5- Genome Variation Flashcards
how do humans differ at the level of their DNA?
humans share 99.7% of DNA, leaving 9 million bases up for variation. differences can be due to coding variation causing visible or pathogenic differences - any position in the genome is polymorphic.
macro-level differences are often associated with disease
micro/molecular level differences are occasionally associated with disease
what is a single nucleotide polymorphism?
genomic variant at a single base position
how does a SNP arise via mismatch repair during DNA replication?
the two DNA strands separate and are used as templates to synthesise complementary strands
a mistake is made and the mismatch repair mechanism should identify and correct it back to its intended Watson-Crick pairing
instead the wrong base is corrected - if the change isn’t deleterious it persists and gets passed on
how did the reference sequence for the human genome come to be?
reference sequence summarises what base most people have at a particular position in the genome. it came to be through comparing the human genomes in different genomes. reference sequences differ between age, race and gender - there are different versions.
in a polymorphic position within the genome, the frequency of that allele can be measured by the MAF score.
what are the evolutionary pressures on a SNV?
SNVs arise by a mutational event such as mismatch repair
evolutionary pressures - gene flow/migration, genetic drift and selection
gene flow - migration resulting in the variant being introduced into a new population.
genetic drift can occur with random change in variant allele frequency through generations - goes up and down arbitrarily
non-random change can occur through positive or negative selection depending on whether the variant is respectively beneficial or pathogenic
what is an STR/microsatellite? how is it inherited?
a series of nucleotides repeated in tandem - can be variation in the number of repeats
can be passed down and inherited with multiallelic possibilities in the number of repeats
what determines the effect of a variant?
where it is - in a gene, coding or non-coding region, intergenic regions. it’s less likely to be harmful in a non-coding region.
what sort of gene it’s in - more likely to be harmful in a key developmental gene, or one that’s been well conserved
how do STRs arise due to polymerase slippage?
STRs arise due to DNA polymerase slippage
DNA polymerase is both a replicative and proof-reading enzyme
when polymerase encounters a repetitive STR region, it adds the same nucleotides multiple times in succession
sometimes polymerase can ‘slip’ along the template and add extra or skip repeat units due to the repetition, creating a bubble in the new strand
DNA repair mechanisms realign the template strand with the new strand by adding or removing STR repeats - this introduces variation into the number of repeats/STRs
what is a copy number variant/CNV?
changes in the number of copies of a DNA segment - encompasses deletions, insertions, duplications, rearrangements
where are STRs seen in the genome? what effect might they have - name one disorder due to the detrimental effect of STRs?
STRs are seen anywhere in the genome but mostly non-coding regions
can affect protein function or gene expression depending on where they are - selected against if the effect is harmful
huntington’s is an expansion disorder of CAG tandem repeats within the huntingtin gene - once the repeats get to a certain size, the effect is detrimental
how can a CNV arise by non-allelic homologous recombination during meiosis?
homologous chromosomes detect their partner to line up for metaphase 1 by detecting regions of sequence similarity
if homologous sequences from different genomic regions align, this is called misalignment. recombination between these regions can result in duplications or deletions of genetic material
where can CNVs be located? what is the effect of CNVs?
tend to be located in intergenic regions, affecting one or more genes or parts of genes.
CNVs can be benign or pathogenic, contributing to genetic disorders and cancer. involved in genetic diversity and evolution.
