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Modern humans have experienced explosive population growth in the past thousand years. We hypothesized that recent human populations have inhabited environments with relaxation of selective constraints, possibly due to the more abundant food supply after the Last Glacial Maximum. The ratio of nonsynonymous to synonymous mutations (N/S ratio) is a useful and common statistic for measuring selective constraints. In this study, we reconstructed a high-resolution phylogenetic tree using a total of 26,419 East Eurasian mitochondrial DNA genomes, which were further classified into expansion and nonexpansion groups on the basis of the frequencies of their founder lineages. We observed a much higher N/S ratio in the expansion group, especially for nonsynonymous mutations with moderately deleterious effects, indicating a weaker effect of purifying selection in the expanded clades. However, this observation on N/S ratio was unlikely in computer simulations where all individuals were under the same selective constraints. Thus, we argue that the expanded populations were subjected to weaker selective constraints than the nonexpanded populations were. The mildly deleterious mutations were retained during population expansion, which could have a profound impact on present-day disease patterns. [ABSTRACT FROM AUTHOR]

The "cost of domestication" hypothesis suggests that the domestication of wild species increases the number, frequency, and/or proportion of deleterious genetic variants, potentially reducing their fitness in the wild. While extensively studied in domesticated species, this phenomenon remains understudied in fungi. Here, we used Saccharomyces cerevisiae, the world's oldest domesticated fungus, as a model to investigate the genomic characteristics of deleterious variants arising from fungal domestication. Employing a graph-based pan-genome approach, we identified 1,297,761 single nucleotide polymorphisms (SNPs), 278,147 insertion/deletion events (indels; <30 bp), and 19,967 non-redundant structural variants (SVs; ≥30 bp) across 687 S. cerevisiae isolates. Comparing these variants with synonymous SNPs (sSNPs) as neutral controls, we found that the majority of the derived nonsynonymous SNPs (nSNPs), indels, and SVs were deleterious. Heterozygosity was positively correlated with the impact of deleterious SNPs, suggesting a role of genetic diversity in mitigating their effects. The domesticated isolates exhibited a higher additive burden of deleterious SNPs (dSNPs) than the wild isolates, but a lower burden of indels and SVs. Moreover, the domesticated S. cerevisiae showed reduced rates of adaptive evolution relative to the wild S. cerevisiae. In summary, deleterious variants tend to be heterozygous, which may mitigate their harmful effects, but they also constrain breeding potential. Addressing deleterious alleles and minimizing the genetic load are crucial considerations for future S. cerevisiae breeding efforts. [ABSTRACT FROM AUTHOR]

Dominance refers to the effect of a heterozygous genotype relative to that of the two homozygous genotypes. The degree of dominance of mutations for fitness can have a profound impact on how deleterious and beneficial mutations change in frequency over time as well as on the patterns of linked neutral genetic variation surrounding such selected alleles. Since dominance is such a fundamental concept, it has received immense attention throughout the history of population genetics. Early work from Fisher, Wright, and Haldane focused on understanding the conceptual basis for why dominance exists. More recent work has attempted to test these theories and conceptual models by estimating dominance effects of mutations. However, estimating dominance coefficients has been notoriously challenging and has only been done in a few species in a limited number of studies. In this review, we first describe some of the early theoretical and conceptual models for understanding the mechanisms for the existence of dominance. Second, we discuss several approaches used to estimate dominance coefficients and summarize estimates of dominance coefficients. We note trends that have been observed across species, types of mutations, and functional categories of genes. By comparing estimates of dominance coefficients for different types of genes, we test several hypotheses for the existence of dominance. Lastly, we discuss how dominance influences the dynamics of beneficial and deleterious mutations in populations and how the degree of dominance of deleterious mutations influences the impact of inbreeding on fitness. [ABSTRACT FROM AUTHOR]

MDC1 (Mediator of DNA damage Checkpoint protein 1) functions to facilitate the localization of numerous DNA damage response (DDR) components to DNA double-strand break sites. MDC1 is an integral component in preserving genomic stability and appropriate DDR regulation. There haven't been systematic investigations of MDC1 mutations that induce cancer and genomic instability. Variations in nsSNPs have the potential to modify the protein chemistry and their function. Describing functional SNPs in disease-associated genes presents a significant conundrum for investigators, it is possible to assess potential functional SNPs before conducting larger population examinations. Multiple sequences and structure-based bioinformatics strategies were implemented in the current in-silico investigation to discern potential nsSNPs of the MDC1 genes. The nsSNPs were identified with SIFT, SNAP2, Align GVGD, PolyPhen-2, and PANTHER, and their stability was determined with MUpro. The conservation, solvent accessibility, and structural effects of the mutations were identified with ConSurf, NetSurfP-2.0, and SAAFEC-SEQ respectively. Cancer-related analysis of the nsSNPs was conducted using cBioPortal and TCGA web servers. The present study appraised five nsSNPs (P1426T, P69S, P194R, P203L, and H131Y) as probably mutilating due to their existence in highly conserved regions and propensity to deplete protein stability. The nsSNPs P194R, P203L, and H131Y were concluded as deleterious and possibly damaging from the 5 prediction tools. The functional nsSNP P194R mutation is associated with skin cutaneous melanoma while no significant records were found for other nsSNPs. The present study concludes that the highly deleterious P194R mutations can potentially induce genomic instability and contribute to various cancers' pathogenesis. Developing drugs targeting these mutations can undoubtedly be advantageous in large population-based studies, particularly in the development of precision medicine. [ABSTRACT FROM AUTHOR]

Local adaptation frequently evolves in patches or environments that are connected via migration. In these cases, genomic regions that are linked to a locally adapted locus experience reduced effective migration rates. Via individual-based simulations of a two-patch system, we show that this reduced effective migration results in the accumulation of conditionally deleterious mutations, but not universally deleterious mutations, adjacent to adaptive loci. When there is redundancy in the genetic basis of local adaptation (i.e., genotypic redundancy), turnover of locally adapted polymorphisms allows conditionally deleterious mutation load to be purged. The amount of mutational load that accumulates adjacent to locally adapted loci is dependent on redundancy, recombination rate, migration rate, population size, strength of selection, and the phenotypic effect size of adaptive alleles. Our results highlight the need to be cautious when interpreting patterns of local adaptation at the level of phenotype or fitness, as the genetic basis of local adaptation can be transient, and evolution may confer a degree of maladaptation to nonlocal environments. [ABSTRACT FROM AUTHOR]

