Genetic Variation & disease

Question 1

what is a karyotype?

Answer 1

when you look at chromosomes down a microscope and then you can line them all up and look at problems

Question 2

what is polymorphism?

Answer 2

genetic variation that is prevelant in population but not in itself, disease causing

Question 3

what is focused testing example and what does it allow us to do?

Answer 3

PCR (polymerase chain reaction)
= allows us to select one small piece of the human genome from a patient (100 to 10,000 bases) and amplify it i.e. make lots of copies of one short stretch of the genome

Question 4

what is one of the requirements for PCR to be useful?

Answer 4

you need to know where to look like what part of genome, within a few hundred base pairs

Question 5

what is affect of mutation on promoter sequence of gene?

Answer 5

then no transcription so no protein produced

Question 6

what happens when splice consensus altered?

Answer 6

mRNA decay (if intron left in) and abnormal or absent protein

Question 7

what are chromosomes recognised by?

Answer 7

-size
-position of centromere
-banding pattern

Question 8

what does a metacentric chromosome look like?

Answer 8

has centromere close to middle
-shorter p arm and longer q arm
-telomere at either end

Question 9

what does an acrocentric chromosome look like?

Answer 9

-has centromere at one end with only satellite DNA (like tRNA’s etc) on short “p” arm

Question 10

when are chromosomes visualised?

Answer 10

at metaphase in mitosis

Question 11

when is a chromosome said to be balanced?

Answer 11

-when there’s a normal amount of each chromosome (all chromosomal material present)

Question 12

when is a chromosome complement said to be unbalanced?

Answer 12

if there’s missing or extra chromosomal material

Question 13

what is affect of base change mutation?

Answer 13

-can have no effect if still codes for same amino acid
-it can code for stop protein producing shorter protein
-it can change amino acid sequence making non-functioning or different protein

Question 14

how do you describe a mutation?

Answer 14

standard nomenclature

Question 15

what are the 2 types of deletion?

Answer 15

-in frame (when 3 deleted so only misses out 1 amino acid, less drastic change)
-out of frame (when only 1 or 2 deletions so whole frame reading thrown off)

Question 16

how do we define normal genome?

Answer 16

by using most common sequence at that point (for example, for caucasian males)

Question 17

what is p.?

Answer 17

change in peptide sequence (amino acid)

Question 18

what is c.?

Answer 18

change in mature mRNA sequence (bases after splicing)

Question 19

what does nomenclature c.4A>T and p.Lys2Ter mean?

Answer 19

it means that at 4th base position adenosine was swapped for thymine which at 2nd amino acid position meant Lys amino acid was terminated

Question 20

what does p.ile122Thrfs nomenclature mean?

Answer 20

the peptide (amino acid) sequence at position 122 ile was swapped to Thr causing frameshift (from nucleotide deletion)

Question 21

what does these key nomeclatures mean?
a) c.267G>A
b) c.267delG
c) c. 267InsA
d) c. 267 + 2T>A

Answer 21

a) at position 267, G swapped for A = substitution
b) at position 267, deletion of G
c) at position 267, insertion of an A
d) at position 267, substitution of an intron for A (means no amino acid sequence as introns = non coding)

Question 22

explain mutation affecting splicing

Answer 22

just after an exon, changing the consensus signal 2 base pairs into the intron - it’s expected to lead to abnormal RNA that would undergo nonsense mediated decay

Question 23

how do you differentiate between polymorphism or disease causing mutation?

Answer 23

does it match expected inheritance?
is it in right gene?
has it been reported before? (some variants are listed)
what does it do to protein?
does it explain a phenotype?

Question 24

what are the 5 classes of variant classification?

Answer 24

class 1 = defo polymorphism

class 2 = probably polymorphism

class 3 = unclassifiable

class 4 = probably pathogenic

class 5 = definetely pathogenic

Question 25

what is Rubenstein Taybi syndrome?

Answer 25

development disorder caused by Aparagine (Asn) turned to stop codon at 120th amino acid in peptide chain

Question 26

what is Baraitser Winter syndrome?

Answer 26

syndrome as a result of mutation affecting splicing by 2 consensus signal base pairs just after exon changed into intron leading to mRNA decay

Question 27

what is aneuploidy?

Answer 27

whole extra or missing chromosomes

Question 28

what is translocation?

Answer 28

rearrangement of chromosomes

Question 29

what is insertion or deletions?

Answer 29

missing or duplicated material on chromosomes

Question 30

what are microdeletions?

Answer 30

changes in chromosome too small to see

Question 31

what is robertsonian translocation?

Answer 31

2 acrocentric chromosomes stuck end to end

Question 32

what does robertsonian translocation lead to?

Answer 32

increased risk of trisomy in pregnancy (extra chromosome)

Question 33

why is aneuploidy better tolerated in X-chromosomes?

Answer 33

because of X inactivation

Question 34

what are reciprical translocations?

Answer 34

when one part of chromosome is exchanged for another, usually balanced

Question 35

what are reproductive risks for unbalanced reciprical translocation?

Answer 35

miscarraige (large segments translocations) and dysmorphic delayed child (small segements)

Question 36

what is difference between robertsonian translocation & reciprical translocation?

Answer 36

In a reciprocal translocation, two different chromosomes have exchanged segments with each other. In a Robertsonian translocation, an entire chromosome attaches to another at the centromere.

Question 37

what is aCGH?

Answer 37

array CGH = now first line of chromosome test and genomewide
also finds lots of polymorphisms
-it can detect any size of imbalance (like microdeletions too)

Question 38

what does array CGH NOT detect?

Answer 38

balanced rearrangements

Question 39

how is aCGH done?

Answer 39

it uses binding of patients DNA to specific known DNA fragments on a slide

Question 40

when is a child mosaic?

Answer 40

when mutation is post-zygotic

Question 41

what is next generation sequencing?

Answer 41

=describes a number of technologies that can sequence large amounts of DNA

=these technologies make it possible to sequence the entire genome of an individual for an acceptable cost, within a short period of time

=majority of current technologies break genomic DNA into fragments and sequence very large number of these fragments

Question 42

what is somatic mosaicism?

Answer 42

describes situation where an individual has a proportion of cells with a different genotype. if this is disease causing mutation that is present then a seemingly healthy parent could have several children with the same genetic disease

-it’s when genetically distinct populations of cells within same individual (instead of getting all genes from parents, mutations during early embryonic development)