Lecture 12: Patterns Of Inheritance PDF

PATTERN OF INHERITANCE: Sex influenced, Sex limited and Holandric genes. The Patterns of Genetic Inheritance Mendelian Non-Mendelian Autosomal Dominant Imprinting Autosomal Recessive Mitochondrial X-linked Recessive Multifactorial X-l...

PATTERN OF INHERITANCE: Sex influenced, Sex limited and Holandric genes. The Patterns of Genetic Inheritance Mendelian Non-Mendelian Autosomal Dominant Imprinting Autosomal Recessive Mitochondrial X-linked Recessive Multifactorial X-linked Dominant Sporadic Y-linked Contiguous gene syndromes 1) Transmission: Are there affected family members in every generation (vertical pattern) or in only a single generation (horizontal pattern)? 2) Sex Differences: What is the ratio of affected males to females? 3) Segregation: Is disease/gene being passed through unaffected females? Is there male to male transmission? What % of children are affected (e.g. all of sons but none of daughters)? …but there are some complicating factors! Non-penetrance Sex-limited/sex influenced New mutation Germ line mosaicism Adult-onset conditions Anticipation Consanguinity Heterogeneity Interaction Pleiotropy  Autosomal Dominant Vertical pattern: multiple generations affected Males and females equally likely to be affected Each child of an affected individual has a 50% chance to be affected Unaffected individuals do pass on the gene Every affected child has an affected parent Autosomal Dominant Non-Penetrance An individual who inherits the disease gene does not develop the disorder The disorder appears to “skip” generations Autosomal Dominant Sex-Limited/Influenced 3 2 3 2 Gene expression limited to specific sex Disorder/trait may appear to “skip” generations Autosomal Dominant New Mutation 3 2 3 An alteration occurs in the egg or sperm that made the affected individual (may be first family member to be affected) Risk of new mutation is associated with advanced paternal age in some disorders (e.g. Achondroplasia) Autosomal Dominant dx 60 Late-onset trait dx 50 dx 45 4 3 4 dx 45 3 2 An individual who inherits the disease gene but does not develop the condition until adulthood Examples: Huntington disease, most hereditary cancer syndromes Autosomal Dominant Lisch nodules Variable Expressivity café-au-lait spots Neurofibromas café-au-lait spots café-au-lait spots Lisch nodules scoliosis Variability of severity of Optic glioma disorder among individuals learning disability neurofibromas with same genotype café-au-lait spots Examples: Neurofibromatosis, Treacher-Collins syndrome Autosomal Recessive Horizontal pattern: single generation affected. Males and females equally likely to be affected Parents of affected child are unaffected gene carriers and have a 1 in 4 or 25% recurrence risk Unaffected siblings have a 2/3 or 67% chance to be carriers. Children of affected individuals are obligate carriers. 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  Mutations responsible for recessive traits usually leads to: Lack of gene expression (e.g: promoter mutations) Lack of protein production (e.g.: mutations that lead to premature termination of translation) Production of a protein with reduced or absent function (e.g: amino acid substitution)  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. Holandric Genes: Holandric genes are those found only on the Y chromosome. Biologically, the Y chromosome causes an offspring to be male rather than female. The holandric genes are inherited solely from a male parent to a male offspring and are referred to as y-linked inheritance. Examples of holandric genes are;  Polygenic Disorders Examples: cancer, schizophrenia, hypertension, diabetes, etc  several genes involved  also environmental influences.  Multiple Allelic Traits Often more than two alleles exist for a particular gene locus. Each individual inherits only two alleles for these genes!!! EX: Human Blood type Inheritance of blood type  Penetrance and Expressivity Penetrance: The proportion of individuals of a specified genotype who show the expected phenotype aa Aa Aa aa Aa aa aa - Autosomal dominant traits occasionally may skip a generation -Rate of penetrance applies to a population not an individual Penetrance cont… 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. 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 (Huntington 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 Neurofibromatosis type 1 - Wide range of expressivity (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 Paternal -developmental delay -hypogonadism Angelman Syndrome -seizures -jerky, uncoordinated movements Maternal -unprovoked smiling/laughter -lack of speech -severe developmental delay 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 Anticipation… 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)  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