Normal Genome Variation

paleogenomics

• some small populations already populated eurasia and interbred with ancient humans

genetic bottlenecks

• population bottlenecks→ events that drastically reduce size of a population

  • migration

  • environment chnages

  • disease

• reduces genetic variation

origins of genetic variation

• uncorrected errors caused by

  • exogenous factors e.g. radiation, chemicals (mostly somatic)

  • endogenous factors

endogenous factors causing variation

• segregation→ aneuploidies

• recombination (translocations)

• DNA replication errors

• inadequate DNA repair mechanisms

classes of DNA variation

1. doesn’t alter DNA content

2. results in a net loss or gain of DNA sequence

types of variation- small changes

• single nucleotide variants/single nucleotide polymorphism

  • more common than 1%= polymorphism

  • less common than 1%= rare variant

• indels

single nucleotide polymorphism (SNPs)

• DNA sequence variation occurring when a single nucleotide in genome differs between members of a species or between paired chromosomes in an individual

• predominantly biallelic

location of non-coding variants

• intronic/intergenic variant

  • between genes or between exons

  • don’t affect resulting protein directly

  • could affect regulation of transcription or splicing

coding exonic variants

• missense variant

• nonsense variant

• synonymous variant → silent change

simple repeats

• repeat length polymorphisms

• not evenly distributed

• highly polymorphic

• prone to slippage

• can cause disease e.g.

instability of simple repeats

• DNA can loop out in replication leading to insertions and deletions

• polymerase enzyme can stall during replication and during replication and templates can misalign→ slippage

copy number variants

• CNV map of human genome documents extent and characteristics of CNVs among the healthy population

formation of CNVs

nonallelic homologous recombination (NAHR) as the mechanism for recurrent genomic rearrangements

distribution of CNVs

• distributed unevenly in genome

• pericentromeric and subtelomeric regions of chromosomes show a particularly high rate of CNV variation

unstable regions→ regions with high numbers of CNVs

• immune response

• drug metabolism

• olfactory receptor genes

negative selection

• mutations that are strongly deleterious will be eliminated by natural selection

• only mutations that have, at worst, a mildly negative effect will be observed as segregating in the population

selection reduced diversity

• reduced diversity is evident in regions of genome that have undergone selective pressure of selective sweeps