X-LINKED RECESSIVE INHERITANCEX-LINKED DOMINANT INHERITANCE

X-LINKED INHERITANCE

dr. Retno Sutomo, Ph.D., Sp.A.

X-LINKED RECESSIVE INHERITANCE

Segregation of X-linked recessive allele

Carrier mother

Segregation of X-linked recessive allele

Affected father

Pedigree of X-linked recessive inheritance

X-linked recessive inheritance: Features

Affects mainly males Affected males are usually born to

unaffected parents Transmission through carrier females No male-to-male transmission All daughters of affected males are carriers

X-linked recessive disorders

De novo mutation in DMD

Complication to X linked pedigreeDe novo mutation

X-linked recessive disease in female is it possible?

1. Mating of an affected father and a carrier mother2. Non-random X inactivation3. Female with single X chromosome4. Translocation of X chromosome5. Androgen insensitivity syndrome (AIS)

Xm X

Xm Xm Xm XmX

Y XmY XY

Mother’s gametes

Fath

er’s

gam

etes

Usually lethal

X-linked recessive disorder in femaleAffected male + carrier female

X-linked recessive disorder in femaleFemale with single X chromosome

45, X0 Turner’s syndrome

X-linked recessive disorder in female

Only one X chromosome is active in each cell, other X chromosome/chromosomes is/are inactivated

Normally, inactivation of X chromosome occurs randomly (by chance) random (balanced) X inactivation The chance for each X chromosome being inactivated in each cell is 50% In normal female (46, XX), mutation in one X chromosome will be compensated

by another active X chromosome In certain condition, most cells activate the defective X chromosome and only

few cells activate the normal one non-random (imbalanced, skewed) X inactivation

Non-random X inactivation

X-linked recessive disorder in female

Translocation of X chromosome segments to autosomes The translocated X chromosome defective/non-functional Mimics individual with single X chromosome for the

associated gene

Translocation of X chromosome

X-linked recessive disorder in female

Phenotypically female but genotypically male (pseudo female) Non-responsiveness of androgen receptor to androgen

stimulation No development of male sex characters

Duchene muscular dystrophy (DMD) in Vietnamese “girl” Karyotipe: 46, XY boy Carries mutation in androgen receptor gene

Androgen insensitivity syndrome

X-LINKED DOMINANT INHERITANCE

X-linked dominant inheritanceCharacteristics

Affects either sex, F > M Females are often less severely affected than males The child of an affected female has a 50% chance of being

affected, regardless the sex For an affected male, all his daughters are affected, but none of

his sons The pedigree resembles autosomal dominant inheritance, except

no male to male transmission excess of affected females

X-linked dominant pedigree

Which one is X-inked dominant inheritance?

X-linked dominant autosomal dominant

In some disorders the condition appears to be lethal in affected males Ex: focal dermal hypoplasia (Goltz syndrome), incontinentia

pigmenti There will be fewer males than expected, half of the females

will be affected and all surviving males will be unaffected Some XLD disorders affects girls almost exclusively and

usually occurs sporadically, since affected females do not reproduce Ex: Rett syndrome gene mapped to Xq24

X-linked dominant inheritanceCharacteristics

X-linked dominant pedigree lethality in male

Xm X

X XXm XX

Y XmY XY

Mother’s gametes

Fath

er’s

gam

etes

POLIFACTORIAL INHERITANCE

Mendelian versus GaltonianMendel discontinuous characters

Tall vs dwarf Green peas vs yellow peas Etc

Galton continuous characters Body height Intelligence etc

Polifactorial inheritance

Environment + genetic factors

GaltoniansRegression to mean

Extremely tall fathers tend to have sons shorter than themselves, extremely short fathers tend to have sons taller than themselves

"Tallness" or "shortness" is not similar to Mendel's pea experiments

The height of the father and the average height of the son are related, but the average height of the son always regresses toward the mean

