Evolutionary Selection and Constraint on Human Knee Chondrocyte Regulation Impacts Osteoarthritis Risk.

During human evolution, the knee adapted to the biomechanical demands of bipedalism by altering chondrocyte developmental programs. This adaptive process was likely not without deleterious consequences to health. Today, osteoarthritis occurs in 250 million people, with risk variants enriched in non-coding sequences near chondrocyte genes, loci that likely became optimized during knee evolution. We explore this relationship by epigenetically profiling joint chondrocytes, revealing ancient selection and recent constraint and drift on knee regulatory elements, which also overlap osteoarthritis variants that contribute to disease heritability by tending to modify constrained functional sequence. We propose a model whereby genetic violations to regulatory constraint, tolerated during knee development, lead to adult pathology. In support, we discover a causal enhancer variant (rs6060369) present in billions of people at a risk locus (GDF5-UQCC1), showing how it impacts mouse knee-shape and osteoarthritis. Overall, our methods link an evolutionarily novel aspect of human anatomy to its pathogenesis.

A nonadaptive explanation for macroevolutionary patterns in the evolution of complex multicellularity.

"Complex multicellularity," conventionally defined as large organisms with many specialized cell types, has evolved five times independently in eukaryotes, but never within prokaryotes. A number of hypotheses have been proposed to explain this phenomenon, most of which posit that eukaryotes evolved key traits (e.g., dynamic cytoskeletons, alternative mechanisms of gene regulation, or subcellular compartments) which were a necessary prerequisite for the evolution of complex multicellularity. Here, we propose an alternative, nonadaptive hypothesis for this broad macroevolutionary pattern. By binning cells into groups with finite genetic bottlenecks between generations, the evolution of multicellularity greatly reduces the effective population size (Ne) of cellular populations, increasing the role of genetic drift in evolutionary change. While both prokaryotes and eukaryotes experience this phenomenon, they have opposite responses to drift: eukaryotes tend to undergo genomic expansion, providing additional raw genetic material for subsequent multicellular innovation, while prokaryotes generally face genomic erosion. Taken together, we hypothesize that these idiosyncratic lineage-specific evolutionary dynamics play a fundamental role in the long-term divergent evolution of complex multicellularity across the tree of life.

The Ingenuity of Bacterial Genomes.

The genomes of bacteria contain fewer genes and substantially less noncoding DNA than those of eukaryotes, and as a result, they have much less raw material to invent new traits. Yet, bacteria are vastly more taxonomically diverse, numerically abundant, and globally successful in colonizing new habitats compared to eukaryotes. Although bacterial genomes are generally considered to be optimized for efficient growth and rapid adaptation, nonadaptive processes have played a major role in shaping the size, contents, and compact organization of bacterial genomes and have allowed the establishment of deleterious traits that serve as the raw materials for genetic innovation.

Emergent evolutionary forces in spatial models of luminal growth and their application to the human gut microbiota.

The genetic composition of the gut microbiota is constantly reshaped by ecological and evolutionary forces. These strain-level dynamics are challenging to understand because they depend on complex spatial growth processes that take place within a host. Here we introduce a population genetic framework to predict how stochastic evolutionary forces emerge from simple models of microbial growth in spatially extended environments like the intestinal lumen. Our framework shows how fluid flow and longitudinal variation in growth rate combine to shape the frequencies of genetic variants in simulated fecal samples, yielding analytical expressions for the effective generation times, selection coefficients, and rates of genetic drift. We find that over longer timescales, the emergent evolutionary dynamics can often be captured by well-mixed models that lack explicit spatial structure, even when there is substantial spatial variation in species-level composition. By applying these results to the human colon, we find that continuous fluid flow and simple forms of wall growth alone are unlikely to create sufficient bottlenecks to allow large fluctuations in mutant frequencies within a host. We also find that the effective generation times may be significantly shorter than expected from traditional average growth rate estimates. Our results provide a starting point for quantifying genetic turnover in spatially extended settings like the gut microbiota and may be relevant for other microbial ecosystems where unidirectional fluid flow plays an important role.

Influence of selection on the probability of fixation at a locus with multiple alleles.

