genetics part i an introduction to genetics part ii mendelism: the basic principles of inheritance...

GeneticsGenetics

Part I An Introduction to GeneticsPart I An Introduction to Genetics

Part II Mendelism: The Basic Principles oPart II Mendelism: The Basic Principles of Inheritancef Inheritance

and Extension of Mendelian and Extension of Mendelian GeneticsGenetics

The Science of Genetics

More than Observation

Experiment – Methodically Working dissection, factorsAnalysisHypothesis

1865 Gregor Mendel*** laws of Inheritance

1879 Walter Flemming Mitosis

1883 Edouard van Beneden Meiosis

1900 the beginning of the modern era of genetics (William Bateson)

1902 Sir Archibald Garrod : association of Mendelian factors with regulation of cellular biochemistry

1940s Delbrück: the phage group

1953 Watson and Crick*** Structure of DNA

2001 Human Genome project***: First draft of human genome sequence……………………………………..

Mendel (1822-1884) and garden pea

1856-1863 – pea experiments

1865 - Mendel published his result“Versuche über Pflanzen-Hybriden” (Experiments in Plant HybridicationPurpose: artificial fertilization undertaken on ornamental plants to obtain new color variants

---- 35 years later

1900 – Re-discovery of laws of hereditary by Hugo de Vries, Carl Correns & Erich von Tschermak-SeyseneggTranslate Mendel’s paper into English by W. Bateson

The Entrance of Mendel Museum

Mendel’s Garden

2006

Genetics in Human History

Blood and Destination

HemophiliaAnother genetic disorder

Prussia

Russia

Spain

Modern genetics

Identification and characterization of disease genes

Cancer geneticsBRCA1 gene

Application in medicine

Diagnosis and treatment(gene chips) (gene therapy)

Gene chips p53 gene

Genetics in modern agriculture

By hybridization and selectionBy genetic engineering

1 2 3 1 2 31: inbred 12: hybrid3: inbred 2 Norman Borlaug and his semidwarf wheat

Varieties of tomatoes

Beaf cattles and sheep by hybridization and selection

The Resistant corn plant (genetically engineered)

The Susceptible corn plant(original)

Genetics and society

Eugenics vs natural selection

Treatment of genetic diseases vs natural selection

Human genome project and new ethical problems

The use of embryonic tissue (cloning and gene therapy)

Cloned mice, cloned sheep and cloned human

Human-mouse hybrid

( Excavation of Srebrenica genocide victims' remains. So far, nearly 3,000 Srebrenica massacre victims have been found, DNA-identified and buried in the Srebrenica Genocide Memorial Center in Potocari. Another 5,000 bags with remains of victims found in nearly 60 mass graves in eastern Bosnia are still waiting to be identified before returned to their families.)

…. massacre - Bosnia

http://srebrenica-genocide.blogspot.com/

The use of DNA fingerprinting:

paternity –many cases aircraft accident – e.g. China airline B-18255 911 – N.Y. World Trade Center tsunami –Indonesia hurricane Katrina and ….

Generation of Mendelian law

the pea experiement

Mendelism: The Basic Principles of Inheritance

Why Mendel used pea as experimental materials

-easy to grow

-Many traits

-Self-fertilization – many true-breeding strains

-Cross fertilization can be achieved manually

(Or he just happened to use garden pea to obtain analyzable results.)

The phenotypes of garden pea (Pisum sativum) that Mendel characterized

Monohybrid crosses

e.g. Tall x Dwarf

F2:Reappearance of Dwarf

F1: only tall phenotype

Genes don’t blend – dominant vs recessiveGenes are inherited as distinct units

P: Cross fertilization

Self-fertilization

The Principle of Dominance

I. Mendel’s experiment

Use true-breeding varieties

Genes come in pairs – two forms of hereditary factors

The biological meaning of the ratio of F2 in Mendel’s monohybrid crosses

Phenotypes & numbers ->

The Principle of Segregation

To formulate genetic hypothesis

Dihybrid crosses – two traits

Coupling phenotypes and genotypes

Punnett square

The Principle of Independent Assortment

Examination of Mendel’s resultObserved number vs expected numberThe too goodness of fit ?

