Lecture 2 - chromosome abnormalities - molecular basis of down syndrome Flashcards
(19 cards)
Why are monosomies, isomies and trisomies of the sex chromosomes more tolerated?
As it is natural to be monosomy for sex chromosomes (all XY individuals are monosomy for X & Y).
What system is used in mammals to cope with monosomies found on sex chromosomes?
X- inactivation. This mechanisms can deal with extra copies of chromosomes. At meiosis, extra sex chromosomes are lost without causing much trouble, so many individuals with sex chromosomes aneuploidy are fertile.
What are causes of trisomy 21?
- Nondisjunction (chromosomes don’t split apart) at meiosis. 95% cases, normally in maternal meiosis I.
- In rare families - paternal non disjunction, most of the errors occur in meiosis II
- Robertsonian translocation - Chromosome 21 & 14 form a hybrid (4% cases) - extra copy of MOST of chromosome 21.
- Mosaics - nondisjunction at mitosis - 1% cases. Cells with different genotypes - some cells 2, some cells 3 copies of chromosome 21. EASY TO MISS
What happens during nondisjunction occurring at meiosis I?
A copy of maternal and paternal chromosome (grandparents) - 2 alleles will be present.
2 cells with 2 copies (different alleles), 2 cells with copies
What happens during nondisjunction occurring at meiosis II?
1 cell - 2 copies of same allele
1 cell - with no copies
2 cells - 1 copy of allele
Explain Robertsonian translocation
Switch at centromere - 2 long arms come together & 2 short arms come together.
- small arm is removed, long arms become (Robertsonian chromosome).
- Meiosis I the chromosomes are split and there is only chromosome 14, leading to monosomy 21.
- The whole of chromosome 21 and Robertsonian chromosome are in a cell that splits to form Trisomy 21 (2.8 approx. chromosome 21).
- can be inherited
What is mosaic?
Nondisjunction mitosis
- Mixture of cells - 46/47 chromosomes. Time at when incorrect division (during development) occurs determine how many cells have 47 chromosome - also determine what tissues present with Down syndrome.
What is the maternal age effect in Down syndrome incidence?
20 years old - 1/2300
40 years old - 1/100
What causes maternal effect?
- oocyte are arrested at diplotene before birth
- Meiosis resume at each menstrual period, which means that the chromosomes in the bivalent must remain properly associated for decades.
- There might be mechanisms contributing to increased maternal nondisjunction related to the effect of maternal age is due to nondisjunction at anaphase I, not anaphase II
What 2 genes are affected due to Down syndrome?
- APP (amyloid precursor protein gene)
- MX1 (interferon-induced protein p78)
How is APP involved in Down syndrome?
- Plagues associated with Alzheimer’s disease are present in all Down syndrome individuals over 40 years old
- Triplication of APP may contribute to increased chance of early-onset Alzheimer’s
How is MX1 involved in Down syndrome?
Associated with mental retardation and morphological features including flat nasal bridge
What are the 2 steps in the first trimester combined test for Down Syndrome?
- Blood test
- Nuchal translucency test
What occurs in the blood test?
The blood test measures the levels of pregnancy-associated plasma protein-A (PAPP-A) and the pregnancy hormone human chorionic gonadotropin (HCG). Abnormal levels associated with Down syndrome.
What occurs in the nuchal translucency test?
Ultrasound measures area on the back of the foetus’ neck (nuchal translucency screening test). High fluid levels in the neck tissue indicate abnormalities
What is NIPT?
Non-invasive pre-natal testing
- Tests maternal blood for fragments of cell-free foetal DNA (from placenta)
- No risk to foetus
- Works for single and twins, but not not multiple pregnancies.
- High detection rate for Down, Edwards and Patau syndrome.
How does NIPT work?
Analysis of small amount of foetal DNA in women’s blood. DNA compared to mother’s DNA and look for extra genetic material from chromosome.
NIPT uses statistical methods to determine likelihood of genetic condition - Bayesian statistical analysis
Foetal fraction % (how much DNA from foetus) percentage must be (>4%). G/A ratio = 1 in normal pregnancy. Foetal genotype is GGA through maternal non-disjunction at meiosis. G/A fragment ration depends on foetal fraction ratio.
- Departure from 1.0 indicated trisomy 21. If foetal fraction is 20%, G/A ratio will be 1.2.
What are SNPs?
Single nucleotide polymorphisms
- chromosome 21 has hundreds of SNPs (doesn’t mean good/bad copy just different). An informative SNP is anything that is different between the mum and the foetus. These differences are essential in knowing whether a sequence comes from a mum or foetus.
How can you determine foetal fraction?
choose another chromosome (where aneuploidy isn’t possible) and use this to determine how much DNA comes from mum and how much comes from the foetus.