Plants exhibit diverse breeding systems, with populations capable of outcrossing, selfing, and/or asexual reproduction. However, interactions between the three reproductive pathways remain not fully clear. Sexual reproduction introduces segregation and recombination, but incurs several costs. Selfing can affect the relative costs and benefits of sexual vs. asexual reproduction. Building population genetic models, I explore how selfing affects the evolution of a sexual reproduction rate modifier via (a) indirect selection due to segregation, (b) indirect selection from changes in recombination rates, and (c) selection from the cost of meiosis and mate limitation. The dominant selective force mediating the evolution of sex is found to vary with the rate of sexual reproduction and selfing, but selective force (a) and (c) are generally stronger than selective force (b). A modifier enhancing sexual reproduction tends to be favored by indirect selection generated by partially recessive, small-effect deleterious mutations, while hindered by highly recessive lethal mutations. Overall, evolution toward higher sexual reproduction is hindered at low sexual reproduction rates and intermediate selfing rates, but favored under high selfing rates. The results suggest that asexual reproduction may precede the evolution of selfing and offer insights into the evolution of mechanisms reducing geitonogamy in partially clonal populations. [ABSTRACT FROM AUTHOR]

Deleterious mutations decrease reproductive fitness and are ubiquitous in genomes. Given that many organisms face ongoing threats of extinction, there is interest in elucidating the impact of deleterious variation on extinction risk and optimizing management strategies accounting for such mutations. Quantifying deleterious variation and understanding the effects of population history on deleterious variation are complex endeavors because we do not know the strength of selection acting on each mutation. Further, the effect of demographic history on deleterious mutations depends on the strength of selection against the mutation and the degree of dominance. Here we clarify how deleterious variation can be quantified and studied in natural populations. We then discuss how different demographic factors, such as small population size, nonequilibrium population size changes, inbreeding, and gene flow, affect deleterious variation. Lastly, we provide guidance on studying deleterious variation in nonmodel populations of conservation concern.

Huntington's disease (HD) is a chronic, inherited neurodegenerative condition marked by chorea, dementia, and changes in personality. The primary cause of HD is a mutation characterized by the expansion of a triplet repeat (CAG) within the huntingtin gene located on chromosome 4. Despite substantial progress in elucidating the molecular and cellular mechanisms of HD, an effective treatment for this disorder is not available so far. In recent years, researchers have been interested in studying cerebrospinal fluid (CSF) as a source of biomarkers that could aid in the diagnosis and therapeutic development of this disorder. Immunoglobulin heavy constant gamma 1 (IGHG1) is one of the CSF proteins found to increase significantly in HD. Considering this, it is reasonable to study the potential involvement of deleterious mutations in IGHG1 in the pathogenesis of this disorder. In this study, we explored the potential impact of deleterious mutations on IGHG1 and their subsequent association with HD. We evaluated 126 single-point amino acid substitutions for their impact on the structure and functionality of the IGHG1 protein while exploiting multiple computational resources such as SIFT, PolyPhen-2, FATHMM, SNPs&Go mCSM, DynaMut2, MAESTROweb, PremPS, MutPred2, and PhD-SNP. The sequence- and structure-based tools highlighted 10 amino acid substitutions that were deleterious and destabilizing. Subsequently, out of these 10 mutations, eight variants (Y32C, Y32D, P34S, V39E, C83R, C83Y, V85M, and H87Q) were identified as pathogenic by disease phenotype predictors. Finally, two pathogenic variants (Y32C and P34S) were found to reduce the solubility of the protein, suggesting their propensity to form protein aggregates. These variants also exhibited higher residual frustration within the protein structure. Considering these findings, the study hypothesized that the identified variants of IGHG1 may compromise its function and potentially contribute to HD pathogenesis. [ABSTRACT FROM AUTHOR]

While haplotype‐specific genetic load shapes the evolutionary trajectory of natural and captive populations, mixed‐haplotype assembly and genotyping hindered its characterization in diploids. Herein, we produced two phased genome assemblies of the critically endangered fish Chinese Bahaba (Bahaba taipingensis, Sciaenidae, Teleostei) and resequenced 20 whole genomes to quantify population genetic load at a haplotype level. We identified frame‐shifting variants as the most deleterious type, followed by mutations in the 5′‐UTR, 3′‐UTR and missense mutations at conserved amino acids. Phased haplotypes revealed gene deletions and high‐impact deleterious variants. We estimated ~1.12% of genes missing or interrupted per haplotype, with a significant overlap of disrupted genes (30.35%) between haplotype sets. Relative proportions of deleterious variant categories differed significantly between haplotypes. Simulations suggested that purifying selection struggled to purge slightly deleterious genetic load in captive breeding compared to genotyping interventions, and that higher inter‐haplotypic variance of genetic load predicted more efficient purging by artificial selection. Combining the knowledge of haplotype‐resolved genetic load with predictive modelling will be immensely useful for understanding the evolution of deleterious variants and guiding conservation planning. [ABSTRACT FROM AUTHOR]

Endangered species generally have small populations with low genetic diversity and a high genetic load. Thuja sutchuenensis is an endangered conifer endemic to southwestern China. It was once considered extinct in the wild, but in 1999 was rediscovered. However, little is known about its genetic load. We collected 67 individuals from five wild, isolated T. sutchuenensis populations, and used 636,151 SNPs to analyze the level of genetic diversity and genetic load in T. sutchuenensis to delineate the conservation units of T. sutchuenensis, based on whole transcriptome sequencing data, as well as target capture sequencing data. We found that populations of T. sutchuenensis could be divided into three groups. These groups had low levels genetic diversity and were moderately genetically differentiated. Our findings also indicate that T. sutchuenensis suffered two severe bottlenecks around the Last Glaciation Period and Last Glacial Maximum. Among Thuja species, T. sutchuenensis presented the lowest genetic load and hence might have purged deleterious mutations efficiently through purifying selection. However, distribution of fitness effects analysis indicated a high extinction risk for T. sutchuenensis. Multiple lines of evidence identified three management units for T. sutchuenensis. Although T. sutchuenensis possesses a low genetic load, low genetic diversity, suboptimal fitness, and anthropogenic pressures all present an extinction risk for this rare conifer. This might also hold true for many endangered plant species in the mountains all over the world.

