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GGE > Genetics 2 - Chromosomes: Structure and Abnormalities > Flashcards

Genetics 2 - Chromosomes: Structure and Abnormalities Flashcards

1
Q

learning outcomes

A
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2
Q

chromosome structure

A

Chromatin = DNA and protein

Protein - histones - tightly packing

1m of DNA into each of cells

Important for structure and control of transcription of DNA

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3
Q

chromatin structure

A

Bead - nucleosome - 150bp

DNA wrapped around

Modification of histones influences transcription

  • Phosphorylation
  • Methylation
  • acetylation
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4
Q

euchromatin

A

gene switched on

active (open) chromatin

unmethylated cytosines (white circles)

acetylated histones

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5
Q

heterochromatin

A

gene switched off

silent (condensed) chromatin

methylated cytosines (red circles)

deacetylated histones

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6
Q

cytogenetics

A
  1. sample nucleated cells you can grow easily - T cells/skin fibroblasts/bone marrow/chorionic villi or amniotic fluid (antenatal)
  2. get chromosomes into a form in which they can be observed and differentiated from each other (metaphase chromosomes - grow the cells to dividing stage)
  3. chemical preparation to arrest cells and lyse nuclei
  4. stain chromosomes (giemsa)
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7
Q

conventional cytogenetics

limitation

A

identify chromosomes by banding patterns

arrange homologs side by side

⇒ karyogram

described as a karyotype

46, XX female and 46, XY male

limitation = resolution

detects GROSS chr changes (> 5Mb)

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8
Q

international system for human cytogenetic nomenclature (ISCN)

A
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9
Q

molecular cytogenetics

MOA

what is it used for

A

probe hybridisation - visualisation of location of specific nucleotide sequence (< 5Mb)

USES

is sequence present and if so on which Chr

are 2 sequences close to each other

preimplantation genetic screening

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10
Q

Fluorescent In Situ Hybridisation

A
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11
Q

multiplex FISH (M-FISH)

A

metaphase chr

detects small Chr rearrangements

uses painting probes

paint whole Chr

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12
Q

structural chr abnormalities

categories

heritability

A

change in chr structure

caused by chr breakage with subsequent abnormal realignment

BALANCED: no gain/loss of genetic content ⇒ often not clinically relevant but relevant if they interrupt a gene with dominant loss of function

Or GOF via fusion of 2 unrelated segments - CML

UNBALANCED: gain or loss of genetic content ⇒ clinically relevant

structural Chr abnormalities are heritable only if in germ line

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13
Q

deletion

A

part of chr deleted

sever effects

large deletions are lethal

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14
Q

occurence of large deletions

example

A

> 5 Mb

visible under microscope (conventional cytogenetics)

e.g. crie-du-chat syndrome (5p)

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15
Q

smaller deletions occurence

how are they visualised

e.g.

A

microdeletions are not visible under light microscope

some visible with FISH

smaller ones using chr oligonucleotide arrays - microarrays

e.g. Smith-Magennis Syndrome del (17p11.2)

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16
Q

duplication

e.g.

A

chr section repeated (often sequentially)

less sever than deletion of Chr section

e.g. Potocki-Lupski syndrome dup(17p11.2)

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17
Q

copy number variants

Mbs

role in….

A

deletions/duplications of genomic sequence

1 Kb → Mbs (variable no of repeats of a particular unit of sequence)

major determinants of human genetic variation - 5-10% of genome is CNVs

can represent functional (disease causing) mutations as well as genomic polymorphisms of uncertain relevance

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18
Q

inversions

e.g.

A

2 breaks occur in chr

part of chr in between is rotated 180 degrees before re-joining

results in looped chr pairs in meiosis I

can cause recombinant chrs if cross over happens within loop

e.g. F8 inversions (intron 22) in haemophilia A

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19
Q

translocation

A

non-homologous chromosomes exchange segments

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20
Q

reciprocal translocation

A

2 chromosomes swap non-homologus sections

chr number and genetic content are unchanged

common

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21
Q

robertsonian translocation

A

break occurs at the short arm of acrocentric chromosomes (13, 14, 15, 21, 22, Y) and results in fusion chr

change in chr number (45) - short p arms lost

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22
Q

Down Syndrome - chr change

A

4% is translocation (familial) DS

rob(14;21) or rob(21;21) + 21

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23
Q

balanced translocations

A

no extra or missing material (reciprocal)

DNA just packaged incorrectly

phenotype usually normal

robertsonian translocations = balanced

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24
Q

robertsonian

A

balanced translocation

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25
Q

unbalanced translocation

A

pathogenic

extra or missing material

miscarriage or baby with multiple congenital abnormalities

parents with balanced reciprocal translocations can generate gametes with balanced or unbalanced chr complement

increased risk for all their children

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26
Q

chronic myeloid leukaemia (CML)

translocation of what chr

type of mutation

associated protein

A

reciprocal translocation between q ends of chr 9 and 22

t(9, 22)(q34.1;q11.2)

philadelphia chr is a somatic mutation - not inherited

BCR-ABL fusion protein with “always on” tyrosine kinase activity that promotes cellular proliferation

