Non-Mendelian inheritance
Introduzido| English | Significado |
|---|---|
| mitochondrial inheritance | mitochondrial inheritance |
| heteroplasmy | heteroplasmy |
| genomic imprinting | genomic imprinting |
| uniparental disomy | uniparental disomy |
| trinucleotide repeat expansion | trinucleotide repeat expansion |
| anticipation/ænˈtɪsɪpeɪʃn/ | anticipation |
Three families that break Mendel's rules
- In one family a condition passes only through mothers. In another, the same missing piece of chromosome 15 causes two different syndromes. In a third, the disease starts earlier in each generation.
- None of this means Mendel was wrong. Each is an extra layer of inheritance, and each leaves its own signature.
Mitochondrial inheritance
- Mitochondria have their own small DNA, and a baby's mitochondria all come from the egg. In mitochondrial inheritance 线粒体遗传 an affected mother can pass the condition to children of both sexes; an affected father passes it to none.
- A pedigree with affected mothers, affected children of both sexes and no transmission from any father points to mitochondrial DNA.
A pedigree shows affected mothers, affected children of both sexes and no transmission from any father. Which pattern fits?
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Mitochondrial DNA comes only with the egg, so fathers pass nothing on.
Heteroplasmy: a lottery in every egg
- A cell holds hundreds of copies of mitochondrial DNA, often a mixture of normal and mutant copies: heteroplasmy 异质性.
- Only a small sample of copies passes into each egg (a bottleneck), so each child receives a different mutant fraction, and severity varies from child to child.
All children of a mother with a mitochondrial DNA variant are affected to the same degree.
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Each egg samples a different fraction of mutant copies, so severity differs between children.
Genomic imprinting
- In genomic imprinting 基因组印记 some genes work only from the copy inherited from one parent; the other copy is silenced by methylation.
- The marks are set in the egg or sperm and reset each generation. If the only working copy is lost, there is no backup.
One deletion, two syndromes
- On chromosome 15 (15q11–q13), loss of the father's copy removes genes that work only from the father: Prader–Willi syndrome. Loss of the mother's copy removes UBE3A, which works only from the mother's copy in neurons: Angelman syndrome.
- Uniparental disomy 单亲二体 (both copies from one parent) gives the same result as a deletion: two maternal copies cause Prader–Willi, two paternal copies cause Angelman.
A child has a 15q11–q13 deletion on the chromosome inherited from the father. Which syndrome is expected?
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The genes lost are the ones that work only from the father's copy; the mother's copies are silenced.
Match each change on chromosome 15 to the syndrome it causes.
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What matters is which parent's working copy is missing.
Repeats that grow
- In a trinucleotide repeat expansion 三核苷酸重复扩增, a three-base repeat lengthens as it passes through meiosis. Huntington disease is CAG: 40 or more repeats always cause disease, and very long repeats, mostly passed by fathers, cause onset in childhood.
- Fragile X is CGG: under 45 is normal, 55–200 is a premutation, and over 200 is a full mutation. Earlier and more severe disease in each generation is anticipation 遗传早现.
Put the fragile X CGG repeat categories in order, from shortest to longest.
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The premutation is the unstable range that can expand to a full mutation when passed on by a mother.
What explains anticipation in Huntington disease?
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Longer repeats cause earlier and more severe disease, and the repeat is unstable in meiosis, especially in sperm.
Worked example: the fragile X mother
- (Fictional) A healthy woman carries a premutation of 120 CGG repeats on one X. Each child has a 1/2 chance of inheriting that X.
- From a mother, a premutation this long almost always expands to a full mutation. A son who inherits it will be affected; a daughter may be milder, because her other X still works in some cells.
A woman carries a fragile X premutation on one of her two X chromosomes. What is the chance, as a percentage, that a son inherits that X?
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A son receives one of his mother's two X chromosomes at random.
Worked example: one mutation, many faces
- (Fictional) A family with a MELAS-type mitochondrial variant: the aunt is deaf, the mother has diabetes, and a cousin has stroke-like episodes. Nobody's father passed it on.
- Each person received a different mutant fraction through the egg bottleneck, and each tissue has its own threshold, so one variant gives many pictures.
Three common slips
- "Every child of an affected mother is equally affected." Heteroplasmy makes severity vary.
- Treating imprinting as dominant or recessive. The clue is which parent the change came from.
- "Anticipation is just better diagnosis." The repeat really lengthens, and it can be measured.
Recap
- Mitochondrial DNA comes only from the mother; heteroplasmy makes severity a lottery.
- Imprinting: the same 15q deletion gives Prader–Willi from the father and Angelman from the mother.
- Repeat expansions grow across generations: Huntington CAG ≥ 40; fragile X CGG premutation 55–200, full mutation over 200.