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ANAT 381 > Aneuploidy > Flashcards

Aneuploidy Flashcards

1
Q

what is normal conceptus

A

haploid gametes produces diploid normal conceptus - spermatozoon plus ovum = conceptus

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2
Q

what is chromosome abnormality

A

Aneuploidy = chromosome segregation goes wrong = 2 types, 2n +1 or 2n-1

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3
Q

describe aneuploidy

A

trisomy/monosomy

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4
Q

describe haploidy

A

one set of chroms

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5
Q

describe polyploidy

A

more than 2n chroms (triploidy, tetraploidy etc)

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6
Q

describe chromosome rearrangements

A

could be translocations, deletions, inversions, duplications

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7
Q

what is maternal age effect in human reproduction

A

direct correlation between age and female repro
females become pregnant at any age = risk of chrom problem but risk goes up as age

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8
Q

what is paternal age effect in human reproduction

A

limited study
associations = older = more likely to produce autistic children and also children with more gene defects

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9
Q

name origins of chromosome abnormalities

A

gametogenesis errors
fertilization
Embryogenesis

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10
Q

describe gametogenesis - origin of chromosome abnormality

A

= m1 and m2
oogenesis
spermatogenesis

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11
Q

describe fertilization - origin of chromosome abnormality

A

dispermic fertilization
digynic fertilization after icsi
parthenogenic activation/chimera

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12
Q

describe embryogenesis - origin of chromosome abnormality

A

mitotic error

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13
Q

describe female - divisions involved in formation of embryo

A

Prophase: after DNA replication, homologous chromosomes pairing, synapsis and recombination, and arrest at the diplotene (dictyate) stage.
Oocyte remain arrested until puberty-follicular growth -LH surge triggers ovulation and resumption of m1 in preovulatory follicle
ovulated egg arrest at MII stage until fertilization - complete MII division

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14
Q

describe male - divisions involved in formation of embryo

A

Mammalian spermatogenesis is an androgen-dependent developmental process. It is driven by interactions between germ cells and somatic cells. Generates a continuous supply of functional sperm and it begins at puberty

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15
Q

describe meiosis 1 - non disjunction

A

one of mechanisms where chrom segregate goes wrong
= trisomy and monosomy

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16
Q

describe normal chrom segregation in meiosis 1 and after fertilization

A

normal, before = each cell has one set chrom and one set chrom in polar body (opp = switch chrom)
after fert = 2n (chromosomes can differ, what is in polar bodies vs oocyte)

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17
Q

describe nondisjunction chrom segregation in meiosis 1 and after fertilization

A

before = can result in disomic (2 chroms in oocyte, none in polar body), or nullsomic (all chroms in polar body)
after fert = trisomy or monosomy

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18
Q

describe predivision of one univalent in meiosis 1 and after fertilization

A

before = instead of dividing at same time = sister chromatids separate early = 23 +1/2 (one full plus half in oocyte, and half in polar body) or 22+ 1/2 (half in oocyte, 1+1/2 in polar body)
after = trisomy or monosomy

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19
Q

describe predivision of both univalent in meiosis 1 and after fertilization

A

before = leads to balanced m2 oocyte but still mistake tho
after = balanced egg, 2n

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20
Q

what is pssc

A

premature separation of sister chromatids

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21
Q

describe meiosis 1 errors

A

recomb failure
premature homologue separation
true nondisjunction
premature sister chromatid separation

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22
Q

describe meiosis 2 errors

A

Nondisjunction
premature sister chromatid separation

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23
Q

describe Aneuploidy in humans: estimated levels at different stages - eggs

A

eggs or polar bodies
karyotyping = 19902, 10-35%
fish = 1990s-present, 20-70%
cgh, snp array, cgh array= 2000s-present, 30-70%
ABNORMALITIES IN EGGS QUITE HIGH

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24
Q

describe aneuploidy in sperm

A

non disjunction - due to mistake in reduction division
if pssc = disomic 2, normal 1 and nullsomic 1 spermatozoa
if true nondisjunction = disomic 2 and nullsomic 2 spermatozoa

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25
Q

describe Aneuploidy in humans: estimated levels at different stages - sperm

A

karyotyping 1980s-1990s, 1-4%
fish = 1990s-present, 1-3%
low in sperm = 1-4%
millions of sperms in ejaculate so much study large numbers of sperm cells in one person
(opposite problem for egg, )

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26
Q

name all techniques used to detect chromosome abnormality in eggs, sperm and embryos

