Adaptive Alleles Research Articles

Human adaptation and population differentiation in the light of ancient genomes.

The influence of positive selection sweeps in human evolution is increasingly debated, although our ability to detect them is hampered by inherent uncertainties in the timing of past events. Ancient genomes provide snapshots of allele frequencies in the past and can help address this question. We combine modern and ancient genomic data in a simple statistic (DAnc) to time allele frequency changes, and investigate the role of drift and adaptation in population differentiation. Only 30% of the most strongly differentiated alleles between Africans and Eurasians changed in frequency during the colonization of Eurasia, but in Europe these alleles are enriched in genic and putatively functional alleles to an extent only compatible with local adaptation. Adaptive alleles—especially those associated with pigmentation—are mostly of hunter-gatherer origin, although lactose persistence arose in a haplotype present in farmers. These results provide evidence for a role of local adaptation in human population differentiation.

Glyphosate Resistance in Perennial Ryegrass (Lolium perenneL.) is Associated with a Fitness Penalty

The net selection effect of herbicides on herbicide-resistance traits in weeds is conditioned by the fitness benefits and costs associated with resistance alleles. Fitness costs play an important evolutionary role preventing the fixation of adaptive alleles and contributing to the maintenance of genetic polymorphisms within populations. Glyphosate is widely used in world agriculture, which has led to the evolution of widespread glyphosate resistance in many weed species. The fitness of glyphosate-resistant and -susceptible perennial ryegrass plants selected from within a single population were studied in two field experiments conducted during 2011 and 2012 under different soil water availability. Glyphosate-resistant plants showed a reduction in height of 12 and 16%, leaf blade area of 16 and 33%, shoot biomass of 45 and 55%, seed number of 33 and 53%, and total seed mass of 16 and 5% compared to glyphosate-susceptible plants in 2011 and 2012, respectively. The reduction in seed number per plant resulted in a 40% fitness cost associated with the glyphosate-resistance trait in perennial ryegrass. Fitness costs of glyphosate-resistant plants were expressed under both conditions of water availability. These results could be useful for designing management strategies and exploiting the reduced glyphosate-resistant perennial ryegrass fitness in the absence of glyphosate selection.

Genome-wide selective sweeps and gene-specific sweeps in natural bacterial populations.

Multiple models describe the formation and evolution of distinct microbial phylogenetic groups. These evolutionary models make different predictions regarding how adaptive alleles spread through populations and how genetic diversity is maintained. Processes predicted by competing evolutionary models, for example, genome-wide selective sweeps vs gene-specific sweeps, could be captured in natural populations using time-series metagenomics if the approach were applied over a sufficiently long time frame. Direct observations of either process would help resolve how distinct microbial groups evolve. Here, from a 9-year metagenomic study of a freshwater lake (2005–2013), we explore changes in single-nucleotide polymorphism (SNP) frequencies and patterns of gene gain and loss in 30 bacterial populations. SNP analyses revealed substantial genetic heterogeneity within these populations, although the degree of heterogeneity varied by >1000-fold among populations. SNP allele frequencies also changed dramatically over time within some populations. Interestingly, nearly all SNP variants were slowly purged over several years from one population of green sulfur bacteria, while at the same time multiple genes either swept through or were lost from this population. These patterns were consistent with a genome-wide selective sweep in progress, a process predicted by the ‘ecotype model' of speciation but not previously observed in nature. In contrast, other populations contained large, SNP-free genomic regions that appear to have swept independently through the populations prior to the study without purging diversity elsewhere in the genome. Evidence for both genome-wide and gene-specific sweeps suggests that different models of bacterial speciation may apply to different populations coexisting in the same environment.

The Genetics Underlying Natural Variation in the Biotic Interactions of Arabidopsis thaliana: The Challenges of Linking Evolutionary Genetics and Community Ecology.

