Constraints on Natural Selection

Natural Selection does not always proceed in the expected direction, because several forces could interfere with the action of Natural Selection

Constraints on Natural Selection 9/12/2018 Constraints on Natural Selection Genetic Variation: Selection can only act on existing genetic variation (we talked about this last lecture) Phylogenetic Inertia (Historical Constraints): can only build on what is there (hard to make wings without appendages) Pleiotropy: one gene might affect more than one trait. So if you alter a gene, it could have multiple effects. So you might not be able to alter that gene Linkage: alleles close together on a chromosome could share a fate just do to physical proximity and undergo selection and be inherited as a unit Genetic Drift will interfere with the action of Natural Selection in small populations

Constraints on Natural Selection 9/12/2018 Constraints on Natural Selection Phylogenetic Inertia (Historical Constraints): can only build on what is there (hard to make wings without appendages) Physical Constraints (anatomical constraints): a structural or anatomical feature could prevent a modification of a trait (brain might not be able to grow if body cannot grow)

Physical Constraint Developmental constraint Constraint in Body Plan If body size increases, brain size has to increase If a larger eye evolves, need a bigger socket (the socket itself is not the target of selection) Analogy: the Spandrels of San Marco

San Marco Cathedral, Venice Gould & Lewontin: The metaphor: The spandrels of San Marco San Marco Cathedral, Venice

San Marco Cathedral, Venice Gould & Lewontin on Physical Constraint: The spandrels of San Marco might not have been created for a reason, but might simply be a by product due to the creation of arches San Marco Cathedral, Venice

Physical Constraints (examples) Limits to brain size due to head size Limits to eye size due to space on face Limits to finger number due to hand size Limits to body size on land

Constraints on Natural Selection 9/12/2018 Constraints on Natural Selection Genetic Variation: Selection can only act on existing genetic variation (we talked about this last lecture) Phylogenetic Inertia (Historical Constraints): can only build on what is there (hard to make wings without appendages) Pleiotropy: one gene might affect more than one trait. So if you alter a gene, it could have multiple effects. So you might not be able to alter that gene Linkage: alleles close together on a chromosome could share a fate just do to physical proximity and undergo selection and be inherited as a unit Genetic Drift will interfere with the action of Natural Selection in small populations

Pleiotropy: when a gene affects many traits or functions 9/12/2018 Pleiotropy: when a gene affects many traits or functions Selection might not be able to act on trait if the gene that encodes the trait is Pleiotropic, and also affects other traits. So, changing the gene could negatively affect the other traits Gene Network Conversely, a seemingly unbeneficial trait might get selected for because the gene that codes for it also enhances fitness Pleiotropy could sometimes lead to evolutionary tradeoffs (you can have evolutionary tradeoffs that are not pleiotropic– between traits encoded by different genes) Proceedings: Biological Sciences ISSN: 0962-8452 (Paper) 1471-2954 (Online) Issue: Volume 271, Number 1554 / November 07, 2004 Pages: 2217 - 2221 Abstract: The Darwinian paradox of male homosexuality in humans is examined, i.e. if male homosexuality has a genetic component and homosexuals reproduce less than heterosexuals, then why is this trait maintained in the population? In a sample of 98 homosexual and 100 heterosexual men and their relatives (a total of over 4600 individuals), we found that female maternal relatives of homosexuals have higher fecundity than female maternal relatives of heterosexuals and that this difference is not found in female paternal relatives. The study confirms previous reports, in particular that homosexuals have more maternal than paternal male homosexual relatives, that homosexual males are more often later-born than first-born and that they have more older brothers than older sisters. We discuss the findings and their implications for current research on male homosexuality.

