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