In the context of global change, predicting the responses of plant communities in an ever-changing biotic environment calls for a multipronged approach at the interface of evolutionary genetics and community ecology. However, our understanding of the genetic basis of natural variation involved in mediating biotic interactions, and associated adaptive dynamics of focal plants in their natural communities, is still in its infancy. Here, we review the genetic and molecular bases of natural variation in the response to biotic interactions (viruses, bacteria, fungi, oomycetes, herbivores, and plants) in the model plant Arabidopsis thaliana as well as the adaptive value of these bases. Among the 60 identified genes are a number that encode nucleotide-binding site leucine-rich repeat (NBS-LRR)-type proteins, consistent with early examples of plant defense genes. However, recent studies have revealed an extensive diversity in the molecular mechanisms of defense. Many types of genetic variants associate with phenotypic variation in biotic interactions, even among the genes of large effect that tend to be identified. In general, we found that (i) balancing selection rather than directional selection explains the observed patterns of genetic diversity within A. thaliana and (ii) the cost/benefit tradeoffs of adaptive alleles can be strongly dependent on both genomic and environmental contexts. Finally, because A. thaliana rarely interacts with only one biotic partner in nature, we highlight the benefit of exploring diffuse biotic interactions rather than tightly associated host-enemy pairs. This challenge would help to improve our understanding of coevolutionary quantitative genetics within the context of realistic community complexity.

Climate adaptation and ecological restoration in eucalypts

Eucalypts are the cornerstone of ecological restoration efforts across the highly modified agricultural landscapes of southern Australia. ‘Local provenancing’ is the established strategy for sourcing germplasm for ecological restoration plantings, yet this approach gives little consideration to the persistence of these plantings under future climates. This paper provides a synopsis of recent and ongoing research that the authors are undertaking on climate adaptation in eucalypts, combining new genomic approaches with ecophysiological evidence from provenance trials. These studies explore how adaptive diversity is distributed within and among populations, whether populations are buffered against change through capacity for phenotypic plasticity, and how this informs provenancing strategies. Results to date suggest that eucalypts have some capacity to respond to future environmental instability through adaptive phenotypic plasticity or selection of putatively adaptive alleles. Despite this, growing evidence suggests that eucalypts will still be vulnerable to change. Provenancing strategies that exploit adaptations found in non-local provenances could thus confer greater climate-resilience in ecological restoration plantings, although they will also need to account for potential interactions between climate adaptations and other factors (e.g. cryptic evolutionary variation, non-climate-related adaptations, herbivory and elevated CO2).

Introgression of Neandertal- and Denisovan-like Haplotypes Contributes to Adaptive Variation in Human Toll-like Receptors

Pathogens and the diseases they cause have been among the most important selective forces experienced by humans during their evolutionary history. Although adaptive alleles generally arise by mutation, introgression can also be a valuable source of beneficial alleles. Archaic humans, who lived in Europe and Western Asia for more than 200,000 years, were probably well adapted to this environment and its local pathogens. It is therefore conceivable that modern humans entering Europe and Western Asia who admixed with them obtained a substantial immune advantage from the introgression of archaic alleles. Here we document a cluster of three Toll-like receptors (TLR6-TLR1-TLR10) in modern humans that carries three distinct archaic haplotypes, indicating repeated introgression from archaic humans. Two of these haplotypes are most similar to the Neandertal genome, and the third haplotype is most similar to the Denisovan genome. The Toll-like receptors are key components of innate immunity and provide an important first line of immune defense against bacteria, fungi, and parasites. The unusually high allele frequencies and unexpected levels of population differentiation indicate that there has been local positive selection on multiple haplotypes at this locus. We show that the introgressed alleles have clear functional effects in modern humans; archaic-like alleles underlie differences in the expression of the TLR genes and are associated with reduced microbial resistance and increased allergic disease in large cohorts. This provides strong evidence for recurrent adaptive introgression at the TLR6-TLR1-TLR10 locus, resulting in differences in disease phenotypes in modern humans.

New Coffee Plant-Infecting Xylella fastidiosa Variants Derived via Homologous Recombination.

Xylella fastidiosa is a xylem-limited phytopathogenic bacterium endemic to the Americas that has recently emerged in Asia and Europe. Although this bacterium is classified as a quarantine organism in the European Union, importation of plant material from contaminated areas and latent infection in asymptomatic plants have engendered its inevitable introduction. In 2012, four coffee plants (Coffea arabica and Coffea canephora) with leaf scorch symptoms growing in a confined greenhouse were detected and intercepted in France. After identification of the causal agent, this outbreak was eradicated. Three X. fastidiosa strains were isolated from these plants, confirming a preliminary identification based on immunology. The strains were characterized by multiplex PCR and by multilocus sequence analysis/typing (MLSA-MLST) based on seven housekeeping genes. One strain, CFBP 8073, isolated from C. canephora imported from Mexico, was assigned to X. fastidiosa subsp. fastidiosa/X. fastidiosa subsp. sandyi. This strain harbors a novel sequence type (ST) with novel alleles at two loci. The two other strains, CFBP 8072 and CFBP 8074, isolated from Coffea arabica imported from Ecuador, were allocated to X. fastidiosa subsp. pauca. These two strains shared a novel ST with novel alleles at two loci. These MLST profiles showed evidence of recombination events. We provide genome sequences for CFBP 8072 and CFBP 8073 strains. Comparative genomic analyses of these two genome sequences with publicly available X. fastidiosa genomes, including the Italian strain CoDiRO, confirmed these phylogenetic positions and provided candidate alleles for coffee plant adaptation. This study demonstrates the global diversity of X. fastidiosa and highlights the diversity of strains isolated from coffee plants.

