Adaptive Protein Divergence Detection Methods (PDF)

11/7/24 Are there more sensitive ways of detecting adaptive protein divergence (compared to dN/dS)? The McDonald-Kreitman (MK) test 1) Under the null hypothesis (neutral evolution), polymorphism and divergence result from genetic drift 2) Therefore, rapidly evolving proteins should also show...

11/7/24 Are there more sensitive ways of detecting adaptive protein divergence (compared to dN/dS)? The McDonald-Kreitman (MK) test 1) Under the null hypothesis (neutral evolution), polymorphism and divergence result from genetic drift 2) Therefore, rapidly evolving proteins should also show high levels of protein polymorphism within species 3) Polymorphic and fixed amino acid variants are compared to polymorphic and fixed synonymous variants 4) Can only detect adaptation if there are many selectively fixed amino acids and can only reject if there are many variants in a gene (won’t work on short genes) 422 422 Logic of the MK test, FK pp.161-162 Expectation of polymorphic and fixed variants under neutrality Synonymous Nonsynonymous Fixed a b b/a = d/c Polymorphic c d An example of a dataset compatible with neutral protein variation Synonymous Nonsynonymous Fixed 10 5 Polymorphic 20 10 423 423 1  11/7/24 A genealogical view of the MK test – remember, polymorphism and divergence are just drift at two different timescales… µNS, µS = neutral mut rate for Nonsynonymous (NS) and syn variants (S) Divergence 4NµNS/4NµS Polymorphism µNS/µS 424 424 An example of a dataset incompatible with neutral protein variation Polymorphism and divergence in the Relish gene of D. melanogaster and D. simulans (Begun and Whitley 2000) Syn. Nonsyn Polymorphic 41 10 Fixed 40 89 G-test = 37.50, P < 10-5 425 425 2  11/7/24 What fraction of protein divergence results from directional selection? From D. simulans population genomics (Begun et al. 2007) - 20% of genes show evidence of adaptive protein evolution - 30-50% of amino acid fixations due to directional selection - Male reproduction These approaches applied to non-coding DNA suggest adaptive evolution of non-coding DNA is also common in flies Current evidence suggests that effects of directional selection on mammalian genomes are smaller than effects on fly genomes. Why might this be? 426 426 Effects of directional selection on linked genomic regions Polymorphism is positively correlated with recombination Drosophila: Begun and Aquadro 1992, Nature Begun et al. 2007, PLoS Biology Humans: Nachman 2001 Trends in Genetics 427 427 3  11/7/24 FK, 6.11 428 428 Pervasive Natural Selection in the Drosophila Genome? PLOS Genetics. 2009 429 429 4  11/7/24 Polymorphism (blue), divergence (red) and crossing-over (green) on the D. simulans X chromosome Begun et al. 2007 How would the correlation of polymorphism and recombination be explained under the neutral theory? 430 430 Begun and Aquadro 1992 431 431 5  11/7/24 The hitchhiking effect (aka, “selective sweep”) 432 432 New beneficial mutation 433 433 6  11/7/24 Reduces polymorphism, but has no effect on divergence at linked sites Scales with selection coefficient and recombination rate Stronger selection/lower recombination = larger hitchhiking effects 434 434 Hitchhiking with recombination, FK 5.14 435 7  11/7/24 Hitchhiking effects are much weaker when the beneficial mutation pre-dates the onset of selection (i.e., selection on standing variation). These hitchhiking events are referred to as “soft-sweeps” FK, 5.16 436 Why is there no effect of hitchhiking on divergence at linked, neutral sites? A genealogical view: alleles from species 1 Time species 2 species 2 No hitchhiking Hitchhiking 437 437 8  11/7/24 Another hypothesis for the correlation between polymorphism and recombination Background selection, FK 6.12 438 438 If many non-synonymous substitutions are adaptive, what would one predict about the correlation between protein divergence and synonymous polymorphism at nearby sites? Correlation between protein divergence (Ka) and synonymous heterozygosity (ps) in D. melanogaster from Andolfatto, 2007, Genome Res. 439 439 9  11/7/24 Pervasive Adaptive Protein Evolution Apparent in Diversity Patterns around Amino Acid Substitutions in Drosophila simulans Shmuel Sattath, Eyal Elyashiv, Oren Kolodny, Yosef Rinott, Guy Sella PLOS Genetics 2011 440 440 Recent, rapid spread of a beneficial allele to intermediate frequency generates long regions of linkage disequilibrium Creates linkage disequilibrium (haplotype homozygosity) 441 441 10  11/7/24 Evolution of lactase persistence FK, pp. 118-119 Tishkoff et al., Nature Genetics, 2007 442 442 A map of recent positive selection in the human genome Voight et al. PLoS Genetics, 2006 Computer simulations showing the effect of the spread of a beneficial allele on the extent