LECTURE 1 and 2_Mendel laws and exceptions from them

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GENERAL GENETICS Genetyka ogólna •

dr. hab. n. med. inż. Anna Stanisławska- Sachadyn

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p. 116 Ch. C, w godz. konsultacji lub indywidualnie, po uzgodnieniu

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Kontakt przez e-mail: [email protected]; ważne sprawy, gospodarz roku

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Celem wykładu będzie zapoznanie Studentów z najważniejszymi odkryciami, prawami i terminami genetyki. Wykład będzie obejmował kluczowe zagadnienia genetyki: zasady dziedziczenia cech i chorób, mechanizmy regulacji ekspresji genów i mechanizmy zmienności genetycznej. Wykład będzie kładł duży nacisk na wyjaśnienie, szczególnie istotnego dla biotechnologów, molekularnego podłoża dziedziczności, zmienności genetycznej i regulacji ekspresji genów. Przedstawiając uniwersalne fundamenty genetyki, wykład będzie podawał też przykłady pokazujące różnorodność sposobów dziedziczenia cech, wariantów genetycznych i mechanizmów regulacji ekspresji genów.

Moje naukowe zainteresowania • • • •

Biologia medyczna, genetyka molekularna Szlak folianowy Polimorfizmy genetyczne Metylacja DNA

WARUNKI ZALICZENIA • 1. ocena z testu • • •

test wyboru na ostatnich zajęciach TYLKO JEDNA odpowiedź ustna - w celu poprawienia oceny, odpowiedź ustna możliwa TYKO POD WARUNKIEM uzyskania z testu co najmniej 40% punktów

• 2. obecność na wykładach • •

obecność na wykładach jest obowiązkowa Obecność będzie sprawdzana wyrywkowo np. kiedy liczba Studentów nie przekroczy połowy stanu (50%) • Efektem nieobecności jest utrata preferencyjnych warunków zaliczenia (następny slajd) - Jedna nieobecność – bez konsekwencji - Za każdą kolejną nieobecność nieusprawiedliwoną odjęcie 5% od wyniku testu. Usprawiedliwienie nieobecności na podstawie oryginału zwolnienia lekarskiego

Punktacja testu – preferencyjne warunki zaliczenia wynik

ocena

60 - 68 %

3.0

68 -76 %

3.5

76 - 84 %

4.0

84 - 92 %

4.5

92 - 100 %

5.0

Pytania kierunkowe • Lista pytań kierunkowych pomoże w przygotowaniu do testu

Literatura • Literatura obowiązkowa: Materiały z wykładu • Literatura uzupełniająca: Genetics: From Genes to Genomes, Mcgraw Hill Higher Education 4/e, 2011, Leland H. Hartwell, Leroy Hood, Michael L. Goldberg, Ann E. Reynolds, Lee M. Silver

Premendelian genetics and Mendel’s discoveries

Genos (γένος) - race, stock, kin a social group claiming common descent, referred to by a single name Gennō (γεννώ ) - to give birth

Understanding of heredity prior the science of genetics

A medievel manuscript showing the degree of consaguinity within which marriage was prohibited Steve Jones, Bóg, geny i przeznaczenie. Co mamy we krwi?,1997

Domesticated plants and animals - selective breeding

saddle (hot blood) horse

draft (cold blood) horse

Perfazja, full blood Arabian horse

from the Ardenne

from Poland http://www.prideofpoland.pl/pl/node/1366

http://www.discover-horse-carriage-driving.com/ardennes-horses.html

Wild wheat

Erebuni Reserve, Armenia (From Wikipedia)

Domestic wheat

(From Wikipedia)

Deceptive concepts: homunculus

Still in the 19th century many microscopists believed in homunculus

Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

Genetics heredity

–

the

science

of

”Genetics” - William Bateson coined the term in a letter to Adam Sedgwick (1905) and later at at the Third International Conference on Plant Hybridization in London in 1906 He popularised the ideas of Gregor Mendel

