Mendelian exceptions 2019. 10. 09.

Ákos Maróti-Agóts PhD 1

Mendelian exceptions, Modern investigation methodes

2019

Ákos Maróti-AgótsProf. László Zöldág

Clickable links in PDF!

Mendelian rules are not always valid?

• Expressivity of genes

Variable expressivity shown by 10 grades of piebald spotting in beagles. Each of these dogs has SP, the allele responsible for piebald spots in dogs. (After Clarence C. Little, The Inheritance of Coat Color in Dogs. Cornell University Press, 1957; and Giorgio Schreiber, Journal of Heredity 9, 1930, 403.)

Variable expressivity occurs when a phenotype is expressed to a different degree among individuals with the same genotype.

Mendelian rules are not always valid?

• Expressivity of genes• Penetrance of genes

Genotypes are the same!

The terms penetrance and expressivity quantify the modification of gene expression by varying environment and genetic background; they measure respectively the percentage of

cases in which the gene is expressed and the level of expression.

Mendelian rules are not always valid?

• Expressivity of genes• Penetrance of genes• Multiple allelism, allelic polymorphism• Epistasis (interlocal gene/allele interaction)• Complementary and epistatic polygenia• Genetic heterogeneity• Linkage and crossing over (intra-chromosomal re-combinations!)• Pleiotropy (other „side” effects of genes)• Sex (chromosome, X, Z)-linked inheritance• Uniparental inheritance (genomic imprinting,• maternal = mitochondrion – mtDNA inheritance)

• Expressivity of genes: varied manifestation of dominant genes in heterozygotes (horse grey colour)• Penetrance of genes: incomplete, percentage at population level (JKD, juvenile kidney disease of dogs, histology positive, clinical signs only 5-10%)• Multiple alleles, allelic series = polymorphism on the same locus

(serial genes in order of dominance or co-dominant inheritance)– 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

Changes in gene effects: Mendelian inheritance is not true (?)

Polymorphic „c” alleles of C-locus (tirosinase), allelic serie in dominance order:

C: normal pigment synthesis cch: chinchillach=cs: Himalayan, Siamese, colourpoint (heat sensitive tyrosinase)cb: blue-eyed albinismc: true or red-eyed albinism

Allelic serie in dominance order – C-locus tirosinase

Mendelian exceptions 2019. 10. 09.

Ákos Maróti-Agóts PhD 2

Recessive albino alleles of C-locus (tirosinase):• Blue-eyed (b = blue) albino, genotype: cbcb• True, red-eyed (oculocutaneous, OCA) albinism in rodents,

rabbits, cats, dogs, breed-character! Genotype: cc

Allelic serie in dominance order – C-locus tirosinase

Genotype (DNA) polymorphism• Prerequisite for population variability and diversity!

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

• Codominant 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

Genotype (DNA) polymorphism

Sanger Sequencing of DNA

https://www.youtube.com/watch?v=3M0PyxFPwkQ

• Colour inheritance: in a single locus more than two allelic variants, polyallelism, allelic or gene polymorphism (agouti and albino locus, thyrosinase 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 histocopatibility complex, HLA, LA, human leucocyte antigen): linked groups/units of polymorphic genes, haplotypes, inherited as „single genes 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: tumournecrosis factor

Phenotype polymorphism

• Epistasis (modifiers): epistatic/hypostatic relation of genes at diff. loci (interlocal interaction of genes) frequently at coat colours

• Complementary and epistatic polygenia: comb types of fowl,e.g.

– Combless (bdbd),– Combed (BdBd, Bredas fowl breed): rose (R), pea (P), walnut (R-P-) and simple (rrpp) comb

• Genetic heterogeneity (mimic genes, diff. genotypes the same phenotype):– mutations at diff. gene loci the same clinical entity, or– diff. mutation at the same gene locus diff. clinical entity or the same

Changes in gene effects: Mendelian inheritance is not true (?)

Epistatic relation (interlocal interaction) between two gene loci (gray, G, agouti, A, and extension, E)

• Epistasis (modifiers): epistatic/hypostatic relation of genes at different loci (interlocal interaction of genes) frequently at coat colours (e.g. gray colourof horses, G)

Varied gene expressivity of grey colour: in place/ time (dapple grey, flea bitten grey)

Epistatic relation (interlocal interaction) between two gene loci

Mendelian exceptions 2019. 10. 09.

Ákos Maróti-Agóts PhD 3

Complementary and epistatic polygenia: comb types and forms of fowl: loci included: combed (Bd) from Bredas breed; rose (R), pea (P), walnut (R-P-) and single (rrpp) comb

Possible genotypes (3 gene loci included):

Combless: bdbd

rose walnut single pea(BdBd; R-/pp) (BdBd; R-/P-) (BdBd; rr/pp) (BdBd; rr/P-)

Complementary and epistatic polygenia

Illumina Sequencing Technology

https://www.youtube.com/watch?v=fCd6B5HRaZ8

Changes in gene effects: Mendelian inheritance is not true (?)