of haplotype homozygosity 443 443 11  11/7/24 A map of recent positive selection in the human genome Voight et al. PLoS Genetics, 2006 Scan for unusual regions of chromosome 2 444 444 Ancient DNA samples support very recent origin of lactase persistence, FK 20.17 445 12  11/7/24 Tibetans have adapted to low oxygen pressure, FK 6.24 Very recent, large changes in frequency likely due to selection 446 Genomic analysis of adaptation to Arctic conditions in the Inuit people of Greenland Metabolism of polyunsaturated fatty-acids (seafood) Matteo Fumagalli et al. Science 2015;349:1343-1347 Published by AAAS 447 13  11/7/24 Modeling Recent Human Evolution in Mice by Expression of a Selected EDAR Variant Cell Volume 152, Issue 4 2013 691 - 702 Figure?1 Origins of 370A (A) Haplotype distribution of the genomic region surrounding V370A , based on 24 SNPs covering ?139 kb. The six most common haplotypes are shown, and the remaining low-frequency hap... http://dx.doi.org/10.1016/j.cell.2013.01.016 Yana?G. Kamberov , Sijia Wang , Jingze Tan , Pascale Gerbault , Abigail Wark , Longzhi Tan , Yajun Yang , Shilin... 448 Population genetic estimates put the favored, derived allele at about 30,000 yrs. old and with a selection coefficient of 0.1. Hypothesis based on correlations is that the allele influenced hair thickness and incisor morphology. Can this hypothesis be tested? 449 449 14  11/7/24 Mice carrying the derived human mutation have thicker hairs Figure?2 Generation of the 370A Mouse (A) Conservation of human and mouse EDAR DD. 370V is in bold with superscript asterisk. (B) Targeting strategy for the introduction of the 370A mutation into the mous... Yana?G. Kamberov , Sijia Wang , Jingze Tan , Pascale Gerbault , Abigail Wark , Longzhi Tan , Yajun Yang , Shilin... Modeling Recent Human Evolution in Mice by Expression of a Selected EDAR Variant Cell Volume 152, Issue 4 2013 691 - 702 http://dx.doi.org/10.1016/j.cell.2013.01.016 450 Some alleles contributing to recent human adaptation have their origin in introgression events from ancient hominins (e.g., EPAS1 and high altitude adaptation in Tibetans). Other examples are pigmentation alleles and alleles possibly associated with diet (Inuits), or the immune system. 451 451 15  11/7/24 Evolution of human skin pigmentation Why did humans evolve darker skin (relative to other apes) The most widely accepted theory posits that is an indirect result of selection on thermoregulation - selection for hair loss - compensatory selection for skin pigmentation 452 (A) Annual mean UVB (305 nm). Nina G. Jablonski, and George Chaplin PNAS 2010;107:8962-8968 ©2010 by National Academ y of Sciences 453 16  11/7/24 Skin color is correlated with latitude Barsh GS (2003) What Controls Variation in Human Skin Color?. PLOS Biology 1(1): e27. https://doi.org/10.1371/journal.pbio.0000027 http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0000027 454 Theories for the evolution of lighter skin. 1) Selection on Vitamin D related traits at high latitudes - UV energy needed to synthesize key intermediates in production of vitamin D - less UV energy at higher latitudes combined with darker skin could result in rickets or other deleterious skeletal phenotypes 2) Folate is required for fertility but is photosensitive. More pigment protecting against folate depletion at low latitudes, but carries a cost and is unnecessary at higher latitudes. 455 17  11/7/24 Tanning is widely viewed as a recent adaptation to seasonally high UV in populations having lower constitutive skin pigmentation 456 SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans, Lamason et al. Science, Dec 2005 457 457 18  11/7/24 SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans, Lamason et al. Science, Dec 2005 458 458 SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans, Lamason et al. Science, Dec 2005 459 459 19  11/7/24 Interestingly, the SLC24A5 allele at high frequency in light-skinned Europeans is not present at high frequency in light-skinned Asian populations. 460 OCA2 makes a major contribution to light skin in Chinese, but not in Europeans From: A Genetic Mechanism for Convergent Skin Lightening during Recent Human Evolution Mol Biol Evol. 2016;33(5):1177-1187. doi:10.1093/molbev/msw003 461 20  11/7/24 The same gene is correlated with pigmentation variation within the Chinese population From: A Genetic Mechanism for Convergent Skin Lightening during Recent Human Evolution Mol Biol Evol. 2016;33(5):1177-1187. doi:10.1093/molbev/msw003 462 Some of the “light skin” alleles spread in the ancestors of Europeans and Asians (2), but a significant amount of lighter pigmentation seems to have evolved independently in these two groups (3, 4) From: The genetic architecture of normal variation in human pigmentation: an evolutionary perspective and model Hum Mol Genet. 