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The Unit of Selection: the level of genetic organization that allows the prediction of the genetic response to selection Fitnesses in population genetics are assigned to genotypic classes of individuals rather than individuals themselves; the genotypic classes can be single locus genotypes, or two locus genotypes, etc. The unit of selection is the level of genetic organization to which a fitness phenotype can be assigned that allows the response to selection to be accurately predicted. This means that the unit of selection must have genetic continuity across the generations. Meiosis and Sexual Reproduction Break Up Multilocus Complexes in Outbreeding Species (as a function of both physical recombination and assortment, and system of mating), Which Reduces the Size of the Unit of Selection. Selection Upon Epistatic Complexes Builds Up Higher Level Units. The Unit of Selection is a dynamic compromise between selection building up complexes and effective recombination breaking them down. The unit of selection can change as the population evolves or experiences altered demographic conditions. Quantitative Genetic Components As a Function of Allele Frequencies: A. 4 allele at ApoE is Rare, A2 at LDLR Common; B. Reversed Genetic Variance 60.00 A. { Epistatic Variance Dominance Variance Additive Variance 50.00 35.00 B. 30.00 40.00 25.00 30.00 20.00 15.00 20.00 10.00 10.00 5.00 0.00 0.00 ApoE & LDLR ApoE LDLR ApoE & LDLR ApoE LDLR Epistasis Is Present, But Recombination Is High: The Unit of Selection Is A Single Locus. Persistence of Fetal Hemoglobin Ameliorates Impact of Sickle Cell Anemia Epistasis Strong, Recombination Weak; The Unit of Selection Is A Multilocus Complex Various Alleles At Loci in the MHC Complex Are Predictive of Multiple Sclerosis, an Autoimmune Disease Extended Haplotype Homozygosity Gregersen, J. W., K. R. Kranc, X. Ke, P. Svendsen, L. S. Madsen, A. R. Thomsen, L. R. Cardon, J. I. Bell, and L. Fugger. 2006. Functional epistasis on a common MHC haplotype associated with multiple sclerosis. Nat. 443:574-577. Epistasis Strong, Recombination Intermediate; The Unit of Selection Is A Multilocus Complex, But Only Selected Haplotype Shows Extensive D: Must Be Constantly Built Up By Selection Recombination is not Uniformly distributed in the human genome, but rather is Concentrated into “hotspots” that Separate regions of low to no Recombination. Region of Overlap of the Inferred Intervals Of All 26 Recombination and Gene Conversion Events Not Likely to Be Artifacts. 18 Number of Recombination Events LD in the human LPL gene 16 14 12 10 8 6 Significant |D’| 4 2 Non-significant |D’| 0 0 1000 2000 3000 4000 5000 (Templeton et al.,AMJHG 66: 69-83, 2000) 6000 7000 8000 9000 10000 Too Few Observations for any |D’| to be significant Neutral Genetic Drift, Stable Population Size Neutral Genetic Drift, Expanding Population Size Negative Selection Positive Positive (Directional) (Diversifying) Selection or Selection or Subdivision Bottleneck Haplotype Network in 5’ Region of LPL 84R 4 49N 17 5'-1 13 23J 7 5'-2 8 5'-4 36J 4 12 5'-3 3 5'-5 17 44N Positive (Directional) Selection 5 16 5'-6 6 4 32J 9 9 2 10 10 17 5'-8 6 18 14 15 5'-7 16 14J 8 8J Haplotype Network in 3’ Region of LPL Positive (Diversifying) Selection 53 3'-11 75R 59 59 3'-10 53 45J 69 30J 41 16J 36 69 36J T-1 3'-9 38 39 41 43 44 46 47 60 66 3'-12 46 43J 40J 63 55 37J 40 58 28J 53 60N 59 45 53 67 34J 56 40 24J 39J 45 3'-4 3'-1 41N 38 54 12J 42N 54N 36 63 3'-2 38 63 9N 3'7 42 50 53N 56N 46N 62 67N 41 40 48N 42 62 T-2 44 50 68 3'-8 50 T-3 78R 42 8J 32J 49N 53 77R 29J 55 44 14J 41 