BCH 4101 Lecture Notes - Lecture 5: Single-Nucleotide Polymorphism, Human Genetic Variation, Dna Replication

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October 2, 2017
Genomic Variation and Mapping
Genetic Variation
Mutation: any permanent alteration in the DNA sequence
-Includes deletion, insertion, substitution, etc.
-Exogenous causes: UV radiation, toxins, chemicals, etc.
-Endogenous causes: errors in DNA replication, errors during recombination, errors during DNA repair mechanisms
-Can have adverse or beneficial effects
Fuel change and evolution
-NB: mutation describes the mutational event or the outcome of the mutation event
Variants: mutations that result in alternative forms of DNA
-NB: must becomes established in the population to be a variant
Mutations that are unique to you do not count
-Common variants: minor allele (least common allele) frequency of at least 1% in the population
-Rare variant: minor allele (least common allele) frequency of <1% in the population
NB: only ~0.1% of the genome varies between humans
Classes of Human Genetic Variation
Single nucleotide variants: varying bases between individuals at the same genetic position
-Single Nucleotide Polymorphisms (SNPs) are the prevalent class of variation amongst individuals
-Occur approximately 1 in 300 nucleotides, so could be up to 10 million SNPs in each human genome
Occurs ~1/109 nucleotides in the germ line
Have been accumulating for a long time (in order to reach 10 million) - very good for studying lineages (ex.
Tracking Neanderthal movements)
-Most commonly found in intergenic regions (neutral effects)
-Can also occur within a gene or regulatory regions
-Can be synonymous (no change in aa sequence) or nonsynonymous (changes aa sequences)
-NB: all SNPs are mutations, but not all mutations are SNPs
-Ex.
Individual 1 TA C T T G AT C T C C G A
Individual 2 TA C T T CAT C T C C G A
Individual 3 TA C T T AAT C T C C G A
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October 2, 2017
Structural variants: all base pairs that differ between individuals and that aren’t SNPs
-Usually 1kb or larger
-Less common than SNPs, but affect more nucleotides total than SNPs because they affect larger blocks of DNA
-Indels (INSertion-DELetion variants):
Generally only affect a few bases (but can be up to several kbs in length)
Coding sequence indels nearly always have a drastic effect on a protein
Can cause frameshifts - produces a different protein than the one that is supposed to be produced
-Copy number variation (CNVs): DNA segment >1kb that is present in variable copy number compared to a
reference genome
NB: doesn’t have to affect >1kb, but this is usually the case
A component of genomic diversity as important than SNPs
Usually detected using CGH
Ex. Huntington: degree of manifestation of the disease depends on the number of tri-nucleotide repeats
-Number of CAG repeats dictates the severity of the disease - codes for glutamine and increased amounts
might cause protein aggregation
20 repeats: normal
30 repeats: normal
50 repeats: late-onset disease
100 repeats: early-onset disease
Accumulating repeats:
-Repeats tend to expand with every generation - tend to accumulate when parents pass on their genes
NB: variants are usually located outside of gene-coding regions unless they have a beneficial effect
-Evolution would not allow them to become stabilized within a population
Individual Genomes
First human genome sequence (2001) was a patchwork of DNA sequences from different individuals
-For a more detailed view of human genetic variation, we need to compare DNA from many different individuals
First individual genome to be fully sequenced belongs to Craig Venter
-Found that:
3.2 million SNPs
290 000 heterozygous insertion/deletion variants (from 1 - 571 bp in size)
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Document Summary

Mutation: any permanent alteration in the dna sequence. Exogenous causes: uv radiation, toxins, chemicals, etc. Endogenous causes: errors in dna replication, errors during recombination, errors during dna repair mechanisms. Can have adverse or bene cial effects: fuel change and evolution. Nb: mutation describes the mutational event or the outcome of the mutation event. Variants: mutations that result in alternative forms of dna. Nb: must becomes established in the population to be a variant: mutations that are unique to you do not count. Common variants: minor allele (least common allele) frequency of at least 1% in the population. Rare variant: minor allele (least common allele) frequency of <1% in the population. Nb: only ~0. 1% of the genome varies between humans. Single nucleotide variants: varying bases between individuals at the same genetic position. Single nucleotide polymorphisms (snps) are the prevalent class of variation amongst individuals. Most commonly found in intergenic regions (neutral effects) Can also occur within a gene or regulatory regions.

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