Evolutionary druggability for low-dimensional fitness landscapes toward new metrics for antimicrobial applications.

The term 'druggability' describes the molecular properties of drugs or targets in pharmacological interventions and is commonly used in work involving drug development for clinical applications. There are no current analogues for this notion that quantify the drug-target interaction with respect to a given target variant's sensitivity across a breadth of drugs in a panel, or a given drug's range of effectiveness across alleles of a target protein. Using data from low-dimensional empirical fitness landscapes composed of 16 ß-lactamase alleles and 7 ß-lactam drugs, we introduce two metrics that capture (i) the average susceptibility of an allelic variant of a drug target to any available drug in a given panel ('variant vulnerability'), and (ii) the average applicability of a drug (or mixture) across allelic variants of a drug target ('drug applicability'). Finally, we (iii) disentangle the quality and magnitude of interactions between loci in the drug target and the seven drug environments in terms of their mutation by mutation by environment (G x G x E) interactions, offering mechanistic insight into the variant variability and drug applicability metrics. Summarizing, we propose that our framework can be applied to other datasets and pathogen-drug systems to understand which pathogen variants in a clinical setting are the most concerning (low variant vulnerability), and which drugs in a panel are most likely to be effective in an infection defined by standing genetic variation in the pathogen drug target (high drug applicability).

Historical fragmentation and stepping-stone gene flow led to population genetic differentiation in a coastal seabird.

Understanding the forces that shape population genetic structure is fundamental both for understanding evolutionary trajectories and for conservation. Many factors can influence the geographic distribution of genetic variation, and the extent to which local populations differ can be especially difficult to predict in highly mobile organisms. For example, many species of seabirds are essentially panmictic, but some show strong structure. Pigeon Guillemots (Cepphus columba; Charadriiformes: Alcidae) breed in small colonies scattered along the North Pacific coastline and feed in shallow nearshore waters year-round. Given their distribution, gene flow is potentially lower and population genetic structure is stronger than in most other high-latitude Northern Hemisphere seabirds. We screened variation in the mitochondrial control region, four microsatellite loci, and two nuclear introns in 202 Pigeon Guillemots representing three of five subspecies. Mitochondrial sequences and nuclear loci both showed significant population differences, although structure was weaker for the nuclear loci. Genetic differentiation was correlated with geographic distance between sampling locations for both the mitochondrial and nuclear loci. Mitochondrial gene trees and demographic modeling both provided strong evidence for two refugial populations during the Pleistocene glaciations: one in the Aleutian Islands and one farther east and south. We conclude that historical fragmentation combined with a stepping-stone model of gene flow led to the relatively strong population differentiation in Pigeon Guillemots compared to other high-latitude Northern Hemisphere seabird species. Our study adds to growing evidence that Pleistocene glaciation events affected population genetic structure not only in terrestrial species but also in coastal marine animals.

Unveiling the Genetic Tapestry: Exploring Rhizoctonia solani AG-3 Anastomosis Groups in Potato Crops across Borders.

The current study was carried out to screen 10 isolates (ARS-01-ARS-10) of Rhizoctonia. solani from potato tubers cv. Kuroda, which were collected from various potato fields in Multan, Pakistan. The isolates were found to be morphologically identical, as the hyphae exhibit the production of branches at right angles and acute angles often accompanied by septum near the emerging branches. Anastomosis grouping showed that these isolates belonged to AG-3. A pathogenicity test was performed against the susceptible Kuroda variety and among the isolates, ARS-05 exhibited the highest mean severity score of approximately 5.43, followed by ARS-09, which showed a mean severity score of about 3.67, indicating a moderate level of severity. On the lower end of the severity scale, isolates ARS-06 and ARS-07 displayed mean severity scores of approximately 0.53 and 0.57, respectively, suggesting minimal symptom severity. These mean severity scores offer insights into the varying degrees of symptom expression among the different isolates of R. solani under examination. PCoA indicates that the severe isolate causing black scurf on the Kuroda variety was AG-3. A comprehensive analysis of the distribution, genetic variability, and phylogenetic relationships of R. solani anastomosis groups (AGs) related to potato crops across diverse geographic regions was also performed to examine AG prevalence in various countries. AG-3 was identified as the most widespread group, prevalent in Sweden, China, and the USA. AG-5 showed prominence in Sweden and the USA, while AG-2-1 exhibited prevalence in China and Japan. The phylogenetic analysis unveiled two different clades: Clade I comprising AG-3 and Clade II encompassing AG-2, AG-4, and AG-5, further subdivided into three subclades. Although AGs clustered together regardless of origin, their genetic diversity revealed complex evolutionary patterns. The findings pave the way for region-specific disease management strategies to combat R. solani's impact on potato crops.