2006;15(suppl_2):R176-R181. doi:10.1093/hmg/ddl217 Hum Mol Genet | © The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected] 463 21  11/7/24 Derived immune and ancestral pigmentation alleles in a 7,000-year- old Mesolithic European (13 March 2014) Geographic location and genetic affinities of the La Braña 1 individual. 464 464 465 465 22  11/7/24 This 7,000 yr. old individual carried the HERC2 rs12913832*C single nucleotide polymorphism (SNP) and the associated homozygous haplotype spanning the HERC2s–OCA2 locus that is strongly associated with blue eye color The genotypic combination leading to a predicted phenotype of dark skin and light eyes is unique and no longer present in contemporary European populations The adaptive spread of light skin pigmentation alleles was not complete in some European populations by the Mesolithic, and the spread of alleles associated with light/blue eye color may have preceded changes in skin pigmentation 466 466 Population genetic data from modern humans supports the idea that light skin is a very recently evolved trait 467 23  11/7/24 Evolution of genetic novelties 468 Gene duplications Gene duplications often result from unequal crossing- over 469 469 24  11/7/24 Many new duplications/deletions may be deleterious (dosage effects, gene disruption) Human phenotypes that may be associated with copy number variants Color-blindness Crohn’s disease Parkinson’s disease Autism HIV susceptibility Other duplications may be neutral or beneficial 470 470 Gene family size evolution in mammals, FK 10.5 471 471 25  11/7/24 Mammalian hemoglobins are a classic case of mammalian duplication 472 472 FK 2.16 473 473 26  11/7/24 Two type of homology: orthology (speciation) vs. paralogy (duplication) FK 2.15 Age of gene duplications can be estimated by their phylogenetic distribution…or by sequence divergence between paralogs and a molecular clock a1 and a2 are more closely related to each other than a1 and b1 474 474 Some duplications originate by retroposition rather than unequal crossing-over FK 10.8 475 475 27  11/7/24 Most new duplications are lost due to drift and mutational decay Duplications may fix and diverge under selection for… 1) fitness benefits of increased dosage (e.g., insecticide resistance) 2) sub- or neo-functionalization 476 476 A potential case of adaptive variation related to gene dosage in humans – amylase FK 10.4 A different classic case can be found in mosquito pesticide resistance Perry et al. Nature Genetics, 2007 477 477 28  11/7/24 Two models for the evolution of novel function via duplication 1) Subfunctionalization (p. 268) Duplication and divergence Performs functions Performs A Performs B A and B Both copies diverge from ancestor 478 478 2) Neo-functionalization Duplication and divergence Performs A Performs A Performs B Selection to retain Selection for ancestral function new function Gene B diverges from ancestor 479 479 479 29  11/7/24 Neofunctionalization of a sodium channel gene was a key to the independent origin of electric organs in two families of fishes FK 10.10 Scn44a has lost expression in muscle and gained expression in electric organ (2X). 480 Snake venom is a cocktail of proteins recruited from multiple ancestral organ expression patterns into venom gland expression 481 481 30  11/7/24 Evolution of “radical” genetic novelties… 482 482 Anti-freeze proteins in antarctic fishes derived from non-coding regions of a digestive enzyme 483 483 31  11/7/24 De novo gene evolution, FK p. 267 Genes derived from non-genic DNA Sequence transcriptomes from testis (T), accessory gland (AG) and ejaculatory duct (ED) 484 Identify homologous sequence that is present in all species but is expressed and carries an open reading frame in only one. mel erecta yakuba ananassae 485 32  11/7/24 Genetic data suggest that these genes are born when cis-acting regulatory mutations “activate” pre-existing ORFs (Zhao et al. 2014) 486 A model for de novo gene evolution 1) “Spurious” transcription, often driven by local cis-acting regulatory mutation 2) Most such transcription will be deleterious - cost of transcription - toxic interactions of RNA/protein with other molecules 3) In rare cases, a gene originates and then spreads under directional selection 487 33  11/7/24 Wu D-D, Irwin DM, Zhang Y-P (2011) De Novo Origin of Human Protein-Coding Genes. PLoS Genet 7(11): e1002379. doi:10.1371/journal.pgen.1002379 around 60 new protein coding genes in humans 488 488 Great variance in genome size is mostly unexplained from an evolutionary view, but variation in highly repetitive DNA (e.g., transposable elements) is part of the story 489 489 34  11/7/24 Most genome size variation in plants and animals is unexplained by gene content FK 10.17 490 490 35