The “cost of domestication” hypothesis suggests that the domestication of wild species increases the number, frequency, and/or proportion of deleterious genetic variants, potentially reducing their fitness in the wild. While extensively studied in domesticated species, this phenomenon remains understudied in fungi. Here, we used Saccharomyces cerevisiae, the world’s oldest domesticated fungus, as a model to investigate the genomic characteristics of deleterious variants arising from fungal domestication. Employing a graph-based pan-genome approach, we identified 1,297,761 single nucleotide polymorphisms (SNPs), 278,147 insertion/deletion events (indels; S. cerevisiae showed reduced rates of adaptive evolution relative to the wild S. cerevisiae. In summary, deleterious variants tend to be heterozygous, which may mitigate their harmful effects, but they also constrain breeding potential. Addressing deleterious alleles and minimizing the genetic load are crucial considerations for future S. cerevisiae breeding efforts.

Fisher's reproductive compensation (fRC) occurs when a species' demography means the death of an individual results in increased survival probability of his/her relatives, usually assumed to be full sibs. This likely occurs in many species, including humans. Several important recessive human genetic diseases cause early foetal/infant death allowing fRC to act on these mutations. The impact of fRC on these genetic conditions has been previously calculated and shown to be substantial as quantified by ω , the fold increase in equilibrium frequencies of the mutation under fRC compared with its absence, i.e. ω = 1.22 and ω = 1.33 for autosomal and sex-linked loci, respectively. However, the impact of fRC on the frequency of the much larger class of semidominant, nonlethal mutations is unknown. This is calculated here as ω = 2 − h * s for autosomal loci and ω up to 2 for sex-linked loci where h is dominance (varied between 0.05 and 0.95) and s is selection coefficient (varied between 0.05 and 0.9). These results show that the actions of fRC can almost double the equilibrium frequency of deleterious mutations with low values of h and/or s (noting that "low" is s ∼0.05 to 0.1). It is noted that fRC may act differentially across the genome with genes expressed early in life being fully exposed to fRC while those expressed later in life may be unaffected; this could lead to systematic differences in deleterious allele frequency across the genome. [ABSTRACT FROM AUTHOR]

Deleterious genetic variation is abundant in wild populations, and understanding the ecological and conservation implications of such variation is an area of active research. Genomic methods are increasingly used to quantify the impacts of deleterious variation in natural populations; however, these approaches remain limited by an inability to accurately predict the selective and dominance effects of mutations. Computational simulations of deleterious variation offer a complementary tool that can help overcome these limitations, although such approaches have yet to be widely employed. In this perspective article, we aim to encourage ecological and conservation genomics researchers to adopt greater use of computational simulations to aid in deepening our understanding of deleterious variation in natural populations. We first provide an overview of the components of a simulation of deleterious variation, describing the key parameters involved in such models. Next, we discuss several approaches for validating simulation models. Finally, we compare and validate several recently proposed deleterious mutation models, demonstrating that models based on estimates of selection parameters from experimental systems are biased toward highly deleterious mutations. We describe a new model that is supported by multiple orthogonal lines of evidence and provide example scripts for implementing this model (https://github.com/ckyriazis/simulations_review). [ABSTRACT FROM AUTHOR]

New mutations provide the raw material for evolution and adaptation. The distribution of fitness effects (DFE) describes the spectrum of effects of new mutations that can occur along a genome, and is, therefore, of vital interest in evolutionary biology. Recent work has uncovered striking similarities in the DFE between closely related species, prompting us to ask whether there is variation in the DFE among populations of the same species, or among species with different degrees of divergence, that is whether there is variation in the DFE at different levels of evolution. Using exome capture data from six tree species sampled across Europe we characterized the DFE for multiple species, and for each species, multiple populations, and investigated the factors potentially influencing the DFE, such as demography, population divergence, and genetic background. We find statistical support for the presence of variation in the DFE at the species level, even among relatively closely related species. However, we find very little difference at the population level, suggesting that differences in the DFE are primarily driven by deep features of species biology, and those evolutionarily recent events, such as demographic changes and local adaptation, have little impact. [ABSTRACT FROM AUTHOR]

Abstract Background Biological mechanisms affecting gametogenesis, embryo development and postnatal viability have the potential to alter Mendelian inheritance expectations resulting in observable transmission ratio distortion (TRD). Although the discovery of TRD cases have been around for a long time, the current widespread and growing use of DNA technologies in the livestock industry provides a valuable resource of large genomic data with parent–offspring genotyped trios, enabling the implementation of TRD approach. In this research, the objective is to investigate TRD using SNP-by-SNP and sliding windows approaches on 441,802 genotyped Holstein cattle and 132,991 (or 47,910 phased) autosomal SNPs. Results The TRD was characterized using allelic and genotypic parameterizations. Across the whole genome a total of 604 chromosomal regions showed strong significant TRD. Most (85%) of the regions presented an allelic TRD pattern with an under-representation (reduced viability) of carrier (heterozygous) offspring or with the complete or quasi-complete absence (lethality) for homozygous individuals. On the other hand, the remaining regions with genotypic TRD patterns exhibited the classical recessive inheritance or either an excess or deficiency of heterozygote offspring. Among them, the number of most relevant novel regions with strong allelic and recessive TRD patterns were 10 and 5, respectively. In addition, functional analyses revealed candidate genes regulating key biological processes associated with embryonic development and survival, DNA repair and meiotic processes, among others, providing additional biological evidence of TRD findings. Conclusions Our results revealed the importance of implementing different TRD parameterizations to capture all types of distortions and to determine the corresponding inheritance pattern. Novel candidate genomic regions containing lethal alleles and genes with functional and biological consequences on fertility and pre- and post-natal viability were also identified, providing opportunities for improving breeding success in cattle.

