Patterns of inheritance

Suna Onengut-Gumuscu, PhDCenter for Public Health Genomics

• Email: so4g@virginia.edu• Human Genetics and Genomics (2006), Korf, 3rd edition, ISBN 0-

6320-456-2• Thompson and Thompson Genetics in Medicine (2007), Nussbaum,

McInnes, Willard, 7th edition, ISBN 978-1-4160-3080-5

Patterns of inheritance

• Family history/ Pedigree• Autosomal recessive• Autosomal dominant• Sex-linked traits• Penetrance and Expressivity• Genetic imprinting• Genetic anticipation

Human genome46 chromosomes• 22 pairs of autosomes• XY male • XX female

Classification of Genetic Disorders

• Chromosomal disorders: Defect is due to an excess or a deficiency in whole chromsomes or chromsome segments (trisomy 21,Turner syndrome, Klinefelter syndrome)

• Single gene defects: Caused by individual mutant genes

• Multifactorial inheritance: Combination of multiple genes and environmental factors. (Complex disease: diabetes mellitus, Crohn’s disease, Multiple sclerosis)

Single gene disorders/ Common disease

• More then 3900 single gene defects have been catalogued

• Rare single gene disorders: usually less then 1 in 100000 births

• Common diseases: determined by combinations of genes interacting with one another and with the environment. Do not fit the characteristic patterns of inheritance observed in single gene defects.

Patterns of Inheritance

• Gregor Mendel (1822-1884) was the first person to describe how certain traits are inherited from generation to generation.

• Early 20th century Archibald Garrod recognized the existence of families in which traits segregated according to Mendel’s laws

Pedigrees in genetics

• Single-gene disorders show patterns of transmission in families

• Family history: 1st step in establishing pattern of inheritance

• Pedigree: A diagram of a family history indicating the family members, their relationship to the proband, and their status with respect to a particular heredity condition

Family history

• In diagnosis• To clarify pattern of inheritance• Provide information if there is variation in expression

among family members• Natural history of a disease

Main symbols used in pedigrees

Inheritance patterns

• Recessive: expressed only when both chromosomes of a pair carry mutant alleles at a locus (2 mutant copies)

• Dominant: expressed when one chromosome of a pair carries a mutant allele at a locus . (1 mutant copy)

Inheritance patterns

• Sex-linked: on the X or Y chromosomes

• Autosomal: on any of the other 22 chromosome pairs

Genetic Terms

• Allele: one variant of a gene or marker

• Genotype: genetic composition for a trait

• Phenotype: physical manifestation of a trait

Inheritance patterns

• Autosomal recessive

Genotype and phenotype correlation with gene locus for an autosomal recessive trait

A aDominant allele Recessive allele

Genotype:

Phenotype:

Homozygous

unaffected

Heterozygous

unaffected

Homozygous

affected

Autosomal Recessive Inheritance

• Autosomal recessive traits are only expressed in individuals who carry two mutant alleles inherited from each parent.

• Autosomal recessive traits usually arise in children of phenotypically normal parents

AA Aa

Aa aa

A

a

A a

Aa

Aa

sperm

eggs

Segregation of an autosomal recessive trait in a pedigree

Autosomal recessive: increased incidence of parental consanguinity

Autosomal Recessive Inheritance

• Usually parents are heterozygous carriers

• Affected individuals are usually born to unaffected parents

• Affected children are homozygous for mutant gene

• In most autosomal recessive diseases males and females are equally likely to be affected

• Carrier couple has a 1 in 4 chance of having affected offspring

• There is an increased incidence of parental consanguinity

Autosomal Recessive Inheritance

• These traits are only expressed in individuals who carry two mutant alleles inherited from each parent.

• Usually due to mutations that reduce or eliminate the function of the gene product (loss-of-function)

• In many cases: mutations that impair or eliminate the function of an enzyme

Oculocutaneous Albinism

• Lack of pigmentation• Fair skin and hair• Decreased visual acuity• Lack of stereoscopic vision• Mutations in the gene encoding

Tyrosinase (lack of Melanin)• Autosomal Recessive Genetic

Transmission

Metabolic pathways involving tyrosine

Most enzyme deficiencies are transmitted as autosomal recessive

Mutations responsible for recessive traits usually leads to:

• Lack of gene expression (eg: promoter mutations)

• Lack of protein production (eg:mutations that lead to premature termination of translation)

• Production of a protein with reduced or absent function (eg: amino acid substitution)

Inheritance patterns

• Autosomal recessive

• Autosomal dominant

Genotype and phenotype correlation with gene locus for an autosomal dominant trait

A aDominant allele Recessive allele

Genotype:

Phenotype:

Homozygous Heterozygous Homozygous

unaffectedaffected

Phenotype expressed in both homozygotes and heterozygotes for a mutant allele

Pedigree illustrating autosomal dominant transmission

Autosomal Dominant Inheritance

• Expressed in heterozygous or homozygous individuals

• Affects an individual of either sex

• Transmitted by either sex

• An affected person usually has at least one affected

parent

• Transmitted to 50 % of offspring

Osteogenesis Imperfecta Type I

• Autosomal Dominant

• Marked by extreme fragility of bones

• Deficient production of the protein collagen leading to abnormal bone matrix

• Muations in COL1A1 or COL1A2 lead to reduced amounts of normal collagen

Autosomal Dominant inheritance/structural gene mutations

Gain-of-function mutation is achondroplasia

• Mutation in the fibroblast growth factor type 3 receptor (FGFR3) leads to Achondroplasia (a form of dwarfism)