Lack of adaptation from standing genetic variation despite the presence of putatively adaptive alleles in introduced sweet vernal grass (Anthoxanthum odoratum)

Population genetic theory predicts that the availability of appropriate standing genetic variation should facilitate rapid evolution when species are introduced to new environments. However, few tests of rapid evolution have been paired with empirical surveys for the presence of previously identified adaptive genetic variants in natural populations. In this study, we examined local adaptation to soil Al toxicity in the introduced range of sweet vernal grass (Anthoxanthum odoratum), and we genotyped populations for the presence of Al tolerance alleles previously identified at the long-term ecological Park Grass Experiment (PGE, Harpenden, UK) in the species native range. We found that markers associated with Al tolerance at the PGE were present at appreciable frequency in introduced populations. Despite this, there was no strong evidence of local adaptation to soil Al toxicity among populations. Populations demonstrated significantly different intrinsic root growth rates in the absence of Al. This suggests that selection on correlated root growth traits may constrain the ability of populations to evolve significantly different root growth responses to Al. Our results demonstrate that genotype-phenotype associations may differ substantially between the native and introduced parts of a species range and that adaptive alleles from a native species range may not necessarily promote phenotypic differentiation in the introduced range.

Molecular mechanisms of dominance evolution in Müllerian mimicry.

Natural selection acting on dominance between adaptive alleles at polymorphic loci can be sufficiently strong for dominance to evolve. However, the molecular mechanisms underlying such evolution are generally unknown. Here, using Müllerian mimicry as a case-study for adaptive morphological variation, we present a theoretical analysis of the invasion of dominance modifiers altering gene expression through different molecular mechanisms. Toxic species involved in Müllerian mimicry exhibit warning coloration, and converge morphologically with other toxic species of the local community, due to positive frequency-dependent selection acting on these colorations. Polymorphism in warning coloration may be maintained by migration-selection balance with fine scale spatial heterogeneity. We modeled a dominance modifier locus altering the expression of the warning coloration locus, targeting one or several alleles, acting in cis or trans, and either enhancing or repressing expression. We confirmed that dominance could evolve when balanced polymorphism was maintained at the color locus. Dominance evolution could result from modifiers enhancing one allele specifically, irrespective of their linkage with the targeted locus. Nonspecific enhancers could also persist in populations, at frequencies tightly depending on their linkage with the targeted locus. Altogether, our results identify which mechanisms of expression alteration could lead to dominance evolution in polymorphic mimicry.

Understanding the contrasting spatial haplotype patterns of malaria-protective β-globin polymorphisms

The malaria-protective β-globin polymorphisms, sickle-cell (βS) and β0-thalassaemia, are canonical examples of human adaptation to infectious disease. Occurring on distinct genetic backgrounds, they vary markedly in their patterns of linked genetic variation at the population level, suggesting different evolutionary histories. βS is associated with five classical restriction fragment length polymorphism haplotypes that exhibit remarkable specificity in their geographical distributions; by contrast, β0-thalassaemia mutations are found on haplotypes whose distributions overlap considerably. Here, we explore why these two polymorphisms display contrasting spatial haplotypic distributions, despite having malaria as a common selective pressure. We present a meta-population genetic model, incorporating individual-based processes, which tracks the evolution of β-globin polymorphisms on different haplotypic backgrounds. Our simulations reveal that, depending on the rate of mutation, a large population size and/or high population growth rate are required for both the βS- and the β0-thalassaemia-like patterns. However, whilst the βS-like pattern is more likely when population subdivision is high, migration low and long-distance migration absent, the opposite is true for β0-thalassaemia. Including gene conversion has little effect on the overall probability of each pattern; however, when inter-haplotype fitness variation exists, gene conversion is more likely to have contributed to the diversity of haplotypes actually present in the population. Our findings highlight how the contrasting spatial haplotype patterns exhibited by βS and β0-thalassaemia may provide important indications as to the evolution of these adaptive alleles and the demographic history of the populations in which they have evolved.

