Bioinformatics and Molecular Evolution Paul G. Higgs and Teresa K. Attwood

1. UST 1st Molecular evolution Bioinformatics and Molecular Evolution Paul G. Higgs and Teresa K. Attwood Jeong, Da Geum

2. Chapter 3 Molecular evolution and population genetics • Chapter Preview • - mutation • - natural selection • - random drift • - Coalescence theory • - Fixation of new mutations in a population • - Fixation probability • - Adaptationist and Neutralist

3. Chapter 3 Molecular evolution and population genetics 3.1 What is Evolution? Evolution Biology Life Life is a self-sustained chemical system capable of undergoing Darwinian evolution • Evolution • - “Survival of the fittest” • - “Change in frequency of genes in a population” • “Heritable changes in a population over many generations” • The Essential factors that define evolution • error-prone self-replication • variation in success at self-replication

4. Molecular evolution and population genetics 3.1 What is Evolution? Point i) error-prone self-replication “Self-replication” – The ability to make copies of itself Dawkins(1976) – “replicator” – a thing that can self-replicate. fundmental replicator-> gene rather than organisms “Error-prone” – Copies are not always identical to the originals. Error is essential for evolution. If there are too many errors, there will be no heredity.

5. Molecular evolution and population genetics 3.1 What is Evolution? Point ii) variation in success at self-replication Limited size of population Possibility of some aspects occurring -Natural selection: Variants with higher fitness will increase in number relative to those with lower fitness -Random drift (chance fluctuation): Change in gene frequency owing to chance effects in a finite sized population rather than to natural selection -Neutral evolution: a mutation whose fitness is equal or close to the fitness of the original sequence that the fate of the mutation is determined by random drift How do gene sequences evolve?

6. Molecular evolution and population genetics 3.2 MUTATIONS Introduce some genetic terminology Locus:A particular position on a chromosome a gene, a molecular marker Alleles:Alternative sequence variants that occur at the same locus polymorphism: having multiple alleles present in the population at a significant frequency ( usually <99%) Haploid:Have a single copy of each locus( most prokaryotic organisms) Diploid:Have two copies of each locus( most eukaryotic organisms)

7. Molecular evolution and population genetics 3.2 MUTATIONS reference:www.geneticsandhealth.com/wp-content/allele.jpg Introduce some genetic terminology Homozygous :individual same allele at a locus Heterozygous:individual with different alleles Mutation:Any change in a gene sequence that can be passed on to offspring (Result of some damages: ex. radiation) DNABASE: A,G : purines C,T/U : pyrimidines Transition: purine -> purine (A<->G) pyrimidine -> pyrimidine(C<->T) Transversion: purine <-> pyrimidine ( A,G <-> C, T)

8. Molecular evolution and population genetics 3.2 MUTATIONS Introduce some genetic terminology Point mutation : A type of mutation that causes the replacement of a single base nucleotide with another nucleotide. synonymous: a substitution at nucleic level that does not lead to change of the amino acid sequence of the protein ex) UUC(F) -> UUU(F) nonsynonymous: one that does change the amino acid missense mutation: code for a different amino acid, vs silent mutation ex)AUA(I) -> AUG(M) nonsense mutation:code for a stop, which can truncate the protein ex) TGG( trp) -> TAG ( stop)

9. Molecular evolution and population genetics 3.2 MUTATIONS Introduce some genetic terminology Indels: insertions and deletions Microsatellites : part of  ’junk’ DNA. Also known as short sequence repeats, e.g. GCGCGCGCGC Frameshift: insertion of deletion can distrupt the grouping of the codons. Inverted: section of DNA can be reversed in direction. Translocated: cut out from one part of a genome and inserted into another

10. Molecular evolution and population genetics 3.3 SEQUENCE VARIATION WITHIN AND BETWEEN SPECIES Patterns of sequence variation gene BRCA1(408 mutations) 1/3 mutations: single nucleotide substitutions. small deletions splice-site mutations Deleterious: a mutation that causes the fitness of a gene to be reduced with respect to the original sequence Advantageous: a mutation that increase the fitness of the sequence Cytogenetic Location: 17q21 Molecular Location on chromosome 17: base pairs 38,449,839 to 38,530,993

11. A group of species known as Afrotheria Synonymous change fig. 3.1: Part of the alignment of the DNA sequences of the BRCA1 gene conservative: between a.a of similar chemical properties tend to be more frequent transition -> transition (easy) transition -> transversion (difficult) fig. 3.2 Alignment of the BRCA1 protein sequence for the same region of the gene as Fig. 3.1