BACKGROUND: Genes exist in a population in a variety of forms (alleles), as a consequence of multiple mutation events that have arisen over the course of time. In this work we consider a locus that is subject to either multiplicative or additive selection, and has n alleles, where n can take the values 2, 3, 4, … . We focus on determining the probability of fixation of each of the n alleles. For n = 2 alleles, analytical results, that are 'exact', under the diffusion approximation, can be found for the fixation probability. However generally there are no equally exact results for n ≥ 3 alleles. In the absence of such exact results, we proceed by finding results for the fixation probability, under the diffusion approximation, as a power series in scaled strengths of selection such as R i , j = 2 N e ( s i - s j ) , where N e is the effective population size, while s i and s j are the selection coefficients associated with alleles i and j, respectively. RESULTS: We determined the fixation probability when all terms up to second order in the R i , j are kept. The truncation of the power series requires that the R i , j cannot be indefinitely large. For magnitudes of the R i , j up to a value of approximately 1, numerical evidence suggests that the results work well. Additionally, results given for the particular case of n = 3 alleles illustrate a general feature that holds for n ≥ 3 alleles, that the fixation probability of a particular allele depends on that allele's initial frequency, but generally, this fixation probability also depends on the initial frequencies of other alleles at the locus, as well as their selective effects. CONCLUSIONS: We have analytically exposed the leading way the probability of fixation, at a locus with multiple alleles, is affected by selection. This result may offer important insights into CDCV traits that have extreme phenotypic variance due to numerous, low-penetrance susceptibility alleles.

Role-reversed polyandry is associated with faster fast-Z in shorebirds.

In birds, males are homogametic and carry two copies of the Z chromosome ('ZZ'), while females are heterogametic and exhibit a 'ZW' genotype. The Z chromosome evolves at a faster rate than similarly sized autosomes, a phenomenon termed 'fast-Z evolution'. This is thought to be caused by two independent processes-greater Z chromosome genetic drift owing to a reduced effective population size, and stronger Z chromosome positive selection owing to the exposure of partially recessive alleles to selection. Here, we investigate the relative contributions of these processes by considering the effect of role-reversed polyandry on fast-Z in shorebirds, a paraphyletic group of wading birds that exhibit unusually diverse mating systems. We find stronger fast-Z effects under role-reversed polyandry, which is consistent with particularly strong selection on polyandrous females driving the fixation of recessive beneficial alleles. This result contrasts with previous research in birds, which has tended to implicate a primary role of genetic drift in driving fast-Z variation. We suggest that this discrepancy can be interpreted in two ways-stronger sexual selection acting on polyandrous females overwhelms an otherwise central role of genetic drift, and/or sexual antagonism is also contributing significantly to fast-Z and is exacerbated in sexually dimorphic species.

Shared xerophytic genes and their re-use in local adaptation to aridity in the desert plant Gymnocarpos przewalskii.

In order to thrive and survive, plant species need to combine stability in the long term and rapid response to environmental challenges in the short term. The former would be reflected by parallel or convergent adaptation across species, and the latter by pronounced local adaptation among populations of the same species. In the present study, we generated a high-quality genome and re-sequenced 177 individuals for Gymnocarpos przewalskii, an important desert plant species from North-West China, to detect local adaptation. We first focus on ancient adaptation to aridity at the molecular level by comparing the genomic data of 15 species that vary in their ability to withstand aridity. We found that a total of 118 genes were shared across xerophytic species but absent from non-xerophytic species. Of the 65 found in G. przewalskii, 63 were under purifying selection and two under positive selection. We then focused on local adaptation. Up to 20% of the G. przewalskii genome showed signatures of local adaptation to aridity during population divergence. Thirteen of the selected shared xerophytic genes were reused in local adaptation after population differentiation. Hence, only about 20% of the genes shared and specific to xerophytic species and associated with adaptation to aridity were later recruited for local adaptation in G. przewalskii.

Virus Evolution Faced to Multiple Host Targets: The Potyvirus-Pepper Case Study.