A
  • Karyotype
  • Fluorescence in situ hybridization (FISH)
  • Whole chromosome painting (SKY)
  • Comparative genome hybridization (CGH), Array CGH, SNP array (chip based)
  • Next Generation Sequencing (NGS)
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27
Q

describe metaphase karyotype -gen

A

5-10ml blood, and will process culture, arrest cells at metaphase stage then see of any issues
gold standard even now

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28
Q

describe metaphase karyotype -sperm

A

studying sperm not easy =
take hamster egg and human sperm and inject and wait for it to condense and see when reach metaphase and then can do G-banded human sperm chromosome spread after ICSI of hamster oocytes= can see sperm chroms since hamsters ones have diff shapes and sizes

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29
Q

describe karyotype of pb and m2 oocyte

A

m2 oocyte metaphase shows extra marker = tetrads
2nd polar body karyotype = except haploid cells, very different to get good spread, not best for clinical cases in eggs

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30
Q

what is fish - describe

A

most common for sperm
want to find out if 1 or 2 copies of chrom 2 =
probe dna complementary to chrom 2 (somewhere on whole chrom) then label with fluorescent dye, = red fluorochrome then denature and hybridize and do metaphase spread = lights up chroms

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31
Q

describe interphase nucleus

A

most cases = count colour = know which fluorochrome attached to each chrom e
Especially in preimplantation embryo

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32
Q

describe fish on sperm

A

label x and y diff colours and see for diff chromosomes
one = abnormal see x and y = xy18, should be haploid tho, if sperm fertilize normal egg = get xxy aneuploidy

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33
Q

name and describe Four methods used for detection of chromosomal copy number variation

A

fish
comparative genome hybridization
array cgh (chip based, need to analyze chromosome complement in sample)
snp microarray

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34
Q

what is principle of cgh/acgh

A

Biopsies cells - dna and then do whole genome amplification
label control dna with red
label biopsy dna with green = unknown
combine and gives yellow
2 results possible =
metaphase cgh = see if colours correct, yellow = normal, more red = 2:1 monosomy, 2:3 more green = trisomy
or do array cgh= use computer to analyze

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35
Q

describe fertilization errors - dispermic

A

3 pronuclei
sperm brings abnormality or fertilized by 2 sperms = triploidy, 3 sets chroms

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36
Q

describe fertilization errors - digynic triploidy

A

especially with icsi
separation of polar body = instead of becoming diff cell= retained 3rd pronuclei

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37
Q

describe mitotic error during embryogenesis

A

affects chrom composition

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38
Q

describe chromosome compositions in preimplantation embryos - 3 types

A

Normal = all euploid
Abnormal = all aneuploid
Mosaic = mix of both

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39
Q

describe chromosome compositions in preimplantation embryos -DESCRIBE abnormal

A

Aneuploid = trisomy/monosomy
polyploid = more than 2n
haploid = one set of chroms
chaotic = random loss or gain of chroms

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40
Q

what does mitotic error do

A

generated mosaic embryo
Embryo develops fast after fertilized = 70-100 cells after 5 days
not proper cell cycle checkpoint = leads to mosaic, could also happen at later stages
more normal blastocyst cells if error early

41
Q

what is mosaicism

A

Mosaicism is the presence of one or more genetically distinct cell lines within an individual/embryo.

42
Q

how to generate mosaicism = 2 ways

A

Post zygotic error in an originally diploid zygote
Post zygotic error in an originally aneuploid zygote

43
Q

describe Post zygotic error in an originally diploid zygote - trisomy 21

A

non disjunction during division = leads to 45,-21 and 47+21 and 2 46, n normal
monosomy lost
so embryo has normal and abnormal for trisomy 21, 46n, 47+21 MIX OF CELLS

44
Q

describe Post zygotic error in an originally aneuploid zygote

A

starts with 47+21 abnormal zygote trisomy 21
during division = anaphase lag so loss of one chrom so it corrects itself
Embryo mix of 46 n and 47+21

45
Q

explain uniparental disomy conceptus

A

Abnormal oocyte + normal gamete from other parent = trisomy conceptus
if corrects early = gets rid of one chrom- could get rid of one from dad, so now the 2 chroms are both from mom
depends on which chrom= if has imprinted genes = can cause issues for implantation and live birth

46
Q

how can we analyze embryos - diagnosing chromosome composition

A

spreading of nuclei on glass slide = interphase nucleus and label and see if normal or abnormal
can also use fish

47
Q

describe fish results - analyzing embryos

A

large portion of embryos mosaic like 47%

48
Q

describe mosaicism throughout preimplantation development

A

randomly took human embryos (must ask patients first, ethics board, after ivf, hard to do), frequency of mosaic embryos heavily increased as move to blastocyst
2 or more distinct cell lines = mosaicism but the embryos make normal babies

