ANSCI 361 1st Edition Lecture 21Outline of Last Lecture I. Pedigree Diagramsa. Recessivei. X-Linkedb. Dominanti. X-LinkedII. mtDNAIII. Threshold EffectIV. WoodlandsOutline of Current Lecture I. General DefinitionsII. Melanin Synthesisa. MC1RIII. Important Conceptsa. 1b. 2i. Tyrosineii. Agoutic. 3i. K Locus, B-DefensinIV. Spotting LocusCurrent LectureDefinitions- Chromosome designationso CFA -- Canis familiariso ECA -- Equus caballuso HAS -- Homo sapiens- Allele designationso aa###aa -- commonly occurring amino acid, Numbered location of the amino acid, Substituted amino acido ###base>base -- numbered location of nucleotide, commonly occurring nucleotide, substituted nucleotideThese notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.- SINE element—Short interspersed nuclear element, repeated DNA sequence derived from retro-transposons- Microphthalmia -- abnormal eye development, prominent third eyelids, small eyes, oftenassociated with other eye abnormalities, blindness and partial deafness- Introgression—Breeding a specific allele into a population, e.g. through repeated backcrosses- Synonymous polymorphism—Base substitution in a coding region that does not alter amino acid sequenceSimplified Overview of Melanin Synthesis- Tyrosine DOPA Dopaquinone- dopaquinone + cysteine -> -> -> pheomelaninor- dopaquinone -> -> -> -> -> eumelaninMelanocortin 1 Receptor Gene- MC1R is the gene symbol, also referred to as Extension locus- DNA polymorphism 1 (wild-type allele, E; mutant allele e)o 914C>T- Amino acid polymorphismo R306tero “Loss of function mutation”o Nonsense mutationo Arginine replaced by premature stop codon- e allele relatively common in dogs- EM allele (mask)- DNA polymorphism 2o 799A>G- Amino acid polymorphismo M264Vo Missense mutation o Methionine replaced by valine- Dominant allele, observable only in fawn or brindle dogsMode of Gene Action- e allele recessive to E and EM- Ee or EMe heterozygote still produces melanocortin receptor in sufficient quantity for expression of black coat color phenotypeMC1R in Other Species- MC1R variants in humans associated witho Red hairo Fair skino Freckles (ephelides)o Increased risk for skin cancer (melanoma)- Occurrence by latitude and corresponding evolutionary history:o Selection against MC1R variants in equatorial areas ?o Selection relaxed in northern latitudes with lesser UV ?o Alleles favored by mate selection ??- MC1R variant in cattleo Basis for red vs. black coat colorImportant Concept #1- Genes and their functions often conserved across species- Specific mutations differ between species- Phenotypic effect of mutations may be similar- Knowledge gained from dog genetics may predict important genes in humans or other species and vice versaImportant Concept #2- One gene may affect multiple phenotypeso Referred to as pleiotropy- MC1R in humans affects:o Hair coloro Skin coloro Frecklingo Risk for skin cancero Pleiotropic effects of genes not always obviousTyrosinase Function- If tyrosinase activity is low and cysteine levels high, then phaeomelanogenesis- If tyrosinase activity is high and cysteine levels low, then eumelanogenesis- Tyrosinase related protein 1 variants usually less active than the wild type- BB genotype produces black eumelanin- bb genotypes (6) produce brown eumelaninAgouti Signal Peptide- Four alleles of varying dominanceo ay > aw > at > a- Agouti protein inhibits interaction of alpha-MSH with MC1R- Characterization of polymorphisms:o ay -- two mis-sense mutations vs awo aw -- wild type alleleo at -- SINE element in intron 1 (Dreger & Schmutz, 2011)-o a -- single mis-sense mutation vs aw- Four alleles of varying dominance- ay > aw > at > a- Phenotypes:o ay _ -- clear redo aw aw, aw at, aw a -- wild type, wolf coloro at at, at a -- black and tan, brown and tan, Saddle tan have same ASIP genotype, but Differ due to interaction with RALY locus (Dreger et al., 2013)o a a -- recessive blackImportant Concept #3- Multiple genes can have complex interactions in determining phenotype- Phenotype dependent on combination of genotypes at multiple loci- EpistasisK Locus, beta-defensin 103 gene- Gene symbol CBD103 (DEFB103 in human)- Mapped to CFA16- Mutation identified as 3 bp deletion in second exon- Causes deletion of glycine (∆G23)- Defensin genes encode small antimicrobial peptides, secreted by epithelial cells- Alleleso KB -- black (dominant)o kbr -- brindleo ky -- permits expression of agouti alleles for phaeomelanin Ancestral gene- CBD103∆G23 function by:o Increased affinity for MC1Ro Increased level of CBD103 mRNA (& protein?) vs Agouti- Dogs are the only mammals in which dominant black coat color is not due to an MC1R mutation.- What type of mutation in MC1R would create a dominant black phenotype (that was notepistatic to the Agouti or K loci) ?Interaction of E, K and A Loci- If a dog is ee at the E locus, its coat will be entirely phaeomelanin based (red/yellow)- Otherwise (it is Ee or EE at the E locus), if it is K_ at the K locus its coat will be entirely eumelanin based (dominant black)- Otherwise (it is Ee or EE at the E locus), if it is kbrkbr or kbrky at the K locus it will be brindled with the color of the phaeomelanin part of the brindling in turn affected by the Agouti alleles present- Otherwise (it is Ee or EE at the E locus, and it is kyky at the K locus), the distribution of eumelanin and phaeomelanin will be determined solely by the Agouti alleles present.Spotting Locus- Microphthalmia-associated transcription factor (MITF)o S Solid colored o si Irish spotting o sp Piebaldo swExtreme white (hypothesized, no molecular
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