Domestic dogs have experienced population bottlenecks, recent inbreeding, and strong artificial selection. These processes have simplified the genetic architecture of complex traits, allowed deleterious variation to persist, and increased both identity-by-descent (IBD) segments and runs of homozygosity (ROH). As such, dogs provide an excellent model for examining how these evolutionary processes influence disease. We assembled a dataset containing 4,414 breed dogs, 327 village dogs, and 380 wolves genotyped at 117,288 markers and data for clinical and morphological phenotypes. Breed dogs have an enrichment of IBD and ROH, relative to both village dogs and wolves, and we use these patterns to show that breed dogs have experienced differing severities of bottlenecks in their recent past. We then found that ROH burden is associated with phenotypes in breed dogs, such as lymphoma. We next test the prediction that breeds with greater ROH have more disease alleles reported in the Online Mendelian Inheritance in Animals (OMIA). Surprisingly, the number of causal variants identified correlates with the popularity of that breed rather than the ROH or IBD burden, suggesting an ascertainment bias in OMIA. Lastly, we use the distribution of ROH across the genome to identify genes with depletions of ROH as potential hotspots for inbreeding depression and find multiple exons where ROH are never observed. Our results suggest that inbreeding has played a large role in shaping genetic and phenotypic variation in dogs and that future work on understudied breeds may reveal new disease-causing variation.

Abstract Background Among six extant tiger subspecies, the South China tiger (Panthera tigris amoyensis) once was widely distributed but is now the rarest one and extinct in the wild. All living South China tigers are descendants of only two male and four female wild-caught tigers and they survive solely in zoos after 60 years of effective conservation efforts. Inbreeding depression and hybridization with other tiger subspecies were believed to have occurred within the small, captive South China tiger population. It is therefore urgently needed to examine the genomic landscape of existing genetic variation among the South China tigers. Results In this study, we assembled a high-quality chromosome-level genome using long-read sequences and re-sequenced 29 high-depth genomes of the South China tigers. By combining and comparing our data with the other 40 genomes of six tiger subspecies, we identified two significantly differentiated genomic lineages among the South China tigers, which harbored some rare genetic variants introgressed from other tiger subspecies and thus maintained a moderate genetic diversity. We noticed that the South China tiger had higher F ROH values for longer runs of homozygosity (ROH > 1 Mb), an indication of recent inbreeding/founder events. We also observed that the South China tiger had the least frequent homozygous genotypes of both high- and moderate-impact deleterious mutations, and lower mutation loads than both Amur and Sumatran tigers. Altogether, our analyses indicated an effective genetic purging of deleterious mutations in homozygous states from the South China tiger, following its population contraction with a controlled increase in inbreeding based on its pedigree records. Conclusions The identification of two unique founder/genomic lineages coupled with active genetic purging of deleterious mutations in homozygous states and the genomic resources generated in our study pave the way for a genomics-informed conservation, following the real-time monitoring and rational exchange of reproductive South China tigers among zoos.

Soybean (Glycine max L.) is a protein and oil crop grown worldwide. Its fitness may be reduced by deleterious mutations, whose identification and purging is desirable for crop breeding. In the published whole-genome re-sequenced data of 2214 soybean accessions, including 221 wild soybean, 1132 landrace cultivars and 861 improved soybean lines, we identified 115,275 deleterious single-nucleotide polymorphisms (SNPs). Numbers of deleterious alleles increased from wild soybeans to landraces and decreased from landraces to modern improved lines. Genes in selective-sweep regions showed fewer deleterious mutations than the remaining genes. Deleterious mutations explained 4.3%–48% more phenotypic variation than randomly selected SNPs for resistance to soybean cyst nematode race 2 (SCN2), soybean cyst nematode race 3 (SCN3) and soybean mosaic virus race 3 (SMV3). These findings illustrate how mutation load has shifted during soybean domestication, expansion and improvement and provide candidate sites for breeding out deleterious mutations in soybean by genome editing and/or conventional breeding focused on the selection of progeny with fewer deleterious alleles.

Background: Biological mechanisms affecting gametogenesis, embryo development and postnatal viability have the potential to alter Mendelian inheritance expectations resulting in observable transmission ratio distortion (TRD). Although the discovery of TRD cases have been around for a long time, the current widespread and growing use of DNA technologies in the livestock industry provides a valuable resource of large genomic data with parent–offspring genotyped trios, enabling the implementation of TRD approach. In this research, the objective is to investigate TRD using SNP-by-SNP and sliding windows approaches on 441,802 genotyped Holstein cattle and 132,991 (or 47,910 phased) autosomal SNPs. Results: The TRD was characterized using allelic and genotypic parameterizations. Across the whole genome a total of 604 chromosomal regions showed strong significant TRD. Most (85%) of the regions presented an allelic TRD pattern with an under-representation (reduced viability) of carrier (heterozygous) offspring or with the complete or quasi-complete absence (lethality) for homozygous individuals. On the other hand, the remaining regions with genotypic TRD patterns exhibited the classical recessive inheritance or either an excess or deficiency of heterozygote offspring. Among them, the number of most relevant novel regions with strong allelic and recessive TRD patterns were 10 and 5, respectively. In addition, functional analyses revealed candidate genes regulating key biological processes associated with embryonic development and survival, DNA repair and meiotic processes, among others, providing additional biological evidence of TRD findings. Conclusions: Our results revealed the importance of implementing different TRD parameterizations to capture all types of distortions and to determine the corresponding inheritance pattern. Novel candidate genomic regions containing lethal alleles and genes with functional and biological consequences on fertility and pre- and post-natal viability were also identified, providing opportunities for improving breeding success in cattle. [ABSTRACT FROM AUTHOR]

Balancing selection is a form of natural selection maintaining diversity at the sites it targets and at linked nucleotide sites. Due to selection favoring heterozygosity, it has the potential to facilitate the accumulation of a "sheltered" load of tightly linked recessive deleterious mutations. However, precisely evaluating the extent of these effects has remained challenging. Taking advantage of plant self-incompatibility as one of the best-understood examples of long-term balancing selection, we provide a highly resolved picture of the genomic extent of balancing selection on the sheltered genetic load. We used targeted genome resequencing to reveal polymorphism of the genomic region flanking the self-incompatibility locus in three sample sets in each of the two closely related plant species Arabidopsis halleri and Arabidopsis lyrata , and used 100 control regions from throughout the genome to factor out differences in demographic histories and/or sample structure. Nucleotide polymorphism increased strongly around the S -locus in all sample sets, but only over a limited genomic region, as it became indistinguishable from the genomic background beyond the first 25–30 kb. Genes in this chromosomal interval exhibited no excess of mutations at 0-fold degenerated sites relative to putatively neutral sites, hence revealing no detectable weakening of the efficacy of purifying selection even for these most tightly linked genes. Overall, our results are consistent with the predictions of a narrow genomic influence of linkage to the S -locus and clarify how natural selection in one genomic region affects the evolution of the adjacent genomic regions. [ABSTRACT FROM AUTHOR]