Mathematical modeling in Genetic analysis

*Symbols and Prediction – mathematic modeling

Using symbols- a methodological breakthrough

Self-fertilization of F2

F2 F3dd Dwarf -> dwarfDD 1/3 tall -> tallDd 2/3 tall -> tall and dwarf

To prove the hypothesis

Genetic symbols

Bateson early 1900 – based on the mutant traitse.g. D (tall) d (dwarf)

When the number of genes > 26 two letter system

Combination of basic gene symbol with an identification symbolcn2, eyD , cch, sh2-6801

Gene symbols for polypeptide gene productHPRT (hypoxanthine-guanine phosphoribosyl transferase)Use upper case letter

Formulating and Testing Genetic Hypothesis - for each trait

HypothesisObserved number

Degree of freedom n-1

Applications of Mendel’s Principles - To predict the outcome of crosses

The Punnett Square Method

The Forked-line Method

The Probability Method

Forked-line method

Probability Method

Empirical data

Abstract idea/ hypothesis

Examination of the hypothesis by statistics or next round of experiments

New problems or next questions

Terminology:

Genes: The fundamental physical and functional unit of heredity. A gene is an ordered sequence of nucleotides located in a particular position on a particular chromosome that encodes a specific functional product

Alleles: Alternative forms of a genetic locus; a single allele for each locus is inherited separately from each parent (e.g., at a locus for eye color the allele might result in blue or brown eyes).. Locus: The position on a chromosome of a gene or other chromosome marker; also, the DNA at that position. The use of locus is sometimes restricted to mean regions of DNA that are expressed

Homozygote: having identical alleles at one or more loci in homologous chromosome segments Heterozygote: having two alleles that are different for a given gene

Genotype: genetic constitution of an organism Phenotype: observable characteristics of an organism produced by the organism's genotype interacting with the environment

Dominant: alleles that determine the phenotype displayed in a heterozygote with another (recessive) allele Recessive: a gene that is phenotypically manifest in the homozygous state but is masked in the presence of a dominant allele .

From Genetics Education Center U. Kansas Medical Centerhttp://www.kumc.edu/gec/glossnew.html

Extension of Mendel’s principle

Part I : Variation of alleles

Genetics 172: 1–6 ( January 2006)

Multiple allelesDominant alleles?Recessive alleles?Multigenes?

Incomplete (partial) dominance

Semidominance

Dosage effect

Use upper and lower case letters

One gene

Codominance(independence of allele function)

e.g. human blood typeABO, MN et al

Inappropriate to use upper and lower case lettersUse superscripts on the symbol for the gene

One gene

Multiple alleles

One gene

Multiple alleles

(Temperature-sensitive)

Use lower case letter to denote a gene. Different alleles are distinguished by a superscript

mutants

Wild-typec, ch, cch and C+: different allels

One gene

Allelic series

c+ > cch > ch > c

Null/amorphic

Hypomorphic (different causes)

?

One gene

Multiple alleles which are codominant

polymorphicLocus- ABO locusGene – ABO blood type geneAllele- A allele, B allele, O allele

One gene

Yellow –lethal – an example of recessive lethal mutation

Yellow: Gray-brown = 2:1

Lethal alleles

One gene

Visible mutations – most are recessive few are dominant

(color, shape et at)

Sterile mutations – reproduction failure sex specific or both sexes dominant or recessive various severity

Lethal mutations – dominant lethals (fresh mutation) recessive lethals (detected by unusual

segregation ratio)

Allelic varations

Penetrance and expressivity

One gene

Penetrance and expressivity

All or none

With variations

One gene

Complementation test

To gene mutations for allelism( only for recessive alleles)

Compound heterozygote)

AaCc*

cc*

Same phenotypeDifferent genes

Genetic heterogeneity: Similar phenotypes caused by mutations in more than one geneLocus heterogeneity

Recessive: loss-of-function- null, amorphic, hypomorphic

Dominant:gain-of-function – neomorphic

hyperfunction

loss of function – dosage effect

How about dominant negative effect? interference of wild-type function gain-of-function ? Or loss of function?

