Mendelian And Non-Mendelian Inheritance

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Autosomal dominant

Back 1

Only takes one copy of the gene to show the problem.

E.g., huntington's

See vertical transmission: people are affected in every generation, parent passing it on to child.

Front 2

Familial hypercholesterolemia

Back 2

Autosomal dominant, homozygotes much more severely affected

Front 3

Mitochondrial Inheritance and Characteristics

Back 3

Sperm do not typically contribute mitochondria to offspring, but the ovum does.

MtDNA chromosomes are circular and do not recombine.

Both sexes affected.
All children of affected mother will have it.
No children of affected father will have it.
Reduced penetrance, variable expressivity, and pleiotropy

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What types of things does mtDNA encode? Replication of mtDNA

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2 kinds of rRNA, 22 tRNAs, and 13 polypeptides that are subunits for enzymes of oxidative phosphorylation

Replicates in the mitochondrian by fission

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Homoplasmy vs. Heteroplasmy

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Whether all the mitochondria have the same mutation (homoplasmy) or not (hetero)

Front 6

replicative segregation

Back 6

in each mitochondria the mtDNA replicate and sort independently. When there's heteroplasmy, the daughter cells may have wide variation in proportion of normal and mutant mitochondria

Not all mitochondria have the problem!

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anticipation

Back 7

As disease tracks through generations, the onset occurs earlier and the disease may be more severe

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What are anticipation and parent of origin effects generally attributed to?

Back 8

Trinucleotide repeats causing disease

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Fragile X Mental Retardation Syndrome: Clinical Features

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Clinical features: 1 in 5k
Most common cause of inherited male retardation

About 1/2 of female carriers have a less severe mental retardation

About 30% of males with premutation develop fragile X associated tremor/ataxia syndrome

About 20% of females develop premature ovarian failure (early menopause)

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Fragile X Mental Retardation Syndrome: Genetic features

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Atypical X-linked with parent of origin effect.

Associated with "fragile" site at X chromosome, but this test is no longer used

Amplified CGG trinucleotide repeats as well as hypermethylation of FMR-1 gene.
Normal gene product is a RNA-binding protein that seems to function as a nucleocytoplasmic shutting protein.

the FMR-1 mutation results in gene silencing

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Premutation alleles of Fragile X

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55-200 repeats

Result in elevated mRNA levels (increased transcription).

Abnormal mRNA-cellular protein interaction (mRNA toxicity)

Leads to a translation block and slightly decreased amount of FMRP. (Gene product of FMR-1)

Can show FragileX Associated Tremor/Ataxia or Premature Ovary Insufficiency

Could also show developmental delays, adhd, autism spectrum disorders.

Abnor

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When does the FMR-1 trinucleotide expansion occur?

Back 12

During oogenesis.

Front 13

Inheritance of premutations and full mutations in Fragile X

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Transmitting males: Males with the premutation can pass it to daughters (not sons, obvi), who will be carriers. The daughters' children are then at risk.

A full mother (with Fragile X)will pass it on to sons, but to only about half of daughter.

A full father (with Fragile X) will not pass it to sons, and pass it to daughters in a stable or reduced form (no expansion of repeats in spermatogenesis)

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Huntington Disease: Clinical features

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Progressive mental and neurological deterioration with chorea, memory loss, and personality changes.

1 in 20k.

Mean age of onset is 35-44 years, but can range from 15-70+

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Huntington Disease: Genetic features

Back 15

Autosomal dominant, fully penetrant, shows anticipation

Amplified trinucleotide repeat

HD gene encodes the protein huntingtin (unknown function). Huntingtin is too long, and collects in the nuclei of neurons, damaging them.

Anticipation is observed when receive the repeat from fathers, probably due to greater expansion of repeat in spermatogenesis

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Myotonic dystrophy:Clinical Features

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Most common adult-onset muscular dystrophy

Progressive muscle wasting and atrophy, myotonia, intellectual impairment, heart problems

1 in 8k

Average age onset 20-25 years

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Myotonic dystrophy:Genetic Features

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Autosomal dominant with anticipation

Two types: caused by repeat expansion in two different genes (locus heterogeneity)

DM1 and DM2

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Mechanism of repeats causing problems.

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Thought to be due to "slippage" during replication

During replication, the replicating strand detaches inappropriately from template strand, slipping from its proper alignment by one repeat length. The mismatched repeat loops out.

When the new strand reassociates with the template strand, the new strand may slip back to align out of register with an incorrect repeat copy. One DNA synthesis is resumed, the misaligned molecule will contain one or more extra copies of the repeat.

If repeat is in coding region (Huntington's) then this can prevent the normal transport/degradation, resulting in toxic accumulation of the mutant proteins.

If it occurs in the untranslated region (Fragile X) expansions can disrupt transcription, RNA processing, or translation. Fragile X : expansion of repeat leads to loss of transcription of FMR1 gene.

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Common features of trinucleotide repeats

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1) Anticipation
2) Parent of origin effect
3) Mitotic and meiotic instability
4) Neurological disorders

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Imprinting

Back 20

Type of parent of origin effect whereby the gene is expressed differently depending on which parent it came from.

Implies there is a sensitive/critical period during development when genetic info is marked.

The imprint must persist stable through DNA replication and cell division (mitosis)

Imprint must be capable of affecting gene expression (usually by methylation silencing)

Imprinting is erased in germ cell line

Appears that only certain genes are imprinted. Imprinting appears essential for normal growth and development.

Appears that maternal imprinting more essential for development of embryo, where paternal imprinting more essential for development of placenta. (A zygote with only maternal genes, eg., a clone, will develop with an impaired placenta, etc.)

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Hydatidiform mole

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A conceptus (diploid paternal) with a phenotype of absent or disorganized fetal tissue and overdevelopment of the extraembryonic membranes

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Ovarian teratoma

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A conceptus (diploid maternal) with tissue that would normally develop into the embryo, but lacks all paternal tissue.

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Prader-Willi vs. Angelman

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Both are derived from deletions in Chromosome 15.

If deletion is paternal (maternal chr. present only) --> PWS

If deletion is maternal (paternal chr. present only) then AS.

Example of imprinting

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What types of chromosomal abnormalities can result in Prader-Willi?

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1) Deletion in paternally inherited Chromosome 15. Maternal 15 is normal

2) Uniparental disomy from mother.

3) Imprinting defect (get chr. 15 from both). This is rare.

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What types of chromosomal abnormalities can result in Angelman

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1) Deletion in maternally inherited Chromosome 15. Paternal 15 is normal. (most common)

2) Uniparental disomy from father.

3) Imprinting defect.
4) UBE3A mutation
5) Unknown

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Trisomy rescue

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Possible mechanism that uniparental disomy occurs. A conceptus that was originally trisomic may try to correct the trisomy by chromosome loss.

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Molecular mechanisms of imprinting

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Methylation of regulatory sequences of genes during oogenesis or spermatogenesis.

Methylation of selected cytosine residues.