Abstract Females and males often have markedly different mortality rates and life spans, but it is unclear why these forms of sexual dimorphism evolve. The unguarded X hypothesis contends that dimorphic life spans arise from sex differences in X or Z chromosome copy number (i.e., one copy in the “heterogametic” sex; two copies in the “homogametic” sex), which leads to a disproportionate expression of deleterious mutations by the heterogametic sex (e.g., mammalian males; avian females). Although data on adult sex ratios and sex‐specific longevity are consistent with predictions of the unguarded X hypothesis, direct experimental evidence remains scant, and alternative explanations are difficult to rule out. Using a simple population genetic model, we show that the unguarded X effect on sex differential mortality is a function of several reasonably well‐studied evolutionary parameters, including the proportion of the genome that is sex linked, the genomic deleterious mutation rate, the mean dominance of deleterious mutations, the relative rates of mutation and strengths of selection in each sex, and the average effect of mutations on survival and longevity relative to their effects on fitness. We review published estimates of these parameters, parameterize our model with them, and show that unguarded X effects are too small to explain observed sex differences in life span across species. For example, sex differences in mean life span are known to often exceed 20% (e.g., in mammals), whereas our parameterized models predict unguarded X effects of a few percent (e.g., 1–3% in Drosophila and mammals). Indeed, these predicted unguarded X effects fall below statistical thresholds of detectability in most experiments, potentially explaining why direct tests of the hypothesis have generated little support for it. Our results suggest that evolution of sexually dimorphic life spans is predominantly attributable to other mechanisms, potentially including “toxic Y” effects and sexual dimorphism for optimal investment in survival versus reproduction.

Background: Among six extant tiger subspecies, the South China tiger (Panthera tigris amoyensis) once was widely distributed but is now the rarest one and extinct in the wild. All living South China tigers are descendants of only two male and four female wild-caught tigers and they survive solely in zoos after 60 years of effective conservation efforts. Inbreeding depression and hybridization with other tiger subspecies were believed to have occurred within the small, captive South China tiger population. It is therefore urgently needed to examine the genomic landscape of existing genetic variation among the South China tigers. Results: In this study, we assembled a high-quality chromosome-level genome using long-read sequences and re-sequenced 29 high-depth genomes of the South China tigers. By combining and comparing our data with the other 40 genomes of six tiger subspecies, we identified two significantly differentiated genomic lineages among the South China tigers, which harbored some rare genetic variants introgressed from other tiger subspecies and thus maintained a moderate genetic diversity. We noticed that the South China tiger had higher FROH values for longer runs of homozygosity (ROH > 1 Mb), an indication of recent inbreeding/founder events. We also observed that the South China tiger had the least frequent homozygous genotypes of both high- and moderate-impact deleterious mutations, and lower mutation loads than both Amur and Sumatran tigers. Altogether, our analyses indicated an effective genetic purging of deleterious mutations in homozygous states from the South China tiger, following its population contraction with a controlled increase in inbreeding based on its pedigree records. Conclusions: The identification of two unique founder/genomic lineages coupled with active genetic purging of deleterious mutations in homozygous states and the genomic resources generated in our study pave the way for a genomics-informed conservation, following the real-time monitoring and rational exchange of reproductive South China tigers among zoos. [ABSTRACT FROM AUTHOR]

When new mutations arise at functional sites they are more likely to impair than improve fitness. If not removed by purifying selection, such deleterious mutations will generate a genetic load that can have negative fitness effects in small populations and increase the risk of extinction. This is relevant for the highly inbred Scandinavian wolf (Canis lupus) population, founded by only three wolves in the 1980s and suffering from inbreeding depression. We used functional annotation and evolutionary conservation scores to study deleterious variation in a total of 209 genomes from both the Scandinavian and neighbouring wolf populations in northern Europe. The masked load (deleterious mutations in heterozygote state) was highest in Russia and Finland with deleterious alleles segregating at lower frequency than neutral variation. Genetic drift in the Scandinavian population led to the loss of ancestral alleles, fixation of deleterious variants and a significant increase in the per‐individual realized load (deleterious mutations in homozygote state; an increase by 45% in protein‐coding genes) over five generations of inbreeding. Arrival of immigrants gave a temporary genetic rescue effect with ancestral alleles re‐entering the population and thereby shifting deleterious alleles from homozygous into heterozygote genotypes. However, in the absence of permanent connectivity to Finnish and Russian populations, inbreeding has then again led to the exposure of deleterious mutations. These observations provide genome‐wide insight into the magnitude of genetic load and genetic rescue at the molecular level, and in relation to population history. They emphasize the importance of securing gene flow in the management of endangered populations. [ABSTRACT FROM AUTHOR]

Small populations are vulnerable to increased genetic load and drift that can lead to reductions in fitness and adaptive potential. By analyzing 66 individual whole genomes of Montezuma Quail (Cyrtonyx montezumae) from multiple populations, we illustrate how genetic load is dynamic over evolutionary time. We show that Montezuma Quail are evolving like a ring species, where the terminal extant populations from Arizona and Texas have been separated for ~16,500 years. The Texas populations have remained small but stable since the separation, whereas the Arizona population is much larger today but has been contracting for thousands of years. Most deleterious mutations across the genome are young and segregating privately in each population and a greater number of deleterious alleles are present in the larger population. Our data indicate that ancestral load is purged during strong bottlenecks, but the reduced efficiency of selection in small populations means that segregating deleterious mutations are more likely to rise in frequency over time. Forward-time simulations indicate that severe population declines in historically large populations is more detrimental to individual fitness, whereas long-term small populations are more at risk for reduced adaptive potential and population-level fitness. Our study highlights the intimate connections among evolutionary history, historical demography, genetic load, and evolutionary potential in wild populations. [ABSTRACT FROM AUTHOR]

