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Transmission Genetics: Heritage from Mendel

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Mendel’s Genetics• Experimental tool: garden pea• Outcome of genetic cross is independent

of whether the genetic trait comes from the male or female parent

• Reciprocal genetic crosses produce the same results

• Many human traits follow this pattern of inheritance

Mendel’s Experiments • Gene : inherited trait• Plants with different

forms of a trait, such as yellow vs. green seeds(alleles) were genetically crossed

• Mendel counted the number of offspring with each trait (F1), (e.g.: green seeds)

• He crossed F1 plants among themselves and counted F2 offspring

Mendel’s Observation

• Genetic cross between parents that “breed true” for a pair of traits, round seeds vs. wrinkled seeds, produces offspring with round seeds only (F1)

• Round seeds are dominant • Each parent has two identical copies of

the genetic information specifying the trait (homozygous) and contributes one in each cross (P1)

Mendel’s Hypothesis

• Round seed parent “AA” = genotype

• Wrinkled seed parent

“aa” = genotype• Round seed parent contributes “A”

gamete to offspring• Wrinkled seed parent contributes “a”

gamete to offspring

Law of Dominance

• Offspring genotype = A + a = Aa heterozygous

• All offspring produce round seeds although they are genetic composites of “Aa” because “A” (round) is dominant to “a” (wrinkled)

Law of Segregation

• F1 genotype =“Aa”= monohybrid• “Aa” parent produces either “A” or “a”

gametes in equal proportion

Law of Segregation

(simple consequence of two chromosomes)

Monohybrid Genetic Cross

• Genetic cross : Aa X Aa produces A and a gametes from each parent

• Punnett square shows four possible outcomes = AA Aa, aA, and aa

• Three combinations = AA, Aa, and aA produce plants with round seeds and display a round phenotype

• Fourth combination = aa displays wrinkled phenotype = recessive

Monohybrid Genetic Cross

C h art T it le : M on oh yb rid g en e tic C ross

1 /4A A

rou n d seed sd om in an t

1 /2A a

rou n d seed sd om in an t

1 /4aa

w rin k led seed srecess ive

P aren ts : A a X A ag am etes : A o r a

each p aren t p rod u ces A an d a g am etes an d con trib u tes on e g am ete a t fe rt iliza tion

Mendelian Ratios

• Genotypic ratios differ from phenotypic ratios since dominant phenotype consists of AA” and “Aa”

• F2 results of monohybrid cross show 3:1 round:wrinkled phenotypic ratio

• Genotypic ratios of monohybrid cross are 1:2:1 = 1/4 AA + 1/2 Aa + 1/4 aa

Testcross Analysis

• Testcross analysis allows geneticist to determine whether observed dominant phenotype is associated with a homozygous “AA” or heterozygous “Aa” genotype

• Genetic cross is performed using a recessive testcross parent = “aa”

Testcross Results

• AA + aa = Aa ; dominants only

parent homozygous

• Aa + aa = 1/2 Aa + 1/2 aa

produces 1/2 dominant, 1/2 recessive parent heterozygous

Dihybrid Cross Ratios

• two different phenotypic traits, such as seed color (yellow vs. green) and

seed shape (round vs. wrinkled) • Analysis of all combinations: (3:1 round :

wrinkled and 3:1 yellow : green) produces 9:3:3:1 phenotypic ratio (round/yellow : round/green : wrinkled/yellow : wrinkled/green

Dihybrid F2

Law of Independent Assortment

• Combinations of individual elements within dihybrid pair generate genotypic ratios for dihybrid cross

• True for any number of unlinked genes• Also a consequence of distinct

chromosomes

Dihybrid Testcross

• WwGg gametes = WG + wG +Wg + wg = 1:1:1:1 ratio;

• double recessive gametes = wg• Offspring = WwGg + wwGg + Wwgg +

wwgg = 1:1:1:1 ratio• Testcross shows that parent is

heterozygous for both traits (dihybrid)

Trihybrid Genetic Cross

• Trihybrid cross = three pairs of elements that assort independently, such as WwGgPp

• For any pair phenotypic ratio = 3:1• For two pairs ratio = 9:3:3:1• Trihybrid: 27:9:9:9:3:3:3:1

Probability Rules

• Addition Rule: The probability of obtaining one or the other of two mutually exclusive events is the sum of their individual probabilities

• Multiplication Rule: The probability of two independent events occurring simultaneously equals the product of their individual probabilities

Mendelian Probabilities

• Dihybrid crosses also follow sum rule and product rule to determine outcome probabilities

• Phenotypic outcome = 9:3:3:1

• Genotypic outcome = 1:2:1:2:4:2:1:2:1

Pedigree Analysis• In humans, pedigree analysis is used to

determine individual genotypes and to predict the mode of transmission of single gene traits

