BCH 410 Unit 3

• Single nucleotide polymorphisms (SNPs)


  Genetic variants, differences of DNA at molecular (sequencing) level, originate from mutations, change to single nucleotide
• Point mutations


  Genetic variants, differences of DNA at molecular (sequencing) level, originate from mutations, change to single nucleotide
• SNPs and point mutations


  Both are genetic variants, which are differences of DNA at molecular (sequencing) level, both originate from mutations, both change a single nucleotide
• SNPs


  • Common genetic variants held in population over time, occur greater than 1% frequency, 10 million in human genome, most common type of human genetic variant, may be beneficial or harmful
• Point mutations


  • Rare genetic variants, occur less than 1% frequency, often due to spontaneous mutation, considered SNPs when talking about humans to avoid stigma of calling people "mutants", not always bad as they can just mean a different nucleotide, but are rarely beneficial so usually bad, if good then become SNPs
• SNP in one population


  Can be a mutation in another population, meaning a variant can be common in some populations but rare in other populations
• SNPs are the most common genetic variances amongst humans
• Copy number variances (CNVs)

  Differences of repeating nucleotide units between people, expansions add additional repeats, contractions delete additional repeats, can cause disease especially if in protein coding region, major contributor to human variation
• Expansions and contractions result in copy number variances
• Most CNVs are normal and harmless, but some are harmful</b>
• CNVs are caused by unrepaired/mis-repaired errors in DNA replication resulting in more or less repeats being added
• Coding SNPs


  Occur within the coding sequence of a gene, can be synonymous (same amino acid) or non-synonymous (different amino acid)
• Non-coding SNPs


  Occur outside the coding sequence of a gene, could be in regulatory sequences or introns, do not affect gene expression unless they impact splicing
• Coding and non-coding SNPs


  May affect gene expression
• Penetrance


  The proportion of people in a population that carry a disease allele and express the disease phenotype (symptoms)
• Complete penetrance


  100% chance of showing symptoms if you have the disease allele, but symptoms can vary
• Incomplete penetrance


  Not 100% chance of showing symptoms if you have the disease allele, high penetrance means the allele is likely to cause the disease, low penetrance means the allele is not likely to cause the disease
• Expressivity


  The extent to which a genotype shows phenotype expression, aka the severity of disease symptoms based on genotype (allele)
• Some diseases may exhibit both complete and incomplete penetrance, such as trinucleotide expansion repeat disorders like Huntington's
• Inherited cancers show incomplete penetrance
• All cancers show variable expressivity
• Penetrance may be sex-specific


  BRCA1 and BRCA2 mutations affect women more than men and increase breast cancer risk
• Hardy-Weinberg principle


  Attempts to use statistics to explain why diseases are not weeded out by evolution, but fails to account for many aspects of genetics
• Hardy-Weinberg is only relevant if mating is random in a large population and there are no disruptive circumstances
• Heterozygote's advantage


  Being a heterozygote causes better fitness than being a homozygote affected or unaffected in a population, not explained by Hardy-Weinberg
• Heterozygote's advantage


  • Sickle cell (heterozygotes are resistant to malaria but not affected by sickle cell), Cystic fibrosis (heterozygotes are resistant to cholera and typhoid)
• The major genetic differences between species are large structural changes, not SNPs
• SNPs are established after speciation, after humans split from primates, which partially explains why they are the most common genetic variance between humans
• SNPs may be held within certain populations and can infer disease risk
• Genomics


  The study of genetics on a large scale, including identifying genetic variances that may be involved in disease development
• Sanger Sequencing


  Applied PCR, determines the sequence of nucleotides in a single/small DNA fragment, good for single genes and copy number variants, but not for entire genomes
• Next Generation Sequencing


  Can sequence entire genomes or transcriptomes, allows study of genetics on a global basis, can sequence a lot of DNA at once but requires a genomic library and has biases against low amounts of DNA
• Genome sequencing can be used to predict genes, but these predictions must be verified in a laboratory setting
• Assembly


  Building a whole or partial genome from nucleic acids, including large genes
• Alignment


  Locating sequence homology, identifying evolutionary relations between sequences, finding repetitive sequences, and finding transposable elements
• Cytogenetic map


  Maps genes relative to band locations on chromosomes, gives an estimate of gene location
• Linkage map


  Maps genes relative to each other using chromosomal crossover events, uses genetic markers and measures genetic distance, not actual physical distance
• Physical map


  Maps genes relative to each other and measures distance in base pairs, relies on genomic sequencing or alignment to known sequences
• Quantitative trait locus (QTL) mapping


  A type of linkage mapping that can identify regions of DNA associated with specific traits, including potential disease-causing genes
• The transcriptome can provide information about alternative splicing and RNA editing that cannot be obtained from the sequenced genome