Uncovering the genetic architecture and evolutionary roots of androgenetic alopecia in African men.

Androgenetic alopecia is a highly heritable trait. However, much of our understanding about the genetics of male pattern baldness comes from individuals of European descent. Here, we examined a novel dataset comprising 2,136 men from Ghana, Nigeria, Senegal, and South Africa that were genotyped using a custom array. We first tested how genetic predictions of baldness generalize from Europe to Africa, finding that polygenic scores from European GWAS yielded AUC statistics that ranged from 0.513 to 0.546, indicating that genetic predictions of baldness in African populations performed notably worse than in European populations. Subsequently, we conducted the first African GWAS of androgenetic alopecia, focusing on self-reported baldness patterns at age 45. After correcting for present age, population structure, and study site, we identified 266 moderately significant associations, 51 of which were independent (p-value < 10-5, r2 < 0.2). Most baldness associations were autosomal, and the X chromosomes does not appear to have a large impact on baldness in African men. Finally, we examined the evolutionary causes of continental differences in genetic architecture. Although Neanderthal alleles have previously been associated with skin and hair phenotypes, we did not find evidence that European-ascertained baldness hits were enriched for signatures of ancient introgression. Most loci that are associated with androgenetic alopecia are evolving neutrally. However, multiple baldness-associated SNPs near the EDA2R and AR genes have large allele frequency differences between continents. Collectively, our findings illustrate how evolutionary history contributes to the limited portability of genetic predictions across ancestries.

What is the value of rotations to insecticide resistance management?

Rotations have been the cornerstone of insecticide resistance management for many decades. In recent years, there has been a resurgence of interest in the use of insecticide mixtures, particularly based on new theoretical models. Here, we present a perspective on the value of rotations to insecticide resistance management, focusing on the interpretation of influential theoretical models. The principles of resistance management have previously been reduced to moderation, saturation and multiple attack. Alongside mixtures and mosaics, rotations have been presented as a strategy of multiple attack in using more than one insecticide. Three explanations have been offered for how rotations delay resistance evolution: counterselection from resistance cost, the relaxation of selection and intergenerational redundant kill. We show that all three explanations can make sense of the comparison of rotations with another resistance-management strategy but have failed to elucidate the principle at work. Overall, we argue that rotations work by moderation, delaying resistance to insecticides through the use of each insecticide less over time. We suggest that the principles of resistance management are recast as moderation, saturation and redundancy. When rotations and mixtures are not conceptualised as competing methods of multiple attack, these strategies can more obviously work together through the complementary principles of moderation and redundancy. Whether solo products or a mixture of products are used, rotations are an effective method of risk management, preserving the arsenal of all effective insecticides for longer. A successful resistance-management plan should make appropriate use of all the principles of resistance management. © 2024 Society of Chemical Industry.

Epidemiologic investigation and genetic characterization of canine respiratory coronavirus in the Southeastern United States.

Canine respiratory coronavirus (CRCoV) is one of the main causative agents of canine infectious respiratory disease (CIRD), an illness whose epidemiology is poorly understood. We assessed the prevalence, risk factors, and genetic characterization of CRCoV in privately owned dogs in the Southeastern United States. We PCR-screened 189 nasal swabs from dogs with and without CIRD clinical signs for 9 CIRD-related pathogens, including CRCoV; 14% of dogs, all diagnosed with CIRD, were positive for CRCoV, with a significantly higher rate of cases in younger dogs and during warmer weather. Notably, the presence of CRCoV, alone or in coinfection with other CIRD pathogens, was statistically associated with a worse prognosis. We estimated a CRCoV seroprevalence of 23.7% retrospectively from 540 serum samples, with no statistical association to dog age, sex, or season, but with a significantly higher presence in urban counties. Additionally, the genomes of 6 CRCoVs were obtained from positive samples using an in-house developed targeted amplicon-based approach specific to CRCoV. Subsequent phylogeny clustered their genomes in 2 distinct genomic groups, with most isolates sharing a higher similarity with CRCoVs from Sweden and only 1 more closely related to CRCoVs from Asia. We provide new insights into CIRD and CRCoV epidemiology in the Southeastern United States and further support the association of CRCoV with more severe cases of CIRD. Additionally, we developed and successfully tested a new amplicon-based approach for whole-genome sequencing of CRCoV that can be used to further investigate the genetic diversity within CRCoVs.

