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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