49 42 44 55 40 53 38J 52 61 50N 64 48 49 3'-6 58 49 81R 46 37 61 45 55 58 56 38 44N 50 44 53 56 59 59 42 51N 63 3'-3 59N 56 61N 3'-5 T-4 36 55 19J 65 63 57 51 65 61 64J 64 35J 20J 36 41 58 67 26J 9 T-1 X 11J T-2 X Node n 15 (16-29) 17 10 17J X T-3 25 Node i X Node k (17-25) 11 Node b X Node c (19-25) 22 5 (56-61) 32J Node j X 28J 24 6 (16-19) 12 36J Node f X Node e X T-2 7 14 (19-29) (16-31) 25J 30 28 35 Recombinants and PostRecombination al Evolution in LPL 46 58 6 35 12J T-2 X Node p 17 (33-35) 40 29 36 6 41 14 67 15 58 18 26J 65N 61 19 Node m 4 30 15J 14J 80R 35 20 (33-44) 50N 49N 42 5NR 26 46N 30 72R 17 q 50 23 9 (29-35) 88R 19 57 58 27 63N 62 38J 26 6NR 30 50 78R 3 (33-35) X T-2 X 4JN 69R 42N 54 1 (27-29) 31 38 53 47N 71R 69 55N 27 22 (33-35) X 83R 27 (27-33) 53 Node g X T-2 8 (29-34) 29 28 (19-33) 19 (33-44) 61 68R X T-2 23 1 55 26 4 T-2 X Node x 29 (64-68) 62 29 23 20 2JNR X T-2 18 27 41 (33-35) Node s X Node r X 62N X 45J 21J 35J 82R Node m X 73R 21 (5-9) 36 2 (13-29) 40 86R 13J 35 53 62 84R 29 18J 44 48N 67N 16 (29-31) 4 34 77R 26 79R X T-2 59 69 26 (23-34) 39J 42 30 49 55 59 Node a X 2JNR 55 41 75R 23 (19-33) 81R 22J Node h X T-4 10 (21-29) 8J 53 3 44N 55 8 44 58N 49 17 76R 35 87R X T-2 T-4 X Node w 38 60 57J 11 Node v X T-3 24 17 15 (18-29) Gene 21 Conversion 33J X Node l 13 u 31 (58-63) 16 20J T-2 X Node t 28 12 (5-9) 14 25 4 (13-29) 23 18 3 Node a X 1JNR 13 6 56 24J 36 2 19 7NR 20 3JNR 30 44 51N 19 85R 59 59 66N 31 54N 63 74R 50 33 41N 12 Recombination Events Occurred Between T-1 Haplotypes With T-2,3, or 4 Haplotypes In All 12 Cases, the 5’ End Was Of The T-1 Type. Under Neutrality, This Has A Probability of (1/2)12 = 0.002. Therefore, the 5’ End Experienced A Selective Sweep Enhanced By Recombination The Unit of Selection: For LPL, the unit of selection is smaller than the gene because of the recombination hotspot in the middle of this locus. Target of Selection: the level of biological organization that displays the phenotype under selection. Targets Below The Level of The Individual: Example: the t-complex in mice and meiotic drive. The t-complex in mice 20 cM region of chromosome17 of the mouse genome that constitutes about 1% of the mouse genome. Inversions suppress most recombination in this region that contains genes for sperm motility, capacitation, binding to the zona pellucida of the oocyte, binding to the oocyte membrane, and penetration of the oocyte – and also notochord development. Because of strong epistasis and low recombination, it behaves as a unit of selection that can be modeled as a single locus. The t-complex in mice Adult Population tt Tt TT Gtt GTt GTT Mechanisms of 1 Producing Gametes (Violation of Mendel's First Law) Gene Pool (Population of Gametes) k (1-k) 1 t T p' = Gtt + kGTt q' = GTT + (1-k)GTt p’=Gtt+ kGTt=Gtt+1/2GTt-1/2GTt+kGTt=p+GTt(k-1/2) p=p’-p=GTt (k-1/ 2) 1/ 2 Need this 1/2 for t-alleles because the meiotic drive is expressed only in males. The t-complex in mice A single Unit of Selection can have more than one Target of Selection At the individual level, the t-alleles affect viability: TT 1 Tt 1-s tt 0 The t-complex in mice A single Unit of Selection can have more than one Target of Selection TT 1 Tt 1-s tt 0 Assume random mating; then meiotic drive changes The gamete frequencies to p’=p+pq(k-1/2): After fertilization, selection at the individual level is governed by: at q(1 s w ) p (w ) Where w q2 2 p q(1 s) The t-complex in mice The total change in allele frequency is: p p p p p p p at p pqk w Change due to selection at the level of the individual; always negative. 