Learning outcomes
Be familiar with the general classes of mutations based on their size and effects on gene expression and function
Chromosome mutation
Alter number of an entire chromosome, not its sequence
Subchromosomal (regional) mutations
Alter the structure of part of one or more chromosomes
Large duplications, deletions, inversions, and translocations
DNA or gene mutations
“Small” changes in DNA sequence
Substitutions, deletions, and insertions of 1-100 kb
Be able to describe the most common polymorphisms in the human genome and their potential effects on gene function and human health
Understand the general causes of chromosomal, subchromosomal, and gene/DNA mutations
Errors in chromosome segregation
Very common
> 1 error in 25-50 meiotic divisions
Non-homologous end joining (NHEJ)
Joining of spontaneous double stranded DNA breaks causes translocations and inversions
When there are spontaneous double stranded breaks, the ends can fuse inappropriately.
Non-allelic homologous recombination
Recombinations between related sequences can also cause duplications, deletions, and inversions
DNA replication
Mutations are rare because of proofreading
< 1 mutation per genome per cell division
DNA damage by mutagens and spontaneous chemical processes
104 to 106 nucleotides damaged per cell per day
Not all damage is repaired
Most common is spontaneous deamination of 5-methylcytosine to thymine at CpG doublets
Somatic mutations
Occur in somatic cells (do not produce gametes)
Found in the descendants of cells in which the mutation occurred
Germline mutations
Occur in germ cells (produce gametes)
Mutations transmitted to offspring
Responsible for most inherited genetic diseases
Be able to draw out how mutations are generated by NHEJ and NAHR, including inversions, translocations, deficiencies, and inversions
Key terms
Chromosome mutation
Alter number of an entire chromosome, not its sequence
Subchromosomal (regional) mutation
Alter the structure of part of one or more chromosomes
Inversions and translocation
Duplication
Deletion
Inversion
Polymorphism that has a huge range in size (a few bp up to > 1 Mb)
Translocation
DNA (gene) mutation
“Small” changes in DNA sequence
Substitutions, deletions, and insertions of 1-100 kb
Reference sequence
Most common sequence in a population
Locus
Segment of DNA occupying a particular location on a chromosome
Allele
Alternative versions of a locus
Wild type allele
Most common allele, usually > 50% of population
Variant (mutant) allele
Less common alleles
Private allele
Very rare alleles
Polymorphism
Alleles with frequency > 1%
Single-nucleotide Polymorphism (SNP)
Single base pair substitutions (usually 2 alleles)
Indel
Insertions and deletions
Most common polymorphisms
Usually ~1-1000 bp in length
Simple: 2 alleles
Microsatellites: 2, 3, or 4 bp unit tandemly repeated up to 25 times
Microsatellite
Copy number variant
Changes in number of copies of DNA segments (~100 to 1 Mb)
Often spans multiple genes
Non-homologous end joining (NHEJ)
Non-allelic homologous recombination (NAHR)
DNA methylation
Dominant
Recessive
Gain-of-function
Loss-of-Function
Amorphic alleles
Completely eliminates gene activity
Example: premature stop codon
Hypomorphic
Reduced gene activity, but not eliminated.
Hypermorphic
Increased gene activity
Example: gene duplication, or deletion in repression sequence
Antimorphic (dominant-negative)
“Poisoned” product. Makes other wild type alleles less effective.
Neomorphic
New function. Gene product does something it shouldn’t
Synonymous mutation
Functionally silent mutations
Nonsynonymous mutation
Change in amino acid
Frameshift mutation
Changes in entire reading frame
Whole genome sequencing of trios (child and biological parents)
There are 1.2 × 10-8 mutations per base pair per generation
There are 75 new mutations received by each child, most are SNPs in non-coding genes and most are benign.
~1 in 200 individuals receive mutation in disease causing genes from their parents
Calculating the frequency of mutations that cause disease
If there are # cases of the disease in ~# births, the mutation rate is # mutations/(# births x 2 genes)