The expected change in fitness under inbreeding due to deleterious recessive alleles depends on the amount of inbreeding load harbored by a population, that is, the load of deleterious recessive mutations concealed in the heterozygous state, and the opposing effect of genetic purging to remove such a load. This change in fitness can be thus predicted if an estimate of the inbreeding load and the purging coefficient (the parameter that quantifies the amount of purging) are available. These two parameters can be estimated in pedigreed populations, as has been shown for populations under random mating. A question arises whether these parameters can also be estimated under other breeding systems as well as whether they allow accurate prediction of the corresponding expected change in fitness. In conservation programs, it is usually recommended to preserve genetic diversity by equalizing contributions from parents to progeny and avoiding inbred matings. Regular systems of inbreeding have also been proposed as breeding conservation strategies to purge the inbreeding load. Using computer simulations, we first test a method to jointly estimate the initial inbreeding load and the purging coefficient in populations subjected to equalization of parental contributions, circular mating, and partial full‐sib mating. Then, using the expected values of the inbreeding coefficient and the variance of family size, as well as the estimates of the inbreeding load and the purging coefficient, we make simple predictions of the change in fitness over generations under these breeding systems and compare them with simulation results. We discuss how these fitness predictions can help undertaking conservation designs under different breeding scenarios. [ABSTRACT FROM AUTHOR]

Sorghum (Sorghum bicolor L.) is a major food cereal for millions of people worldwide. The sorghum genome, like other species, accumulates deleterious mutations, likely impacting its fitness. The lack of recombination, drift, and the coupling with favorable loci impede the removal of deleterious mutations from the genome by selection. To study how deleterious variants impact phenotypes, we identified putative deleterious mutations among ∼5.5 M segregating variants of 229 diverse biomass sorghum lines. We provide the whole-genome estimate of the deleterious burden in sorghum, showing that ∼33% of nonsynonymous substitutions are putatively deleterious. The pattern of mutation burden varies appreciably among racial groups. Across racial groups, the mutation burden correlated negatively with biomass, plant height, specific leaf area (SLA), and tissue starch content (TSC), suggesting that deleterious burden decreases trait fitness. Putatively deleterious variants explain roughly one-half of the genetic variance. However, there is only moderate improvement in total heritable variance explained for biomass (7.6%) and plant height (average of 3.1% across all stages). There is no advantage in total heritable variance for SLA and TSC. The contribution of putatively deleterious variants to phenotypic diversity therefore appears to be dependent on the genetic architecture of traits. Overall, these results suggest that incorporating putatively deleterious variants into genomic models slightly improves prediction accuracy because of extensive linkage. Knowledge of deleterious variants could be leveraged for sorghum breeding through either genome editing and/or conventional breeding that focuses on the selection of progeny with fewer deleterious alleles.

Most population isolates examined to date were founded from a single ancestral population. Consequently, there is limited knowledge about the demographic history of admixed population isolates. Here we investigate genomic diversity of recently admixed population isolates from Costa Rica and Colombia and compare their diversity to a benchmark population isolate, the Finnish. These Latin American isolates originated during the 16th century from admixture between a few hundred European males and Amerindian females, with a limited contribution from African founders. We examine whole-genome sequence data from 449 individuals, ascertained as families to build mutigenerational pedigrees, with a mean sequencing depth of coverage of approximately 36×. We find that Latin American isolates have increased genetic diversity relative to the Finnish. However, there is an increase in the amount of identity by descent (IBD) segments in the Latin American isolates relative to the Finnish. The increase in IBD segments is likely a consequence of a very recent and severe population bottleneck during the founding of the admixed population isolates. Furthermore, the proportion of the genome that falls within a long run of homozygosity (ROH) in Costa Rican and Colombian individuals is significantly greater than that in the Finnish, suggesting more recent consanguinity in the Latin American isolates relative to that seen in the Finnish. Lastly, we find that recent consanguinity increased the number of deleterious variants found in the homozygous state, which is relevant if deleterious variants are recessive. Our study suggests that there is no single genetic signature of a population isolate.

PNMT is a protein-coding gene that codes for the Phenylethanolamine N-methyltransferase enzyme. It is primarily associated with neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. In the present study, over 17 different sequence-based and structure-based tools as well as 4 MSA tools and a ConSurf server were used to screen the highly deleterious single nucleotide polymorphisms (SNPs) of PNMT. Out of 286 missense SNPs, five were found to be deleterious (Y35D, I78N, I78S, G79D and L217Q) after the screening process. This was followed by performing oncogenic and phenotypic analysis, modelling of mutant proteins, structural analysis, STRING analysis, and post-translational modification (PTM) analysis. Finally, molecular dynamics simulations analysis was performed in duplicates to understand the impact of deleterious mutations on the stability of PNMT. All five mutations were predicted to be oncogenic and PTM analysis revealed that mutation Y35D occurs at a tyrosine kinase phosphorylation site. [ABSTRACT FROM AUTHOR]

Recent advances in genome resequencing have led to increased interest in prediction of the functional consequences of genetic variants. Variants at phylogenetically conserved sites are of particular interest, because they are more likely than variants at phylogenetically variable sites to have deleterious effects on fitness and contribute to phenotypic variation. Numerous comparative genomic approaches have been developed to predict deleterious variants, but the approaches are nearly always assessed based on their ability to identify known disease-causing mutations in humans. Determining the accuracy of deleterious variant predictions in nonhuman species is important to understanding evolution, domestication, and potentially to improving crop quality and yield. To examine our ability to predict deleterious variants in plants we generated a curated database of 2,910 Arabidopsis thaliana mutants with known phenotypes. We evaluated seven approaches and found that while all performed well, their relative ranking differed from prior benchmarks in humans. We conclude that deleterious mutations can be reliably predicted in A. thaliana and likely other plant species, but that the relative performance of various approaches does not necessarily translate from one species to another.

