Lecture 2

Learning outcomes

1. 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

2. Be able to describe the most common polymorphisms in the human genome and their potential effects on gene function and human health

3. 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

4. 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)