2019.09.26. UNIVERSITY OF VETERINARY MEDICINE - BUDAPEST DEPARTMENT OF ANIMAL BREEDING NUTRITION AND LABORATORY ANIMAL SCIENCE SECTION FOR ANIMAL BREEDING AND GENETICS Gene effects, Mendelian exceptions László Zöldág prof. emer. Mendel’s laws in simple inheritance (for monogenic traits!) Preconditions: monogenic, single locus, location on different chromosomes, not X-linked! 1. Homozygosity of parents • 2. Uniformity and reciprocity (criss-cross) in F1 generation: – identity of genotype and phenotype in case of homozygous parents, – independently which of parents carries the dominant or the recessive genes. • 3. Segregation in F2 generation (1:2:1, 3:1): reappearance of parental characteristics in F2 generation • 4. Independent and free segregation and new combinations of genes at diff. loci (9:3:3:1 segregation in case of two loci): inter-chromosomal or Mendelian recombination in mono-, di-, tri- and polyhybrid crossings. 1 2019.09.26. Exceptions for Mendelian Rules: Terminology • Varied expressivity of dominant genes (white spotting and grey colour in horses, epigenetics) • Incomplete penetrance of dominant genes (%, canine JKD) • Multiple alleles, allelic polymorphism (on the same locus) • Epistasis (interlocal interaction of genes, coat colours - oligogenie) – Complementary or epistatic oligogenie (comb types of fowl, coat colours) • Genetic heterogeneity (mimic genes, diff. genotypes the same phenotype) • Linkage and crossing over (intrachromosomale recombination) • Pleiotropy (dosage effect or linkage, „side” effects of genes, Polledness in goats, lethal genes, FecX in sheep) • Sex-X(Z)-linked inheritance (sexing, auto-sexing chicks, X-linked diseases) • Uniparental inheritance (genomic imprinting, maternal inheritance – mtDNA) Changes in gene effects: Mendelian inheritance is not true (?) • Expressivity of genes: – Varied manifestation of dominant genes in heterozygotes, and recessive genes in homozygotes. – Varying expression of the same gene in individual phenotype is possible. • Explanation: mRNA transcription and translation (transcription factors, epigenetics). • By chance phenomenon: migration of melanocytes during embryonic development. – Examples: grey colour in horses, white colour and white spotting in more species (horses and dogs). 2 2019.09.26. Grey-horses (G-, varying expressivity with age) Thoroughbred-Arab „White” horse (Shagya) Dapple grey Flea bitten (Lipizzan) (Hung. Sporthorse) Tobiano and Overo white spotting (varying expressivity of dominant gene in Paint/Pinto horse breeds: Tobiano homozygote/heterozygote (To/To; To/to) Overo homozygote/heterozygote (O/O; O/o) 3 2019.09.26. Varying gene-expressivity of white (p, piebald) spotting in dogs (English Bulldog, Landseer, Pyrenean Shepherd, The same genotype: spsp) Epigenetics • Epigenetics, epigenomics: changes, modifications to DNA in gene expression and transcriptions. Not DNA-based inheritance: – Transcription factors. – (miRNA). – Influence of cytoplasmatic factors on nuclear DNA • DNA-methylation, acetylation, • histone modifications and associations to DNA, • cell memory. – Individual and transgenerational inheritance and environmental effects: acquired characteristics (not DNA- based) can be inherited through cell memory for 2-3 generations. – X-chromosome inactivation, maternal effects, environmental effects (nutrition) – Genomic imprinting (uniparental inheritance): gene inactivation, gene silencing: regulation, switching on and off of gene expressions in gametes. 4 2019.09.26. Changes in gene effects: Mendelian inheritance is not true (?) • Penetrance of genes: – Differences of the dominant gene in heterozygotes. – Penetrance may be complete (100%) or – Incomplete (?%), percentage at population level. – Example: JKD, juvenile kidney disease of dogs, histology positive, clinical signs only 5-10%). Dominance with incomplete penetrance (Example: JRG, Juvenile Renal Dysplasia in dogs) • Many breeds of dogs are affected with JRD, common phenotype: characterized by immature glomeruli, and/or tubules. • Penetrance refers to the population frequency that the phenotype (or some characteristics of the disease) is observed. • If, for example, the penetrance is 75%, then the chances of offspring to develop a disease are 3 out of 4. • In the case of JRD, the penetrance is low. – Estimated to be about 2-5% (max 10%). – Therefore only a small number of individuals with the mutation will show clinical signs of the disease. • However, they can pass the disease on to their offspring (dominance!). • This is why a genetic test is crucial to manage JRD; this is the only way to eliminate this disorder. 