GENETIC VARIATION Flashcards
what is a mutation?
changes in the base sequence that typically occur very much less than in 1% of the population
how does genetic variation arise?
occurs at >1%, and presumably arose from a mutation that was positively selected during evolution
what is DNA variation described as?
as DNA polymorphism
how common are rare variants?
occur at less than 1% but are distinct from mutations
how so mutations arise/
strand breakage base loss base change DNA crosslinking DNA replication error
what is strand breakage?
several nucleotides may be lost before end-joining (an error prone process)
what is base loss?
glycosidic bond is broken or enzymatically cleaved
what is base change?
guanine is oxidised to 8-oxoguanine and then base-pairs with adenine, cytosine loses an amine group to become uracil and base-pairs with adenine. Thymidine glycol just blocks replication. Polyaromatic carbons found in cigarette tar cause bulky DNA adducts
what is DNA cross linking?
UV light cause cyclobutane dimers, and anticancer agent cis-platinum causes adjacent guanines to cross link
what is DNA replication error?
some errors not corrected
what happens when DNA repair mechanism fail?
Lead to genetic damage that isn’t repaired or repaired inaccurately (change in DNA sequence)
what are the health consequences of genetic damage?
Cancer susceptibility
Progeria (accelerated ageing)
Neurological defects
Immunodeficiency
what does a mutation cause?
hereditable change in DNA sequence and chromosome number, form or structure
how do changes in DNA sequence arise?
due to errors in DNA replication
why is the mutation rate important?
too low and organisms cannot adapt, too high and information cannot be retained
how do genetic changes arise?
as a consequence of mutation
what is recombination?
crossover events in meiosis
has a huge impact on variation
what is a point mutation?
Changes to a single nucleotide (substitution)
Missense and nonsense mutations
Insertions and deletions
give examples of chromosome mutations
polyploidy
aneuploidy
chromosome rearrangement
what is polyploidy?
Multiple sets of chromosomes
what is aneuploidy?
abnormal number
Extra or missing chromosome
what is chromosome rearrangement?
Parts moved to other chromosomes
what is missense mutations?
A change in the nucleotide sequence that results in a change to the AA sequence
give examples of missense mutations
Includes point mutations and frameshifts
what effect do missense mutation have?
May or may not have an effect on protein function
loss of function
gain of function
what is nonsense mutation?
A change in the nucleotide sequence that results in a premature stop codon
what is nonsense mutation caused by?
by point mutations and frameshifts
what do nonsense mutation result in?
in a non-functional protein
PAH, mutations in the BMPR2 gene
Duchenne muscular dystrophy
how does Duchenne muscular dystrophy occur?
arises due to mutations that introduce a premature stop codon in the dystrophin gene
what are insertions/deletions?
Removal of one to several million nucleotides
how common are insertions/deletions?
5-10-% of all mutants
what do small insertions/deletion cause?
Small ones often cause frame
shifts resulting in missense/
nonsense
give examples of haploinsufficient
Majority of α-Thalassemias
Associated with melanoma
what is an elctropherogram?
e
what are simple tandem repeats?
same bits of sequence repeated lots of times, one after the other throughout the human genome
what can happen to expanding trinucleotide repeats during replication?
these can increase in copy number
how many diseases are caused by expanding trinucleotide repeats?
around 17 diseases
give examples of diseases caused by expanding trinucleotide
Huntington’s Disease
Fragile X syndrome
Kennedy Disease
Myotonic Dystrophy
when do CAG repeats occur?
in Huntington’s Disease
what do CAG repeats encode?
a poly-glutamine region in a number of proteins
what is Huntington’s disease?
A genetic disease – involuntary muscle movements and dementia
what is transposons?
Sequences of DNA that can move around the genome
how common are transposons?
Often regularly repeated throughout the genome
what do transposons act as?
act as recombination hotspots
what is retrotransposons?
Analogous to a ‘copy and paste’ system
Exhibit an intermediate RNA stage, prior to insertion into the genome
what are DNA transposons
Simply ‘cut and paste’ the transposable element (TE)
what are Alu repeats ?
The most abundant mobile element in the human genome
what are SINEs?
short interspersed elements
what are LDL receptors?
removes ‘bad’ cholesterol from the body (FH, atherosclerosis)
what do LDL receptors contain?
has a large number of Alu repeats, which may be responsible for the large number of pathogenic deletions in this 45 kb gene
what is selective pressure?
s
what is the selective pressure for malaria?
SP for erythrocytes with sickle cell haemoglobin (Hb S) mutation – cause sickle cell anaemia but provide protection against malaria
what is normal Hb susceptible to?
to death from malaria
what effect does the Sickle cell trait have on malaria?
one gene for haemoglobin A and one gene for haemoglobin S - greater chance of surviving malaria (do not suffer adverse consequences from the Hb S gene)
what effect does the Sickle cell diseases have?
susceptible to death - complications of sickle cell disease
but shows heterozygote advantage
how do cancers have an effect?
they acquire distinct characteristics during their evolution
what are tumours?
derived from a single ancestral cell that acquires more mutations to evolve from benign proliferation to malignant
how so tumours develop?
These mutations are selected as they proliferate more and also lead to genome instability (accelerated mutation rate)
what is haploinsufficiency?
when one copy is deleted, or inactivated by a mutation, so you only have one copy functioning
what does haploinsuffiecienct mean?
it means one functional gene on it’s own is not enough
is loss of function mutants recessive or dominant?
tend to be recessive
why does loss of function mutants tend to be recessive?
Feedback loops upregulate the production of the normal gene in heterozygotes
50% of the gene product is sufficient
what is dosage effect ?
d
what does dosage effect cause?
Gene product is part of a quantitative signalling system
Gene products compete to determine a metabolic or developmental switch
how do gene products combine in a fixed stoichiometry?
Need both α and β globins to combine to make Hb in Thalassemia (anaemia)
If α-globin chain affected by mutation – α-thalassemia (same with β)
how much genetic variation do single nucleotide changes represent?
75%
how often do differences between parental genomes occur?
every 1000bp, but mostly are in non-coding regions
what do 25% of genetic variation represent?
structural changes mainly in copy number variation
how can genetic changes increase our risk of/susceptibility to disease?
Rare high risk variant and high penetrance Rare low penetrance mutation/variation and moderate risk
Common low risk and low penetrance variant
what is penetrance?
how frequently the disease is manifested
how much of our DNA encodes for proteins?
1.2%
how much effect do most mutations have?
little effect as they are either silent mutations (don’t change the encoded amino acid) or are in regulatory regions with no discernable effect
what other effects can mutations have?
Some are harmful and if reduce reproductive success will be gradually eliminated.
Some are beneficial and become prevalent by positive selection.