Gregor Mendel 20.07.1822 (Heinzendorf bei Odrau) – 6.01.1884 (Brno) – an Augustinian monk from Brno (Moravia) (German Brünn)

Cloister garden and microscope

1862 r. Gregor Mendel

Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

Mendel’s background and inspiration: education • Mendel’s education: - first theology (1844-48) - then mathematics, physics, chemistry, botany, plant physiology, paleontology at the University of Vienna (1851-53) • + Darwin’s ”On the origin of species”

Mendel’s experimental setup 1. Garden pea -

large numbers (Mendel examined 29,000 plants 1856-1866)

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relatively short growing season (60 days from a seed to producing seeds)

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Pure breeding lines (pol. czyste linie) developed after 8 generations

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Controlled mating by cross pollination – separated from external fertilization, anthers removal to prevent self-pollination

2. Skilled experimentalist (e.g. discrimination beetween long and short stem, removing anthers)

Pure breeding plants and cross pollination

The experimental organism: Pisum sativum (garden pea) Fast reproduction, produces many seeds, Growing from early spring, maturity 60 days after planting Cross-polination – controlled fertilization

Ovule - pol. Zalążek Anthers – pol. Pręciki Stigma – pol. Znamię Pollen – pol. Pyłek kwiatowy

Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

Examined ”either or” antagonistic traits (discrete)

Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

Discovery of dominant and recessive traits - counting and statistics

Monohybrid – having two different alleles of one gene

Filial – pol. pokolenie

Recessive trait (green) re-appears – blending refuted

Also reciprocal crosses (”green” pollen + „”yellow” eggs) – a similar result - Y:G 3:1 reciprocal cross – pol. krzyżówka odwrotna Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

Mendel’s first law: the law of segregation Prawo czystości gamet The two alleles for each trait separate (segregate) during gamete formation and then unite at random, one from each parent, at fertilization W czasie tworzenia gamet każda para alleli ulega segregacji, a gameta zawiera tylko jeden allel danego genu. Mendel’s laws reflect the probability rule – true in large populations Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

Punnett square is visualizing the results of segregation. Introduced by Reginald Punnett (a mathematician) in 1906.

How does the parent pass only one allele to its progeny?

Each gamete receives only one allele for each trait

Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

How to explain 3:1 ratio Mendel proposed: • Units of inheritance (presently known as genes) in two alternative forms (presently known as alleles) inherited one from each parent • The observed trait is a combination of these alternative forms • There are recessive and dominant alleles

Verifying the 1st law in further crosses How to distinguish YY from Yy???

Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

Verifying the 1st law in further crosses How to distinguish YY from Yy???

Testcross (krzyżówka testowa) distinguishes Yy from YY

Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

Mendel’s second law Dihybrid crosses reveal the 2nd law Dihybrid – two genes, each have two different alleles

Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

Counting

The inheritance of color is unaffected by the inheritance of shape

Phenotypic ratio: 9:3:3:1

Mendel’s laws reflect the probability rule – true in large populations Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

Mendel’s second law Law of Independent Assortment / Prawo niezależnej segregacji cech

During gamete formation, different pairs of alleles segregate independently of each other

Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

Mendel’s second law Law of Independent Assortment / Prawo niezależnej segregacji cech

• During gamete formation, different pairs of alleles segregate independently of each other • Geny należące do różnych par alleli dziedziczą się niezależnie i są przekazywane do gamet oddzielnie, na zasadzie segregacji losowej

The third law • Mendel's third law (also called the law of dominance) explains the relation between the dominant and recessive alleles

homozygotes and heterozygotes recessive and dominant traits genotype / phenotype

Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

Versuche über Pflanzenhybriden (Experiments on Plant Hybrids)

Mendel’s discoveries were first presented in 1865, during the meeting of Natural Science Society of Brno, published in 1866 http://astro4.ast.vill.edu/mendel/versuche.htm

Molecular basis – unknown to Mendel SBE1 gene mutation responsible for seed wrinkling discovered in 1991 (126 years after Mendel’s finding)

