Pedigree Analysis in Human Genetics

Chapter 4

Patterns of Inheritance

!  Patterns in the pedigree are used to determine how a trait is inherited •  Autosomal dominant •  Autosomal recessive •  X-linked dominant •  X-linked recessive •  Y-linked •  Mitochondrial inheritance

OMIM

I

II

1 2 3

1 2

P

Pedigrees

I

II 1 2 3

Male

Female

Mating Mating between relatives (consanguineous)

Parents and children. Roman numerals symbolize generations. Arabic numbers symbolize birth order within generation (boy, girl, boy)

Monozygotic twins

or

or

or

or

P P

d. 1910 d. 1932

Unaffected individual

Affected individual

Proband; first case in family that was identified

Known heterozygotes

Carrier of X-linked recessive trait

Indicates date of death

Pedigrees, cont.

Dizygotic twins

Offspring of unknown sex

Aborted or stillborn offspring

Deceased offspring

Questionable whether individual has trait

Asymptomatic/ presymptomatic

Infertility

or

? ?

Pedigrees, cont.

Autosomal Recessive Traits

!  Characteristics of autosomal recessive traits •  For rare traits, most affected individuals have

unaffected parents •  All children of affected parents are affected •  The risk of an affected child with heterozygous

parents is 25%

Some Autosomal Recessive Traits

Pedigree: An Autosomal Recessive Trait Example: Cystic Fibrosis

!  Cystic fibrosis •  A fatal recessive genetic disorder associated with

abnormal secretions of the exocrine glands

The CF Gene and Organ Systems Affected by Cystic Fibrosis Cystic Fibrosis Gene Product

!  CFTR protein controls the movement of chloride ions across the plasma membrane

Example: Sickle Cell Anemia

!  Sickle cell anemia •  An autosomal recessive disorder •  Produces abnormal hemoglobin (blood transport

protein)

Autosomal Dominant Traits

!  Characteristics of autosomal dominant traits •  Every affected individual has at least one affected

parent (except in traits with high mutation rates) •  If an affected individual is heterozygous and has

an unaffected mate, each child has a 50% chance of being affected

•  Two affected individuals can have an unaffected child

Some Autosomal Dominant Traits Pedigree: An Autosomal Dominant Trait

Example: Marfan Syndrome

!  Marfan syndrome •  An autosomal dominant genetic

disorder that affects the skeletal system, cardiovascular system, and eyes

Flo Hyman

Aorta

Area of aorta

effected in Marfan

syndrome

Pulmonary artery

Right auricle

Left ventricle

Right ventricle

Vena cava

Right auricle

Right ventricle

Left ventricle

Marfan Syndrome Normal Heart

Sex Linked Traits

!  X-linked •  Pattern of inheritance that results from genes

located on the X chromosome

!  Y-linked •  Pattern of inheritance that results from genes

located only on the Y chromosome

Distribution of Sex Chromosomes

X and Y: Human Sex Chromosomes Males Have Hemizygous Genes

!  Hemizygous •  A gene present on the X chromosome that is

expressed in males in both the recessive and dominant condition

X-Linked Dominant Traits

!  Affected males produce all affected daughters and no affected sons

!  A heterozygous affected female will transmit the trait to half of her children •  Sons and daughters are equally affected

!  On average, twice as many daughters as sons are affected

Pedigree: Hypophosphatemia

X-Linked Recessive Traits

!  X-linked recessive traits affect males more than females because males are hemizygous for genes on the X chromosome

X-Linked Recessive Inheritance

!  Affected males receive the mutant allele from their mother and transmit it to all of their daughters, but not to their sons •  Daughters of affected males are usually

heterozygous •  Sons of heterozygous females have a 50%

chance of being affected

Pedigree: X-Linked Recessive Inheritance Example: Color Blindness

!  Color blindness •  Defective color vision caused by reduction or

absence of visual pigments •  Three forms: red, green, and blue blindness

Testing For Color Blindness Color Blindness: The Eye

!  Defects in cone proteins cause color blindness

Duchenne Muscular Dystrophy

!  Dystrophin proteins that normally stabilize the muscle cells during contraction are defective •  Plasma membranes are

torn apart by muscle contraction, causing death of muscle tissue

Genetics in Society: Hemophilia and History

Paternal Inheritance: Y Chromosome

!  Only males have Y chromosomes •  Genes on the Y chromosome are passed directly

from father to son

!  All Y-linked genes are expressed •  Males are hemizygous for genes on the Y

chromosome

Some Genes on the Y Chromosome

Pedigree: Y-Linked Traits Some Mitochondrial Disorders

Mitochondrial Inheritance

!  Mitochondria (and genetic disorders caused by mutations in mitochondrial genes) are maternally inherited

!  Mitochondria are transmitted from mothers to all their offspring through the cytoplasm of the egg

Pedigree: Mitochondrial Inheritance

Age-Related Phenotypic Expression

!  Huntington disease •  An autosomal dominant disorder associated with

progressive neural degeneration and dementia •  Adult onset is followed by death in 10 to 15 years

!  Porphyria •  An autosomal dominant disorder that leads to

intermittent attacks of pain and dementia •  Symptoms first appear in adulthood

Porphyria variegata -Pleiotropy

King George III

Symptoms: Red urine, Abdominal pain, Constipation, Rapid pulse, Stupor, Delirium, Convulsions, Madness

Two Aspects of Phenotypic Variation

!  Penetrance •  The probability that a disease phenotype will appear

when a disease-related genotype is present (e.g. Polydactyly or Camptodactyly).

•  25% penetrance means that only 1/4 of the population with the disease-related genotype show the phenotype.

!  Expressivity •  The range of phenotypic variation associated with a

given phenotype (e.g. Camptodactyly: one hand or both hands affected)

Incomplete Penetrance

!  Camptodactyly •  A dominant trait (immobile, bent little fingers) with

variable expression

no penetrance

both hands affected

one hand affected