Pleiotropy: when a gene affects many traits or functions 9/12/2018 Pleiotropy: when a gene affects many traits or functions Difficult to select on a gene that affects multiple traits: Because, changing the gene could negatively affect the other traits Conversely, a seemingly unbeneficial trait might get selected for because the gene that codes for it also enhances fitness, due to beneficial impacts on another trait Antagonistic Pleiotropy could lead to evolutionary tradeoffs Proceedings: Biological Sciences ISSN: 0962-8452 (Paper) 1471-2954 (Online) Issue: Volume 271, Number 1554 / November 07, 2004 Pages: 2217 - 2221 Abstract: The Darwinian paradox of male homosexuality in humans is examined, i.e. if male homosexuality has a genetic component and homosexuals reproduce less than heterosexuals, then why is this trait maintained in the population? In a sample of 98 homosexual and 100 heterosexual men and their relatives (a total of over 4600 individuals), we found that female maternal relatives of homosexuals have higher fecundity than female maternal relatives of heterosexuals and that this difference is not found in female paternal relatives. The study confirms previous reports, in particular that homosexuals have more maternal than paternal male homosexual relatives, that homosexual males are more often later-born than first-born and that they have more older brothers than older sisters. We discuss the findings and their implications for current research on male homosexuality.

Antagonistic Pleiotropy: when one gene controls for more than one trait where at least one of these traits is beneficial to the organism's fitness and at least one is detrimental to the organism's fitness. Pawlowski, B., Dunbar, R. I. M. and Lipowicz, A. 2000 Evolutionary fitness: Tall men have more reproductive success. Nature 403: 156.

Hard to select on a gene that affects multiple traits (pleiotropy) Antagonist pleiotropy can lead to trade offs Water retention might be good for desiccation resistance, but also cause hypertension High estrogen could increase fertility, but also increase cancer (estrogen has many targets in the body, and many consequences) Some genes (“Thrifty genes”) are helpful in famines but also lead to diabetes and obesity (https://docs.google.com/viewer?a=v&q=cache:pgRlIhEJligJ:www2.uah.es/salud-y-enfermedad/pdf/The%2520double%2520puzzle%2520of%2520diabetes.pdf+&hl=en&gl=us&pid=bl&srcid=ADGEESgMnHzClSUTNI0ZGz690SR4Dq-SzAVrwRfKILLhBESRcADGmLWJZAUg0IKftVhXpxQumQ0Ox8zixtrylo9xmuZLG30zXRue2M-Xl3GB7XYwxxS0PQZjFlJaoZ6rAOqF0KSuEC5I&sig=AHIEtbT8VrWAgqBRyM46mdeCd3AycemudQ)Ta

Antagonist pleiotropy can lead to evolutionary trade offs (we are interested in fitness trade offs) Mutations at single genes that cause high estrogen levels could increase fertility (trait 1), but also cause cell proliferation in breast and ovarian tissue (trait 2) leading to cancer (estrogen has many targets in the body, and many consequences) In HIV, slow and careful reverse transcriptase confers AZT resistance (trait 1), but slow growth rate (trait 2) Sickle Cell Anemia - heterozygote for the Hb locus (HgbS) leads to resistance to malaria (removal of parasite from blood, trait 1) but lower oxygen carrying capacity (trait 2)

Not all Evolutionary Tradeoffs are due to Antagonistic Pleiotropy Evolutionary tradeoffs could arise between traits encoded by multiple genes With limited resources, there would be evolutionary tradeoffs between growth and reproduction There could be tradeoffs between lifespan and reproduction

Constraints on Natural Selection 9/12/2018 Constraints on Natural Selection Genetic Variation: Selection can only act on existing genetic variation (we talked about this last lecture) Phylogenetic Inertia (Historical Constraints): can only build on what is there (hard to make wings without appendages) Pleiotropy: one gene might affect more than one trait. So if you alter a gene, it could have multiple effects. So you might not be able to alter that gene Linkage: alleles close together on a chromosome could share a fate just do to physical proximity and undergo selection and be inherited as a unit Genetic Drift will interfere with the action of Natural Selection in small populations

Linkage Definition: The tendency for certain alleles to be inherited together due to their physical proximity on the chromosome Human linkage map Phenotypic evolution could arise due to linkage (≠adaptation): Genes might experience an evolutionary shift because another gene closely linked on the chromosome is under selection (selective sweep, genetic hitchhiking) This is a genetic mechanism of evolutionary change that is NOT adaptive