The genomic echoes of the last Green Sahara on the Fulani and Sahelian people.

The population history of the Sahara/Sahelian belt is understudied, despite previous work highlighting complex dynamics.1,2,3,4,5,6,7 The Sahelian Fulani, i.e., the largest nomadic pastoral population in the world,8 represent an interesting case because they show a non-negligible proportion of an Eurasian genetic component, usually explained by recent admixture with northern Africans.1,2,5,6,7,9,10,11,12 Nevertheless, their origins are largely unknown, although several hypotheses have been proposed, including a possible link to ancient peoples settled in the Sahara during its last humid phase (Green Sahara, 12,000-5,000 years before present [BP]).13,14,15 To shed light about the Fulani ancient genetic roots, we produced 23 high-coverage (30×) whole genomes from Fulani individuals from 8 Sahelian countries, plus 17 samples from other African groups and 3 from Europeans as controls, for a total of 43 new whole genomes. These data have been compared with 814 published modern whole genomes2,16,17,18 and with relevant published ancient sequences (> 1,800 samples).19 These analyses showed some evidence that the non-sub-Saharan genetic ancestry component of the Fulani might have also been shaped by older events,1,5,6 possibly tracing the Fulani origins to unsampled ancient Green Saharan population(s). The joint analysis of modern and ancient samples allowed us to shed light on the genetic ancestry composition of such ancient Saharans, suggesting a similarity with Late Neolithic Moroccans and possibly pointing to a link with the spread of cattle herding. We also identified two different Fulani clusters whose admixture pattern may be informative about the historical Fulani movements and their later involvement in the western African empires.

Getting it right: Teaching undergraduate biology to undermine racial essentialism.

How we teach human genetics matters for social equity. The biology curriculum appears to be a crucial locus of intervention for either reinforcing or undermining students' racial essentialist views. The Mendelian genetic models dominating textbooks, particularly in combination with racially inflected language sometimes used when teaching about monogenic disorders, can increase middle and high school students' racial essentialism and opposition to policies to increase equity. These findings are of particular concern given the increasing spread of racist misinformation online and the misappropriation of human genomics research by white supremacists, who take advantage of low levels of genetics literacy in the general public. Encouragingly, however, teaching updated information about the geographical distribution of human genetic variation and the complex, multifactorial basis of most human traits, reduces students' endorsement of racial essentialism. The genetics curriculum is therefore a key tool in combating misinformation and scientific racism. Here, we describe a framework and example teaching materials for teaching students key concepts in genetics, human evolutionary history, and human phenotypic variation at the undergraduate level. This framework can be flexibly applied in biology and anthropology classes and adjusted based on time availability. Our goal is to provide undergraduate-level instructors with varying levels of expertise with a set of evidence-informed tools for teaching human genetics to combat scientific racism, including an evolving set of instructional resources, as well as learning goals and pedagogical approaches. Resources can be found at https://noto.li/YIlhZ5. Additionally, we hope to generate conversation about integrating modern genetics into the undergraduate curriculum, in light of recent findings about the risks and opportunities associated with teaching genetics.

SNPtotree-Resolving the Phylogeny of SNPs on Non-Recombining DNA.