RA Fisher (1918):continuous characters governed by a large number of independent mendelian factors (polygenic characters)

Polygenic characters Polyfactorial characters

Tradition in human genetics Mendelian genetics Non-mendelian genetics

The spectacular advances of 1970-1990 were entirely in mendelian genetics

Investigation of nonmendelian characters remained largely limited to statistical studies of family resemblances

Complex statistical methodology Feeling of a poor investment of research effort compared

to mapping and cloning genes for mendelian characters Many studies concerned sensitive areas of behavioral

genetics such as the heritability of IQ violent controversies and a

distastefully confrontational style of argument often reigned

Poor advancement of studyon multifactorial characters

Multifactorial inheritanceCharacteristics

Several, but not an unlimited number, loci are involved in the expression of the trait

There is no dominance or recessivity at each locus The loci act in concert in an additive fashion, each adding or

detracting a small amount from the phenotype. The environment interacts with the genotype to produce the final

phenotype.

Most affected children have normal parents Most geniuses come from normal parents, most mentally challenged

come from normal parents Recurrence risk increases with the number of affected children

in a family Recurrence risk increases with severity of the defect

A more severely affected parent is more likely to produce an affected child

Consanguinity slightly increases the risk for an affected child

Multifactorial inheritanceCharacteristics

Multifactorial determination of disease

The balance between angels and devils

Influence of environment on phenotypic distribution

INBREEDING

Inbreeding Mating between related individuals Consanguinity "mixing of the blood.“ Although some plants successfully self-fertilize (the most

extreme case of inbreeding), biological mechanisms encourage cross-fertilization

Inbreeding in human In general, inbreeding in human populations is rare Many customs and laws prevent marriages between

closely related individuals when two partners are related their chance to have a

baby with a disease or birth defect is higher than the background risk in the general population.

Effect of inbreeding

Many genetic diseases are recessive only people inherit two disease alleles develop the disease

All individuals carry several single alleles for genetic diseases Close relatives have more genes in common than unrelated

individuals higher chance of inbred parents have the same disease alleles higher risk for their child inherits homozygous for a recessive disease

Case study

At any locus the chance that cousins share an allele inherited from a common parent is one-eighth

If each parent has one copy of the allele % offspring to inherit this allele from both parents = 1/4

Thus, the risk the offspring inherit two copies of the same allele is 1/8 × 1/4, or 1/32, about 3 percent

Overall, the risk associated with having a child affected with a recessive disease as a result of a first cousin mating is approximately 3 percent, in addition to a baseline risk of 3 to 4 % all couples face

Inbreeding coefficient (F)

Probability that two genes at any locus in one individual are identical by descent (common ancestor)

The larger the F the more closely related the parents are Homozygosity

Allozygosity two alleles are alike but unrelated (not copies of the same ancestral allele)

Autozygosity two alleles have identity by descent (i.e., are copies of the same ancestral allele)

Thus, inbreeding coefficient: The probability of autozygosity May range from zero (no inbreeding) to one (it is certain an individual is

autozygous)

Any benefit of inbreeding?

Improve specific characteristics

Facilitate genetic study gene mapping

Any benefit of inbreeding?Improve specific characteristics

Inbreeding commonly practiced in animal breeding to enhance specific characteristics (e.g. milk production)

But, if genes controlling unselected traits are also influenced deleterious effects

Moreover, inbreeding results in decreased genetic diversity

Inbred populations relatively homogeneous in both genetics and environment rich resource for genetic studies

Homozygosity mapping identify several recessive mutations in inbred groups Search for regions of alleles at genetic loci that are linked to one

another and are homozygous In affected individual the two alleles at the disease locus will

have descended from a common ancestor Tightly linked markers (identifiable DNA segments) surrounding

the disease locus tend to come from the same ancestral chromosome and identical on both homologous chromosomes.

Any benefit of inbreeding?Valuable resource for genetic study

Human inbreeding

Just don’t do it!

Finally…….