module 2 - detailed

• why are host genetics important for disease?

  direct cause of disease, influence essentially all diseases and traits of interest, influence or determine treatment options and efficacy, may aid in diagnosis or prognosis of disease
• what is personalized medicine?

  tailoring of medical treatment to the individual characteristics of each patient
• why is personalized medicine important?

  shifts emphasis from reaction to prediction and prevention

  enables selection of optimal therapies

  allows for more accurate prognosis
• what does congenital mean?

  present at birth
• what does genetic mean?

  caused or influenced by genes
• genetic disease are almost always congenital but cngenital disease may or may not be genetic
• what is a gene?

  the entire nucleic acid sequence that is necessary for the syntehsis of a functional polypeptide
• what are mutations?

  differences in DNA sequence in an individual that are rare in a population and may be unique to the individual or family line
• what are polymorphisms?

  differences in DNA sequence that are found in many individuals, at a specified frequency usually 1% or greater of a population
• if mutations are transmitted to progeny and become established in the population they may become polymorphisms
• what is an allele?

  one of two or more alternative forms of a gene located at the corresponding site on homologous chromosomes
• what is a 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
• what is genotype?

  the genetic makeup of an organism
• what is phenotype?

  observable traits, results of genetics, environment or combination
• what is the central dogma of molecular biology?

  DNA is transcribed into RNA, RNA is spliced into mRNA, mRNA is translated into protein
• what causes muscular hypertrophy in whippets?

  a nonsense polymorphism in the MSTN gene causes defective myostatin protein
• what are the functions of proteins?

  enzymes, hormones, transport proteins, structural proteins, receptors, and signaling proteins
• how does variation in proteins affect phenotypes?

  structure: variation in primary structure may affect secondary, tertiary, and quaternary structure

  quantity: variation in regulatory regions and number of gene copies can influence amount of protein produced

  modifications: variation in primary structure can affect post translational modifications
• How does variation affect protein function?

  gain of function, loss of function, and influence function of another protein
• gain of function is uncommon in inherited disease, it is common in neoplasia
• loss of function is common in simple mendelian disease, it ranges from complete loss of function to subtle effects
• what are some examples of gain of function?

  overexpression, receptor permanently on in absence of ligand, enzyme acquires new substrate specificity
• what are the mechanisms of loss of function?

  deletion, insertion, disrupt gene structure, prevent promoter function, destabilize mRNA, prevent correct splicing, introduce frameshift, introduce nonsense mutation, replace an essential amino acid, prevent post-transcriptional/translational processing, prevent correct cellular localization of product
• what are common genetic variations?

  single nucleotide polymorphisms, insertions/deletions, short sequence and interspersed repeats, and large scale variation
• what are examples of large scale variations?

  insertions and deletions, inversions, translocations, and duplications
• what are the effects of single nucleotide polymorphisms?

  mostly no effect, alter amino acid sequence, affect transcript abundance, influence protein translation and modification
• how do SNPs alter amino acid sequence?

  codon changes, alternate start/stop, and splicing
• how do SNPs affect transcript abundance?

  promoter efficiency and message stability
• how do SNPs influence protein translation and modification?

  codon usage bias, signal sequence, glycosylation and ubiquitination
• what are some examples of SNP coding changes?

  missense and nonsense coding changes
• how does local variation influence gene expression?

  affects amount of mRNA transcribed and affects mRNA stability
• how does local variation affect the amount of mRNA transcribed?

  in the promoter region, creation or elimination of TFBS or DNA polymerase recognition sites

  nucleosomal interaction, alternative splicing, autoregulation, DNA stability, curvature, and flexibility
• less than 50% of genes exhibit allelic variation in expression
• SNPs influence premRNA splicing
• what causes dilute coat color phenotype?

  an SNP in the MLPH exon 1 5' splice donor region affects gene expression
• what are indel polymorphisms in coding regions?

  insertion/deletion of amino acid residues, frameshifts, and nonsense
• what are indel polymorphisms outside coding regions?

  changes in gene structure
• how does a 3 bp deletion affect protein function?

  normal to significant change
• how does a 1 bp deletion affect protein function?

  likely significant change
• how does a 2 bp deletion affect protein function?

  significant change or complete loss