• Linkage and crossing over: close and remote genes on the same chromosome can be linked or exchanged. Results new genetic combinations by intra- chromosomal re-combinations!• Linkage: Inevitable, complete and in most species partial. Close genes on the same chromosomes are linked (AB, ab).

– In swine: Ha blood antigen and stress sensitivity;– in fowl: linkage of F (frizzled) and I (white plumage)genes;– linkage groups (MHC haplotypes);– cat: white coat and deafness;– rabbit: hair length and solid colour etc.

• Crossing over: Exchange of remote genes between homologous chromosomes in first meiotic division (AB, ab ↔ Ab, aB).

– Process by which new combinations of linked genes are formed is called

crossing-over.– Basis for variability, occurs frequently,– can be utilized in relative positioning of genes and mapping. Unit of gene distance: 1cM

Double crossing over of linked traits Crossing over: segregation of closely linked traits

double crossing over (M-m exchange)

recombinations, F-I, frizzle and white

Mendelian exceptions 2019. 10. 09.

Ákos Maróti-Agóts PhD 4

Ion Torrent™ next-gen sequencing

https://www.youtube.com/watch?v=DyijNS0LWBY

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Changes in gene effects: Mendelian inheritance is not true (?)

• Pleiotropy (or dosis effect, „side” effects of genes)– lethal genes: manx cats, homozygotes are lethal– Polledness in goats: Polled homozygous (PP) female goats are intersexes and a proportion of males are sterile

• X(Z)-linked inheritance: uniformity, reciprocity and segregation rules are limitedly true

• Uniparental inheritance:– Genomic imprinting: gene inactivation, methylization in one of the sexes during gametogenesis– Maternal inheritance: mitochondrion, mtDNA,mitochondrion diseases

Pleiotropy (at polledness): Polled homozygous (PP) femalegoats are intersexes and a proportion of males are sterile

Sex influenced expression in Dorset sheepBoth sexes are fertile in sheep, Vendeen, F, no pleiotropy)

Changes in gene effects: Mendelian inheritance is not true (?)

• Sex chromosomes– Mammals: XX, XY;– birds: ZZ, ZW;– sex ration 50%, homo- and heterogametic males andfemales, haploid sex in honey bee and other insects

• Sex (gender) may be: genetic, gonadic, phenotypical, behavioural

• Sex determination (SD): may be genetic (genotype, sex chromosomes, GSD, CSD) and environmental (temperature, TSD)– Male sex is determined by Y-linked SRY-gene (sex- determining region on Y-chromosome)– Female sex: General principle is female sexual development! XX are needed! Complications may be: freemartins, intersexes, tfm-syndrome, Turner disease etc.

SEX DETERMINATION Genetic (genotype, sex chromosomes, GSD, CSD) and environmental (temperature, TSD) sex determination in vertebrates

Mendelian exceptions 2019. 10. 09.

Ákos Maróti-Agóts PhD 5

SEX-LINKED INHERITANCE

• Sex (chromosome)-linked inheritance (XLD XLR, YL) and traits– Y(W) chromosome rarely inherits (hairy ears in man)– X(Z) chromosomes may transmit many traits– Uniformity, reciprocity and segregations (Mendelian rules)are only limitedly true

• Sex-limited inheritance and traits: manifestation only in one of the sexes (inherited by both sexes), milk and egg production, prolificacy, kryptorchismus, white heifer disease in shorthorn cattle

• Sex influenced inheritance and traits: expression in both sexes but differently, meat production, muscling, racing performance, horns in Dorset sheep etc.

• Phenotype sexing (cloacal eminence)• Feather colour and feathering (feather growth) genes are Z-linked, in criss-cross inheritance: F1 is not uniform!• Breeding homozygous lines first! (males are homozygous recessive, females dominant hemizygotes in crossings)• Genes for sexing fowl– Silver dominant (S-) and gold (ss) feather: Rhode island red males (ZsZs) × Sussex or Wyandotte white females (ZSW): F1 will be different in colour: ZSZs ; ZsW

– Slow dominant (K) and rapid, fast (kk) feathering in chickens: fast ZkZk males × slow ZKW females: F1will be different in feather growth: ZKZk ; ZkW

– Barred, barring (B-) and black (bb) feather colour: Rhode island black males (ZbZb) × barred Plymouth females (ZBW): F1 will be different in colour: ZBZb; ZbW

Use of Z-linked inheritance for detecting sex of day-old chicks: sexing

Dosis effect in Z-linked inheritance: auto- sexing character (colour-sex links)• Auto-sexing character: homo- and heterogametic sexes (homo-and hemizygotes) are different in colour due to dosage effect• In genetically pure, homozygous lines in young and adult age!

