host genetics are an important direct cause of disease, host genetics influence essentially all diseases and other traits of interest, host genetics may influence or determine treatment options and efficacy, functional evaluation of host genetics may aid in diagnosis or prognosis of disease
personalized medicine: tailoring of medical treatment to the individual characteristics of each patient
shifts emphasis from reaction to prediction and prevention, enables selection of optimal therapies, allows for more accurate prognosis
congenital: present at birth
gnetic: caused or influenced by genes
genetic diseases are almost always congenital but congenital diseases may or may not be genetic
what is a gene?
a DNA segment that contributes to a phenotype or function
the entire nucleic acid sequence that is necessary for the synthesis of a functional polypeptide
mutation: differences in DNA sequence in an individual that are rare in a population and may be unique to the individual or family
polymorphism: differences in DNA sequence that are found in many individuals, at a specified frequency (usually 1% or greater of population)
if mutations are transmitted to progeny and become established in the population may become polymorphisms
allele: one of tow or more alternative forms of a gene located at the corresponding site (locus) on homologous chromosomes
locus: the specific site of a gene (or other functional site) on a chromosome, all the alleles of a particular gene occupy the same locus
genotype: the genetic makeup of an organism
what we measure of the genetic makeup at a specific site or set of sites
phenotype: an individuals observable traits
the result of genetics, environment, and commonly the interaction of both
central dogma: DNA, transcription, RNA, splicing, mRNA, translation, protein
variation in the MSTN gene responsible for hypertrophy in whippets: nonsense polymorphism in specific MSTN mRNA causes defective myostatin protein
functions of proteins: enzymes, hormones, transport proteins, structural proteins, receptors, signaling proteins
variation in proteins affects structure, quantity, and modification phenotypes
variation in proteins affects structure: variation in primary structure may affect secondary, tertiary, and quaternary structure
variation in proteins affects quantity: variation in regulating regions may affect amount of protein produced, number of gene copies can affect amount of protein produced
variation in proteins affects modifications: variation in primary structure can affect post-translational modifications
gain of function: uncommon in inherited disease, common in neoplasia
loss of function: common in simple mendelian disease, range from complete loss of function to subtle effects
variation in proteins may influence function of other proteins
gain of function mutations include overexpression, receptor permanently on in the absence of ligand, enzyme acquires new substance substrate specificity, and ion channels inappropriately open
loss of function mutations include deletion, insertion, disrupt gene structure through translocation or inversion, prevent the promoter working through mutation or methylation, destablize mRNA through polyadenylation site mutation and nonsense mediated RNA decay, prevent correct splicing through inactivating donor or acceptor splice sites or activating cryptic splice sites, introduce a frameshift, convert a codon into a stop codon, replace an essential amino acid, prevent post transcriptional/translational processing, prevent correct cellular localization of product
common genetic variations: single nucleotide polymorphisms, insertion and deletion (indels), short sequence or interspersed repeats, large scale variation
effects of SNPs: mostly no effect, alter amino acid sequence (codon changes, alternate start or stop codons, and splicing), affect transcript abundance (promoter efficiency and message stability), influence protein translation and modification (codon usage bias, signal sequence, glycosylation, ubiquitination)
missense SNP coding change: change protein
nonsense SNP coding change: change to stop codon
local variation influencing gene expression: affect amount of mRNA transcribed (promoter region, nucleosomal interaction, alternative splicing, autoregulation, affecting DNA structure), affect mRNA stability (alternative splicing)
>50% of genes exhibit allelic variation in expression
SNPs influence preMRNA splicing
SNP in MLPH exon 1 5' splice donor region affects gene expression and confer dilute coat color
insertion/deletion polymorphisms in coding regions: indel of AA residues, frameshifts, nonsense
insertion/deletion polymorphisms outside coding regions: changes in gene structure
3 base pair deletion: normal to significant change
1 base pair deletion: likely significant change
2 base pair deletion: significant change or complete loss
short sequence repeats:
microsatellites: 1-6 base motifs, perfect or imperfect
minisatellites: >10 base motifs
interspersed repeats: LINEs and SINEs
transposable elements randomly inserted into genome