Abstract Small, isolated populations present a challenge for conservation. The dueling effects of selection and drift in a limited pool of genetic diversity make the responses of small populations to environmental perturbations erratic and difficult to predict. This is particularly true at the edge of a species range, where populations often persist at the limits of their environmental tolerances. Populations of cisco, Coregonus artedi, in inland lakes have experienced numerous extirpations along the southern edge of their range in recent decades, which are thought to result from environmental degradation and loss of cold, well‐oxygenated habitat as lakes warm. Yet, cisco extirpations do not show a clear latitudinal pattern, suggesting that local environmental factors and potentially local adaptation may influence resilience. Here, we used genomic tools to investigate the nature of this pattern of resilience. We used restriction site‐associated DNA capture (Rapture) sequencing to survey genomic diversity and differentiation in southern inland lake cisco populations and compared the frequency of deleterious mutations that potentially influence fitness across lakes. We also examined haplotype diversity in a region of the major histocompatibility complex involved in stress and immune system response. We correlated these metrics to spatial and environmental factors including latitude, lake size, and measures of oxythermal habitat and found significant relationships between genetic metrics and broad and local factors. High levels of genetic differentiation among populations were punctuated by a phylogeographic break and residual patterns of isolation‐by‐distance. Although the prevalence of deleterious mutations and inbreeding coefficients was significantly correlated with latitude, neutral and non‐neutral genetic diversity were most strongly correlated with lake surface area. Notably, differences among lakes in the availability of estimated oxythermal habitat left no clear population genomic signature. Our results shed light on the complex dynamics influencing these isolated populations and provide valuable information for their conservation.

RNA viruses have high mutation rates, with the majority of mutations being deleterious. We examine patterns of deleterious mutation accumulation over multiple rounds of viral replication, with a focus on how cellular coinfection and heterogeneity in viral output affect these patterns. Specifically, using agent-based intercellular simulations we find, in agreement with previous studies, that coinfection of cells by viruses relaxes the strength of purifying selection and thereby increases the rate of deleterious mutation accumulation. We further find that cellular heterogeneity in viral output exacerbates the rate of deleterious mutation accumulation, regardless of whether this heterogeneity in viral output is stochastic or is due to variation in the cellular multiplicity of infection. These results highlight the need to consider the unique life histories of viruses and their population structure to better understand observed patterns of viral evolution. [ABSTRACT FROM AUTHOR]

Females and males often have markedly different mortality rates and life spans, but it is unclear why these forms of sexual dimorphism evolve. The unguarded X hypothesis contends that dimorphic life spans arise from sex differences in X or Z chromosome copy number (i.e., one copy in the "heterogametic" sex; two copies in the "homogametic" sex), which leads to a disproportionate expression of deleterious mutations by the heterogametic sex (e.g., mammalian males; avian females). Although data on adult sex ratios and sex‐specific longevity are consistent with predictions of the unguarded X hypothesis, direct experimental evidence remains scant, and alternative explanations are difficult to rule out. Using a simple population genetic model, we show that the unguarded X effect on sex differential mortality is a function of several reasonably well‐studied evolutionary parameters, including the proportion of the genome that is sex linked, the genomic deleterious mutation rate, the mean dominance of deleterious mutations, the relative rates of mutation and strengths of selection in each sex, and the average effect of mutations on survival and longevity relative to their effects on fitness. We review published estimates of these parameters, parameterize our model with them, and show that unguarded X effects are too small to explain observed sex differences in life span across species. For example, sex differences in mean life span are known to often exceed 20% (e.g., in mammals), whereas our parameterized models predict unguarded X effects of a few percent (e.g., 1–3% in Drosophila and mammals). Indeed, these predicted unguarded X effects fall below statistical thresholds of detectability in most experiments, potentially explaining why direct tests of the hypothesis have generated little support for it. Our results suggest that evolution of sexually dimorphic life spans is predominantly attributable to other mechanisms, potentially including "toxic Y" effects and sexual dimorphism for optimal investment in survival versus reproduction. Impact Summary: Females and males are dimorphic for a wide range of traits, including the average lengths of their life spans. Sex differences in life span are both conspicuous and variable among species. For example, in mammals, females live ∼20% longer than males (on average), whereas in birds, males live ∼10% longer than females. One leading explanation for these patterns—the unguarded X hypothesis—argues that sex differences in life span emerge from the distinct sex chromosomes that females and males inherit. For many species, one sex (e.g., female mammals; male birds) carries two copies of each X‐linked gene, whereas the other carries one. Because harmful mutations are partially recessive, the sex with only one copy of the X is more prone to expressing them, and that sex should therefore have a shorter average life span. This prediction of the unguarded X hypothesis is qualitatively consistent with observations of sex‐ratio bias in adults and sexual dimorphism for longevity (e.g., mammalian males have one copy of the X and have shorter lives than females). However, there are other possible explanations for these patterns, making it unclear how much the unguarded X explains species diversity for sex‐specific longevity. We developed a mathematical model for the contribution of unguarded X effects to sex differences in survival and life span, and used data on mutation rates and their effects on survival and fitness to quantify the importance of the unguarded X across species. The model, when combined with current data, suggests that the unguarded X hypothesis cannot explain the conspicuous sex differences in life span that are commonly reported in animal species, particularly vertebrates. Our results suggest that the unguarded X is an unlikely general explanation for the evolution of sexually dimorphic life spans, which gives weight to alternative mechanisms, including "toxic Y" effects and sex differential selection via trade‐offs between survival and reproduction. [ABSTRACT FROM AUTHOR]

Demographic history and mutational load are of paramount importance for the adaptation of the endangered species. However, the effects of population evolutionary history and genetic load on the adaptive potential in endangered conifers remain unclear. Here, using population transcriptome sequencing, whole chloroplast genomes and mitochondrial DNA markers, combined with niche analysis, we determined the demographic history and mutational load for three threatened whitebark pines having different endangered statuses, Pinus bungeana, P. gerardiana and P. squamata. Demographic inference indicated that severe bottlenecks occurred in all three pines at different times, coinciding with periods of major climate and geological changes; in contrast, while P. bungeana experienced a recent population expansion, P. gerardiana and P. squamata maintained small population sizes after bottlenecking. Abundant homozygous-derived variants accumulated in the three pines, particularly in P. squamata, while the species with most heterozygous variants was P. gerardiana. Abundant moderately and few highly deleterious variants accumulated in the pine species that have experienced the most severe demographic bottlenecks (P. gerardiana and P. squamata), most likely because of purging effects. Finally, niche modeling showed that the distribution of P. bungeana might experience a significant expansion in the future, and the species' identified genetic clusters are also supported by differences in the ecological niche. The integration of genomic, demographic and niche data has allowed us to prove that the three threatened pines have contrasting patterns of demographic history and mutational load, which may have important implications in their adaptive potential and thus are also key for informing conservation planning., (© 2024 Society for Experimental Biology and John Wiley & Sons Ltd.)

