Natural Selection Ryan D. Hernandez [email protected] 1 The Effect of Positive Selection Adaptive Neutral Nearly Neutral Mildly Deleterious Fairly Deleterious Strongly Deleterious "2 The Effect of Positive Selection Adaptive! Neutral Nearly Neutral Mildly Deleterious Fairly Deleterious Strongly Deleterious "3 Coding regions tend to have the lowest levels of diversity in the genome 4 What are the predominant evolutionary forces driving human genomes?! Eyre-Walker & Keightley ~40% of amino acid substitutions (2009) were advantageous 10-20% of amino acid substitutions Boyko et al (2008) were advantageous 10% of the genome affected by Williamson et al (2007) selective sweeps 5 Diversity levels around a selective sweep Thornton et al (2007): Simulation of patterns of neutral diversity around a selective sweep 6 The footprint of adaptive amino acid substitutions Neutral diversity levels … Amino acid substitution Reflects the typical strength of selection Reflects the fraction of • Goal: compare the pattern amino acid substitutions around amino acid that are adaptive substitutions to the pattern … n substitutions around synonymous substitutions. 7 Other organisms... Drosophila NS SYN Sattath et al (2011) estimate ~13% of amino acid substitutions were adaptive. 8 Observed Patterns of Diversity Around Human Substitutions 9 Hernandez, et al. Science (2011) Other organisms... Drosophila Chimpanzee NS SYN NATURE PLANTS DOI: 10.1038/NPLANTS.2016.84 ARTICLES Maize Teosinte a 1.1 b 1.1 0.008 0.013 1.0 1.0 0.007 Pairwise diversity Pairwise 0.011 0.9 0.9 diversity Pairwise 0.8 0.006 0.8 0.009 0.7 0.7 0.005 1.2 0.009 1.2 0.6 1.0 0.6 0.013 0.8 0.006 0.007 Diversity/neutral diversity Diversity/neutral Diversity/neutral diversity Diversity/neutral 0.004 0.8 0.009 0.6 0.5 0.5 0.4 0.003 Synonymous 0.4 0.005 Synonymous −0.15 −0.05 0.05 0.15 0.4 Non-synonymous 0.003 0.4 −0.15 −0.05 0.05 0.15 Non-synonymous 0.005 Beissinger , −0.002 −0.001 0.000 0.001 0.002 −0.002 −0.001 0.000 0.001 0.002 10 Distance to nearest substitution (cM) Distance to nearest substitution (cM) et al. (2016) Figure 3 | Relative diversity versus distance to nearest substitution in maize and teosinte. a,b, Pairwise diversity surrounding synonymous and missense substitutions in maize (a)andteosinte(b). Axes show absolute diversity values (right) and values relative to mean nucleotide diversity in windows ≥0.01 cM from a substitution (left). Lines depict a loess curve (span of 0.01) and shading represents bootstrap-based 95% confidence intervals. Inset plots depict a larger range on the x-axis. 28 singleton-based estimator of the population mutation rate θ =4N e missense substitutions in either subset of the data (Supplementary μ and published values of the mutation rate29 (see Methods for Fig. 3). Taken together, these data suggest hard sweeps do not details). This yields a much higher estimate of the modern maize play a major role in patterning genic diversity in either maize effective population size at N m ≈ 993,000. Finally, we employed a or teosinte. model-free coalescent approach30 to estimate population size change using a subset of six genomes each of maize and teosinte. Diversity is strongly influenced by purifying selection. In the case Though this analysis suggests non-equilibrium dynamics for teo- of purifying or background selection, diversity is reduced in sinte not included in our initial model, it is nonetheless broadly functional regions of the genome via removal of deleterious consistent with the other approaches, identifying population iso- mutations7. We investigated purifying selection in maize and lation beginning between 10,000 and 15,000 generations ago, a teosinte by evaluating the reduction of diversity around genes. clear domestication bottleneck, and ultimately rapid population Pairwise diversity is strongly reduced within genes for both maize expansion in maize to an extremely large extant size of ≈109 and teosinte (Fig. 4a) but recovers quickly at sites outside genes, (Supplementary Fig. 2). Our assessment of the historical demogra- consistent with the low levels of linkage disequilibrium generally phy of maize and teosinte provides context for subsequent analyses observed in these subspecies22. The reduction in relative diversity of linked selection. is more pronounced in teosinte, reaching lower levels in genes and occurring a across wider region. Hard sweeps do not explain diversity differences. When selection Our previous comparison of synonymous and missense substi- increases the frequency of a new beneficial mutation, a signature of tutions has low power to detect the effects of selection acting on reduced diversity is left at surrounding linked sites5. To evaluate multiple beneficial mutations or standing genetic variation, whether patterns of such ‘hard sweeps’ could explain observed because in such cases diversity around the substitution may be differences in diversity between genic and intergenic regions of reduced to a lesser degree35. Nonetheless, such ‘soft sweeps’ are the genome, we compared diversity