Mendelian inheritance patterns • Involve genes directly influencing traits • Obey Mendel’s laws • Include • Dominant / recessive relationships • Gene interactions • Phenotype-influencing roles of sex and environment (MF inheritance) • Most genes of eukaryotes follow a Mendelian inheritance pattern • Some genes do not follow a Mendelian inheritance pattern
Imprinting • Definition of genomic imprinting: • For some genes, although we have two copies, one on each chromosome, only one copy is active or expressed, the copy from the mother or the father. • Expression of these genes is variable, but it depends on which parent it came from. • Imprinting does not occur on every chromosome.
Normal development in mammals requires a genetic contribution from the mother (maternal) and father (paternal). • But there are also imprinted genes which are only expressed from the maternal or paternal chromosome. • So, phenotypic expression of the disease can vary according to the mutated allele inherited from father or mother.
Imprinting: The different expressions of the alleles by their inheritance from their parents.
Imprinting:How is expression controlled? • Imprinting occurs by a pattern of methylation • The copy of the gene to be inactivated is coated with methyl groups. • Methylation prevents that gene from being expressed. • This takes place before fertilization, in the egg and sperm cells and is orchestrated by an imprinting center.
Overall result in imprinting: • Allows a gene to be expressed from one allele/the other is methylated and therefore inactive • Expression is parent specific • Mechanisms of disease in imprinting disorders include: • Deletion • Imprinting Defect • Uniparental disomy • Gene mutation • All mechanisms result in a lack of expression of a gene that should be expressed.
The differences of gene expressions between maternal inheritance and paternal inheritance are the results of genomic imprinting. • Imprinting doesn’t change DNA sequence, but it affects gene expression. • It is not a mutation, it is a gene inactivation.
Imprinting occurs during gametogenesis and it marks some genes from the mother or father. • After the conception, the expression of imprinted alleles of the embryo is inactivated in all of the somatic cells. This affect continues postnatally during the cell divisions.
The allele from the egg PWS IC AS Me The allele from the sperm IC PWS AS Me IC=imprinting center
Prader-Willi Syndrome • Neonatal and infantile central hypotonia with poor suck leading to feeding problems and/or failure to thrive. • Hyperphagia begins between ages 2-6 years • Characteristic facial features: narrow bifrontal diameter, almond-shaped eyes, down turned mouth • Hypogonadism • Developmental delay/mild to moderate mental retardation • Small hands and feet for height age • Myopia (60-70% of individuals)
In 70% of the cases there is a cytogenetic deletion of 15q11-q13 which is inherited from father. • So, this part (15q11-q13) of the patients’ genome is only from their mother.
Three Different Mechanisms of Prader-Willi Syndrome (A) In 70% of the cases there is a cytogenetic deletion of 15q11-q13 which is inherited from father. (B) Both of chromosome 15’s are inherited from mother, no parental chromosome 15 is present in 25 % of the patients. (C) There is a methylation defect in the critical region of PWS at the chromosome 15 inherited from the father in less than 5% of the patients.
Angelman Syndrome • Characteristics: • Severe developmental delay or MR • Severe speech impairment • Movement disorder-ataxia, jerky limb movements • Unique behavior: • Frequent, inappropriate laughter, excitability, happy demeanor, hand-flapping, • Acquired microcephaly by age 2 years • Seizures, starting before 3 years of age-of any type • Strabismus • Wide mouth, wide-spaced teeth • Affinity for water
Angelman syndrome (AS) • Nearly in 70% of the patients, there is a deletion in the same region of chromosome 15 which is inherited from mother. • So, this part (15q11-q13) of the patients’ genome is only from their father.
Another reason of AS is the function loss of UBE3A gene (ubiquitine-protein ligase) on chromosome 15 inherited from mother. • This gene is usually expressed in the allele from mother and affects especially central nervous system. • In 3-5% of AS patients, both of chromosome 15’s are inherited from father (paternal uniparental disomy).