Genetic variants on non-recombining DNA and the hierarchical order in which they accumulate are commonly of interest. This variant hierarchy can be established and combined with information on the population and geographic origin of the individuals carrying the variants to find population structures and infer migration patterns. Further, individuals can be assigned to the characterized populations, which is relevant in forensic genetics, genetic genealogy, and epidemiologic studies. However, there is currently no straightforward method to obtain such a variant hierarchy. Here, we introduce the software SNPtotree v1.0, which uniquely determines the hierarchical order of variants on non-recombining DNA without error-prone manual sorting. The algorithm uses pairwise variant comparisons to infer their relationships and integrates the combined information into a phylogenetic tree. Variants that have contradictory pairwise relationships or ambiguous positions in the tree are removed by the software. When benchmarked using two human Y-chromosomal massively parallel sequencing datasets, SNPtotree outperforms traditional methods in the accuracy of phylogenetic trees for sequencing data with high amounts of missing information. The phylogenetic trees of variants created using SNPtotree can be used to establish and maintain publicly available phylogeny databases to further explore genetic epidemiology and genealogy, as well as population and forensic genetics.

Soft selection reduces loss of heterozygosity in asexual reproduction.

The adaptive value of sexual reproduction is still debated in evolutionary theory. It has been proposed that the advantage of sexual reproduction over asexual reproduction is to promote genetic diversity, to prevent the accumulation of harmful mutations or to preserve heterozygosity. Since these hypothetical advantages depend on the type of asexual reproduction, understanding how selection affects the taxonomic distribution of each type could help us discriminate between existing hypotheses. Here, I argue that soft selection, competition among embryos or offspring in selection arenas prior to the hard selection of the adult phase, reduces loss of heterozygosity in certain types of asexual reproduction. Since loss of heterozygosity leads to the unmasking of recessive deleterious mutations in the progeny of asexual individuals, soft selection facilitates the evolution of these types of asexual reproduction. Using a population genetics model, I calculate how loss of heterozygosity affects fitness for different types of apomixis and automixis, and I show that soft selection significantly reduces loss of heterozygosity, hence increases fitness, in apomixis with suppression of the first meiotic division and in automixis with central fusion, the most common types of asexual reproduction. Therefore, if sexual reproduction evolved to preserve heterozygosity, soft selection should be associated with these types of asexual reproduction. I discuss the evidence for this prediction and how this and other observations on the distribution of different types of asexual reproduction in nature is consistent with the heterozygosity hypothesis.

Genomic Instability Evolutionary Footprints on Human Health: Driving Forces or Side Effects?

In this work, we propose a comprehensive perspective on genomic instability comprising not only the accumulation of mutations but also telomeric shortening, epigenetic alterations and other mechanisms that could contribute to genomic information conservation or corruption. First, we present mechanisms playing a role in genomic instability across the kingdoms of life. Then, we explore the impact of genomic instability on the human being across its evolutionary history and on present-day human health, with a particular focus on aging and complex disorders. Finally, we discuss the role of non-coding RNAs, highlighting future approaches for a better living and an expanded healthy lifespan.

Detection and in silico characterization of banana bunchy top virus in West Bengal, India: relevance to global genetic diversity and population structure.

Banana bunchy top disease is one of the major prevailing virus diseases associated with banana cultivation, spreading rapidly within a small scale of time. Till date there are only few extensive reports of completely sequenced isolates in India. A study was conducted to detect BBTV infection across 12 districts in West Bengal (WB) where extensive prevalence of the disease was ascertained. In silico characterization of the six genome components were accomplished which showed 84.90-99.86% similarity with other BBTV isolates reported worldwide. The phylogenetic analysis based upon DNA R and DNA S suggested formation of monophyletic cluster of majority of the WB isolates and its close association with Tripura, Manipur, Australia and Africa isolates indicating diversion from geographical differentiation. Dynamics of evolutionary pattern such as genetic diversity including Tajima's D test and Fu Li's Fs test, average number of nucleotide differences (K), Polymorphic sites (S); Fst distance; Mismatch distribution plot; Haplotype network, and selection pressure were performed based upon geographical distribution of the virus. Population genetics analysis of both Pacific Indian Ocean group and South East Asian group of the global BBTV population revealed low nucleotide diversity, high haplotype diversity, high gene flow within the group, and negative or purifying selection constraint indicating recent population expansion. Hence, this study portrays Indian subcontinent as the possible hotspot for rapid demographic expansion from a small virus population size, contributing valuable addition to the currently available information on BBTV worldwide. Supplementary Information: The online version contains supplementary material available at 10.1007/s13337-023-00815-0.