ID: 253: Evolution of antiviral factors in primates

We have dissected the evolutionary history of host-virus interactions between primate genomes and various viruses including retroviruses, poxviruses and polyomaviuses. Our evolution-guided functional virology approach has revealed not just an ancient history of genetic conflicts facing primate antiviral genes, but also the means to identify the specificity domains by virtue of signatures of rapid evolution. We highlight the use of such approaches to identify multiple, independently acting antiviral specificiaty domains in the primate antivial Mx GTPase proteins. These case studies of antiviral genes have revealed many common ‘evolutionary rules’ of genetic adaptation, using which it may be possible to even infer the action of past viral infections, even those that may not have left imprints in host genomes – a form of indirect ‘paleovirology’ (study of ancient viruses). More recently, we have discovered that one previously unappreciated form of viral adaptation is via ‘gene-accordions’ that facilitate acquisition of adaptive alleles.

The Role of Standing Variation in Geographic Convergent Adaptation.

The extent to which populations experiencing shared selective pressures adapt through a shared genetic response is relevant to many questions in evolutionary biology. In this article, we explore how standing genetic variation contributes to convergent genetic responses in a geographically spread population. Geographically limited dispersal slows the spread of each selected allele, hence allowing other alleles to spread before any one comes to dominate the population. When selectively equivalent alleles meet, their progress is substantially slowed, dividing the species range into a random tessellation, which can be well understood by analogy to a Poisson process model of crystallization. In this framework, we derive the geographic scale over which an allele dominates and the proportion of adaptive alleles that arise from standing variation. Finally, we explore how negative pleiotropic effects of alleles can bias the subset of alleles that contribute to the species' adaptive response. We apply the results to the malaria-resistance glucose-6-phosphate dehydrogenase-deficiency alleles, where the large mutational target size makes it a likely candidate for adaptation from deleterious standing variation. Our results suggest that convergent adaptation may be common. Therefore, caution must be exercised when arguing that strongly geographically restricted alleles are the outcome of local adaptation. We close by discussing the implications of these results for ideas of species coherence and the nature of divergence between species.

Combining niche modelling and landscape genetics to study local adaptation: A novel approach illustrated using alpine plants

Understanding the factors that shape adaptive genetic variation across species niches has become of paramount importance in evolutionary ecology, especially to understand how adaptation to changing climate affects the geographic range of species. The distribution of adaptive alleles in the ecological niche is determined by the emergence of novel mutations, their fitness consequences and gene flow that connects populations across species niches. Striking demographical differences and source—sink dynamics of populations between the centre and the margin of the niche can play a major role in the emergence and spread of adaptive alleles. Although some theoretical predictions have long been proposed, the origin and distribution of adaptive alleles within species niches remain untested.In this paper, we propose and discuss a novel empirical approach that combines landscape genetics with species niche modelling, to test whether alleles that confer local adaptation are more likely to occur in either marginal or central populations of species niches. We illustrate this new approach by using a published data set of 21 alpine plant species genotyped with a total of 2483 amplified fragment length polymorphisms (AFLP), distributed over more than 1733 sampling sites across the Alps. Based on the assumption that alleles that were statistically associated with environmental variables were adaptive, we found that adaptive alleles in the margin of a species niche were also present in the niche centre, which suggests that adaptation originates in the niche centre.These findings corroborate models of species range evolution, in which the centre of the niche contributes to the emergence of novel adaptive alleles, which diffuse towards niche margins and facilitate niche and range expansion through subsequent local adaptation. Although these results need to be confirmed via fitness measurements in natural populations and functionally characterised genetic sequences, this study provides a first step towards understanding how adaptive genetic variation emerges and shapes species niches and geographic ranges along environmental gradients.

Local interspecies introgression is the main cause of extreme levels of intraspecific differentiation in mussels.

Structured populations, and replicated zones of contact between species, are an ideal opportunity to study regions of the genome with unusual levels of differentiation; and these can illuminate the genomic architecture of species isolation, and the spread of adaptive alleles across species ranges. Here, we investigated the effects of gene flow on divergence and adaptation in the Mytilus complex of species, including replicated parental populations in quite distant geographical locations. We used target enrichment sequencing of 1269 contigs of a few kb each, including some genes of known function, to infer gene genealogies at a small chromosomal scale. We show that geography is an important determinant of the genomewide patterns of introgression in Mytilus and that gene flow between different species, with contiguous ranges, explained up to half of the intraspecific outliers. This suggests that local introgression is both widespread and tends to affect larger chromosomal regions than purely intraspecific processes. We argue that this situation might be common, and this implies that genome scans should always consider the possibility of introgression from sister species, unsampled differentiated backgrounds, or even extinct relatives, for example Neanderthals in humans. The hypothesis that reticulate evolution over long periods of time contributes widely to adaptation, and to the spatial and genomic reorganization of genetic backgrounds, needs to be more widely considered to make better sense of genome scans.

