module 2

• why are genetics important for disease?

  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