Linkage Definition: The tendency for certain alleles to be inherited together due to their physical proximity on the chromosome Human linkage map Consequence: Selection at a locus (gene) might cause selection at many other genes closely linked on a chromosome, even if there is no reason for those other genes to evolve

Constraints on Natural Selection 9/12/2018 Constraints on Natural Selection Genetic Variation: Selection can only act on existing genetic variation (we talked about this last lecture) Phylogenetic Inertia (Historical Constraints): can only build on what is there (hard to make wings without appendages) Pleiotropy: one gene might affect more than one trait. So if you alter a gene, it could have multiple effects. So you might not be able to alter that gene Linkage: alleles close together on a chromosome could share a fate just do to physical proximity and undergo selection and be inherited as a unit Genetic Drift will interfere with the action of Natural Selection in small populations

Genetic Drift and Natural Selection Because of the randomness introduced by Genetic Drift, Natural Selection is less efficient when there is genetic drift Thus, Natural Selection is more efficient in larger populations, and less effective in smaller populations

Selection acts only on genes that are expressed Remember that selection acts on the phenotype… the traits that are expressed, given the genotype

Adaptation vs Plasticity

Conceptual Confusions 9/12/2018 Conceptual Confusions Trait variation is often assumed to be due to Adaptation, when the differences might be due to Phenotypic Plasticity or nonadaptive genetic causes

The Problem: People often wish to jump to the conclusion that a trait change they see is the result of adaptation (Natural Selection) However, that is not always the case. There are other mechanisms that could cause phenotypic variation This is what Stephen Jay Gould called the “Adaptationist Paradigm”

The Problem: Adaptations are ubiquitous, but demonstrating that a particular trait is an adaptation is not always easy

The Problem Need to distinguish genetically-based differences from plastic (environmentally-induced) differences Need to distinguish adaptive genetically-based differences (due to Natural Selection) from nonadaptive genetically-based differences (due to other forces)

Example in which adaptation and plasticity were poorly distinguished: The Bell Curve, 1994 by Murray and Hernstein Murray and Hernstein used IQ score differences to make the argument that African-Americans are genetically (and evolutionarily) less intelligent than European and Asian-Americans Scientifically, there are key flaws in their argument

Their argument has key flaws: (1) Not account for environmental effects on IQ intelligence is known to be a plastic trait, affected by pollution (lead), nutrition, cognitive stimulation, etc. (2) Correlation is associative, not causative If IQ and “race” are correlated, it does not mean that race is responsible for IQ A third factor could be correlated with both race and IQ that might actually be the underlying cause

Fischer reanalyzed Murray and Hernstein’s data and found that socio-economic status was a stronger determinant of IQ scores than race, even in their examples (Inequality by Design: Cracking The `Bell Curve' Myth) Rigorous tests are required to determine whether or not IQ is genetically based in human populations (later in the lecture)

Components of Phenotypic Variation Quantitative traits are controlled by many loci, many of which with small effects. For quantitative traits, we depict the sources of variation as follows: Phenotypic variation (VP) is a result of variation that is due to both genetic effects (VG), and variation due to environmental factors (VE) and their interaction (VGxE) VP = VG + VE + VGxE So, some of the variation could be due to genetic causes, but some might be induced by the environment (as a result of gene expression).

In other words: VP = VG + VE + V(GxE) VG: Genetically based (and heritable) differences, resulting from natural selection (adaptation) or other genetic factors (genetic drift, etc) VE: Differences that are inducible by the environment by a given genotype (acclimation, phenotypic plasticity)

AND Not All Heritable Variation is due to Adaptation (Natural Selection)!!! Phenotypic change and variation could have other causes: Plasticity: Changes that are not due to genetic changes, but due to changes in gene expression: Phenotypic Plasticity (including nonheritable epigenetic modifications) Changes that are Genetic, but NOT adaptive: Genetic Drift: random chance Linkage and Genetic Hitchhiking: Genetic changes that occur because the gene was right next to another gene on a chromosome that was under selection Physical or structural Constraints (like the Spandrels)