The SBE1 gene encoding starch branching enzyme SBE1 deficient plants, less sucrose build-up, more sucrose in young seeds, water uptake through osmosis, water lost while maturing, wrinkling Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

Hawkweed (latin Hieracium, pol. Jastrzębiec) – the plant which stopped Mendel Suggested by Karl Wilhelm Naegeli, a Swiss biologist, Mendel attempted to confirm his finding by examining Hieracium With no success • The plant forms seed by apomixis (asexually) • Without fertilization • They are clones

Phot from Wikipedia

Rediscovery of Mendel’s laws 1900

Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

Mendel’s laws are universal • For sexually reproducing organisms including protozoans, fungi, plants, animals and humans • There are multiple extensions and exceptions. • E.g. most human traits are multigenic • One gene may mask the presence of another gene (epistasis)

Traits previously believed to be Mendelian • Skin color • Eye color • Hair color • Morton's toe • Tongue rolling • Ability to taste phenylthiocarbamide • Widow's peak • Detached (dominant) or attached (recessive) earlobes

Mendel’s work was unappreciated before 1900 • Mendel’s article was not forgotten. • Often cited between 1866-1900 but with the reference to Mendel’s expertise as a plant breeder. • Numerical analyses did not seem attractive. • His request to replicate his experiments remained without response. • Finally Mendel became the abbott (1868) and abandoned his research.

Mendel’s notes on his pea plant results

http://www.dnalc.org/view/16173-Gallery-3-Gregor-Mendel-s-Experimental-Results.html

Mendel's laws are preserved for allelic genes in the case of: total dominance - the dominant feature is revealed in the heterozygote phenotype. Exceptions from Mendel's laws: Incomplete dominance - indirect heterozygote phenotype between the dominant and recessive homozygote phenotype. Codominance - both features are revealed in the heterozygote phenotype. Sex-lined inheritance

Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

Exceptions from Mendel’s laws In traits determined by one gene we can observe: • Incomplete dominance • Codominance • Recessive lethal allele • Pleiotropy

Incomplete dominance

Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

Incomplete dominance

•Single gene •two alleles •three colours

Pol. Lwia paszcza

Leland H. Hartwell et al., Genetics: From Genes to Genomes, McGraw-Hill, 2011

Codominance

The IA and IB alleles are codominant because the red blood cells of an IAIB heterozygote have both kinds of sugars on their surface.

Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

One gene, 3 alleles, 4 genotypes

Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

A, B and H antigens ABO blood group transferase A, alpha 1-3-N-acetylgalactosaminyltransferase; transferase B, alpha 1-3-galactosyltransferase

Antigen H + N-acetyl-galactosamine

Antigen H + galactosamine Chen X, Andreana PR, Wang PG. Carbohydrates in transplantation. Curr Opin Chem Biol. 1999 Dec;3(6):650-8.

ABO gene variants • ABO gene is organized in 7 exons, sequence spans over 18 kb of genomic DNA. • The single nucleotide deletion, found in a large number (but not all) of O alleles and responsible for the loss of the activity of the enzyme, is located in exon 6. • Substitutions responsible for alterations at two sites (L266M and G268A) determine the A or B specificity of the enzyme • Those two sites reside at the active site of the enzyme and the replacement in the A enzyme, of L by M and G by A, results in an alteration of the shape of the active site pocket, so that a smaller size UDP-Gal, rather than UDPGalNAc, becomes preferentially accomodated as a substrate.