The wealth of variability amongst genes controlling immunity against potyviruses in pepper (Capsicum spp.) has been instrumental in understanding plant-virus co-evolution and major determinants of plant resistance durability. Characterization of the eukaryotic initiation factor 4E1 (eIF4E1), involved in mRNA translation, as the basis of potyvirus resistance in pepper initiated a large body of work that showed that recessive resistance to potyviruses and other single-stranded positive-sense RNA viruses resulted from mutations in eukaryotic initiation factors in many plant crop species. Combining mutations in different eIF4Es in the same pepper genotype had complex effects on the breadth of the resistance spectrum and on resistance durability, revealing a trade-off between these two traits. In addition, combining eIF4E1 mutations with a quantitatively resistant genetic background had a strong positive effect on resistance durability. Analysing the evolutionary forces imposed by pepper genotypes onto virus populations allowed identifying three key factors improving plant resistance durability: the complexity of mutational pathways involved in virus adaptation to the plant resistance, the decrease of competitivity induced by these mutations on the virus and the intensity of genetic drift imposed by plant genotypes on the virus during its infection cycle.

Limits to selection on standing variation in an asexual population.

We consider how a population of N haploid individuals responds to directional selection on standing variation, with no new variation from recombination or mutation. Individuals have trait values z1,…,zN, which are drawn from a distribution ψ; the fitness of individual i is proportional to [Formula: see text] . For illustration, we consider the Laplace and Gaussian distributions, which are parametrised only by the variance V0, and show that for large N, there is a scaling limit which depends on a single parameter NV0. When selection is weak relative to drift (NV0≪1), the variance decreases exponentially at rate 1/N, and the expected ultimate gain in log fitness (scaled by V0), is just NV0, which is the same as Robertson's (1960) prediction for a sexual population. In contrast, when selection is strong relative to drift (NV0≫1), the ultimate gain can be found by approximating the establishment of alleles by a branching process in which each allele competes independently with the population mean and the fittest allele to establish is certain to fix. Then, if the probability of survival to time t∼1/V0 of an allele with value z is P(z), with mean P¯, the winning allele is the fittest of NP¯ survivors drawn from a distribution ψP/P¯. The expected ultimate change is ∼2log(1.15NV0) for a Gaussian distribution, and ∼-12log0.36NV0-log-log0.36NV0 for a Laplace distribution. This approach also predicts the variability of the process, and its dynamics; we show that in the strong selection regime, the expected genetic variance decreases as ∼t-3 at large times. We discuss how these results may be related to selection on standing variation that is spread along a linear chromosome.

The coalescent in finite populations with arbitrary, fixed structure.

The coalescent is a stochastic process representing ancestral lineages in a population undergoing neutral genetic drift. Originally defined for a well-mixed population, the coalescent has been adapted in various ways to accommodate spatial, age, and class structure, along with other features of real-world populations. To further extend the range of population structures to which coalescent theory applies, we formulate a coalescent process for a broad class of neutral drift models with arbitrary - but fixed - spatial, age, sex, and class structure, haploid or diploid genetics, and any fixed mating pattern. Here, the coalescent is represented as a random sequence of mappings [Formula: see text] from a finite set G to itself. The set G represents the "sites" (in individuals, in particular locations and/or classes) at which these alleles can live. The state of the coalescent, Ct:G→G, maps each site g∈G to the site containing g's ancestor, t time-steps into the past. Using this representation, we define and analyze coalescence time, coalescence branch length, mutations prior to coalescence, and stationary probabilities of identity-by-descent and identity-by-state. For low mutation, we provide a recipe for computing identity-by-descent and identity-by-state probabilities via the coalescent. Applying our results to a diploid population with arbitrary sex ratio r, we find that measures of genetic dissimilarity, among any set of sites, are scaled by 4r(1-r) relative to the even sex ratio case.

Temporal genomics help in deciphering neutral and adaptive patterns in the contemporary evolution of kelp populations.