• FGFR3 promotes differentiation of cartilage into bone.• Gain-of-function mutation constitutively activates the

receptor causing premature conversion of the growth plate into bone.

p.Gly380Arg

Inheritance patterns

• Autosomal recessive

• Autosomal dominant

• Sex-linked traits

X-linked inheritance

X XUnaffected Affected

Female

Homozygous

Wild-type

Heterozygous Homozygous

mutant

Male

Y Y

X-linked recessive inheritance

• Affects mainly males

• Affected males are usually born to unaffected parents

• Females may be affected if the father is affected and the mother is a carrier, or occasionally as a result of nonrandom X-inactivation

X-linked dominant inheritance

• Affects either sex

• Females are often more mildly and more variably affected than males

• The child of an affected female has a 50 % chance of being affected

• For an affected male, all his daughters but none of his sons are affected

Y-linked inheritance

• Affects only males• Affected males always have an affected father• All sons of an affected man are affected

Mutations in Y-linked genes usually lead to male infertility therefore usually not passed on to future generations.

Penetrance and Expressivity

Penetrance: The proportion of individuals of a specified genotype who show the expected phenotype

- Autosomal dominant traits occasionally may skip a generation

-Rate of penetrance applies to a population not an individual

aa Aa

Aa

Aa

aa

aaaa

Age-related penetrance in late-onset diseases:

In late –onset disease although genotype is present at birth the phenotype may not manifest until adult life (Huntigton disease, progressive neurodegenaration)

Penetrance and Expressivity

Penetrance: The proportion of individuals of a specified genotype who show the expected phenotype

Expressivity: The range of phenotypes expressed by a given genotype

Neurofibromatosis type 1

(Autosomal dominant)

-Tumors along peripheral nerves

-Patches of brown pigmentation on skin

-Bone deformities

-Learning disabilities

-Brain tumors

- Penetrance is high

- Wide range of expressivity

Genomic Imprinting

• Certain genes are expressed only from the maternal or paternal chromosome

• Genomic Imprinting: Differential expression of maternally and paternally derived genes.

• Expression of the disease phenotype depends on whether the mutant allele has been inherited from the mother or the father.

Genomic Imprinting

- The specific gene copy to be inactivated is always determined by the parent of origin

-Is a dynamic process: the “imprint” has to be erased and reset in each generation

-The “imprint” is reset in germ cells

-If a mutant gene is imprinted, sex of the parent it was inherited from plays a role in the expression of the disease phenotype

Deletions on chromosoome 15 can result in Prader-Willi or Angelman syndrome

Prader-Willi Syndrome

-initial failure to thrive

-distinctive facial features

-developmenta delay

-hypogonadism

Angelman Syndrome

-seizures

-jerky, uncoordinated movements

-unprovoked smiling/laughter

-lack of speech

-severe developmental delay

Paternal

Maternal

Anticipation

• Symptoms in certain genetic disorders tend to be more severe and have earlier age of onset from generation to generation.

• Unstable repeat expansions: characterized by expansion of a segment of DNA consisting of repeating units of three or more nucleotides in tandem

Slipped mispairing mechanism in the expansion of unstable repeats

Unstable Repeat expansion Diseases

Disease Inheritance pattern Repeat Gene

Repeat Numbers

Normal Affected

Huntington Disease Autosomal dominant CAG HD <36 >40

Fragile-X X-linked CGG FMR1 <60 >200

Myotonic dystrophy Autosomal dominant CTG DMPK <30 80-2000

Friedrich ataxia Autosomal recessive AAG FRDA <34 36-100

Huntington Disease

• Triplet repeat expansion (CAG repeat leading to expansion of polyglutamine)

• Autosomal dominant

• Progressive neurodegenerative disorder

• Anticipation: there is an earlier and earlier age of onset from generation to generation

Age of onset/ number of CAG repeats

Pathogenesis of disease due to unstable repeat expansions

• Expansion of noncoding repeats that cause a loss of protein function by impairing transcription. - Fragile X syndrome: Presence of more then 200 copies of CGG repeat in the 5’ UTR of FMR1 leads to over methylation of cytosines in the promoter

• Expansion of noncoding repeats that confer novel properties on the mRNA. - Myotonic dystrophy 1: (3’ UTR of DMPK) CTG >80 copies. Excessive binding of RNA-binding proteins quench normal RNA splicing mechanism in the cell

• Expansion of a codon leading to novel features- Huntington Disease: CAG>40 long polyglutamine sequences,

damage specific neurons

Factors affecting pedigree patterns

• Penetrance• Expressivity• Age of onset• Imprinting• Anticipation• Occurrence of new mutations• X inactivation

OMIM

• Online Mendelian Inheritence in Man

• http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim• A catalog of genes and human traits• Each entry has a unique six-digit MIM number. Entries that

begin with

1 (100000- ) Autosomal loci or phenotypes (entries created before May 15, 1994)

2 (200000- )

3 (300000- ) X-linked loci or phenotypes

4 (400000- ) Y-linked loci or phenotypes

5 (500000- ) Mitochondrial loci or phenotypes

6 (600000- ) Autosomal loci or phenotypes (entries created after May 15, 1994)

-Mouse Genome informatics: http://www.informatics.jax.org/

-OMIA – Online Mendelian Inheritance in Animals: http://omia.angis.org.au/