1 2 Change due to selection at the level of the gamete; always positive. The t-complex in mice Molecular Drive (Dover) “The nuclear genomes of eukaryotes are subject to a continual turnover through unequal exchange, gene conversion, and DNA transposition. … Both stochastic and directional processes of turnover occur within nuclear genomes.” Holliday Model Double-Strand Break Model Gene Conversion Unequal gene conversion Equal gene conversion Double-Strand Break Model Holliday Model Gene Conversion Can Be A Major Source of Genetic Variation in Multigene Families Takuno, S. et al. Genetics 2008;180:517-531 Gene conversion increases the number of haplotypes in multigene systems, particularly when the tract length is short. If there is diversifying selection (e.g., MHC, S alleles), selection often favors these new haplotypes, even if the source of the converted segment is a pseudogene. Unequal gene conversion Equal gene conversion Walsh (Genetics 105: 461-468, 1983) 1 Locus, 2 Allele Model (A and a) Such That: = the probability of an unequal gene conversion event = the conditional probability that a converts to A given an unequal conversion occurs 1-=the probability of getting a 1:1 ratio of Mendelian Segregation =probability of segregation yielding only A alleles 1=probability of segregation yielding only a alleles Then the segregation ratio A:a in Aa heterozygotes is: 1/ (12 )+ :1/2(1- )+ 1or k:1-k where k= 1/2(1- )+ A is fixed if k> 1/2, and a is fixed if k< 1/2, at a rate dependent upon the frequency of heterozygotes in the population Extension of Walsh’s Model To Include Molecular Drive ,, Drift (Nev), and System of Mating/Population Subdivision (f) Probability of Fixation of a Neutral Mutation = 1/(2N) Probability of Fixation of a Mutation With Biased Gene Conversion = 2(2k 1)N ev (1 f ) when 4N ev (1 f )(2k 1) 1 N (2k 1)N ev (1 f )e 4 N ev (2k1)(1 f ) N when 4N ev (1 f )(2k 1) 1 Thus, the evolutionary impact of gene conversion interacts with and is modulated by traditional evolutionary forces. For example, as f goes down, the probability of fixation of a biased gene conversion allele goes up. Molecular Factors Do Not Override Traditional Evolutionary Forces; Rather, They Strongly Interact With Them Transposition Transposition: Mutator A flower of Petunia hybrida transposon genotype derived from the inbred line W138 showing a large number of white-pink sectors (see Ramulu et al., ANL10: 19-21, 1998). Transposition: Evolutionary Co-option (or exaptation) Percentage of TE-derived residues in miRNA genes. Human miRNA gene sequences Human mature miRNA sequences MICRORNAS (miRNAs) are small, 22-nt-long, noncoding RNAs that regulate gene expression. In animals, miRNA genes are transcribed into primary miRNAs (pri-miRNAs) and processed by Drosha to yield 70- to 90-nt pre-miRNA transcripts that form hairpin structures. Mature miRNAs are liberated from these longer hairpin structures by the RNase III enzyme Dicer. Drosha acts in the nucleus, cleaving the pri-miRNA near the base of the hairpin stem to yield the pre-miRNA sequence. The premiRNA is then exported to the cytoplasm where the stem is cleaved by Dicer to produce a miRNA duplex. One strand of this duplex is rapidly degraded and only the mature 22-nt miRNA sequence remains. The mature miRNA associates with the RNA-induced silencing complex (RISC), and together the miRNA–RISC targets mRNAs for regulation. miRNAs have been implicated in a variety of functions, including developmental timing, apoptosis, and hematopoetic differentiation Piriyapongsa, J. et al. Genetics 2007;176:1323-1337 Transposition: Evolutionary Co-option (or exaptation) TE’s (brown segments) have been co-opted for both transcriptional and posttranscriptional regulation. Can build up regulatory networks in evolution. Feschotte. 