The impact of climate change on populations will be contingent upon their contemporary adaptive evolution. In this study, we investigated the contemporary evolution of 4 populations of the cold-water kelp Laminaria digitata by analyzing their spatial and temporal genomic variations using ddRAD-sequencing. These populations were sampled from the center to the southern margin of its north-eastern Atlantic distribution at 2 time points, spanning at least 2 generations. Through genome scans for local adaptation at a single time point, we identified candidate loci that showed clinal variation correlated with changes in sea surface temperature (SST) along latitudinal gradients. This finding suggests that SST may drive the adaptive response of these kelp populations, although factors such as species' demographic history should also be considered. Additionally, we performed a simulation approach to distinguish the effect of selection from genetic drift in allele frequency changes over time. This enabled the detection of loci in the southernmost population that exhibited temporal differentiation beyond what would be expected from genetic drift alone: these are candidate loci which could have evolved under selection over time. In contrast, we did not detect any outlier locus based on temporal differentiation in the population from the North Sea, which also displayed low and decreasing levels of genetic diversity. The diverse evolutionary scenarios observed among populations can be attributed to variations in the prevalence of selection relative to genetic drift across different environments. Therefore, our study highlights the potential of temporal genomics to offer valuable insights into the contemporary evolution of marine foundation species facing climate change.

Historical museum samples reveal signals of selection and drift in response to changing insecticide use in an agricultural pest moth.

In response to environmental and human-imposed selective pressures, agroecosystem pests frequently undergo rapid evolution, with some species having a remarkable capacity to rapidly develop pesticide resistance. Temporal sampling of genomic data can comprehensively capture such adaptive changes over time, for example, by elucidating allele frequency shifts in pesticide resistance loci in response to different pesticides. Here, we leveraged museum specimens spanning over a century of collections to generate temporal contrasts between pre- and post-insecticide populations of an agricultural pest moth, Helicoverpa armigera. We used targeted exon sequencing of 254 samples collected across Australia from the pre-1950s (prior to insecticide introduction) to the 1990s, encompassing decades of changing insecticide use. Our sequencing approach focused on genes that are known to be involved in insecticide resistance, environmental sensation, and stress tolerance. We found an overall lack of spatial and temporal population structure change across Australia. In some decades (e.g., 1960s and 1970s), we found a moderate reduction of genetic diversity, implying stochasticity in evolutionary trajectories due to genetic drift. Temporal genome scans showed extensive evidence of selection following insecticide use, although the majority of selected variants were low impact. Finally, alternating trajectories of allele frequency change were suggestive of potential antagonistic pleiotropy. Our results provide new insights into recent evolutionary responses in an agricultural pest and show how temporal contrasts using museum specimens can improve mechanistic understanding of rapid evolution.

Divergent lineages in a young species: The case of datilillo (Yucca valida), a broadly distributed plant from the Baja California Peninsula.

PREMISE: Globally, barriers triggered by climatic changes have caused habitat fragmentation and population allopatric divergence. Across North America, oscillations during the Quaternary have played important roles in the distribution of wildlife. Notably, diverse plant species from the Baja California Peninsula in western North America, isolated during the Pleistocene glacial-interglacial cycles, exhibit strong genetic structure and highly concordant divergent lineages across their ranges. A representative plant genus of the peninsula is Yucca, with Y. valida having the widest range. Although a dominant species, it has an extensive distribution discontinuity between 26° N and 27° N, suggesting restricted gene flow. Moreover, historical distribution models indicate the absence of an area with suitable conditions for the species during the Last Interglacial, making it an interesting model for studying genetic divergence. METHODS: We assembled 4411 SNPs from 147 plants of Y. valida throughout its range to examine its phylogeography to identify the number of genetic lineages, quantify their genetic differentiation, reconstruct their demographic history and estimate the age of the species. RESULTS: Three allopatric lineages were identified based on the SNPs. Our analyses support that genetic drift is the driver of genetic differentiation among these lineages. We estimated an age of less than 1 million years for the common ancestor of Y. valida and its sister species. CONCLUSIONS: Habitat fragmentation caused by climatic changes, low dispersal, and an extensive geographical range gap acted as cumulative mechanisms leading to allopatric divergence in Y. valida.

Drift drives the evolution of chromosome number I: The impact of trait transitions on genome evolution in Coleoptera.