49
Q

describe type of mosaicism

A

2-4 cell = mostly diploid aneuploid and diploid chaotic, continues untill morula
but by time reach blastocyst = diploid polyploid or diploid aneuploid

50
Q

describe proportions of polyploid cells in blastocysts - good quality

A

polyploid cells important for invasion of endometrium during implantation
normal = have fewer percentage of polyploid cells

51
Q

describe proportions of polyploid cells in blastocysts - poor quality

A

higher % of polyploid cells
if fetus tetra or triploid = miscarriage
still do not know what % is normal or abnormal

52
Q

describe Mixoploidy in Blastocysts of Domestic Species

A

Present in many animals - domestic species

53
Q

Mechanism of mitotic error in embryos - what causes gains and losses

A

non disjunction
anaphase lag
Chromosome demolition
chromsome replication

54
Q

Mechanism of mitotic error in embryos - what causes losses alone

A

anaphase lag
Chromosome demolition

55
Q

Mechanism of mitotic error in embryos - what causes gain and loss for same chromosome

A

non disjunction

56
Q

describe overall chromosome abnormality in embryos from older women

A

were much higher than younger patients

57
Q

when is mosaicism present

A

mosaicism is present throughout the pre-implantation development

58
Q

describe chaotic embryos

A

chaotic embryos are higher in poor quality embryos compared to good quality embryos

59
Q

what increases with advanced maternal age

A

Aneuploidy rate increases with advanced maternal age

60
Q

when does chromosome mosaicism have effects

A

only during preimplantation embryo dev and it has no clinical implications post implantation

61
Q

describe significance of abnormal cells - 4

A

Abnormal cells are lethal - could be but depends on % of polyploid, most cells with chaotic = arrest
Abnormal cells are loss = not necessarily true, depends on % cells left
Abnormal cells become allocated to te = yes, did mouse studies, if make chimera (tetra + normal cells) = all tetra goes to te
Abnormal cells co exist

62
Q

describe pathogenesis of chromosomal mosaicism and its effect on early human dev - gen

A

~15 weeks amniocentesis or chorionic villi sample and see what cells are like

63
Q

describe pathogenesis of chromosomal mosaicism and its effect on early human dev - 3 types

A

fetus mosaic placenta normal
confined placental mosaicism = fetus fine but issues with pregnancy
both fetus and placenta mosaic

64
Q

describe pathogenesis of chromosomal mosaicism and its effect on early human dev - post zygotic trisomic rescue through placental mosaicism

A

postzygotic chromosome loss = leads to 2 possibilities
non mosaic trisomic fetus + mosaic placenta with confinement of diploidy to trophoblast
or
trisomic placenta and non moasic diploid fetus

happens in embryos but corrected *uniparental disomy = baby has some issues but mostly fine - diploid baby

65
Q

what will post fertilization mitotic error result in

A

in constitutional chromosomal mosaicism - the mechanism by which it arises is not fully understood.

66
Q

what does distribution of mosaicism in conceptus depend on

A

timing, cell lineage(s) involved, cell viability, and chromosome involved

67
Q

describe origin of mosaicism - 2

A

meiotic or mitotic origin
Meiotic mosaicism often have adverse effect on the conceptus such as trisomy zygote rescue, due to the presence of uniparental disomy in the embryo/fetus and/or due to dysfunction of a trisomic placenta

68
Q

what can mosaicism be

A

tissue specific
normal karyotype in lymphocytes does not exclude the presence of mosaicism elsewhere in the conceptus

69
Q

what is main cause of infertility

A

due to pregnancy wastage due to chrom abnormality

70
Q

describe chromosomal imbalance and pregnancy loss - reasons

A

Trisomies
Monosomies
Triploidies
Multiple Aneuploidies
Tetraploid and structura

71
Q

describe trisomy 16

A

most common trisomy observed in product of conception studies
never seen in live born
advanced mat age, always loss, non viable

72
Q

describe trisomy 21 and 22

A

next most common 2 = equally as common

73
Q

describe survivable chromosomal imbalance

A

only a few full non-mosaic aneuploidies are observed in live-born apart from sex chromosome abnormalities

For example:
Trisomy 21, Trisomy 13,
Trisomy 18…

74
Q

describe trisomy 21

A

diagnose by checking blood = use peripheral blood standard
47, xy+21
down syndrome
most still birth or features of down syndrome

