epmmeebristolacuk 1 Published review Erzurumluoglu et al Apr 2015 BioMed Research International 2 Who was Gregor Mendel Augustinian monk Czech Republic Founder of modern genetics ID: 935124
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Slide1
Mendelian Inheritance
Mesut Erzurumluoglu
epmmee@bristol.ac.uk
1
Slide2Published review
Erzurumluoglu et al. Apr 2015. BioMed Research International
2
Slide3Who
was
Gregor
Mendel?Augustinian monk, Czech Republic.Founder of ‘modern’ geneticsStudied segregation of traits in the garden pea (Pisum sativum) beginning in 1854Presented & published his theory of inheritance in 1865.“Versuche über Pflanzen-Hybriden”“Experiments in Plant Hybridization”Mendel was “rediscovered” in 1902Posthumously Death: 1884
3
Slide4Why did Mendel choose peas?
4
Source:
Mawer S. Gregor Mendel: Planting the Seeds of Genetics
Slide5Experiment – Flower colour
5
Slide66
In his breeding experiments, Mendel did the following, and tracked heritable characteristics for three
generations:
1) Mated two true breeding parents to produce a hybrid. True-breeding parents are called the P generation. Hybrid offspring are called the F1 generation.2) He then allowed the F1 generation to self-pollinate. The offspring of this group are called the F2 generation.
Mendel’s experiments
Slide7Purple
Flowers
Parental
Generation(True breeding plants)XF2 Generation(Ratio 3:1)All plants hadpurple flowersWhiteFlowersF1 Generation(Hybrids)
7
Slide88
Slide99
Locus: A
location in the genome (e.g.
‘flower colour locus’, Chr 1 at position 5005). Plural: lociAllele: Alternate forms of a gene (e.g. pink flower allele, white flower allele, P, p)Genotype: Both alleles at the locus form a genotype (e.g. PP, Pp, pp) Homozygous: Contains identical alleles for a character e.g. AA, TT, CC, GG (or PP, pp)
Heterozygous
:
Contains
two different alleles for a
character
e.g. AT, GC, CA (or Pp)
Phenotype:
An
organism’s
traits (e.g. eye
colour
, height, disease)
Terms
Slide1010
Similarities
between parent and offspring are due to the transmission of discrete elements called
‘genes’.There are multiple versions of the same gene (each alternate version of the gene is called an allele).Each parent has two alleles. The two alleles separate during sex cell formation (i.e. ‘Meiosis’) Segregation (1st Law)Each organism inherits two (2) alleles; one allele from each parent.
Which
allele an organism inherits from a parent is random (50% probability
)
Independent assortment
(2
nd
Law)
Mendel’s Laws
Slide11Purple
Flowers
P
XF2 GenerationPurple flowersWhiteFlowersF1 Generation
PP
pp
Pp
p
P
P
p
PP
Pp
pP
pp
Punnett
Square
11
Slide1212
If a single copy of an allele results in the same phenotype as two copies irrespective of the second allele, the allele is said to be
dominant
over the second allele.E.g. PP and Pp both produce purple flowers. Therefore P is dominant to p.If an allele must occur in both copies of the gene to yield a phenotype, then it is recessive.E.g. only pp produces white flowers. Therefore p is recessive to P.*Dominant and Recessive alleles*This is Mendel’s third law (i.e. Law of Dominance)
Slide1313
Smooth
Ss
WrinkledssXYou have two pea plants. One is true breeding for wrinkled seeds, the other is a round seed/wrinkled seed hybrid. Smooth seeds are dominant to wrinkled seeds. If we were to cross the two, what is the expected ratio of smooth to wrinkled seeds. Use a Punnett Square to illustrate your answer.
Exercise 1
Slide1414
S
s
ssSs
Ss
ss
ss
Smooth
Wrinkled
Smooth
Wrinkled
Smooth : wrinkled
1
:
1
Answer
Slide1515
Let us assume for the moment that eye colour is a simple monogenic trait which follows simple Mendelian inheritance (the reality
is slightly more complicated*)
Let us assume that the eye colour locus consists of two alleles, a brown allele and a blue allele. Brown is dominant to blue, therefore heterozygous individuals (Bb) exhibit brown eyes.If this is the case, why do so many people have blue eyes?~70% of white populationProblem*see http://www.ncbi.nlm.nih.gov/pubmed/20944644
Slide1616
Using a
Punnett
Square to reveal genotype: Carry out a ‘testcross’ By breeding an organism of unknown genotype with an organism with a homozygous recessive trait, we can determine the genotype of the unknown individual. The ratio of phenotypes in the offspring (F1 generation) is used to determine unknown genotype. Test Cross
Slide17Dominant Phenotype
X
All offspring purple
Genotype Pp?Recessive phenotype
(Genotype PP or Pp?)