5 2019.09.26. Changes in gene effects: Mendelian inheritance is not true (?) • Multiple alleles, allelic series, allelic variants = polymorphism on the same locus; serial genes – allelic variants in order of dominance or co-dominant inheritance. – One pair (gene – allele) in an organism (on homologous chromosomes). – Increase of combinations in populations. – Examples: colour inheritance, albinism (alleles: C, cch , ch, cb, c), blood group systems, MHC haplotypes etc.) – SNP (single nucleotide polymorphism = point mutation): very common sort of multiple alleles. Genotype (DNA) polymorphism (more allelic variants on the same locus at population level) • Prerequisite for variability and diversity of populations! • General feature of genome and individuals, detectable: – In genotype: chromosome structures and molecular level (genes, alleles, microsatellites etc) and – in phenotype: colour, biochemical constituents, proteins and enzymes, blood groups. • Co-dominant inheritance: blood groups, proteins, enzymes. • Gene/allele (coding DNA sequences): polymorphic systems based frequently on SNP (single nucleotide polymorphism = point mutations). • Microsatellites (not coding, inactive DNA sequences): polymorphism on different number of repeating units. 6 2019.09.26. Polymorphic „c” alleles of C-locus (tyrosinase), allelic series in dominance hierarchy in rabbits: C: normal pigment synthesis cch: chinchilla ch=cs: Himalayan, Siamese, colourpoint California rabbits (heat sensitive tyrosinase, OCA2) cb: blue-eyed albinism c: true or red-eyed albinism (OCA1) OCA = oculocutaneous albinism Polymorphic „c” alleles of C-locus (tyrosinase), allelic series in dominance order in cats: C: normal pigment synthesis (tabby) ch=cs: Himalayan, Siamese, colourpoint cats (heat sensitive tyrosinase, OCA2) cb: blue-eyed albinism c: true or red-eyed albinism (OCA1) 7 2019.09.26. Alleles and genotypes of locus C: cch, cs (=ch), cb, c. (heat sensitive tyrosinase variants, colourpoints, Siamese, Himalayan cats, Albinism) cscs, Siamese cscs, Himalayan cc: red-eyed albino • Allelic polymorphism and varying gene expression (in age, pups are born dark!) • A (agouti, agouti signaling protein, ASIP): polymorphic alleles, dominance hierarchy: Ay > Aw or A+> at > a. Colours: DNA-test. – Ay, fawn/sable (yellowish, reddish, darker tips), – aw or a+: wild, wolf colour, pale grey, banded; – at: black and tan, tan points; saddle or blanket; at at or ata – aa: only recessive black (Shetland Sheepdog and German Shepherd). 8 2019.09.26. Phenotype polymorphism (gene products, proteins) • Colour inheritance: in a single locus more than two allelic variants, polyallelism, allelic or gene polymorphism (agouti and albino locus, tyrosinase mutations) • Blood groups: blood group systems (in a system more than two alleles or factors) • Biochemical (protein and enzyme) polymorphic systems: albumin, transferrin, lactoferrin, alpha-, beta- and kappa-caseins, LDH, GPX etc. • MHC (major histocompatibility complex, immunsystem, HLA, LA, human leukocyte antigen, BLA, bovine): linked groups/units of polymorphic genes, haplotypes, inherited as „single gene or locus” – MHC class I: β2-microglobulins, – MHC class II: B-lymphocytes and macrophage’s histoglobulins, presentation of antigens to T-lymphocytes, – MHC class III: complements, heat shock proteins, TNF: tumour necrosis factor Changes in gene effects: Mendelian inheritance is not true (?) • Epistasis (modifiers): epistatic/hypostatic relation of genes at different loci (interlocal interaction of genes) frequently at coat colours (oligogenie). • Epistasis - complementary or epistatic oligogenie: comb types of fowl, coat colours e.g. – Combless (bdbd), – Combed (BdBd, Bredas fowl breed): • rose (R), • pea (P), • walnut (R-P-) and • simple (rrpp) comb 9 2019.09.26. Epistatic relation (interlocal interaction) between three gene loci (grey, G, agouti, A, and extension- melanokortin receptor, E) • Epistasis (modifiers): epistatic/hypostatic relation of genes at different loci (interlocal interaction of genes) frequently at coat colours (e.g. grey colour of horses, G) Varied gene expressivity of grey colour: territorial/ age (dapple grey, flea bitten grey) Interlocal interactions: G- and A-/aa locus A-/G-/E- ee/G- aa/G-/E- G- and E-/ee locus Complementary or epistatic oligogenie: comb types and forms of fowl: loci included: combed (Bd) from Bredas breed; rose (R), pea (P), walnut (R-P-) and simple (rrpp) comb. Possible genotypes (3 gene loci included), allelic combinations: Combless: bdbd Combed: BdBd rose (BdBd; R-/pp), walnut (BdBd; R-/P-), pea (BdBd; rr/P-), simple (BdBd; rr/pp). 10 2019.09.26. Changes in gene effects: Mendelian inheritance is not true (?) • Genetic heterogeneity (mimic genes, different genotypes - the same or similar phenotype): – frequently at genetic diseases (COL, collagen diseases - dermatosparaxis, PRA, progressive retinal atrophy of dogs, colours etc).