Main Ideas: Somatic Mosaicism: - Individual is a mosaic of cells with different genotypes"- Frequently a post-zygotic event (occurs after fertilization)"- Chimerism a rare mechanism for congenital mosaicism"- X-inactivation (females) yields mosaic patterns of gene expression (aka in a way females are mosaic as well) Germline Mosaicism: "- Special case of mosaicism where the parents has no clinical manifestation, but has multiple affected children"- Mutation not present in the blood of parent"- Mutation be detected in other parental cells (skin, cheek cells, sperm)"Dynamic Mutations: - Caused by a small # (3, 4, 5) of nucleotide repeats that expand in #"- Expansions lead to disease"- Repeats can expand in germ cells"- Parent of origins effeccts are present"- Coding sequence: Paternal expansion: HD"- Non-coding sequence: Maternal expansion: Myotonic dystrophy, Fragile X"- Unstable repeats result in anticipation"- Earlier presentation"- More severely affected offspring than parents Objectives 1) To understand the concept of mosaicism, how somatic or germinal mosaicism may occur, and the implications of these states in transmission of genetic traits. 2) To be familiar with the concept of genetic anticipation, and to understand how trinucleotide repeat mutations can display this phenomenon. 1) To understand the concept of mosaicism, how somatic or germinal mosaicism may occur, and the implications of these states in transmission of genetic traits. - Mosaicism: the presence of at least 2 genetically different cell lines in a single individual"- Somatic: cells of body are mosaic"- Germline"- can be both: gonasomalmosaicism"- Somatic mosaicism"- mutation occurs during embryonic development, can be patchy or generalized"- for many point mutations this can occur after fertilization of the egg by the sperm= post-zygotic event (mitotic division mut)"- Ex. McCune-Albright syndrome: gain of function somatic mutation (excess of a growth hormone). Cafe au lait spots and fibrous dysplasis of bones. - Chimerism (= another type of mosaicism)"- have 2 or more populations of cells that originated from more than 1 zygote"- freq. in cattle= freemartin (female calf interacted with twin brother in womb-->carries 2 cell lines)"- now being found in humans as significant"- Twinning: have cells from fraternal twin"- fetal cells found in a mom after pregnancy"- can be a desired outcome ex. after a bone marrow transplant--individ is now a chimera of howthey began life"- Germline Mosaicism - Deteced when you observe a child in a fam with an inherited dominant or X-linked trait where the mutation can't be demonstrated in a parent and parent is clinically unaffected"- special case of somatic mosaicism"- don't find mutation in normal blood testing, but other parental tissue may have it (skin, sperm, cheek)"- tough to diff. between this and low gradde somatic mosaicism"- common in some autosomal dominant and x-linked conditions"- ex. osteogenesis imperfecta (brittle bone disease). 10% recurrence risk in new cases in a fam due to germline mosaicsm"- Recurrence Risks for S or G mosaicism - risk for following offspring is variable, not the same as Mendelian. Difficult to determine risk."- risk is less than if mosaic parent was fully affected with the condition (less than risk from Mendelian)"- Can't tell the fam w/apparently sporadic X-linked or autosomal dom disorder that the risk of recurrence is 0 2) To be familiar with the concept of genetic anticipation, and to understand how trinucleotide repeat mutations can display this phenomenon. - Dynamic mutations: disorders of unstable repeat expansion"- Group of neurological conditions caused by expansion of nucleotide repeat units"- Each condition has the repeat in a specific part of the gene"- Not a typical disease mech, unique to this group of diseases"- Common themes of dynamic mutations"- gene contains a repetitive element"- gene is unstable if expanded"- element is polymorphic= diff between individs"- element can happen in any part of the gene, but is specific to each disease"- anticipation is seen in pedigrees= increase in prevalence or severity throughout generations"- risks differ depening on the parent of origin for mutation"- Pathogenic mechanisms of unstable repeats"- alteration of RNA splicing function ex. Mytonic dystrophy"- in MD: mutation produces an abnormal RNA, expanded RNA made rather than a protein= "toxic RNA""- alters function of splicing factors, thus affecting RNA splicing of other genes"- autosomal dominant, mom has heightened risk for baby"- loss of function ex. Fragile X"- in Fragile X: X-linked cognitive disability syndrome, primarily a behavorial pheno, physical features seen best after puberty (long face, prom. forehead, large ears)"-appears semi-dominant"- Sherman paradox: 20% of obligate hemizygotes (they "should" be affected) are normal. Men who appear to be "carriers. 30% of carrier heterozygotes are affected. This means women who were affected."- Solved: the repetitive element can increase in size if there are > 44 copies of the repeat"- repeat expansion occurs mainly if inherited from mom (thru maternal meiosis)"- there are varying classes of repeat sizes: normal, gray zone (may go to pre, won't to full), premutation (at risk for full), and full mutation"- premutations are meiotically unstable and progress to full mutations causing observed anticipation"- person with premutation= at risk for sons and daughters with Fragile X, though patient is not affected"- Carriers at risk for FXTAX (fragile x ataxia syndrome) and premature ovarian failure= early menopause"- Condition worsens through generations= anticipation"- loss of gene expression, gene important for synaptic function"- gain of function ex. Huntington disease"- HD:"- Autosomal dom., typical onset age 30-50, progressive loss of motor control, dementia and affective disorder. Fatal. "- age of onset varies based on expansion size and parent of origin. Expansion size up, age of onset earlier."- Severity correlates with a higher # of repeats"- Larger expansions inherited from the dad in unstable fashion= paternal expansion on the autosome"- Accumulation of protein aggregates in nuclear and cytoplasm of neuron-->neuronal cell death, brain atrophy"- triplet repeat expansion in the Huntington gene that can expand"- affected homozygs are phenotyp just like heterozygs. heterzyg. knock out mice= fine, so lacking the protein is fine. knockin mice with the expanded
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