(Genotype pp)
p
p
P
P
Pp
Pp
Pp
Genotype PP?
1:1 ratio of colours
p
p
P
p
Pp
Pp
pp
Pp
pp
17
Slide1818
We are unable to manipulate mating patterns of humans for experimentation.
Traits are studied by gathering information and placing it into a family tree.
The inter-relationships among parents and children across generations are called the family pedigree.Mendelian inheritance in Humans
Slide1919
Example Pedigree
Deceased male
Unaffected male
Affected female
Affected male
Unaffected female
Slide2020
For monogenic traits, we can specify the underlying genetic model with
three (sometimes *four)
parameters:Mode of inheritance (e.g. autosomal, X-linked, mitochondrial)Disease allele frequency (e.g. using H-W equation)Penetrance, or probability of being affected given a certain disease locus genotypeSlide in appendixComplex traits will be discussed in next shortcourse!Slide in appendix *for complications see appendix
Disease locus model
Slide2121
First address for Mendelian geneticists!
Slide2222
Affected individuals
are usually heterozygous (e.g. Pp)
Disease will occur in all generationsRare homozygotes can be equally or more severely affectedDisease affects both genders equallyRecurrence risk for sibs and children is ½Often have late onset (and reduced penetrance)Affected people often able to reproduce even if disease is fatal.Example: Huntington’s disease
dd
Dd
dd
dd
dd
dd
Dd
Dd
Dd
Dd
Dd
D = Dominant disease allele
d = Recessive normal allele
Mode of Inheritance (
MoI
) 1:
Autosomal dominant
Slide2323
Affected individuals are homozygous; heterozygotes are u
naffected
Both sexes equally affectedSometimes causes ‘heterozygote advantage’E.g. Sickle cell disease and malariaCan ‘skip’ generations
On average, 25% of children of two carriers are affected
Consanguinity
is often high between parents of patients
Especially for very rare AR disorders
Often onset is in childhood
Examples:
Cystic
fibrosis, AR intellectual disability
Dd
Dd
Dd
dd
DD
D = Dominant normal allele
d = Recessive disease allele
MoI
2:
Autosomal recessive (AR)
Slide2424
Males = XY, Females = XX
For genes carried on X chromosome inheritance depends
on: (i) Whether the mother or father was the mutation carrier (ii) Sex of the offspring (iii) Dominant or recessiveSex-linked inheritance
Slide2525
Affected females are
heterozygous (mostly),
affected males hemizygous Frequency of affected females is twice the frequency of affected malesDisease is transmitted by mothers to children of both sex; by fathers, only to daughters50% of children of affected mothers, and 100% of daughters of affected fathers, are affectedE.g. Fragile X syndrome
d / -
D / d
D / d
d / -
d / -
d / d
D / -
d / -
d / -
D / d
D = Disease allele
d = Normal allele
MoI
3:
X-linked Dominant
Slide2626
Usually only males are affected
Disease is transmitted by carrier mothers to 50% of sons
On average, 50% of daughters of carrier mothers are also carriers100% of daughters of affected males are carriersE.g. Red-green colour blindness (Slide in appendix)
.
.
.
D / d
D / -
d / -
D / d
D / -
D / D
d / -
D / -
D / d
D / -
MoI
4:
X-linked Recessive
D = Disease allele
d = Normal allele
Slide2727
Why no
MoI
5?Y-linked or mitochondrial?No disorder linked to Y chromosome so farThink about how it would be (slide in appendix)…Mitochondrial DNA (mtDNA) not nuclear thus does not fit into Mendelian inheritance (slide in appendix)Strictly maternally inheritedTo all children – regardless of sexComplex disorders are called ‘complex’ because they do not follow a distinct inheritance pattern (slide in appendix) – due to polygenicity and environmental factors
Slide2828
Genotype frequencies and allele frequencies are stable across
generations
If population obeys H-W equation, it is said to be in H-W equilibriumH-W equilibrium assumptions in appendixGenotype frequencies are equal to the product of the relevant allele frequencies. If locus alleles are:A = with frequency pa = with frequency q where p + q = 1
Then
the three genotypes:
AA
Aa
aa
have respective frequencies:
p
2
2pq
q
2
(p
2
+ 2pq + q
2
= 1)
Hardy-
Weinburg
equation
Slide2929
How many people carry Cystic Fibrosis causal allele?