Mimicking the last step of gene elongation: hints from the bacterial hisF gene.

Gene elongation consists in an in-tandem duplication of a gene and divergence and fusion of the two copies, resulting in a gene constituted by two divergent paralogous modules. Many present-day proteins show internal repeats of amino acid sequences, generated by gene elongation events; however, gene elongation is still a poorly studied evolutionary molecular mechanism. The most documented case is that of the histidine biosynthetic genes hisA and hisF, which derive from the gene elongation of an ancestral gene half the size of the extant ones. The aim of this work was to experimentally simulate the possible last step of the gene elongation event occurred during hisF gene evolution under selective pressure conditions. Azospirillum brasilense hisF gene, carrying a single nucleotide mutation that generates a stop codon between the two halves of the gene, was used to transform the histidine-auxotrophic Escherichia coli strain FB182 (hisF892). The transformed strain was subjected to selective pressure (i.e., low concentration/absence of histidine in the growth medium) and the obtained mutants were characterized. The restoration of prototrophy was strongly dependent on the time of incubation and on the strength of the selective pressure. The mutations involved the introduced stop codon with a single base substitution and none of the mutants restored the wild-type codon. Possible correlations between the different mutations and i) E. coli codon usage, ii) three-dimensional structures of the mutated HisF proteins, and iii) growth ability of the mutants were investigated. On the contrary, when the experiment was repeated by mutating a more conserved codon, only a synonymous substitution was obtained. Thus, experiments performed in this study allowed to mimic a possible gene elongation event occurred during the evolution of hisF gene, evidencing the ability of bacterial cells to modify their genome in short times under selective conditions.

Assortative mating and mate-choice contributes to the maintenance of a developmental dimorphism in Streblospio benedicti.

Assortative mating, where individuals non-randomly mate with respect to phenotype or genotype, can occur when preferences between potential mates have evolved. When such mate preferences occur in a population it can drive evolutionary and phenotypic divergence. But the extent to which assortative mating, mate preference, and development are evolutionarily linked remains unclear. Here we use Streblospio benedicti, a marine annelid with a rare developmental dimorphism, to investigate if mate-choice could contribute to developmental evolution. For S. benedicti two types of ecologically and phenotypically similar adults persist in natural populations, but they give rise to distinctly different offspring with alternative life-histories. This dimorphism persists despite the absence of post-zygotic reproductive barriers, where crosses between the developmental types can produce phenotypically intermediate offspring. How this life-history strategy evolved remains unknown, but assortative mating is a typical first step in evolutionary divergence. Here we investigate if female mate-choice is occurring in this species. We find that mate preferences could be contributing to the maintenance of alternative developmental and life-history strategies.

An Overview of Deep Generative Models in Functional and Evolutionary Genomics.

Following the widespread use of deep learning for genomics, deep generative modeling is also becoming a viable methodology for the broad field. Deep generative models (DGMs) can learn the complex structure of genomic data and allow researchers to generate novel genomic instances that retain the real characteristics of the original dataset. Aside from data generation, DGMs can also be used for dimensionality reduction by mapping the data space to a latent space, as well as for prediction tasks via exploitation of this learned mapping or supervised/semi-supervised DGM designs. In this review, we briefly introduce generative modeling and two currently prevailing architectures, we present conceptual applications along with notable examples in functional and evolutionary genomics, and we provide our perspective on potential challenges and future directions.

Analysis of the genetic loci of pigment pattern evolution in vertebrates.

Vertebrate pigmentation patterns are amongst the best characterised model systems for studying the genetic basis of adaptive evolution. The wealth of available data on the genetic basis for pigmentation evolution allows for analysis of trends and quantitative testing of evolutionary hypotheses. We employed Gephebase, a database of genetic variants associated with natural and domesticated trait variation, to examine trends in how cis-regulatory and coding mutations contribute to vertebrate pigmentation phenotypes, as well as factors that favour one mutation type over the other. We found that studies with lower ascertainment bias identified higher proportions of cis-regulatory mutations, and that cis-regulatory mutations were more common amongst animals harbouring a higher number of pigment cell classes. We classified pigmentation traits firstly according to their physiological basis and secondly according to whether they affect colour or pattern, and identified that carotenoid-based pigmentation and variation in pattern boundaries are preferentially associated with cis-regulatory change. We also classified genes according to their developmental, cellular, and molecular functions. We found a greater proportion of cis-regulatory mutations in genes implicated in upstream developmental processes compared to those involved in downstream cellular functions, and that ligands were associated with a higher proportion of cis-regulatory mutations than their respective receptors. Based on these trends, we discuss future directions for research in vertebrate pigmentation evolution.

