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Fundamental Molecular Biology
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- 1Mutations - Basics- Changes in DNA (or RNA) of a cell (or virus)
- Some inherited, not all
- Essential for evolution
- ~200 de novo (new) mutations per human child
- ~20 billion new mutations per year - 2Mutations - Origins- Errors in replication
- Damage to DNA
- Inheritance in germ line
- Not passed on in somatic cells, so they are a genetic dead end
- UV radiation causes Thymine dimers, which can lead to frame shift mutations - 3Mutations - Consequences- Most affect unimportant regions of DNA, such as areas between genes
- Most are silent (have no noticeable effect)
- Consequences are dependent on mutation type and position
- Effect on an organism or population dependent on if the mutation is dominant or recessive - 4Recessive Mutations - Examples (Albinism)- Albinism
--Body cannot convert tyrosine to melanin
-- Leads to lack of skin and hair pigmentation - 5Mutations - Recessive or Dominant4 Rules of Thumb
-1- Think from point of view of the mutant allele (e.g. mutant is recessive to wild type, NOT wild type is dominant to mutant)
-2- Remember that genes make gene products, which are what affect phenotype
-3- MOST recessive mutations are loss-of-function mutations, and MOST loss-of-function mutations are recessive (complete loss-of-function = null allele)
-4- MOST dominant mutations are gain-of-function and MOST gain-of-function mutations are dominant
-Most mutations (~95%) are recessive, as it is easier to damage something than make it work differently or better - 6Dominant Mutations - Importance- Evolution: dominance effects how a mutation behaves in a population
- Gene therapy strategy: how to treat mutations
- Informs biology: e.g. wingless mutant flies: does the normal gene product make or prevent a wing (recessive wingless mutation = normal product makes a wing, dominant wingless mutation = normal product prevents a wing) - 7Dominant Mutations - Gain of FunctionGain of function can mean:
- more than a normal function
- a whole new function - 8Dominant Mutations - Examples (Achondroplasia)- Achondroplasia
-- Mutation in FGFR3 receptor
-- FGFR3 slows limb growth when activating receptor
-- Achondroplasia "locks" receptor on, causing massive reduction in limb growth
-- Only ~20% of those with achondroplasia have a parent who also has it - 9Recessive Mutations - Examples (PKU)- PKU (Phenylketonuria)
-- Body cannot convert phenylalanine to tyrosine
-- Leads to build up of phenylpyruvic acid, which causes progressive brain disfunction - 10Dominant Mutations - Examples (Huntington's Disease)- Huntington's Disease
-- Progressive neurodegeneration
-- Carriers (heterozygotes) have the phenotype, so is a dominant autosomal mutation
-- Mutation increases length of polyglutamine tract on the end of the Huntingtin protein, making the protein a neurotoxin
-- It is a dominant, lethal mutation, which is rare - 11Genomes - Basics- Genome sequence consists of genes (37.1% of genome) and intergenic DNA (62.9% of genome)
- Human genome is ~3 billion base pairs, but is diploid so ~6 billion base pairs
- Humans have ~20,441 protein coding genes, compare to the ~35,679 protein coding genes in rice - 12Genomes - Types of Genes- Homologs: genes shared by different species, originally from a common ancestor
- Orthologs: genes evolved from common ancestral gene, retain the same function in the course of evolution
- Paralogs: genes related by duplication within a genome, evolve new divergent functions - 13Mutations - Types (INDELS)- INDELS
-- Insertions/Deletions
-- Can be very small (1bp, 2bp)
-- Can affect protein product of a gene
-- Can affect function of non-coding RNA - 14Mutations - Types (CNVs)- CNVs
-- Copy Number Variants
-- Variations in the number of repeats of a segment of DNA in a chromosome
-- Typically 500bp to 1 million bp segments
-- Account for most of the variation between the genomes of individuals of the same species - 15Mutations - Types (Point Mutations/Variants)- Point Mutations/Variants
-- best understood and easiest to study
-- some are private (~200 de novo mutations per human), some are fairly common (<1% of alleles in a population, called "variants"), and some are very common (>1% of alleles, called "polymorphisms") - 16Mutations - Types (SNPs)- SNPs
-- Single Nucleotide Polymorphisms
-- Some are rare (between 1% and 4.9% allele frequency), and some are common (5% or greater allele frequency)
-- Can affect the protein product of a gene
-- Can affect function of non-coding RNA if they occur there
-- Can affect regulatory regions of the genome
-- MOST are silent
-- A common SNP occurs approximately every 1000 base pairs in human genome, so humans have 3 million common SNP loci - 17Allele Frequency- Allele frequency (allele A) = (no. of A)/total
- Express allele frequencies as decimals - 18Hardy-Weinberg Equilibrium- Hardy-Weinberg equilibrium predicts that allele and genotype frequencies in a population remain constant from one generation to the next
- For a given pair of allele frequencies, p and q the equation is p^2 + 2pq + q^2 = 1
- Most SNPs are in Hardy-Weinberg equilibrium
- But some are not, possibly due to: non-random mating (e.g. inbreeding), the population is not homogeneous, the population is (or recently was) very small, and natural selection
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- Fundamental Topics in Biology Fichas sobre Fundamental Molecular Biology, creado por Matthew Orr el 15/11/2017.
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- Matthew Orr
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