Patterns of inheritance Suna Onengut-Gumuscu, PhD Center 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 genome 46 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 Some traits cluster in families.

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 In general autosomal disorders will effect affect males and females equally

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 Dominant 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 A a Aa sperm eggs AA Aa aa

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 Mutant alleles for recessive disorders are generally rare. 2. In heterozygote individuals one normal gene copy is able to compensate for the mutant allele and prevent the disease from occurring.

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 Phenylalanine is converted to tyrosine by phenylalanine hydroxylase, the enzyme blocked in phenylketonuria. Lack of homogentisic acid oxidase leads to alkaptonuria. Deficiency of tyrosinase leads to albinism.

Most enzyme deficiencies are transmitted as autosomal recessive A heterozygote still has enough wild type enzyme to carry out the reaction while individuals homozygote for a mutation does not make enough enzyme to complete the reaction.

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 Dominant allele Recessive allele Genotype: Phenotype: Homozygous Heterozygous unaffected affected 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 Mutations in genes for structural proteins often result in dominantly transmitted disorders Collagen: major structural protein of the body; it represents a complex family of subunits that aggregate in different combinations in different tissues.

Autosomal Dominant inheritance/structural gene mutations Only 25 % of the collagen triple helices formed are fully functional

Gain-of-function mutation is achondroplasia p.Gly380Arg 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.

Inheritance patterns Autosomal recessive Autosomal dominant Sex-linked traits

X-linked inheritance Male Female X Y X Y Homozygous Wild-type Unaffected Affected Female Males: Males are hemizygous for genes on the X chromosome Homozygous Wild-type Heterozygous Homozygous mutant

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 and recessive patterns of inheritance are distinguished based on phenotypes of heterozygous females. Random X-inactivation in females cause some difficulty in determining inheritance pattern. X-linked transmission lack male to male transmission

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 aa Aa Penetrance: Not all individuals who carries a genotype associated with a phenotype will express the phenotype. Penetrance is less then 100% when individuals who have the appropriate genotype phenotypically are normal. - Autosomal dominant traits occasionally may skip a generation -Rate of penetrance applies to a population not an individual

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 - Penetrance is high - Wide range of expressivity Neurofibromatosis type 1 (Autosomal dominant) Tumors along peripheral nerves Patches of brown pigmentation on skin Bone deformities Learning disabilities Brain tumors

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 Many genes include regions of simple sequence repeats (di-, tri-, tetra-repeats). Usually the copy number an individual carries has no impact on phenotype. But there is a subset of genes where the copy number of repeats may have a significant effect on phenotype once a certain number of repeat sequence is present (Huntington Disease, Fragile-X, Myotonic dystrophy)

Slipped mispairing mechanism in the expansion of unstable repeats

Unstable Repeat expansion Diseases 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 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 http://www.ncbi.nlm.nih.gov/sites/entrez?db=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/