The
prevalence of cystic fibrosis in Caucasians is about 1 in 2500Assuming that all cases of cystic fibrosis are due to the action of one particular recessive mutation, what is the allele frequency of this mutation in the population? HINT: Use the Hardy-Weinberg equationWhat is the frequency of the heterozygotes (i.e. carriers) in the population?
Exercise 2
Slide3030
C
= Dominant
wild-type allele c = Recessive disease allelep = frequency of wild-type allele q = frequency of cystic fibrosis alleleFreq. of diseased individuals = Freq(genotype = cc) =
1
in 2500
So q
2
= 1/2500
Therefore q =
1/50
and p = 49/50 (1 – 1/50)
Freq.
of heterozygote carriers = 2pq
=
2 x (49/50) x (1/50)
≈
.0392
≈ 4%
Approx. 1
in 25
White Europeans
is a
carrier (heterozygote)!!!
Answer
Slide31Learning Objectives
Be aware of Mendel and the significance of his early breeding experiments
Know Mendel’s principles of segregation and independent assortment and how they relate to current genetic
knowledgeBe able to discuss concepts of DominanceSex-linked inheritanceBe able to identify features of (monogenic) autosomal or X-linked, and dominant or recessive diseases31
Slide32Thank You
Any questions?
Please look back at the slides
again once you complete the short-course(s)32
Slide33Appendices
Test your knowledge at:
http://
biology.kenyon.edu/courses/biol114/TUTORIAL/inherit1/inherit1c.html33
Slide3434
Penetrance is the conditional probability of having the phenotype P given the genotype G:
Pr
(P|G)We have encountered examples of penetrance parameters before, they are the familiar dominant and recessive examplesi.e. For a Autosomal Dominant Mendelian disease where D denotes the disease allele:Pr(P | G = DD) = 1Pr(P | G = Dd) = 1Pr(P | G = dd) = 0Penetrance may depend on various factors, such as the genotype at another locus, sex, age, imprinting
Penetrance
Slide3535
Random
mating (i.e. no consanguinity or endogamy)
No migrationNo inbreedingNo selection related to genotypeA large population (preferably infinite)No new mutationsHardy-Weinburg equilibrium assumptions
Strong assumption!
Slide3636
Protanopia
is a
colour vision deficiency in which the red retinal photoreceptors are absent affecting red-green hue discriminationDeuteranopia is a colour vision deficiency in which the green retinal photoreceptors are absent affecting red-green hue discriminationBoth due to a defective gene cluster on the X chromosomeMuch more common in malesRed-Green Colour blindness
Slide3737
Y-Linked
MoI
?
Slide3838
Mitochondrial
MoI
Slide3939
Females have two copies of genes on their X chromosome (XX) whereas males only have one (XY)
To ensure the same gene dosage between males and females, one of these chromosomes is inactivated in females
Which chromosome is inactivated may differ from cell to cell and is random in most mammalsThe Calico CatComplications: X chromosome inactivation
Slide4040
One gene affects the expression of another gene
Phenotype depends on the interaction between genotypes at different loci.
In the case of 2 loci, the familiar 9:3:3:1 ratio will not be observedE.g. Black and Yellow LabradorAlleles at the different loci may still assort independentlyComplications: Epistasis
Slide4141
Complications: Epistasis
Slide4242
B = Black
b = brown
E/e = gold locusTwo loci:Independent assortment, but ratio is not what we would predict (9:4:3)Complications: Epistasis
More info:
www.nature.com/scitable/topicpage/epistasis-gene-interaction-and-phenotype-effects-460
Slide4343
Complementation
O
ccurs when organisms with different homozygous recessive mutations produce the wild-type phenotypeE.g. a change in wing structure in fliesNo simple examples in humans (so far)!Co-dominance Incomplete dominance*see www.biologycorner.com/bio2/genetics/notes_incomplete_dominance.html
*Many other complications!
Slide4444
Complex disorders/traits
(e.g. Obesity, Height)
PolygenicMore than one gene involvedSometimes tens or even hundreds of genes involvedEnvironmental factors can also affect outcomeE.g. smoking and lung cancerThink of how a complex trait may look if we were to analyse a family pedigree…