2008. Nat Rev Genet 9:397-405. Transposition: Direct Phenotypic Effects Transposition: Horizontal & Vertical Transfer Anxolabehere et al. Mol. Biol. Evol. 5: 252-269, 1988 Transposition: Horizontal Transfer Comparison of a) species and b) P-element phylogenetic histories. Diagonal lines unite P-element clades with the species from which they were sampled. From Silva, J.C. and M.G. Kidwell. Horizontal Transfer and Selection in the Evolution of P Elements. Mol Biol Evol 17(10): 1542-1557, 2000. Transposition: Horizontal Transfer Transposition: Horizontal Transfer Unequal Exchange Unequal Exchange Can Also Create New Types of Genes Unequal Exchange: Concerted Evolution Gene Duplication Without Concerted Evolution Gene Duplication With Concerted Evolution Unequal Exchange: Concerted Evolution Gentile, K.L., W.D. Burke and T.H. Eickbush. Multiple Lineages of R1 Retrotransposable Elements Can Coexist in the rDNA Loci of Drosophila. Mol Biol Evol 18(2): 235245, 2001. Unequal Exchange: Concerted Evolution Model of Weir et al. J. Theor. Biol. 116: 1-8, 1985 n=number of repeats in a multigene family N=ideal population size m=neutral mutation rate per repeat per generation 1/(2N)=probability of fixation of new mutant at homologous sites =probability of a repeat converting a paralogous repeat to its state (Molecular drive exists such that a neutral mutant will eventually go to fixation at all paralogous sites as well) 1/(2Nn)=probability of fixation of a new mutant at all homologous and paralogous sites 2Nnm=expected number of new mutants per generation Rate of neutral evolution in multigene family evolving in concert = (2Nnm´1/(2Nn)=m= Same neutral rate as if it were a single locus! Unequal Exchange: Concerted Evolution Recall that the time to neutral coalescence of all homologous copies of a gene to a common ancestral form = 4N The time to neutral coalescence of all homologous and paralogous copies in a multi-gene family to a common ancestral form = 2/(1-) where is the Maximum of one of two forms: 1. 1-1/(2N) or 2. 1- In the first case [>1/(2N); that is molecular drive is more powerful than drift], then t= 2/{1-[1-1/(2N)]} = 2/[1/(2N)] = 4N = the same rate of coalescence as a single locus and no effect of ! In the second case (<1/(2N); that is molecular drive is weak compared to drift), dominates the coalescence process! Therefore, molecular drive has its biggest evolutionary impact when it is Weak compared to drift. Under these conditions, the multigene family will have much diversity among paralogous copies within a chromosome. Concerted Evolution With Selection Simple co-dominant model: start with fixation of a allele, fitness aa is 1 mutation creates A allele, with fitness of Aa being 1+s, and AA 1+2s Under Neutrality, Probability of Fixation of A is: 1/(2N) Kimura showed that fixation probability here is: Where p is the initial frequency; that is, 1/(2N) Concerted Evolution With Selection Mano, S. et al. Genetics 2008;180:493-505 Considered a similar model, but now assume that we have a multigene family with n copies and that the mutant A allele can spread due to molecular mechanisms leading to concerted evolution. Then, the probability of fixation of A is given by: Concerted evolution has the effect to increase the "effective" population size, so that weak selection works more efficiently in a multigene family – the opposite of Dover! Molecular Drive Does NOT Negate The Importance of Other Evolutionary Forces. Molecular Drive INTERACTS With Other Evolutionary Forces In Determining the Path of Evolution.