Genomic Variation Flashcards
What is a genetic variant?
A genetic variant is a difference between two (or more) people in some part of their DNA sequence
It may be a single base, a whole chromosome, or somewhere in between
It is usually heritable but not always
define locus
A position in the genome
define autosome
The non-sex chromosomes (1-22)
define allele
One form of a genetic variant
define genotype
The two alleles present at a locus
define haplotype
Allele order on one chromosome
what are the 3 possible genotypes in the pop?
AA – Common homozygote
Aa – Heterozygote
aa – Rare homozygote
what is the minor allele freq?
(MAF) is the frequency of the less common allele and can be a number between 0 and 0.5 or a percentage.
Two populations of the same species need not have the identical frequencies for the same allele
name primary seq variations
+SNPS
InDels
CNVs
name epigenetic variation
dna methylations
histone modification
name chromosomal variation
inversions
translocationg
aneuploidy
mosaicism
what is an SNP
single nucleotide polymorphism - change in a single base
generated by mismatch repair during mitosis
why does seq variation occur?
errors in DNA replication and repair
In proofreading, the DNA pol reads the newly-added base before adding the next one so a correction can be made.
The polymerase checks whether the newly-added base has paired correctly with the base in the template strand. If it is the correct base, the next nucleotide is added.
If an incorrect base has been added, the enzyme makes a cut at the phosphodiester bond and releases the incorrect nucleotide. This is performed by the exonuclease action of DNA pol III.
Once the incorrect nucleotide has been removed, a new one will be added again.
Explain SNP formation in steps
During DNA replication the two strands will separate and will be used as templates to synthesise complementary strands.
If that goes well then we should end up with two identical copies.
However, when synthesising this strand, instead of incorporating an A, a G has been incorporated.
The mismatch repair mechanism will identify this mistake and correct it so that the bases are a standard Watson-Crick base pair
If this change occurs in the gametes and isn’t deleterious then it will get passed on to the next generation
As time goes on it can spread through the population.
Name the types of SNPs
Non-Synonymous Synonymous Promoter Terminator Splicing Insertion/deletion Neutral
What are non-synonymous SNPs
These change a three-base codon sequence and the amino acid in the gene product.
1)Missense
Change from one amino acid to another
can be Conservative, e.g. Leucine to Isoleucine
or
Non-conservative, e.g. Glycine to Histidine
2)Nonsense
These change an amino acid codon into a stop codon, causing premature truncation of the protein.
what are non-synonymous SNPs
These change the codon but due to codon degeneracy they have no effect on the amino acid composition
e.g. ….TTG… changed to …CTG…
Both are Leucine codons and the protein would be unaffected
what are promoter SNPs
Changes in the gene promoter may alter the level of gene expression.
e.g. ….TATAAA… to ….TAGAAA….
Would remove the basal TATA box and could drastically reduce or abolish transcription of the gene
what are terminator SNPs
These could affect the correct termination and polyadenylation of the messenger RNA
e.g. …AATAAA… to …AATAGA…
In alpha-globin this change disrupts the polyadenylation signal making the mRNA unstable
what are splicing SNPs
These lead to the creation or deletion of splice donor, acceptor or branch sites, affecting the final mRNA and hence protein.
e.g. …CAGGTAAGT… to …CAGATAAGT…
Removes the underlined splice donor site leading to utilisation of a different or cryptic splice site.
what are InDels?
SNPs that are the result of a deletion/insertion of a single base.
Alters the subsequent reading frame, may affect the position of a binding site, or may even be neutral
what are neutral SNPs
These are changes in the DNA that are in areas where they are predicted to have no discernible effect
However, “neutral” SNPs do not always remain as such
what is the rs number?
unique identifier given to each SNP
Example of a causal SNP
Melanocortin 1 receptor (MC1R)
Explain MC1R
αMSH binds leads to eumelanin synthesis
MSH does not bind therefore phaeomelanin synthesis
SNPs affect binding and therefore red hair, freckling, pale skin are common
example of causal InDel
Delta F508 in CF
exlain delta f508
CTT deleted in gene this deletes amino acid 508 in protein, which is phenylalanine
Ctfr protein fails to fold correctly, becomes protease-sensitive and is degraded before it can enter the golgi
what are microsatellites?
Number of repeats varies between individuals (short tandem repeats) (simple sequnce repeats)
Total length of microsatellite sequence varies between individuals
what is the polymerase slippage model?
during replication, polymerase slippage and subsequent reattachment may cause a bubble to form in the new strand.
Slippage is thought to occur in sections of DNA with repeated patterns of bases (such as CAG). Then DNA repair mechanisms realign the template stranf with the new strand and the bubble is straighened out, resulting double helix this expanded.
Polymerase slippage cannot occur in DNA wihout repeating partterns of bases
example of causal microsatellite
Triplet repeat disorders
Increasing length of a 3-base repeat sequence correlates with increasing chance of disease#
Huntington’s Disease
Poly-Glutamine repeat (CAG)
6-35 repeats typically unaffected
36->120 affected
what is a minisatellite?
variable number tandem repeats
what are mini satellites widely used for?
Widely used for forensic DNA fingerprinting and for paternity testing because they have large numbers of alleles
what is a copy number variant?
Typically defined as sequences greater than 1kb that have different copy numbers in different people
the simplest type of copy number variation is…
is the presence or absence of a sequence
what is non-allelic homologous recombination?
a form of homologous recombination that occurs between two lengths of DNA that have high sequence similarity, but are not alleles
what are the types of chromosomal abnormalities and define
Numerical – aneuploidy, loss or gain
Structural – translocations, deletions, insertions, inversions, rings
Mosaicism – different cell lineages
Chromosome abnormalities are present in:
60% of early spontaneous miscarriages
4-5% of still births
7.5% of all conceptions, 0.6% of live births
Explain mosaicism
Mosaicism is where there is more than one cell lineage in a tissue, i.e. some cells might have an extra chromosome 21 and others have the normal number (see later). This is due to mitotic non-disjunction. How early it happens determines how many tissues and which tissues the genetic abnormality might affect. A late non-disjunction event may have no visible effect whereas an early one might have severe effects.
What is aneuploidy?
Numerical abnormalities involving the loss or gain of one or more chromosomes
define monosomy
loss of a single chromosome is almost always lethal
define trisomy
gain of one chromosome can be tolerated
define tetrasomy
gain of two chromosomes can be tolerated
example of a trisomy
trisomy 21: down syndrome
biggest risk factor of down syndrome?
increased maternal age
what is non-disjunction?
failure of homologous chromosomes or sister chromatids to separate properly during cell division.
causes of trisomy 21?
90% maternal origin of extra chromosome
Non-disjunction in meiosis I (75%) or II (25%)
what is a translocation?
the transfer of genetic material from one chromosome to another when a chromosome break occurs during meiosis or mitosis.
can be either, normal, balance or unbalanced
translocations and down syndrome?
4% of all down cases
robertsonian - breakage of acrocentric chromosomes (13,14,15,21,22) and fusion of their long arms
mosaicism and downs?
1% of all down cases
children less severley affected
caused by mitotic non-disjunction
