Post on 08-Jul-2020
Genealogy, traits with
Mendelian mode of
inheritance in pedigrees
author: Jaroslav Kotlas
presented by František Liška
2020
presentation available at
https://el.lf1.cuni.cz/mendelian/
Repetition
Gregor Johann Mendel (1822 – 1884)
Augustinian monk - Brno (g. Brunn)
experiments with Pissum sativum (garden
pea)
1865 – results presented (lecture)
1866 – publication
garden pea has 7 pairs of chromosomes
7 traits (mono-, di-, tri-, hybridism)
statistic used for results
Repetition
monogenic (“mendelian”) traits
one gene = one trait
Repetition
Gist of Mendel´s experiments
(one trait – monohybridism)
P generation red flower x white flower
(parental, pure lines) AA x aa
Gametes A a
F1 generation red flower
(first filial) Aa
Gametes A a 50%
50%
Repetition – Punnett square
A a
A AA Aa
a Aa aa
Repetition
Scheme of Mendel´s experiments
(one trait – monohybridism)
P generation red flower x white flower
(parental, pure lines) AA x aa
gametes A a
F1 generation red flower
(first filial) Aa
F2 generation red flower + white flower
(second filial) AA, Aa, Aa,aa
Repetition
Mendelian „laws“
• the law of uniformity which states that after crossing of two homozygotes of different alleles the progeny of the first filial generation (F1) are all identical and heterozygous
Repetition
Mendelian „laws“the law of segregation
which postulates segregation ratio in F2 and Bc
generation:
• genotype ratio (monohybridism) 1:2:1
• phenotype ratio (monohybridism)
- complete dominance 3:1
- incomplete dominance 1:2:1
(codominance)
• backcross 1:1
Repetition
Mendelian „laws“
• the law of independent assortmentwhich states that different segregating traits are transmitted independently
phenotype ratio (dihybridism)
complete dominance 9:3:3:1
backcross 1:1:1:1
Criteria for Autosomal Dominant
Inheritance (AD)
• The phenotype appears in every
generation, each affected person has an
affected parent.
Exceptions: new mutations, disorder is
not expressed (nonpenetrant)
late onset disorders
• Any child of an affected parent has a 50% risk
of inheriting the trait.
There may be in a single family wide
deviation from the 1:1 ratio.
Criteria for Autosomal Dominant
Inheritance (AD)
• Phenotypically normal family members
do not transmit the pathological
phenotype to their children.
Cave: nonpenetrance or mild
expression or late onset disorders.
• Males and females are both affected.
They transmit the phenotype to children
of either sex. Male to male transmission
can occur.
Autosomal Dominant Inheritance (AD)
More than 4 000 traits affecting about 10% of humans
Examples:
• Polycystic kidney disease 1 : 1000 (over 40y)
• Familial adenomatous polyposis coli
1 : 10 000 (over 20y)
• Huntington disease 1 : 10 000 (over 40y)
• Retinoblastoma 1 : 20 000 (over 20y?)
• Achondroplasia 1 : 10 000 inborn
• Neurofibromatosis 1 : 5 000 (over 20y)
• Congenital cataracts 1 : 6500 inborn
• Inborn deafness/mutism 1 : 7 500 inborn
• Dentinogenesis imperfecta 1 : 8 000 inborn
Typical pedigree chart for AD
I
II
1
3
2
2 51 6
III
4
1 2 3 4 5 6 7
Polycystic kidney disease
Familial adenomatous polyposis coli
Retinoblastoma
Achondroplasia
Neurofibromatosis
Dentinogenesis Imperfecta:
Criteria for Autosomal Recessive
Inheritance (AR)
• The phenotype appears in the sibship of
the affected member (proband) only.
• (not parents or offspring)
• The recurrence risk for each sib of the
affected member is 25%.
• The parents of the affected person are
more often consanguineous.
• Males and females are equally likely to
be affected.
Autosomal Recessive Inheritance (AR)
• More than 5-7000 traits affecting 0,5% of human beings
• Some of them more frequent in genetic isolates (eg. Ashkenazy Jews)
Examples:
• Cystic fibrosis 1 : 2 500 inborn
• Adrenogenital syndrome 1 : 6 000 inborn
• Phenylketonuria 1 : 6 000 inborn
• Albinism 1 : 10 000 inborn
• Microcephaly 1 : 20 000 inborn
• Errors of metabolism (comp.) 1 : 1 000 inborn
Typical pedigree charts for AR
I
II
321
III
4
1 2 3 4
1 2 3 4
I
II321
III
4
1 2 3 4
1 32 4
1 2
IV
5
5
Cystic Fibrosis
Adrenogenital syndrome
Phenylketonuria
Albinism
Microcephaly
Criteria for X linked Recessive
Inheritance (XR)
The incidence of the trait is much higher in males than in females.
The gene is transmitted from the affected man through all his
daughters (carriers).
The carrier´s son has a 50% risk to be affected.
The gene is never transmitted from father to son but it is transmitted
to all his daughters.
The gene may be transmitted through a series of carrier females
Heterozygous females are usually unaffected, but some may express
the condition in variable severity.
Expression may depend on X chromosome inactivation (Lyon´seffect)
X linked Recessive Inheritance (XR)
About 300 traits affecting 0,2% of males (except of color
blindness). Chromosome X contains 1672 genes (NCBI
MapView)
Examples:
Color blindness 1 : 12 many variants
Haemophilia A 1 : 5 000
Duchenne muscular dystrophy 1 : 5 000 – 10 000
high rate of new mutations
Haemophilia B 1 : 15 000
Testicular feminization 1 : 20 000
Agamaglobulinemia 1 : 80 000
Typical pedigree chart for XR
I
II3
3
4
2 51 6III
4
1 2 3 4 5 6 7
1 2
IV
1 2
Duchenne muscular
dystrophy
Criteria for X linked Dominant Inheritance (XD)
Affected males with normal mates have no affectedsons and all their daughters are affected
The children of both affected male and affected femalehave 50% risk of inheriting the phenotype.
(This is the same as in autosomal dominant pedigreepattern).
Affected females are about twice as common asaffected males.
Affected females typically have milder (though variable)expression of the phenotype.
(Females are heterozygous, male are hemizygous.)
A few traits, affecting about 0,1% of human beings.
Examples: vitamin D resistant rickets
Vitamine D resistant rickets
Typical pedigree chart for XD
I
II
1
3
2
2 51 6
III
4
1 2 3 4 5 6 7
Criteria for Y linked Inheritance
Only father to the son transmission of the trait
(supposed)
Only males are affected.
! Some genes are on the pseudoautosomal
region and undergo recombination!
Examples:
Sex determining region on Y (SRY)
1:10 000 sex reversal (males with karyotype 46,XX or vice versa)
AZF (= azoospermia factor, male infertility)
Mitochondrial Inheritance
Strictly it is „nonmendelian“
Maternal transmission only
variability in penetrance and expressivity,
partly because of diferent % of mutant
mitochondria („heteroplasmy“). >70-80% of
mutant mitochondria may be required for
symptoms to occur
! most mitochondrial genes are coded by
nuclear genome, proteins then transported
into mitochondria – autosomal or X-linked
inheritance
Mitochondrial Disease
Frequency 1:10000.
Examples:
AID, aminoglycoside-induced deafness;
LHON, Leber hereditary optic neuropathy;
MELAS, mitochondrial encephalopathy, lactic acidosis
and stroke-like episodes;
MERRF, myoclonic epilepsy and ragged-red fibres;
MIDD, maternally-inherited diabetes and deafness;
NARP, neurogenic weakness, ataxia and retinitis
pigmentosa