Chromosomes Flashcards
What are fragile sites
Segments of uncoiled chromatin liable to show gaps and breaks, low gene content, high LINES, arise when cells exposed to conditions damaging the Dna repair process
Which fragile sites are pathogenic
FraxA Xq27.3 and FraxE Xq28
How are fragile sites classified?
Frequency and culture conditions.
Properties of constitutive heterochromatin
AT rich, inert satellite Dna, dark c band
What causes heterochromatin variation
Instability of satellite Dna
Role of alpha satellite Dna
Centromere development, facilitate proper segregation
3 types of satellite dna
Alpha: 3/5% human genome, role in centromere development and proper segregation. Beta and gamma: on X chromosome, has role in preventing heterochromatin spreading
Example of inversion variant
Inv(9)(p11q12), inv(2)(p11.2q13), inv(y)(p11.2q11.2)
What are uBCAs
Directly transmitted unbalanced Chr abnormalities . Copy number of multiple genes increase or decrease by 1. Unique to family. Compatible with fertility. 5,8,18 most freq.
Example of euchromatic variant
Var(16)(p11.2p11.2)verse blue duo of dark g band 16p11.2. Additional copies of cassette. Normal =4 EV=10-12
What is a euchromatic variant EV
Cnv of segments polymorphic in population and only detectable when reach certain number of copies. Resemble dups.
Frequency of autosomal reciprocal translocation
1:500
How do you risk assess outcome of balanced translocation
Literature eg Schinzel, ecaruca, size of segment, de novo?, which chromosome? HAL
Freq of robertsonians
1:1000
Risks to robertsonian carrier
Upd, unbalanced offspring in female carriers 10-15%, in male carriers
Impact of sex Chr ; autosomal translocation
Disrupt sex vesicle can cause infertility
Possible outcome from a balanced paracentric inversion
Unequal XO in loop-> dicentric and acentric , XO outside loop -> normal and balanced
Outcomes from peri centric inversion
Outside loop-> normal and balanced, inside loop-> normal, balanced, recdup p and recdup q
Risk of abnormal offspring from inter chromosomal insertion
50% (live born risk depend on size of imbalance)
Risk from intrachromosomal insertion
Small ins 20-30%, large ins 5-10%
Freq of insertions
1:80,000
Outcomes from interchromosomal insertion
Small-> independent synapsing and get normal,balanced, del,dup. Large-> forms quadrivalent and recombinant chromosomes.
What are lcr’s
Low copy repeats, unstable architecture and permit Dna recombinations via nahr.
What is a contiguous gene syndrome
Loss/gain multiple adjacent genes
What are low copy repeats
10-400kb, >97% homology, low numbers in genome- 5-10%
Syndromes mediated by lcr’s
Williams, pws/as, sms/ptls
Possible origins of structural rearrangements
Nhej, mmej, Bfb cycle, FoStes, mmbir, chromothripsis
What is most common human translocation
T(11;22)(q23;q11)
Mechanism of robertsonian formation
Centric fusion, whole arm translocation, break in both arms (dicentric), misdivision of centromere, u true exchange -> isochromosome
Clinical relevant isodicentrics
Idic(22)(q11.2) cat eye syndrome, idic(15q)
Meiosis errors
Anaphase lag, premature sister chromatid separation, non disjunction
G band dark band characteristics
Heterochromatin, gene poor, low histone acetylation, LINES
G band light characteristics
Euchromatic, GC rich, height histone acetylation, sines
List normal variation seen on human chromosomes
Het variation. Satellite variation. Inversion variants eg 9,2. Fragile sites. uBCAs. Euchromatic variant eg var(16)(p11.2p11.2)
Which is most common SMC
Idic(15) most common region duo q11-13 including pwacr.. Severe DD, autism, epilepsy. Ass with AMA.
Causes and % of each for T18
90% Maternal NDJ meiosis, 5% paternal meiotic NDJ, 5% mosaic
Example of emerging microdel syndrome
19p13.2. 7n, shirt, heart, scoliosis, early puberty, DD, language delay
Location DSCR
21q22.3
Origins and % of errors leading to Down syndrome
70% maternal meiosis 1. 20% mat meiosis 2. 5% pat meiosis, 5% mosaic
Freq of ABCR
1/500
How can ABCR lead to abnormal phenotype
Gene disruption at bkpts. Cryptic imbalance. Position effect. Disturb imprinting. Upd. Xi. Mosaicism. IF,
ACGH has shown many ABCR are actually cryptically unbalanced - what % of 2 break and CCR are unbalanced
2 break 37% and CCR 90%. This imbalance could be at breakpoints or elsewhere
What is position effect variegation (PEV)
Variable but stable inhibition of gene exp due to juxtaposition of euchromatic gene with heterochromatin. Het spreads and silences gene.
% markers derived from acrocentric X
70%
% markers seen in sub fertile popn
0.125% 3x higher than general pop
Example of new marker related syndrome
+der(22)t(8;22). One of few recurrent human translations. Ear and extremity abnormalities, mild mr. Variable phenotype. Sheridan et al 2010
Examples of marker syndromes
i12p, i(18p), +der(22)t(11;22), idic(15), ces invdup (22q11.2-pter)