12. Molecular evolution and population genetics 3.4 GENEALOGICAL TREES AND COALESCENCE • 3.4.1 Adam and Eve • Coalescence :the merging of lineages in backwards time • – To trace the lines of descent of a gene back through the generation • mitochondrial DNA:is inherited through the maternal line (all) • mitochondria eve, 200000 years ago, • non african sequence : 52000 +/- 27000 • “out of Africa” hypothesis: all descended from an African population • plate 3.1 • Y chromosome DNA:is inherited through the paternal line (male) • -“Y-chromosome Adam”, 59000 years ago Thompson et al.(2000) • No reason why Adam and Eve should have existed in the same time and same place • Patterns of migration of men and women over time may also have been different Fig3.3 Illustration of the coalescence process. Each circle represents one gene copy. Bold lines show the lines of descent of genes in the current generation. Thin lines show lines of descent that do not lead to the current generation. Shaded circles show the inheritance of two different mutation

13. Molecular evolution and population genetics 3.4 GENEALOGICAL TREES AND COALESCENCE 3.4.2 A model of the coalescence process _ P(T) = (1-1/N)T-1 * 1/N P(T) = 1/N * –T/N

14. Molecular evolution and population genetics 3.5 THE SPREAD OF NEW MUTATIONS 3.5.1 Fixation of neutral mutations P fix = 1/N U fix = Nu * P fix = u

15. Molecular evolution and population genetics 3.5 THE SPREAD OF NEW MUTATIONS 3.5.2 Simulation of random drift and fixation P(n) = CnN an(1-a) N-n The probability of fixation is 1/N Fig. 3.4 Simulation of the spread of neutral mutations through a population under the influence of random drift

16. Molecular evolution and population genetics 3.5 THE SPREAD OF NEW MUTATIONS 3.5.3 Introducing selection s = selection coefficient Fig. 3.5 Simulation of the spread of advantageous mutations through a population (a) For selection coefficient s = 0.05 both selection and random drift are important. (b) For s = 0.2 selection dominates random drift. The dashed lines show the predictions of the deterministic theory in Box 3.2

17. Molecular evolution and population genetics 3.6 NEUTRAL EVOLUTION AND ADAPTATION Extremely advantageous s >>1 pfix ≒ 1 slightly advantageous mutation s<<1, Ns>>1 Nearly neutral mutation Ns<<1 Fig.3.6 Fixation probability in a population of N = 200 as a function of selection coefficent s, for both advantageous and deleterious mutations. When Ns<<1, both types of mutation behave as nearly neutral mutations.

18. Molecular evolution and population genetics 3.6 NEUTRAL EVOLUTION AND ADAPTATION • Natural selection – Positive selection (due to select new variants) • Adaptations at the sequence level • Adaptationists – people who argue that positive selection is • the major driving force in molecular evolution • Neutralists – neutral evolution is a major role

19. Molecular evolution and population genetics 3.6 NEUTRAL EVOLUTION AND ADAPTATION • NEW Technique for selection test • Allozymes: • Variant forms of an enzyme that are coded for • by different alleles at the same locus • -many protein loci are polymorphic • -only detects a fraction of the sequence variation • that is present • RFLPs (Restriction fragment length polymorphisms): • Restriction enzymes will cut a long section of DNA into fragments • that can be separated by electrophoresis • mitochondrial DNA • difference in fragment lengths: polymorphism in the DNA • Recent: DNA Sequencing

20. Molecular evolution and population genetics 3.6 NEUTRAL EVOLUTION AND ADAPTATION • Adaptationists: • Positive selection removes deleterious alleles, • hence reduces the number of polymorphic loci • Selective scenarios for maintenance of polymorphisms • advantageous and disadvantageous( maintenance of both alleles) • Heterozygotes have a higher fitness than homozygotes

21. Molecular evolution and population genetics 3.6 NEUTRAL EVOLUTION AND ADAPTATION Neutralist: polymorphism is a constant process of - creation of new alleles by mutation - loss of old alleles due to random drift - measure of variability : heterozygosity average heterozygosity: Nu N: populatio size u: mutation rate Nu>= 1: mean heterozygosity will be large and most loci will be polymorphic Nu<<1 mean heterozygosity will be low few polymorphic loci Features of neutral theory -calculation using null hypothesis (selection or not) -large fluctuation in quantities

22. Molecular evolution and population genetics 3.6 NEUTRAL EVOLUTION AND ADAPTATION A selective sweep: the reduction or elimination of variation among the nucleotides in neighbouring DNA of a mutation as the result of recent and strong natural selection. stabilizing selection (purifying selection) : ① genetic diversity decreases as the population stabilizes on a particular trait value Codon bias: Codon usage because of codon redundancy all but two amino acids are coded for by more than one triplet. Different organisms often show particular preferences for one of the several codons that encode the same given amino acid.

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