around missense and still expected to occur more frequently in functional regions of synonymous substitutions between either maize or teosinte and the genome and could provide an alternative explanation to purify- the sister genus Tripsacum. If a substantial proportion of missense ing selection for the observed reduction of diversity at linked sites in mutations have been fixed because of hard sweeps, diversity genes. To test this possibility, we performed a genome-wide scan for around these substitutions should be lower than around selection using the H12 statistic, a method expected to be sensitive synonymous substitutions. We observe this pattern around the to both hard and soft sweeps36. Qualitative differences between causative amino acid substitution in the maize domestication maize and teosinte in patterns of diversity within and outside locus tga1 (Supplementary Fig. 1), likely to be the result of a hard genes remained unchanged even after removing genes in the top sweep during domestication31. Genome-wide, however, we observe 20% quantile of H12 (Supplementary Fig. 7A). We interpret these no differences in diversity at sites near synonymous versus combined results as suggesting that purifying selection has predo- missense substitutions in either maize or teosinte (Fig. 3). minantly shaped diversity near genes and left a more pronounced Previous analyses have suggested that this approach may have signature in the teosinte genome because of the increased efficacy limited power because a relatively high proportion of missense sub- of selection resulting from differences in long-term effective stitutions will be found in genes that, because of weak purifying population size. selection, have higher genetic diversity32. To address this concern, we took advantage of genome-wide estimates of evolutionary con- Population expansion leads to stronger purifying selection in straint33 calculated using genomic evolutionary rate profile modern maize. Motivated by the rapid post-domestication (GERP) scores34. We then evaluated substitutions only in subsets expansion of maize evident in our demographic analyses, we of genes in the highest and lowest 10% quantile of mean GERP reasoned that low-frequency—and thus younger—polymorphisms score, putatively representing genes under the strongest and might show patterns distinct from pairwise diversity, which is weakest purifying selection. As expected, we see higher diversity determined primarily by intermediate frequency—therefore around substitutions in genes under weak purifying selection, but comparably older—alleles. Singleton diversity around missense we still found no difference in diversity near synonymous and and synonymous substitutions (Supplementary Fig. 4) appears NATURE PLANTS | VOL 2 | JULY 2016 | www.nature.com/natureplants 3 © 2016 Macmillan Publishers Limited. All rights reserved The Effect of Negative Selection Adaptive Neutral Nearly Neutral Mildly Deleterious Fairly Deleterious Strongly Deleterious "11 Site-Frequency Spectrum 0.6 Neutral Model Deleterious 0.5 Excess of rare 0.4 mutations 0.3 0.2 Proportion of SNPs 0.1 0.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Derived alleles in sample of 16 chromosomes 12 The Effect of Negative Selection Consequences:! Some proportion of chromosomes eliminated each generation! ➡ Decreased effective population size (f0Ne)! {➡ Decreased neutral variation ( f0π )! Background selection While neutral variation can be lost, some neutral mutations may increase in frequency 13 Background selection (BGS) • Definition: The reduction of diversity at a neutral locus due to the effects of linked deleterious selection • Can estimate the effect of BGS by comparing observed diversity at neutral sites compared to the level of diversity you would expect under neutrality! • π/π0 14 Earlier Theoretical Work Hudson & Kaplan (1995) U f =exp 0 −s + R ✓ ◆ U = deleterious mutation rate s = selection coefficient R = recombination rate 15 Effect of Recombination With recombination, neutral mutations can escape the grip of deleterious mutations. 16 Multiple Targets of Deleterious Mutations Consider a chromosome composed of neutral loci and deleterious loci. 17 Drosophila Deleterious Background Selection 161 1 0.0100 Chromosome 3 l o 8 Observed Predicted 0.0075 A sh = 0.03 e 0 sh =0.02 0 sh =0.005 0.00501 oo: 4 z A n n A D 0.0025 - 0.ooOot. , . P . , . I . 0 500 1000 1500 2000 Physical Position (band) FIGURE 4.-Observed and predicted levels of DNA variation as a function of physical position on the third chromosome of D. rnehnogaster. The observed data, from left to right, are from the following loci: Lspl-y, Hsp26, Sod, Est6, ft, tru, PC, Antp,Gld, MtnA, Hsp7OA, 7y, Ubx, Rh3, E(#), T1, and Mlc2. The DNA variation at MtnA is an estimate of x from LANGE et ul.( 1990) as reported in BEGUNa nd AQUADRO(1 992). The observed level of DNA variation at Hsp7OA is an estimate of 7r from LEIGHBROWN ( 1983) as reported in BEGUNa nd AQUHudsonADRO( 1992).T he othe r o&bse rvKaplaned values are estimat es(1995) of 6' provided by E.