Critique of the “Adaptationist Programme” Gould & Lewontin 1979 Critique of the “Adaptationist Programme” Gould & Lewontin 1979. The Spandrels of San Marco and the Panglossian Paradigm: A Critique of the Adaptationist Programme. One of the most important papers in Evolutionary Biology They critique the “Adaptationist” and “Panglossian Programme” that assumes that a phenotypic change is the result of adaptation Gould & Lewontin point out that not all phenotypic variation or phenotypic evolution is the result of adaptation

San Marco Cathedral, Venice Gould & Lewontin: The spandrels of San Marco San Marco Cathedral, Venice

San Marco Cathedral, Venice Gould & Lewontin on Physical Constraint: The spandrels of San Marco might not have been created for a reason, but might simply be a by product due to the creation of arches San Marco Cathedral, Venice

Adaptation Requires Natural Selection Requires polymorphism in a population MUST have an effect on Fitness Is a frequency (%) change in a population There must be a Selective Force

How can you tell if a trait evolved as a result of adaptation? (1) The trait must be heritable (2) The differences between populations are genetically based differences rather than inducible differences (plasticity) (3) The trait has fitness consequences (promotes survival, performance, and number of offspring) (If a trait evolved due to genetic drift, linkage or pleiotropy, the change is genetic, but may confer no fitness advantage)

Phenotypic Plasticity Definition: Differences in phenotype that a genotype exhibits across a range of environments Some traits with a plastic component: intelligence, height, temperature tolerance, salinity tolerance, muscle mass…

Acclimation (≠ Adaptation) 1) Result of Phenotypic Plasticity 2) Not heritable 3) Short term or developmental response within a single generation 4) Arises through differential gene expression or other regulatory mechanism rather than natural selection

Nature (genetics) vs Nurture (environment) Both environment and genetics affect many traits, but need to experimentally or statistically separate these factors How? Example: Common-garden experiment Having appropriate controls Statistically assessing the effect of environment

This is a general problem This type of problem is a factor in all studies that attempt to associate a gene with a trait You need to account for the effects of environment For example, problems arise when different labs attempt to associate a gene with a disease using laboratory mice that have been reared under different conditions

Types of Plasticity Short-term reversible Development acclimation: generally irreversible Genotype --> Development --> Phenotype Within normal tolerance range In response to Stress

Plasticity can be depicted graphically as a Reaction Norm Response Environment Reaction Norm: the function which describes the plastic response

Response Environment In the case of plasticity, the different phenotypes in different environments are NOT the result of Adaptation… The Genotype(s) in the environments are NOT changing The differences between them are due to differences in response (such as gene expression) in different environments

Dodson, SI. 1989. Predator induced reaction norms Dodson, SI. 1989. Predator induced reaction norms. BioScience 39:447–452

Predator induced formation of helmets in Daphnia Hebert and Grewe, 1985

Genotype x Environment Interaction 9/12/2018 The next 4 slides are optional because of lack of time Genotype x Environment Interaction VP = VG + VE + V(GxE)  this last interaction term Changes in rank or level of performance among genotypes when tested in different environments Reveals genetic variation for plasticity Could reflect tradeoffs between fitness of different genotypes in different environments

Trade-offs in different environments 9/12/2018 When lines cross, the implication is that different environments will select for different phenotypes Response Environment Trade-offs in different environments

Size big small hot cold Temperature 9/12/2018 Select for this reaction norm in cold environments big Size small Select for this reaction norm in hot environments cold hot Temperature Could get selection for different reaction norms (different plasticity) in different environments

9/12/2018 Genetic variation for plasticity can be determined by examining the significance of the interaction term from an Analysis of Variance (ANOVA) Genetic Variation for Plasticity No Genetic Variation for Plasticity Response Environment Environment

Example: Human IQ Data Data: Many studies use survey data on human populations in the US (not a common-garden experiment, where environment is held constant) Did not statistically account for differences in environment A correlation is associative, and not necessarily causative

Problems with data and statistical analysis: Several reanalyses have found that socio-economic status (and historical factors) was a stronger determinant of IQ scores than “race.” Socio-economic status could reflect nutrition, access to education, etc.