Genetic architecture of human brain evolution.

Comparative studies of hominids have long sought to identify mutational events that shaped the evolution of the human nervous system. However, functional genetic differences are outnumbered by millions of nearly neutral mutations, and the developmental mechanisms underlying human nervous system specializations are difficult to model and incompletely understood. Candidate-gene studies have attempted to map select human-specific genetic differences to neurodevelopmental functions, but it remains unclear how to contextualize the relative effects of genes that are investigated independently. Considering these limitations, we discuss scalable approaches for probing the functional contributions of human-specific genetic differences. We propose that a systems-level view will enable a more quantitative and integrative understanding of the genetic, molecular and cellular underpinnings of human nervous system evolution.

Evolutionary Genetics and Admixture in African Populations.

As the ancestral homeland of our species, Africa contains elevated levels of genetic diversity and substantial population structure. Importantly, African genomes are heterogeneous: They contain mixtures of multiple ancestries, each of which have experienced different evolutionary histories. In this review, we view population genetics through the lens of admixture, highlighting how multiple demographic events have shaped African genomes. Each of these historical vignettes paints a recurring picture of population divergence followed by secondary contact. First, we give a brief overview of genetic variation in Africa and examine deep population structure within Africa, including the evidence of ancient introgression from archaic "ghost" populations. Second, we describe the genetic legacies of admixture events that have occurred during the past 10,000 years. This includes gene flow between different click-speaking Khoe-San populations, the stepwise spread of pastoralism from eastern to southern Africa, multiple migrations of Bantu speakers across the continent, as well as admixture from the Middle East and Europe into the Sahel region and North Africa. Furthermore, the genomic signatures of more recent admixture can be found in the Cape Peninsula and throughout the African diaspora. Third, we highlight how natural selection has shaped patterns of genetic variation across the continent, noting that gene flow provides a potent source of adaptive variation and that selective pressures vary across Africa. Finally, we explore the biomedical implications of population structure in Africa on health and disease and call for more ethically conducted studies of genetic variation in Africa.

Understanding the contemporary high obesity rate from an evolutionary genetic perspective.

The topic of obesity is gaining increasing popularity globally. From an evolutionary genetic perspective, it is believed that the main cause of the high obesity rate is the mismatch between environment and genes after people have shifted toward a modern high-calorie diet. However, it has been debated for over 60 years about how obesity-related genes become prevalent all over the world. Here, we review the three most influential hypotheses or viewpoints, i.e., the thrifty gene hypothesis, the drifty gene hypothesis, and the maladaptation viewpoint. In particular, genome-wide association studies in the recent 10 years have provided rich findings and evidence to be considered for a better understanding of the evolutionary genetic mechanisms of obesity. We anticipate this brief review to direct further studies and inspire the future application of precision medicine in obesity treatment.

The racist origins, racialist connotations, and purity assumptions of the concept of "admixture" in human evolutionary genetics.

The concept of admixture is currently widely being used, both in population genetics research and in DNA ancestry testing discourse. It is assumed to describe the process of gene flow between 2 previously distinct populations that eventually become admixed because of this flow. The concept per se does not require pure or unadmixed populations; the changes are relative and what matters is the level of admixture before and after the event under consideration. However, in this paper, we argue that the concept of admixture as currently used assumes the existence of pure or unadmixed categories. These do not need to have actually existed but to be able to exist in principle. We argue that this is a problematic notion that accrues from the racialist origins of the term admixture, which, as a result, is based on assumptions about purity. We suggest that scientists should be very cautious in their use of this term, especially in science education and communication. We also suggest that the term admixture should be better replaced by terms denoting similarity rather than difference.