Genomic Evidence that Sexual Selection Impedes Adaptation to a Novel Environment

Sexual selection is widely appreciated for generating remarkable phenotypic diversity, but its contribution to adaptation and the purging of deleterious mutations is unresolved. To provide insight into the impact of sexual selection on naturally segregating polymorphisms across the genome, we previously evolved 12 populations of Drosophila serrata in a novel environment employing a factorial manipulation of the opportunities for natural and sexual selection. Here, we genotype more than 1,400 SNPs in the evolved populations and reveal that sexual selection affected many of the same genomic regions as natural selection, aligning with it as often as opposing it. Intriguingly, more than half of the 80 SNPs showing treatment effects revealed an interaction between natural and sexual selection. For these SNPs, while sexual selection alone often caused a change in allele frequency in the same direction as natural selection alone, when natural and sexual selection occurred together, changes in allele frequency were greatly reduced or even reversed. This suggests an antagonism between natural and sexual selection arising from male-induced harm to females. Behavioral experiments showed that males preferentially courted and mated with high-fitness females, and that the harm associated with this increased male attention eliminated the female fitness advantage. During our experiment, females carrying otherwise adaptive alleles may therefore have disproportionally suffered male-induced harm due to their increased sexual attractiveness. These results suggest that a class of otherwise adaptive mutations may not contribute to adaptation when mating systems involve sexual conflict and male mate preferences.

Rampant Parasexuality Evolves in a Hospital Pathogen during Antibiotic Selection.

Horizontal gene transfer threatens the therapeutic success of antibiotics by facilitating the rapid dissemination of resistance alleles among bacterial species. The conjugative mobile element Tn916 provides an excellent context for examining the role of adaptive parasexuality as it carries the tetracycline-resistance allele tetM and has been identified in a wide range of pathogens. We have used a combination of experimental evolution and allelic frequency measurements to gain insights into the adaptive trajectories leading to tigecycline resistance in a hospital strain of Enterococcus faecalis and predict what mechanisms of resistance are most likely to appear in the clinical setting. Here, we show that antibiotic selection led to the near fixation of adaptive alleles that simultaneously altered TetM expression and produced remarkably increased levels of Tn916 horizontal gene transfer. In the absence of drug, approximately 1 in 120,000 of the nonadapted E. faecalis S613 cells had an excised copy of Tn916, whereas nearly 1 in 50 cells had an excised copy of Tn916 upon selection for resistance resulting in a more than 1,000-fold increase in conjugation rates. We also show that tigecycline, a translation inhibitor, selected for a mutation in the ribosomal S10 protein. Our results show the first example of mutations that concurrently confer resistance to an antibiotic and lead to constitutive conjugal-transfer of the resistance allele. Selection created a highly parasexual phenotype and high frequency of Tn916 jumping demonstrating how the use of antibiotics can lead directly to the proliferation of resistance in, and potentially among, pathogens.

A Mutant Chaperonin That Is Functional at Lower Temperatures Enables Hyperthermophilic Archaea To Grow under Cold-Stress Conditions.