• Auto-sexing genes:– pigmentation inhibitor gene (II, I-) in Texan and King pigeons (homogametic males are lighter)– Barring (BB, B-) in chickens (homogametic males are lighter)– Grey (sd, sdsd) feather of geese (homogameticmales are lighter colour, „white”, Pilgrim goose)• To distinguish from sex dimorphism!

Auto- sexing character (colour-sex links)

Fluorescent In-Situ Hybridization-FISH

https://www.youtube.com/watch?v=zxAKdf-8LCw

Mendelian exceptions 2019. 10. 09.

Ákos Maróti-Agóts PhD 6

• Uniformity of F1 in both sexes: if males are homozygous dominant in crossings• Dwarf poultry (dwarfism): Z-linked recessive gene (dw), intensive growth is dominant, regulates GH receptors and growth

– Practical application in broiler chicken production (dwarf, dw homozygous maternal lines are more economical!)– Crossing: dwarf females (ZdwW) × intensive growth males (ZDwZDw)→ F1 will be intensive growth (ZDwZdw , ZDwW)– ZdwW × ZDWZDW → F1 uniform: ZDWZdw , ZDWW both sexes of F1!

Use of Z-linked inheritance to produce uniform F1

Both sexes are of intensive growth

Normal growth line Dwarf line

Use of Z-linked inheritance to produce uniform F1 generation• Uniformity of F1 in both sexes: if males are homozygousdominant in crossings!

• To produce white feather in geese (white is important):– White feather (silver dilution, Sd) of geese is dominant, grey colour (wild, sd) is recessive.– Crossing dominant white (SdSd) males × grey females (sd-) → F1 (Sdsd, Sd-) can be used for white feather production.– ZSdZSd × Zsd-→ F1 uniform: ZSdZsd, ZSd-, both sexes are!

Use of Z-linked inheritance to produce uniform F1

• Tortoiseshell (calico) cats (XOXo): also called as X-inactivation in female Mammals or lyonism, gene dosage compensation between male and female sexes

• X-linked fecundity gene in sheep: FecX prolificacy gene: homozygotes are sterile, have non-functional ovaries (negative dosage effect)

X-linked diseases (in mammals males, in birds females are affected! If dominant mutation: females are less severly diseased due to the X- inactivation)

Hemophilia A (VIII) and B (IX) in dog (recessive males: XhY) Duchenne Muscular dystrophy (DMD, dystrophin, Xmd): Golden Retriever, Belgian SheepdogNephritis (X-linked recessive and dominant): Samoyed, SpanielTremor (shaker disease, myoclonia): hypomyelinogenesis, Spaniel

Severe combined immunodeficiency (SCID, X-linked recessive) Antimasculine and antifeminine lethal genes in mammals and fowl

X-linked inheritance in mammals

Only in female Mammals: By chance 50- 50 % of maternal and paternal X- chromosomes are inactivated in somatic cells.Importance for understanding the pathophysiology of X-linked dominant diseases (less severe in females!) • Expression in both sexes and only one of parents inherits!

• 1. Genomic imprinting, gene inactivation maternal or paternal: 3 genotype (allelic) variations (callipyge, muscular hypertrophy dominant gene of sheep):– CLPGP - activated during spermatogenesis and expressed in somatic cells– clpg - no mutated gene– CLPGM - inactivation during oogenesis and not expressed in somatic cells

Uniparental inheritance

• 2. Maternal inheritance: mitochondrion diseases (to distinguish maternal effects!)

Mendelian exceptions 2019. 10. 09.

Ákos Maróti-Agóts PhD 7

Maternal effect = complex: genetic (mitochondrion, nucleus) and environmental components

Classical experiments:1. Pony × shire horse crossing(polygene)2. Transfer of black and adipose mouse embryos in white mice (sigle gene)

Maternal effect

• Varied expressivity of genes (horse gray colour)• Incomplete penetrance of genes (%, canine JKD)• Multiple alleles, allelic polymorphism• Epistasis (interlocal interaction of genes, coat colours)• Complementary and epistatic polygenia (comb types of fowl)• Genetic heterogeneity (mimic genes, diff. genotypes the samephenotype)• Linkage and crossing over (intrachromosomal recombination)• Pleiotropy (dosage effect, „side” effects of genes, Polledness in goats, lethal genes, FecX in sheep)• Sex-X(Z)-linked inheritance (sexing, autosexing chicks, X- dosage compensation in mammals)

• Uniparental inheritance (genomic imprinting, maternal inheritance – mtDNA)

Exceptions for Mendelian Rules: Summary Thank you for attention!