Impact of environment must be accounted for: There is an IQ gap between blacks and whites in America, Japanese and Koreans in Japan, Ashkenazi and Sephardic Jews in Israel, and Protestants and Catholics in Northern Ireland. As economic conditions improve for the subordinated groups, the gaps are reduced A common-garden experiment has never been performed on humans with respect to IQ scores to determine actual genetic differences with environmental effects removed Do not know of any study of IQ that has effectively controlled for socio-economic differences

Most Importantly, Must distinguish (1) genetically based differences from phenotypic plasticity AND (2) genetic differences due to adaptations (natural selection) vs other causes of genetic differences (drift, just different mutations arising in different populations, etc. Many experiments fail to do this Examples: drug response, hormone replacement therapy

How to distinguish between genetically based traits vs How to distinguish between genetically based traits vs. phenotypic plasticity? Animal Model Analyses: Determine how much of a trait is due to additive, dominance, genetic variance etc (quantitative genetic methods) – not cover here Common-garden experiment: rear different populations in a common environment to remove the effects of environmental plasticity, and determine how much variation is remaining (and due to genetic effects). Molecular Genetic Approaches: transgenic or gene knockout studies, to determine the impacts of particular genes on a trait

If the phenotypic change is genetically based, How to detect if the change was due to selection? Selection in the Wild: Look at selection response in nature (R= h2S, breeder’s equation) Selection Experiments (Experimental Evolution): Impose selection on a population, then examine evolutionary shift Genetic Signatures of Selection: Look for genetic signatures of natural selection in the DNA sequences

Is the trait change genetically based? 9/12/2018 Is the trait change genetically based?

What is a common-garden Experiment? An Experiment in which individuals from different populations or species are reared under identical conditions (can be over a range of conditions) Remove differences due to environmental plasticity

Different Populations Example: Different Populations A saltwater population and a freshwater population of a small crustacean (copepod) show differences in salinity tolerance. Are the differences due to simply being reared at different salinities, or are the differences due to genetically based differences? And three separate experiments were performed where the parentals were reared at a common salinity for 0, 2, and 5 generations prior to experimentation In this case 0 generations at 5 PSU, meaning that they were reared at their native salinities

Different Populations Common Garden Experiment Different Populations Rear under common conditions To determine the differences when the environment is held constant And three separate experiments were performed where the parentals were reared at a common salinity for 0, 2, and 5 generations prior to experimentation In this case 0 generations at 5 PSU, meaning that they were reared at their native salinities

Different Populations Common Garden Experiment If the populations still differ under common-garden conditions, the differences are genetically based. But are these genetic differences the result of adaptation? (or some other genetic cause) Different Populations And three separate experiments were performed where the parentals were reared at a common salinity for 0, 2, and 5 generations prior to experimentation In this case 0 generations at 5 PSU, meaning that they were reared at their native salinities

Molecular genetic approaches to determine the genetic basis of a trait Is that gene causing the trait? Transgenics, gene knockout studies, CRISPR gene editing, RNAi, etc. Generally use model systems, such as mice, fruit flies, C. elegans, etc.

9/12/2018 Detecting Selection

Laboratory Selection Experiments But is salinity really the factor causing the evolutionary physiological change? Perform selection experiments to test whether the evolutionary change happens in response to salinity alone. But then the question is, salinity really the factor that caused the evolutionary change?… many factors might change during saline to freshwater invasions in the wild, such as food, pH, temperature fluctuations, etc. To address these questions, we performed selection experiments to test whether the evolutionary response could take place due to salinity alone We took the ancestral saline populations, and imposed selection for freshwater tolerance across 12 generations

Selection in the Lab saline ancestors Control Selection in the Lab Selection for several generations Take the saline population and then imposed selection for freshwater tolerance Compare the populations before and after selection Do the selection lines show the same evolutionary shift to fresh water as the wild population? ancestor freshwater selected lines 5 5 5 So, we performed selection experiments and produced artificial freshwater populations. We took saline ancestral populations and brought them down in salinity and selected for freshwater tolerance over 7 generations and then maintained them at fresh water for an additional 5 generations. We did this twice from each saltwater ancestral population. And we did this from multiple saltwater populations (St. Lawrence and Gulf). We also maintained a control at high salinity. reared at compromised salinity to remove effects of acclimation We then the ancestral population with freshwater selected lines, and measured enzyme activity across salinities. acclimate at same salinity 5 15 Common garden experiment at the end of the selection