Thermococcus kodakarensis grows optimally at 85°C and possesses two chaperonins, cold-inducible CpkA and heat-inducible CpkB, which are involved in adaptation to low and high temperatures, respectively. The two chaperonins share a high sequence identity (77%), except in their C-terminal regions. CpkA, which contains tandem repeats of a GGM motif, shows its highest ATPase activity at 60°C to 70°C, whereas CpkB shows its highest activity at temperatures higher than 90°C. To clarify the effects of changes in ATPase activity on chaperonin function at lower temperatures, various CpkA variants were constructed by introducing single point mutations into the C-terminal region. A CpkA variant in which Glu530 was replaced with Gly (CpkA-E530G) showed increased ATPase activity, with its highest activity at 50°C. The efficacy of the CpkA variants against denatured indole-3-glycerol-phosphate synthase of T. kodakarensis (TrpCTk), which is a CpkA target, was then examined in vitro. CpkA-E530G was more effective than wild-type CpkA at facilitating the refolding of chemically unfolded TrpCTk at 50°C. The effect of cpkA-E530G on cell growth was then examined by introducing cpkA-E530G into the genome of T. kodakarensis KU216 (pyrF). The mutant strain, DA4 (pyrF cpkA-E530G), grew as well as the parental KU216 strain at 60°C. In contrast, DA4 grew more vigorously than KU216 at 50°C. These results suggested that the CpkA-E530G mutation prevented cold denaturation of proteins under cold-stress conditions, thereby enabling cells to grow in cooler environments. Thus, a single base pair substitution in a chaperonin gene allows cells to grow vigorously in a new environment. Thermococcus kodakarensis possesses two group II chaperonins, cold-inducible CpkA and heat-inducible CpkB, which are involved in adaptation to low and high temperatures, respectively. CpkA might act as an "adaptive allele" to adapt to cooler environments. In this study, we compared the last 20 amino acids within the C termini of the chaperonins and found a clear correlation between the CpkA-type chaperonin gene copy number and growth temperature. Furthermore, we introduced single mutations into the CpkA C-terminal region to clarify its role in cold adaptation, and we showed that a single base substitution allowed the organism to adapt to a lower temperature. The present data suggest that hyperthermophiles have evolved by obtaining mutations in chaperonins that allow them to adapt to a colder environment.

LEA: An R package for landscape and ecological association studies

Summary Based on population genomic and environmental data, genomewide ecological association studies aim at detecting allele frequencies that exhibit significant statistical association with ecological gradients. Ecological association studies can provide lists of genetic polymorphisms that are potentially involved in local adaptation to environmental conditions through natural selection. Here, we present the R package LEA that enables users to run ecological association studies from the R command line. The package can perform analyses of population structure and genome scans for adaptive alleles from large genomic data sets. It derives advantages from R programming functionalities to adjust significance values for multiple testing issues and to visualize results. This note also illustrates the main steps of ecological association studies and the typical use of LEA for analysing data sets based on R commands.

Naturally occurring diversity helps to reveal genes of adaptive importance in legumes.

Environmental changes challenge plants and drive adaptation to new conditions, suggesting that natural biodiversity may be a source of adaptive alleles acting through phenotypic plasticity and/or micro-evolution. Crosses between accessions differing for a given trait have been the most common way to disentangle genetic and environmental components. Interestingly, such man-made crosses may combine alleles that never meet in nature. Another way to discover adaptive alleles, inspired by evolution, is to survey large ecotype collections and to use association genetics to identify loci of interest. Both of these two genetic approaches are based on the use of biodiversity and may eventually help us in identifying the genes that plants use to respond to challenges such as short-term stresses or those due to global climate change. In legumes, two wild species, Medicago truncatula and Lotus japonicus, plus the cultivated soybean (Glycine max) have been adopted as models for genomic studies. In this review, we will discuss the resources, limitations and future plans for a systematic use of biodiversity resources in model legumes to pinpoint genes of adaptive importance in legumes, and their application in breeding.

Enhancing the mathematical properties of new haplotype homozygosity statistics for the detection of selective sweeps

Soft selective sweeps represent an important form of adaptation in which multiple haplotypes bearing adaptive alleles rise to high frequency. Most statistical methods for detecting selective sweeps from genetic polymorphism data, however, have focused on identifying hard selective sweeps in which a favored allele appears on a single haplotypic background; these methods might be underpowered to detect soft sweeps. Among exceptions is the set of haplotype homozygosity statistics introduced for the detection of soft sweeps by Garud et al. (2015). These statistics, examining frequencies of multiple haplotypes in relation to each other, include H12, a statistic designed to identify both hard and soft selective sweeps, and H2/H1, a statistic that conditional on high H12 values seeks to distinguish between hard and soft sweeps. A challenge in the use of H2/H1 is that its range depends on the associated value of H12, so that equal H2/H1 values might provide different levels of support for a soft sweep model at different values of H12. Here, we enhance the H12 and H2/H1 haplotype homozygosity statistics for selective sweep detection by deriving the upper bound on H2/H1 as a function of H12, thereby generating a statistic that normalizes H2/H1 to lie between 0 and 1. Through a reanalysis of resequencing data from inbred lines of Drosophila, we show that the enhanced statistic both strengthens interpretations obtained with the unnormalized statistic and leads to empirical insights that are less readily apparent without the normalization.