Chromosomal mutations such as fusions and fissions are often thought to be deleterious, especially in heterozygotes (underdominant), and consequently are unlikely to become fixed. Yet, many models of chromosomal speciation ascribe an important role to chromosomal mutations. When the effective population size (Ne) is small, the efficacy of selection is weakened, and the likelihood of fixing underdominant mutations by genetic drift is greater. Thus, it is possible that ecological and phenotypic transitions that modulate Ne facilitate the fixation of chromosome changes, increasing the rate of karyotype evolution. We synthesize all available chromosome number data in Coleoptera and estimate the impact of traits expected to change Ne on the rate of karyotype evolution in the family Carabidae and 12 disparate clades from across Coleoptera. Our analysis indicates that in Carabidae, wingless clades have faster rates of chromosome number increase. Additionally, our analysis indicates clades exhibiting multiple traits expected to reduce Ne, including strict inbreeding, oligophagy, winglessness, and island endemism, have high rates of karyotype evolution. Our results suggest that chromosome number changes are likely fixed by genetic drift despite an initial fitness cost and that chromosomal speciation models may be important to consider in clades with very small Ne.

Drift drives the evolution of chromosome number II: The impact of range size on genome evolution in Carnivora.

Chromosome number is a fundamental genomic trait that is often the first recorded characteristic of a genome. Across large clades, a common pattern emerges: many or even most lineages exhibit relative stasis, while a handful of lineages or species exhibit striking variation. Despite recent developments in comparative methods, most of this heterogeneity is still poorly understood. It is essential to understand why some lineages have rapid rates of chromosome number evolution, as it can impact a variety of other traits. Previous research suggests that biased female meiotic drive may shape rates of karyotype evolution in some mammals. However, Carnivora exhibits variation that this female meiotic drive model cannot explain. We hypothesize that variation in effective population size may underlie rate variation in Carnivora. To test this hypothesis, we estimated rates of fusions and fissions while accounting for range size, which we use as a proxy for effective population size. We reason fusions and fissions are deleterious or underdominant and that only in lineages with small range sizes will these changes be able to fix due to genetic drift. In this study, we find that the rates of fusions and fissions are elevated in taxa with small range sizes relative to those with large range sizes. Based on these findings, we conclude that 1) naturally occurring structural mutations that change chromosome number are underdominant or mildly deleterious, and 2) when population sizes are small, structural rearrangements may play an important role in speciation and reduction in gene flow among populations.

Beyond simple adaptation: Incorporating other evolutionary processes and concepts into eco-evolutionary dynamics.

Studies of eco-evolutionary dynamics have integrated evolution with ecological processes at multiple scales (populations, communities and ecosystems) and with multiple interspecific interactions (antagonistic, mutualistic and competitive). However, evolution has often been conceptualised as a simple process: short-term directional adaptation that increases population growth. Here we argue that diverse other evolutionary processes, well studied in population genetics and evolutionary ecology, should also be considered to explore the full spectrum of feedback between ecological and evolutionary processes. Relevant but underappreciated processes include (1) drift and mutation, (2) disruptive selection causing lineage diversification or speciation reversal and (3) evolution driven by relative fitness differences that may decrease population growth. Because eco-evolutionary dynamics have often been studied by population and community ecologists, it will be important to incorporate a variety of concepts in population genetics and evolutionary ecology to better understand and predict eco-evolutionary dynamics in nature.

Tightly Constrained Genome Reduction and Relaxation of Purifying Selection during Secondary Plastid Endosymbiosis.

Endosymbiosis, the establishment of a former free-living prokaryotic or eukaryotic cell as an organelle inside a host cell, can dramatically alter the genomic architecture of the endosymbiont. Plastids or chloroplasts, the light-harvesting organelle of photosynthetic eukaryotes, are excellent models to study this phenomenon because plastid origin has occurred multiple times in evolution. Here, we investigate the genomic signature of molecular processes acting through secondary plastid endosymbiosis-the origination of a new plastid from a free-living eukaryotic alga. We used phylogenetic comparative methods to study gene loss and changes in selective regimes on plastid genomes, focusing on green algae that have given rise to three independent lineages with secondary plastids (euglenophytes, chlorarachniophytes, and Lepidodinium). Our results show an overall increase in gene loss associated with secondary endosymbiosis, but this loss is tightly constrained by the retention of genes essential for plastid function. The data show that secondary plastids have experienced temporary relaxation of purifying selection during secondary endosymbiosis. However, this process is tightly constrained, with selection relaxed only relative to the background in primary plastids. Purifying selection remains strong in absolute terms even during the endosymbiosis events. Selection intensity rebounds to pre-endosymbiosis levels following endosymbiosis events, demonstrating the changes in selection efficiency during different origin phases of secondary plastids. Independent endosymbiosis events in the euglenophytes, chlorarachniophytes, and Lepidodinium differ in their degree of relaxation of selection, highlighting the different evolutionary contexts of these events. This study reveals the selection-drift interplay during secondary endosymbiosis and evolutionary parallels during organellogenesis.