Recessive lethal allele AA – agouti - several bands of light and dark pigment with black tips (look grey)

AyA – yellow fur (yellow pheomelanin pigment) and also adult obesity

AyAy combination is lethal 2:1 instead of 1:2:1 ratio

Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

• 5' sequence in the Ay mRNA corresponds to the 5'untranslated sequence of another gene: Raly • Raly has the potential to encode a RNA-binding protein that is normally expressed throughout development • The Ay mutation disrupts the structure and expression of the Raly gene

Michaud EJ1, Bultman SJ, Stubbs LJ, Woychik RP. The embryonic lethality of homozygous lethal yellow mice (Ay/Ay) is associated with the disruption of a novel RNA-binding protein. Genes Dev. 1993;7:1203-13

Pleiotropy – one gene – two (or more) traits

Leland H. Hartwell et al., Genetics: From Genes to Genomes, McGraw-Hill, 2011

More than one non-allelic gene can determine a particular feature (genes in different loci): - Complementation - Recessive epistasis - Dominant Epistasis

Complementation – Albinism: TWO RECESSIVE ALLELES OF ONE GENE produce the phenotype

Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

Complementation TWO DIFFERENT DEFECTIVE GENES IN EACH PARENT AND HEARING OFFSPRING

Two deaf parents can have hearing offspring - Mutations in two different genes

! 50 genes are necessary to produce normal hearing

Leland H. Hartwell et al., Genetics: From Genes to Genomes, McGraw-Hill, 2011

Non-complementation THE SAME DEFECTIVE GENES IN EACH PARENT AND DEAF OFFSPRING

Two deaf parents may produce all deaf children - Both parents carry mutations if the same genes.

Leland H. Hartwell et al., Genetics: From Genes to Genomes, McGraw-Hill, 2011

Complementary gene action 9:7 ratio of purple to white F2 plants indicates that at least one dominant allele for each gene is necessary for the development of purple colour

Leland H. Hartwell et al., Genetics: From Genes to Genomes, McGraw-Hill, 2011

Possible biochemical explanation of complementation Two enzymes corresponding to A and B alleles are necessary to produce purple pigment

Leland H. Hartwell et al., Genetics: From Genes to Genomes, McGraw-Hill, 2011

Epistasis - the interaction of one nonallelic gene with the phenotypic manifestation of a second nonallelic gene in a way that only one of these genes is phenotypically revealed. Epistatic gene - a gene that inhibits the phenotypic manifestation of another gene (hypostatic). Hypostatic gene - a gene whose phenotypic manifestation is inhibited.

Recessive epistasis The golden labrador retriever are homozygous in the recessive eallele – which masks the effect of another allelic gene: B or b. In dogs with the E allele: - the B allele is responsible for the black color of the fur - the bb genotype is responsible for the brown color.

Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

Recessive epistasis The hh genotype masks the presence of IA and IB genes An example of recessive epistasis

Epistatic to the gene determining ABO blood types. The hh individuals do not produce substance H needed to for the addition of A and B sugars on the surface of red blood cells. Leland H. Hartwell et al., Genetics: From Genes to Genomes, McGraw-Hill, 2011

Dominant epistasis – a dominant allele in one locus masks the presence of gene in another locus

Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

Phenotypic ratios disclose the type of gene interactions

Summer squash – type of pumpkin

Genetics: From Genes to Genomes. Hartwell LH, Hood L, Goldberg ML, Reynolds AE, Silver LM. Published by McGraw-Hill, 2011

PENETRANCE - the frequency with which the gene determining the trait manifests itself, e.g. mutations in the RB gene - penetrance of approx. 90%, causes retinoblastoma (retinoblastoma) EXPRESSIVENESS - the degree of phenotypic manifestation of the gene, e.g. pronounced in von Recklinghausen disease (NF1, neurofibromatosis)

Multigenic inheritance: two-gene model

•Eye color inheritance does not follow a simple Mendelian pattern. •Two-gene model better describes the inheritance of eyecolor. •In fact, eye-color inheritance is more complex.

Human Genetics: Concepts and Applications, Ricki Lewis, McGraw-Hill, 2005, 6-th edition

Bell-curve

The frequency distribution of eye colours forms the characteristic bellshaped curve for a polygenic trait Human Genetics: Concepts and Applications, Ricki Lewis, McGraw-Hill, 2005, 6-th edition

Genes and environment Genetic contribution could be either predominant, partial or none

Human Genetics: Concepts and Applications, Ricki Lewis, McGraw-Hill, 2005, 6-th edition