Gene -> polypeptidesOne gene – one enzymeMutations -> alteration of polypeptides -> mutant phenotypes

Dominant negative

Explanation of dominant an recessive phenotypes at protein level

Extension of Mendel’s principle

Part II : Genetic interactions

a x b

Two independent genes affect one trait

More than one genes

9:3:3:1

EpistasisEpistatic gene – to eliminate expression of the alternative phenotypes of another gene, and inserts its own phenotype instead

- to act before the genes they cancel, in some biochemical or developmental sequence

GenotypeC-P-ccP-C-pp

Precursor →Intermediate→anthcyaninC P

+++

+-+

+--

Case 1 : A biosynthesis pathway

Precursor product→ phenotype

Gene A

Gene B

Synthetic enhancement

Case 2: a parallel pathway

More than one genes

Case 3: A regulatory pathway

inhibitorsccG-ccgg

white:yellow:green = 12:3:1

More than one genes

Pleiotropic A gene affects many aspects of the phenotype

e.g. PKU-accumulation of toxic materials → mental retardation-interference of melanin synthesis →light color of hair-accumulation of specific compounds

Interconnections between biochemical and cellular pathways that the gene control

e.g. defect in DNA repair defect in transcription regulation

The genetic basis of continuous phenotypic variation

1918 Ronald A Fisher-Multiple gene-Multiple environmental factors

A bell-shaped distribution

Quantitative genetics

Pedigree analysis

Mendelian Principles in Human Genetics

- can not make controlled crosses- family record ( i.e. pedigree analysis)- do not produce many progeny

- mistaken paternity- time (for late onset symptoms)- family tendency ≠ heredity- congenital abnormality ≠ hereditary abnormality

Patterns of Single-Gene inheritance

Single-gene trait – Mendelian inheritance

>3% human genes -> clinically significant disorders

Childhood diseases ( mostly)

Pedigree analysis ( retrospective analysis)

Family history

Extramarial mating

Synbols used in pedigree charts

Dominant Recessive

autosomal

X-linked X-linked dominant X-linked recessive

Autosomal dominant Autosomal recessive

X-linked genes in male : hemizygous

in female : X chromosome inactivation

Autosomal recessive inheritance

Typical pedigree

Parents Risk of offspringsCarrier x carrier R/r x R/r ¼ R/R, ½ R/r. ¼ r/r

¾ unaffected, ¼ affected

Carrier x affected R/r x r/r ½ R/r. ½ r/r½ unaffected, ½ affected

Affected x affected r/r x r/r r/r onlyAll affected

Factors – gene frequency, carrier frequency

[ ]n!x!y!

pxqy

Bionomial probabilities -to calculate the outcomes of offsprings- for genetic counseling

Probability that R is Aa = 2/3Probability that R is AA = 1/3

Risk that T is aa= (probability that R is Aa) x (probability that R transmits a, assuming that R is Aa)= 2/3 x 1/2= 1/3

Genotyping makes risk assessment more precise

An example of genetic counseling The risk that T is affected

Autosomal recessive inheritance

consanguinity

Characteristics of Autosomal Recessive (AR) Inheritance

1. An AR recessive phenotype, if it appears in more than one member of a kindred, typically is seen only in the sibship of the proband, not in parents, offspring, or other relatives. (exceptions: consanguinity, high gene frequency)

2. For most autosomal recessive disease, males and females are equally likely to be affected. exception: sex-influenced disorder)

3. Parents of an affected child are asymptomatic carriers of mutant alleles. (at clinical level)

4. The parents of the affected person may in some cases be consanguineous. This is especially likely if the gene responsible for the condition is rare in the population.