Uniparental Disomy • A unique feature to imprinted conditions is uniparental disomy (UPD): when a child inherits both copies of a chromosome from one parent • Isodisomy • Inheritance of two copies of the same homolog from the one parent • Heterodisomy • Inheritance of two different homologs from one parent
Uniparental disomy usually arises due to an error in meiosis. • Trisomic rescue • Nondisjunction in either the egg or sperm leads to two chromosomes • With fertilization, the fetus would have three chromosomes: trisomy for a specific chromosome. • Occasionally, the cell can sense this alteration and undergo loss of one chromosome: termed trisomy rescue • This leads to two chromosome in the cell • At a rate of 66-70%, there will be a normal composition-1 maternal, 1 paternal • UPD in nearly 35% of the patients • Always will be heterodisomy • Monosomic rescue • Fertilization of a nullisomic (A genetic condition involving the lack of one of the normal chromosomal pairs for a species=2n-2) gamete by a gamete with subsequent duplication of the monosomic chromosome-leads to isodisomy UPD. • Gamete complementation • Fertilization of a nullisomic gamete by a disomic gamete for the same chromosome-iso or heterodisomy
UPD shows that PWS and AS are occurred by the activation loss of the genes on 15q11-13 inherited from father and mother, respectively. • In addition to chromosomal deletion and UPD, there is also a defect of the imprinting center in PWS and AS patients.
UPD of a part of chromosome 11 (11p15) causes Beckwith-Wiedemann Syndrome. • Affected children are huge in the birth. • Big tongue • Umbilical hernia • Severe hypoglycemia • There are severe complications of renal and hepatic systems.
Mosaicism • Definition: • Mosaicism describes the occurrence of cells that differ in their genetic component from other cells of the body.
Mosaicism • Mosaicism is caused when a mutation arises early in fetal development. • All cells derived from that mutation will also contain that mutation. • The resulting individual will be a mixture of cells, some with the mutation and some without the mutation. • How early in development the mutation occurs will determine which tissue(s) and what percentage of cells will have the mutation. • Mosaicism • Germline: affecting only egg or sperm cells • Somatic: affecting cells other than egg or sperm cells • Combination of both.
Germline Mosaicism • A person with a germline mosaicism • Will not be affected with the disorder caused by the mutation because the mutation is not in the other cells of the body. • Genetic testing using blood or tissue samples (other than germline tissue) from individuals who only have a germline mutation will be negative for the mutation.
A mosaic germline mutation is significant because it can be passed to offspring. • All the cells of the child developing from that germ cell will have the mutation and therefore exhibit the disease-if autosomal dominant mutation • The recurrence risk is difficult to determine • depends on the proportion of germline cells with the mutation, which can not be determined through testing. • Based on family studies, the risk for another affected child may be 1-30% depending on both the proportion of mutated germ cells and the disorder in question.
Germline mosaicism can be observed with any inheritance pattern, but it is most commonly seen with autosomal dominant and X-linked disorders. • Usually, when unaffected parents have a child with an autosomal dominant mutation—de novo mutation/sporadic mutation
Germline mosaicism has been observed in a number of conditions, including • Achondroplasia • Osteogenesis imperfecta • Duchenne muscular dystrophy.
Somatic Mosaicism • An individual with a somatic mutation will express the phenotype of that mutation depending on how many and which cells are affected. • Typically, individuals with somatic mosaicism exhibit a milder phenotype • since only a proportion of cells contain the mutation • because the mutation is confined to a finite segment of the body.
Examples of genetic disorders that have demonstrated somatic mosaicism • Down syndrome • Neurofibromatosis (NF). • This is termed segmental NF in which only one part of the body is affected. • Cancer • A cancer cell can arise from somatic mutations in genes that control replication of the cell or death of the cell. • The affected individual therefore has somatic mosaicism for these mutations.
Somatic and Germline Mosaicism • When a mutation occurs very early in development it may be present in • Somatic and germline cells • The individual therefore may have a mild form of the disorder and be at risk of passing the mutation to offspring.
Limited Placental Mosaicism • There is no defect in the fetus, but placenta is mosaic (usually trisomic). • For example, karyotype of fetus is 46,XX, but karyotype of placenta is 46,XX/47,XX,+15. • This can cause phenotypically abnormal fetus or newborn though euploid karyotype.
Anticipation 75 63 • It is for autosomal dominant inherited diseases. • Disease is more severe and it has early age onset according to the previous generations. • In the future generations, disease has more severe symptomes. 44
Triplet Repeats • Definition: • An expansion of a segment of DNA that contains a repeat of 3 nucleotides (triplet repeat) such as CAGCAGCAG . . . CAG. • Huntington disease: • CAG • Fragile X: • CGG • Myotonic Dystrophy: • CTG • Freidrich AtaxiA: • AAG