Detecting signatures of selection in DNA sequences So, how does one detect Natural Selection in a population? Many types of tests: use signatures of Linkage Disequlibrium, reduced variation (Selective Sweep), genetic deviation (Phi- ST) The challenge is distinguishing natural selection from signatures of Genetic Drift

RNA Codons In the case of amino acids Mutations in Position 1, 2 lead to Amino Acid change Mutations in Position 3 often don’t matter

> 1 Simplest Test: Ka/Ks Test Nonsynonymous substitution rate Ka Synonymous substitution rate Ks Need coding sequence (sequence that codes proteins) Ks is used here as the “control”, proxy for neutral evolution A greater rate of nonsynonymous substitutions (Ka) than synonymous (Ks) is used as an indication of selection (Ka/Ks >1) Substitution rate: out of all the possible number of mutations, how many fixed > 1

> 1 Ka/Ks Test Nonsynonymous substitution rate Ka Synonymous substitution rate Ks In the absence of selection, you’d expect Ks = Ka, and for Ka/Ks = 1 A greater rate of nonsynonymous substitutions (Ka) than synonymous (Ks) is used as an indication of positive selection (Ka/Ks >1) If Ks > Ka, or Ka/Ks < 1, that would suggest purifying selection, that selection might be preserving amino acid composition > 1

Examples: Adaptation or not? A plant grows taller to obtain more sunlight Weeds in cornfields (corn is tall) are on average taller than weeds of the same species in soybean fields in order to obtain more sunlight

Examples: Adaptation or not? A plant grows taller to obtain more sunlight Plasticity Weeds in cornfields (corn is tall) are on average taller than weeds of the same species in soybean fields in order to obtain more sunlight Not enough information

Examples: Adaptation or not? Weeds in a cornfield have been found to grow taller than those in soybean fields when both populations are reared in common-garden conditions Taller weeds in the cornfields survive and a greater rate and leave more offspring Weeds in a cornfield have been found to grow taller than those in soybean fields when both populations are reared in common-garden conditions : There are genetic differences.. But are they adaptive? The trait must have fitness consequences

Examples: Adaptation or not? Weeds in a cornfield have been found to grow taller than those in soybean fields when both populations are reared in common-garden conditions They are genetically different, but not know for sure if it is adaptation (could be linkage, genetic drift) Taller weeds in the cornfields survive and a greater rate and leave more offspring Very like to be Adaptation Weeds in a cornfield have been found to grow taller than those in soybean fields when both populations are reared in common-garden conditions : There are genetic differences.. But are they adaptive? The trait must have fitness consequences

Which of the following is an example of a pleiotropic effect that would likely lead to an evolutionary tradeoff? (a) A gene that increases reproduction also shortens life span (b) A gene that encodes for high sprint speed is negatively correlated with another gene that encodes for low muscle mass (c) A gene that causes deafness also causes blindness (d) A gene that encodes for blue eyes also increases the risk for cataracts (e) A gene that increases reproduction also reduces susceptibility to disease

16. Which of the following cases provides the best evidence for adaptation (due to natural selection)? (a) When two populations of mice, one from the North and one from the South, are reared in the same conditions in the lab, the population from the North has larger body size than the Southern population (b) Two populations of rabbits differ in coat color. When they are reared under the same conditions, the differences in coat color remain. The genes underlying coat color show signatures of positive selection. (c) A plant that is reared on more nutritious soil grows taller than other plants that are grown on nutrient deficient soils (d) A population of frogs living on green foliage has green skin, whereas a population of frogs living on brown foliage has brown skin (e) Two populations of birds differ in beak size. The differences remain when they are reared under common-garden conditions. The alleles frequencies at the genes for beak size differ between the two populations.

1-a 2-b