• To construct a pedigree, the pattern of transmission of a phenotypic trait among individuals in a family is used to determine whether the mode of inheritance is dominant or recessive

• Pedigree analysis is used to study single gene disorders, such as Huntington’s Disease, a progressive neurodegenerative disorder

Pedigree Analysis: Dominance• Dominant phenotypic traits usually appear in

every generation of a pedigree

• About 1/2 the offspring of an affected individual are affected

• The trait appears in both sexes if the gene is not on the X chromosome

Dominant Single Gene Disorders

Tran sm iss ion P rob ab ilit ies fo r D om in an t S in g le G en e Tra its

A aa ffec ted h e te rozyg o te

p rob = 1 /2A = d e fec tive g en e tic e lem en t

aan on affec ted recess ive

p rob = 1 /2a = n on a ffec ted g en e tic e lem en t

m os t com m on c rossA a X aa

A a = a ffec tedaa = n on a ffec ted

Pedigree Analysis: Recessive

• Pedigree analysis can used to distinguish dominant vs. recessive modes of inheritance for traits determined by single genes

• Analysis of patterns of transmission of recessive genes is used to identify carriers of recessive traits which cannot be determined by direct phenotypic analysis

• Recessive traits occur in individuals whose parents are phenotypically dominant

Inheritance of Recessive Genes

• Two phenotypically dominant people who produce a child with a recessive genetic disorder: 1/4 probability that any of their children will be affected and 1/2 that they will be carriers

Recessive Genetic Disorders

In h eritan ce o f R ecess ive S in g le G en e D isord ers

A Ap rob = 1 /4

n on affec ted

A ap rob = 1 /2

carrie r

aap rob = 1 /4

a ffec ted

m os t com m on c rossA a X A a

A = n on a ffec ted g en ea = a ffec ted g en e

Incomplete Dominance

• Heterozygote phenotype is intermediate between dominant and recessive phenotypes (snapdragons)

• F1 of cross between dominant (red) and recessive (ivory) plants shows intermediate phenotype (pink)

• F2 products show identical phenotypic and genotypic ratios

Multiple Alleles/Co-dominance

• For some traits more than two alleles exist in the human population

• ABO blood groups are specified by three alleles which specify four blood types

• ABO blood group inheritance also illustrates principle of co-dominance in which both alleles contribute to the phenotype in the heterozygote

• Antibodies are proteins which bind to stimulating molecules = antigens

Multiple Alleles/Co-dominance• IA and IB are dominant to IO, genotype AIO =

type A; IBIO = type B

• IA and IB are co-dominant; each allele specifies antigen: genotype IAIB = type AB

• IO = is recessive genotype IOIO

Biochemical Genetics

• Many recessive genes code for enzymes which carry out specific steps in biochemical pathways

• Mutations which alter the structure of genes block enzyme production if both copies of the gene are defective

• Disorders were termed “inborn errors of metabolism” by Garrod

Biochemical Genetics• Recessive genes often

contain mutations which block the formation of gene product (ww)

• Heterozygotes which contain one recessive gene copy (Ww) may produce only 1/2 the amount of protein specified by the homozygous dominant (WW) which contains two functional copies of the gene

Biochemical Genetics

• Heterozygotes (Ww) may still produce sufficient gene product to display dominant phenotype = round seed; genotype = carrier

• For some genes reduction of gene product by 1/2 in the heterozygote may be physiologically significant, especially for structural proteins = dominant disorders

Biochemical Genetics

• Variable expressivity refers to genes that are expressed to different degrees in different individuals, e.g.: severity of an inherited disease

• Incomplete penetrance means that the phenotype predicted from a specific genotype is not always expressed, e.g.: individual inherits mutant gene but shows no effect

Genetic Epistasis• Epistasis alters Mendelian

9:3:3:1 phenotypic ratios in dihybrid inheritance

• In epistasis, two sets of genetic elements interact to produce a single phenotype, which modifies the observed phenotypic ratios

• Mendelian pattern of inheritance

Genetic Complementation• Complementation tests are used to determine if

different phenotypes result from variations in one gene

• Homozygous recessive genotypes which are genetically crossed can only produce a dominant phenotype if the recessive genetic elements are located on different genes

Genetic Complementation

• A mutant screen is an experiment which generates mutations which affect specific phenotypes

• Multiple alleles refer to the various forms of a gene

• Wildtype refers to the phenotype for a specific trait most commonly observed

Genetic Complementation

• The complementation test groups mutants into allelic classes called complementation groups

• Lack of complementation = two mutants are alleles of the same gene

• Principle of Complementation: two recessive allelic mutations produce mutant phenotype; two non-allelic recessive mutations show no effect