7- Non-classical Inheritance and Chromosomal Disorders Flashcards
Tri-nucleotide-Repeat mutations
Expansion of stretch of trinucleotides
- usually C and G
- Results in unstable DNA
- impairs gene function
- Coding regions: usually codes for Glutamine, results in protein dysfunction and accumulation and apoptosis, common to neurodegenerative disorders
- Noncoding: can cause suppression of protein function
What diseases are related to trinucleotide repeat mutations?
Fragile X syndrome
Freidrich Ataxia
Myotonic dystrophy
huntington’s disease
Possible mechanism of trinucleotide repeat mutations
During replication one replication sequence slips out and bubbles out, but still connected
Machinery thinks it’s gone so adds another.
Next time it’s replicated it reads all of it and copies the extra one too.
Anticipation
Associated with diseases like myotonic dystrophy.
More recent generations develop symptoms earlier or more severe than previous generations.
Usually associated with expansion of trinucleotide repeats.
Mutations in mitochondrial genes
Rare and variable Only maternal inheritance 37 genes: --24 encode for tRNA and rRNA --13 for respiratory chain proteins Thousands of copies present -- possibility of mixes of wild type and mutant type -- random distribution of daughter cells
Both males and females affected
- – if only male affected then not passed on.
- – all offspring of female are affected
Examples of epigenetic inheritance
X inactivation
Genomic imprinting.
Imprinting and Epigenetics
Sometimes maternal or paternal allele is transcriptionally silenced by epigenetic mechanisms.
If non-silenced allele is the one missing or mutated, disease can result.
Angleman’s syndrome
Angleman’s gene (UBE3A) should be expressed from maternal chromosome. Fathers should be silenced.
If deletion occurs on maternal chromosome there is not correct expression of gene.
Symptoms:
- developmental delays (lack of crawling)
- minimal or no speech
- ataxia
- frequent smiling and excessive laughter
Prader-Willi syndrome
Micro deletion of paternal chromosome, means that protein is not produced
Symptoms:
- behavioral
- delayed puberty
- constant hunger/ obesity
- intelectual disability
- short stature
Gonadal/Germline Mosaicism
Phenotypically normal parent has unobservable mutation, mutation present in gametes.
Multigenic disorders (Complex or Multifactorial disorders)
Many polymorphisms, each with modest effect and low penetrance, are inherited collectively
Different polymorphisms can vary in significance with some increasing the risk
Some poly. are common in multiple related conditions
Environmental influences can affect complex traits, but familial clustering must be present
Range of levels of severity
How many chromosomes are present in a somatic cell?
46
22 homologous pairs of autosomes
2 gonosomes
Karyotype nomenclature
p, q, 17q, 46
Karyotype= metaphase chromosomes arrested and stained to show distinctive G binding in order to study the size and number of chromosomes
p- small arm
q- long arm
17q= long arm of chromosome 17
46, XX= female 46, XY= male
Aneuploidy, and what are the mechanisms?
Wrong number of chromosomes in a cell.
Nondisjunction- FAIL TO SEPARATE during mitosis or meiosis. one daughter cell receives one extra, one receives one less.
Anaphase lag- one chromosome lags behind and is left outside of the nucleus and degraded.
What diseases are associated with monosomy?
Turner syndrome- gonosomal monosomy
All autosomal monosony known are inconsistent with live birth.
What disease are associated with trisomy?
Patau- trisomy 13
Edwards- trisomy 18
Down syndrome- trisomy 21
Chromosomal Mosaicism
Caused by a mitotic error early in development
Results in two or more populations of cells with different chromosome complements
Most often in sex chromosomes
Nonchromosomal Mosaicism
Does not affect chromosomal complement number.
Example, after fertilization one cell develops mutation and gives it to every other cell derived from that one. Other cells did not get mutated so they are ‘normal’
Chimera
An individual made up of two genetically distinct populations of cells arising from more than one zygote
What is a ring chromosome?
example?
deletion at both ends of the chromosome, then the ends fuse.
ex. ring chromosome 20 syndrome- associated with epilepsy.
Also can happen on 13, 14 and 15 with intellectual disability
Clinical relevance of inversion mutation
Chromosome 9
Isochromosome
One arm lost and the other duplicated.
Results in two small or two large arms.
Translocation
One section of chromosome relocated to another.
Balanced- even exchange of material
unbalanced- uneven exchange, one normal and one translocated
Robertsonian- between two afrocentric chromosomes, a large and small arm (mostly non-coding p arm)
- makes one extra long and one extra small(usually lost)
- – usually non-coding or highly redundant and can support life
Robertsonian translocation
between two afrocentric chromosomes, a large and small arm (mostly non-coding p arm)
- makes one extra long and one extra small(usually lost)
- – usually non-coding or highly redundant and can support life