5. The recurrence risk for each sib of the proband is 1 in 4.

Patterns of autosomal dominant inheritance

Variable expressivity

A carrier

Incomplete penetrance-> can lead to incorrect assignment of genotypes

ExpressivityLobe mutation in Drosophila

Hapsburg jaw

Penetrance and expressivity

All or none

With variations

New mutations

Environmental effect

Phenylketonuria (PKU)

By nutrition

Pattern baldnessBy gender ( hormone dependent)

♂: homozygotes and heterozygotes♀: homozygotes

Fly mutant shibire

By temperature (ts mutant)

Action of a gene(phenotype)

Environment(biological/physical)

Other genes(specific gene or “genetic background)

Clinical symptoms of autosomal dominant disorders

Homozygotes are severer than heterozygotes.

Sex-limited phenotype in AD

Uneven sex ratio (i.e. M:F 1:1)

e.g. male-limited precocious puberty (familial testoxicosis)

Characteristics of Autosomal Dominant (AD) Inheritance

1. The phenotype usually appears in every generation, each affected person having an affected parent. (exceptions: new mutation, nonpenetrant,variable expressivity)

2. Any child of affected parent has a 50% risk of inheriting the trait. (considerations: successful birth of a diseased child)

3. Phenotypically normal family members do not transmit the phenotype to their children. (exceptions: nonpenetrance, variable expressivity, sex-limited phenotype)

4. Males and females are equally likely to transmit the phenotype, to children of either sex. (exceptions: sex-limited phenotype, genetic lethality)

5. A significant proportion of isolated cases are due to new mutation.

X-linked inheritance

Genotypes Phenotypes

Males XH (hemizygous) unaffected

Xh (hemizygous) affected

Females XH / XH unaffected

XH / Xh *depending on X-inactivation

Xh /Xh affected

The Lyon hypothesis of random X chromosome inactivation in female somatic cells

1. In X/X mammals, only 1 X is transcriptionally active. The inactive X is heterochromatic and appears in the interphase cells as Barr body.

2. Inactivation occurs early in embryonic life. completion: the end of first week of development (100 cells)

3. The inactive X may be either the paternal or the maternal X in any one X/X cell.

Dosage compensationVariability of the expression in heterozygous femalesmosaicism

Regions of X-chromosome that escape X-inactivation

Pseudoautosomal region of X chromosome : shared by X and Y escape from X-inactivation

Outside pseudoautosomal region with related copies of genes on the Y chromosome

Outside pseudoautosomal region without related copies of genes on the Y chromosome

X-linked recessive inheritance

Affected homozygous female due to consanguinity

Characteristics of X-linked recessive (XR) Inheritance

1. The incidence of the trait is much higher in males than in females.

2. Heterozygous females are usually unaffected. (unbalanced X-inactivation)

3. The gene responsible for the condition is transmitted from an affected man through all his daughters.(exception: genetic lethality) Any of his daughters’s sons has a 50% chance of inheriting it.

4. The gene is never transmitted directly from father to son.(a rare exception: uniparental disomy)

5. The gene may be transmitted through a series of carrier females.

6. A significant proportion of isolated cases are due to new mutation.

Typical X-linked dominant inheritance

X-linked dominant inheritance with male lethality

Incotinentia pigmenti

Characteristics of X-linked dominant (XD) Inheritance

1. Affected males with normal mates have no affected sons and no normal daughters. (exception: unbalanced inactivation of X chromosome)

2. Both male and female offspring of female carriers have a 50% risk of inheriting the phenotype. The pedigree pattern is the same as that seen with autosomal dominant inheritance.

3. For rare phenotypes, affected females are about twice as common a affected males, but affected females typically have milder expression of the phenotypes.

Pseudoautosomal inheritance

Pseudoautosomal region of X chromosome : shared by X and Y escape from X-inactivation

Maternal inheritance of mitochondrial mutations