok in normal dogs toxic; affects ivermectin, anticancer, antidiarrheal drugs; doses that are approved for dogs by FDA are within level that is ok for dogs with 2 copies MDR1; collies V affected by this; have to be carful not to use bulk drugs split by weight, treat for sarcastic mange without MDR1 test, or use garlic with these dogs
ALT and genetics
mutation on chromosome 13 affects ALT levels in dogs; heterozygous are in normal reference range with each homozygous on either side of it; effects where values land if dog is in liver failure this is important to be aware of
importance of companies like 23 and me
have 10s of millions of people in their database which is more than you can get for research studies
- have Died genes for freckles, photic sneeze reflex, asparagus anosmia, asthma risk factors, Parkinson’s and other important dis, also associations for educational attainment, age of recproduciton ect
mitochondria genome
does not recombine only passed down matrilineally
animal genome testing
have over 200 known key mutations in dogs for large mendilian traits; difference btwn embark and wisdom panel is number of markers used
wisdom pannel and optimal selection
baed on power density arrays (~2000 markers) suitable for overall ancestry estimation (and for optimal selection) trait and dx mutation testing
- doing research stuff so need dense arrays for GWAS
- low density array less expensive than high density array
embark pannel
based on high density array (~200,000 markers) suitable for local ancestry estimation, trait and dx mutation testing, linkage testing for updated results, and genetic mapping
- high density array more expensive than low density array
what can these tests tell you
- can tell you level of wolfiness (based on selective sweeps btwn dogs and wolves)
- predicted adult weight
- genetic age (if you give dog age it can give you genetic age based on aging on small dogs relative to big dogs, this is NOT based on DNA sequence change with aging because that isn’t a thing)
- get summary of dis you can test for risk for and carrier for
- can also find out what parts of chromosomes consistent with what breeds (embark)
- can get genetics behind coat color varriation
- inbreeding coefficient (embark catches these; useful to breeders)
- can find dog family nearby
Inbreeding info
look at graph of pedigree coefficient of inbreeding vs genetic inbreeding coefficient and see what the level actually is
dog matchmaking
there are sites that allow you to look for dogs that are clear for certain traits or at risk of certain traits and you can decide who to breed to based on this also looks at inbreeding coefficient and theorizes potential offspring and their expected colors
merele coat pattener
looked at associations and found chromosome 18 position had high association; don’t know if this is causal variant or just a related variant so can email owners and check and see if those dogs also have blue eyes and find that
GWAS SNP is related but duplication is far more related so duplication is probably causal variant (not every dog with it has blue eyes but the vast majority do)
Ethical considerations of genetic testing
- how much certainly should be required in genetic results
- should we only test for actionable diseases
- who owns the data you or the company doing the sequecing
- what should be done with incidental findings (ie someone gets test to figure out metabolic issues but have genes for macular degeneration do you tell them especially if there is something they can do about it)
- where to we draw line regarding prenatal testing? If a fetus has gene for Huntington’s do you abort? What about alzheimers?
- what about 3rd parties (close relatives genes are tied into yours what if they don’t want the info out there, tribe/ can (some tribes don’t believe in genetic testing but what if one member does, insurance (can’t discriminate based on genetic status if you’re an insurance company its illegal in people not in dogs)
advantages of personalized medicine in companion animals vs humans
- fewer ethical concerns with testing (dog doesn’t care who dad is)
- less regulatory burden (but this means can get some bad tests too)
- tests can be more predictive for complexx traits (bc simpler genetic architecture for many traits)
- many breeds more distinguishable than human popluatoins
- inbreeding greater impact in many animal breeds
- companion animals servie as great translational model
companion animals as model for translational research
- cats and dogs more genetically similar to humans than mice
- more similar in size, longevity, and envionment
- genes and sometimes mutations often identical
- quality vet care (similar diagnoses and treatments)
Doberman narcolepsy
genomic sequencing in dobermans lead to finding genes in people that caused this that previously hadn’t been known to be a narcoleptic varriant
Duchenne’s muscular dystrophy in goldens
humans and dogs have same mutation in same gene; have population of dogs who they breed who have this; one golden had this but didn’t display signs nor did his puppies because of compensatory mutation in Jagged1
possible disadvantages of personalized medicine in companion animals
- breeders and breed clubs have huge influence on standers and breed preferences if they misunderstand genetic results can lead to subpar decision making and issues for the breed down the road
- differences btwn breeds so test that are predictive in one breed may not be predictive in another
- lack of regulatory overbite means genetic testing quality in companion animals v dependent on quality of lab/company
comprehensive genetic screen doesn’t mean animal is
free of genetic defects because can’t test all of the genetic dxs bc dnt know variants for all of them
