Lecture 12 - Genome variation Flashcards
How many years ago was the human population in Africa 10,000?
60,000 - 90,000
What is population bottleneck?
Population bottleneck is an event that drastically reduces the size of a population: migration, environment changes, disease
What do genetic bottlenecks reduce?
Genetic Variation
What do mutations promote?
Diversity
How many base pairs do we have in our diploid genome?
We have a diploid genome of (2x) 3x109 base pairs
how many base pairs do any two people have different?
about 6 x 106 base pairs (0.1 of genome)
How many mutations are there in each diploid genome?
70
What do mutation rates increase with?
Rate increases with paternal age
Non-germline mutation rates up to 20 fold higher
How identical is the population?
99.9%
Origin of genetic variation?
Exogenous factors (radiation, chemicals – mostly somatic)
Endogenous factors
Segregation (Aneuploidies e.g. Downs syndrome, Edwards syndrome)
Recombination (translocations)
DNA replication errors (mispaired bases, slippage)
Inadequate DNA repair mechanisms (e.g. mismatch repair, base excision repair)
What are the two classes of genetic mutation?
- Variation that does not alter the DNA content (number of nucleotides remains unchanged)
- Variation that results in a net loss or gain of DNA sequence
Give examples of Variation that results in a net loss or gain of DNA sequence?
Can be large (whole chromosome) or small (single nucleotide)
Most DNA changes are small scale and have no obvious effect on phenotype – neutral variation
Give examples of Variation that does not alter the DNA content (number of nucleotides remains unchanged)
Single nucleotide replacements
- Balanced translocations and inversions
What percentage of our DNA is poorly conserved?
90%
what percentage of all variation is caused by single nucleotide variants?
90%
what percentage of all variation is caused by Indels (1-10)?
9%
what percentage of all variation is caused by Indels (11-100 nucleotides)?
0.9%
what percentage of all variation is caused by CNVs >100 nucleotides?
0.1%
What is classed as polymorphism?
More common that 0.01 (1%)
What is classed as rare variant?
Less common than 0.01 (1%) =
What are indels?
Indels = insertion or deletion of one or more nucleotides
What are Single Nucleotide Polymorphisms (SNPs)?
DNA sequence variation occurring when a single nucleotide (A, G, C, T) in the genome differs between between members of a species or between paired chromosomes in an individual.
How many of SNPs are identifed?
~175 million identified
(Predominantly diallelic)
What is the minor allele frequency?
the frequency of the less common variant in a population
Intronic variant characteristics?
Between genes or between exons
Do not affect resulting protein directly
Could affect regulation of transcription or splicing
What is a missense variant?
An amino acid change
(nonsynonymous)
What is a nonsense variant?
Change of amino acid to a stop codon, which leads to nonsense mediated mRNA decay or protein truncation
What is a synonymous variant?
The codon sequence for the amino acid is changed but the same amino acid is still encoded for. E.g. GGC and GGU both code for Glycine
What can simple repeats cause?
diseases such as Huntington’s disease, Fragile X syndrome etc.
Simple repeats characteristics?
- Repeat length polymorphisms
- Thousands
- Not evenly distributed
- Highly polymorphic
- Prone to slippage
What percent of the human genome contributes to CNVs?
4.8-9.7% from 50 bp
What are CNVs?
Copy number variation refers to a circumstance in which the number of copies of a specific segment of DNA varies among different individuals’ genomes. The individual variants may be short or include thousands of bases. These structural differences may have come about through duplications, deletions or other changes and can affect long stretches of DNA.
What is the formation of CNVs caused by?
Nonallelic homologous recombination (NAHR) as the mechanism for recurrent genomic rearrangements.
How are CNVs distrobuted?
CNVs are distributed unevenly in the genome
What is the telomere-to-telomere consortium?
Filled in the missing 151 Mb of DNA using long read sequencing technologies
- Able to map the full genome
What will happen to mutations that are strongly deleterious?
They will be quickly eliminated by natural selection
Where is reduced diversity evident?
Reduced diversity is evident in regions of the genome that have undergone selective pressure or selective sweeps
what is a high AMY1A copy number thought to be?
High AMY1A copy number is thought to be a beneficial adaptation that spread as human diets increasingly became rich in insoluble starch.
Population Structure Facts:
Differences between human populations account for only a small fraction of total variance in allele frequencies
Individuals can be correctly assigned to their population using genetic variation data
Most (85%-90%) human genetic variation is found within populations and only an additional 10-15% of variation is found between them.
Even when the most distinct populations are considered and hundreds of loci are used, individuals are frequently more similar to members of other populations than to members of their own.
What does Africa have much more variation?
Because they didn’t go through population bottleneck