75
Q

describe trisomy 21 - medical issues

A

many issues
cannot see what problems embryo will have even tho can see chrom abnormality

Gastrointestinal obstruction -3%
Respiratory infections = Common
Leukemia = 15-20 X
Congenital heart defect - 40%
Moderate to severe mental retardation - 100%
Development: Early intervention program

76
Q

describe trisomy 18

A

47,xy+18 edwards syndrome
possible live birth, most lost

under 46 = probably die or sex chrom issue, above 46= bad news generally

77
Q

describe trisomy 18 - medical features

A

exhibiting characteristic facial features, short sternum, overlapping fingers with clenched fists, and clubfoot
probably wont live long

78
Q

describe trisomy 13

A

47, xy,+13
patau syndrome
live birth
autosomal trisomies = severe

79
Q

describe trisomy 13 - medical features

A

holoprosencephaly = defects, probbaly never take babies home, 6m-12m
Defect of the brain, affects facial features, causing closely spaced eyes, and sometimes cleft lip and palate

80
Q

name sex chromosome abnormalities - 4

A
  • Turnersyndrome(XO)
  • Klinefeltersyndrome(XXY)
  • TripleXormore(XXX/XXXX..)
  • XYY
81
Q

what is only monosomy to go to live birth

A

TURNER SYNDROME XO

82
Q

what are some effects of turner syndrome

A

short stature-broad chest
-low hairline
-low set ears
-small fingernails
-characteristic facial features
-poor breast development
-ear infections and hearing loss
-high waist to hip ratio (hips are not much bigger than the waist)
Approx. 99%of all fetuses with Turner syndrome results SA - first trimester
-Affects 1 in every 2,500 girl

83
Q

describe turner syndrome

A

only about 1%, 45x survive, 99% do not survive (lost through spont abort)
Hook and Warburton hypothesis that most surviving ones are ‘cryptic’ mosaics Rescue cell line may have viable karyotype= cells correct = possibility of normal cells somewhere, in some cells but not all, peripheral blood shows xo thp

84
Q

what is klinefelter syndrome

A

47, xx7
probable cause =
xx oocyte + y sperm
or x oocyte + xy sperm

85
Q

what is klinefelter syndrome - x inactivation

A

Most genes from the extra X undergo inactivation, but some escape and serve as the putative genetic cause of the syndrome

85
Q

what is klinefelter syndrome - who it affects

A

Affects one in 660 men

86
Q

what is klinefelter syndrome - phenotype

A

from “near-normal” (no intellectual issues) to a significantly affected individual

86
Q

what is klinefelter syndrome - syndrome characterized by

A

varying degrees of cognitive, social, behavioral, and learning difficulties and in adulthood additionally primary testicular failure with small testes, hypergonadotropic hypogonadism, tall stature, and eunuchoid body proportion

87
Q

what is klinefelter syndrome - when diagnosed

A

Most of them diagnosed later in life – mostly during fertility work up

87
Q

what is klinefelter syndrome - infertility

A

47,XXY is identified in 11% of azoospermic men and in 3% of infertile men and thus represents the most common genetic cause of infertility
no sperm in ejaculate, maybe one = if mosaic = find some sperm

88
Q

what is klinefelter syndrome medical treatment

A

Medical treatment is mainly testosterone replacement therapy to alleviate acute and long-term consequences of hypogonadism
most only realize when trying to make fam

88
Q

describe 47, XYY male fertility

A

Most males with 47,XYY syndrome have normal sexual development and are fertile
some may be fine, fertile no repro issues

88
Q

describe 47, XYY male - who

A

Affects -1 in 1,000 newborn boy

89
Q

describe 47, XYY male - syndrome associated with

A

an increased risk of learning disabilities, delayed development of speech and language skills. Delayed development of motor skills (such as sitting and walking), weak muscle tone (hypotonia), hand tremors or other involuntary movements

89
Q

describe 47, XYY male - small percent

A

A small percentage of males with 47,XYY syndrome are diagnosed with autistic spectrum disorders

90
Q

describe 47, XYY male twin brothers

A

two twin brothers. The shorter has a normal XY chromosome complement. The taller one has an XYY complement

90
Q

What is the possible mechanism in generating this extra Y-chromosome in non mosaic males? -47, XYY

A

parental nondisjunction at m2 resulting in extra y chromosome
yy sperm + x oocyte = xyy male

91
Q

describe Post zygotic error in an originally diploid zygote - triple xxx

A

non disjunction = 45,x 47,xxx 46,xx 46,xx
cell lines survive = individual is mix of alll

ANAT 381 (24 decks)

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