GOF mutation for haematopoietic stem cells

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27
Q

acute promyelocytic leukaemia (APML)

results in

presence of _____ in blood smears ⇒ APML

A

cancer of bone marrow/WBCs

abnormal accumulation of immature granulocytes (promyelocytes) in bone marrow

shortage of normal WBCs, RBCs and platelets

presence of promyelocytes containing multiple Auer rods on peripheral blood smear is highly suggestive of APML

characteristic cytogenetic abnormality in 95%

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28
Q

type of mutation (APML)

chr involved

A

reciprocal translocation between chr 15 and chr 17 t(15;17)q(24;21)

somatic mutation - not inherited

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29
Q

symptoms of APML

A

bruising

bleeding

susceptible to infection

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30
Q

how can APML be seen

A

on conventional karyotype

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31
Q

fusion protein of APML

A

PML-RARα

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32
Q

MCQ

A
33
Q

things to remember

A
34
Q

ploidy

A

no of complete sets of chr in a cell and hence the no of possible alleles for autosomal/pseudoautosomal genes

35
Q

how is ploidy defined

A

in terms of genetic content (n) or chromosome number/amount of DNA (c)

N changes when type of genetic content changes, not with replication of chromatids

C changes when the chr number changes e.g. following DNA replication (S phase)

36
Q

baby of a man and woman

A
37
Q

meiosis in baby

A
38
Q

homologous recombination in meiosis

A
39
Q

when does recombination occur

A

during meiosis I

homologs align

crossover

separate the homologous chr

paired chromatids stay together

Haploid (1n) after meiosis I

MEIOSIS II

chromatids separate

4 cells - haploid gametes after meiosis II

2 with mixture

40
Q

crossover in sex chromosomes

A

FEMALES

X chr pairing is similar to autosomes

MALES

X and Y chr do pair

crossing over occurs at a small section at tip of short arm (pseudo-autosomal region)

41
Q

purpose of sex in biology

A

generate genetic diversity

42
Q

how many possible chr combinations in gametogenesis

A

> 8 million

223 or 2n

43
Q

numerical chr abnormalities

A

change in chr number

arise from errors in mitosis and meiosis

not inherited - de novo

44
Q

euploidy

A

normal diploid chr complement (2n) of 46 chr (46, XX or 46, XY)

45
Q

haploid

A

(n) normal chr no in the gametes of 23 chr (23, X or 23, Y)

46
Q

aneuploidy

A

chr no varies from normal diploid complement

47
Q

patau syndrome chr complement

A

47, XY, + 13

48
Q

polyploidy

A

multiples of the haploid chr complement of > 2n

49
Q

triploidy

A

triple chr complement (3n) e.g. 69, XXX

50
Q

trisomy

A

3 copies of a chr

51
Q

Edward’s syndrome

A

47, XX, +18

52
Q

monosomy

A

1 copy of a chr

53
Q

turner syndrome

A

46, X

only viable monosomy

54
Q

interphase FISH

what does it analyse

what is there no need for

efficiency

what does it detect

A

analyse nuclear DNA

analyse amniocentesis directly

no need to grow cells

partial info in < 24 hours

detects common trisomies e.g. chr 18 (photo)

55
Q

klinefelter syndrome

A

47, XXY

56
Q

47, XXX

A

female

mostly normal

57
Q

47, XYY

A

male

tall

mostly normal

58
Q

patau syndrome

A

47, XY, + 13

59
Q

translocation down syndrome

A

46, XY, rob(14;21)(q10;q10), +21

60
Q

karyotype for CML

A

46, XX, t(9, 22)(q34.1;q11.2)

61
Q

trisomy 21/Down’s

A

47, XY, +21

62
Q

balanced robertsonian translocation

A

45, XX, rob(14;21)(q10;q10)

63
Q

symptoms of Down’s

A

floppy - hypotonic

single crease across his palm

large tongue

atypical facial features

only autosomal trisomy compatible with survival into adulthood

variable degree of intellectual disability

increased risk of congenital defects of heart and digestive system

decline in cognitive function is common after 50

alzheimer’s in 50%

64
Q

survival rate of Edward’s and Patau’s

A

rare to survive into adulthood

65
Q

normal chr number

A
66
Q

trisomy and monosomy

A
67
Q

why is recurrence more likely in oogonia vs sperm

+ greater risk with older age of mother

A

long phase of meiosis in females

ageing of oocytes

sperm - turnover in meiosis I is quick

68
Q

how could DS arise if there was a normal number of chromosomes (46 XY)

A
69
Q

another way that trisomy/monosomy can occur, apart from NDJ

A

robertsonian translocation

break occurs at short arm of ACROCENTRIC chromosomes (13, 14, 15, 21, 22, Y) and results in a fusion chr and risk of trisomy/monosomy in children

4% of DS is translocation (familial) DS

rob(14;21) or rob(21;21)

70
Q

how can a parent with robertsonian translocation have a healthy child

A

short arm - no important genetic info

RISK FOR OFFSPRING OF THESE CHILDREN

71
Q

can a parent with a robertsonian translocation resulting in an isochromosome 21 have a healthy child

A
72
Q

case

A

APML

can be diagnosed with FISH (preferrably) or conventional karyotyping

73
Q

RAR gene - FISH and APML

A

retinoic acid receptor

controls differentiation of WBCs beyond promyelocyte (Chr 17)

74
Q

PML - FISH and APML

A

functions in haematopoiesis and late erythropoiesis

tumour suppressor gene

chr 15

75
Q

PML-RARα - FISH and APML

A

protein function

WBC stuck at promyelocyte stage and proliferate abnormally

76
Q

what do probes normally do

what do they do in APML

A

probes normally hybridise to different chromosomes

in APML, both probes hybridise to just 1 chr (PML-RAR fusion) chr 17

77
Q

treatment of acute promyelocytic leukaemia

A

ATRA (All Trans Retinoic Acid)

vit A derivative

interacts with RARα to induce cell differentiation and apoptosis

vit A derivatives can play a role in managing this type of leukaemia

help blood cells to differentiate

78
Q

things to remember

A

GGE (33 decks)

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