Quantifying stochastic establishment of mutants in microbial adaptation.

Studies of microbial evolution, especially in applied contexts, have focused on the role of selection in shaping predictable, adaptive responses to the environment. However, chance events - the appearance of novel genetic variants and their establishment, i.e. outgrowth from a single cell to a sizeable population - also play critical initiating roles in adaptation. Stochasticity in establishment has received little attention in microbiology, potentially due to lack of awareness as well as practical challenges in quantification. However, methods for high-replicate culturing, mutant labelling and detection, and statistical inference now make it feasible to experimentally quantify the establishment probability of specific adaptive genotypes. I review methods that have emerged over the past decade, including experimental design and mathematical formulas to estimate establishment probability from data. Quantifying establishment in further biological settings and comparing empirical estimates to theoretical predictions represent exciting future directions. More broadly, recognition that adaptive genotypes may be stochastically lost while rare is significant both for interpreting common lab assays and for designing interventions to promote or inhibit microbial evolution.

Neolithic expansion and the 17q21.31 inversion in Iberia: an evolutionary approach to H2 haplotype distribution in the Near East and Europe.

The chromosomal region 17q21.31 harbors a 900 kb inversion polymorphism named after the microtubule-associated protein tau (MAPT) gene. Since no recombination occurs, two haplotypes are recognized: a directly oriented variant (H1) and an inverted variant (H2). The H2 haplotype features a distribution pattern with high frequencies in the Near East and Europe, medium levels in South Asia and North Africa, and low levels elsewhere. Studies of this genomic region are relevant owing to its likely association with numerous neurodegenerative diseases. However, the causes underlying the geographic distribution of the haplotype frequencies remain a bone of contention among researchers. With this work, we have intended to outline a plausible hypothesis on the origin of the high European H2 frequencies. To that end, we have analyzed an extensive population database (including three new Iberian populations) to explore potential clinal variations of H2 frequencies. We found a sigmoidal frequency cline with an upward trend from South Asia to Europe. The maximum value was detected in the Basques from Gipuzkoa province (0.494) with the curve's inflection point in the Near East. From our results, we suggest that the most likely scenario for high H2 frequencies in Europe would be a founding event in the Near East during the late Paleolithic or early Neolithic. Subsequently, such H2 overrepresentation would have reached Europe with the arrival of the first Neolithic farmers. The current frequencies and geographic distribution of the 17q21.31 inversion suggest that the founding events mainly affected the H2D subhaplotype.

Rapid genetic adaptation to a novel ecosystem despite a large founder event.

Introduced and invasive species make excellent natural experiments for investigating rapid evolution. Here, we describe the effects of genetic drift and rapid genetic adaptation in pink salmon (Oncorhynchus gorbuscha) that were accidentally introduced to the Great Lakes via a single introduction event 31 generations ago. Using whole-genome resequencing for 134 fish spanning five sample groups across the native and introduced range, we estimate that the source population's effective population size was 146,886 at the time of introduction, whereas the founding population's effective population size was just 72-a 2040-fold decrease. As expected with a severe founder event, we show reductions in genome-wide measures of genetic diversity, specifically a 37.7% reduction in the number of SNPs and an 8.2% reduction in observed heterozygosity. Despite this decline in genetic diversity, we provide evidence for putative selection at 47 loci across multiple chromosomes in the introduced populations, including missense variants in genes associated with circadian rhythm, immunological response and maturation, which match expected or known phenotypic changes in the Great Lakes. For one of these genes, we use a species-specific agent-based model to rule out genetic drift and conclude our results support a strong response to selection occurring in a period gene (per2) that plays a predominant role in determining an organism's daily clock, matching large day length differences experienced by introduced salmon during important phenological periods. Together, these results inform how populations might evolve rapidly to new environments, even with a small pool of standing genetic variation.