• Multiple sequence alignment of 18392 SARS-CoV-2 genomes for 71 countries. • Phylogenetic analysis to identify virus clades. • Mutation points as SNPs are identified in each clade. • Top 10 signature SNPs are identified in each clade. • Signature SNPs are characterized using PROVEAN, Polyphen-2 and I-Mutant 2.0. Since the emergence of SARS-CoV-2 in Wuhan, China more than a year ago, it has spread across the world in a very short span of time. Although, different forms of vaccines are being rolled out for vaccination programs around the globe, the mutation of the virus is still a cause of concern among the research communities. Hence, it is important to study the constantly evolving virus and its strains in order to provide a much more stable form of cure. This fact motivated us to conduct this research where we have initially carried out multiple sequence alignment of 15359 and 3033 global dataset without Indian and the dataset of exclusive Indian SARS-CoV-2 genomes respectively, using MAFFT. Subsequently, phylogenetic analyses are performed using Nextstrain to identify virus clades. Consequently, the virus strains are found to be distributed among 5 major clades or clusters viz. 19A, 19B, 20A, 20B and 20C. Thereafter, mutation points as SNPs are identified in each clade. Henceforth, from each clade top 10 signature SNPs are identified based on their frequency i.e. number of occurrences in the virus genome. As a result, 50 such signature SNPs are individually identified for global dataset without Indian and dataset of exclusive Indian SARS-CoV-2 genomes respectively. Out of each 50 signature SNPs, 39 and 41 unique SNPs are identified among which 25 non-synonymous signature SNPs (out of 39) resulted in 30 amino acid changes in protein while 27 changes in amino acid are identified from 22 non-synonymous signature SNPs (out of 41). These 30 and 27 amino acid changes for the non-synonymous signature SNPs are visualised in their respective protein structure as well. Finally, in order to judge the characteristics of the identified clades, the non-synonymous signature SNPs are considered to evaluate the changes in proteins as biological functions with the sequences using PROVEAN and PolyPhen-2 while I-Mutant 2.0 is used to evaluate their structural stability. As a consequence, for global dataset without Indian sequences, G251V in ORF3a in clade 19A, F308Y and G196V in NSP4 and ORF3a in 19B are the unique amino acid changes which are responsible for defining each clade as they are all deleterious and unstable. Such changes which are common for both global dataset without Indian and dataset of exclusive Indian sequences are R203M in Nucleocapsid for 20B, T85I and Q57H in NSP2 and ORF3a respectively for 20C while for exclusive Indian sequences such unique changes are A97V in RdRp, G339S and G339C in NSP2 in 19A and Q57H in ORF3a in 20A. [ABSTRACT FROM AUTHOR]

The genetic load in the human genome has important ramifications for assisted reproductive technology (ART), human reproduction and fertility more generally. Here, we discuss these topics in the light of evolutionary genetic theory, the technological revolution in ART and the advances in the fields of genomics and bioinformatics. [ABSTRACT FROM AUTHOR]

Abstract Objective Domestication of wild animals results in a reduction in the effective population size, and this could affect the deleterious mutation load of domesticated breeds. Furthermore, artificial selection will also contribute to the accumulation of deleterious mutations due to the increased rate of inbreeding among these animals. The process of domestication, founder population size, and artificial selection differ between cattle breeds, which could lead to a variation in their deleterious mutation loads. We investigated this using mitochondrial genome data from 364 animals belonging to 18 cattle breeds of the world. Results Our analysis revealed more than a fivefold difference in the deleterious mutation load among cattle breeds. We also observed a negative correlation between the breed age and the proportion of deleterious amino acid-changing polymorphisms. This suggests a proportionally higher deleterious SNPs in young breeds compared to older breeds. Our results highlight the magnitude of difference in the deleterious mutations present in the mitochondrial genomes of various breeds. The results of this study could be useful in predicting the rate of incidence of genetic diseases in different breeds.

The distribution of fitness effects (DFE) has considerable importance in population genetics. To date, estimates of the DFE come from studies using a small number of individuals. Thus, estimates of the proportion of moderately to strongly deleterious new mutations may be unreliable because such variants are unlikely to be segregating in the data. Additionally, the true functional form of the DFE is unknown, and estimates of the DFE differ significantly between studies. Here we present a flexible and computationally tractable method, called Fit∂a∂i, to estimate the DFE of new mutations using the site frequency spectrum from a large number of individuals. We apply our approach to the frequency spectrum of 1300 Europeans from the Exome Sequencing Project ESP6400 data set, 1298 Danes from the LuCamp data set, and 432 Europeans from the 1000 Genomes Project to estimate the DFE of deleterious nonsynonymous mutations. We infer significantly fewer (0.38-0.84 fold) strongly deleterious mutations with selection coefficient |s| > 0.01 and more (1.24-1.43 fold) weakly deleterious mutations with selection coefficient |s| < 0.001 compared to previous estimates. Furthermore, a DFE that is a mixture distribution of a point mass at neutrality plus a gamma distribution fits better than a gamma distribution in two of the three data sets. Our results suggest that nearly neutral forces play a larger role in human evolution than previously thought.

Abstract The genetic load in the human genome has important ramifications for assisted reproductive technology (ART), human reproduction and fertility more generally. Here, we discuss these topics in the light of evolutionary genetic theory, the technological revolution in ART and the advances in the fields of genomics and bioinformatics.

Whole-genome duplication (polyploidization) is among the most dramatic mutational processes in nature, so understanding how natural selection differs in polyploids relative to diploids is an important goal. Population genetics theory predicts that recessive deleterious mutations accumulate faster in allopolyploids than diploids due to the masking effect of redundant gene copies, but this prediction is hitherto unconfirmed. Here, we use the cotton genus (Gossypium), which contains seven allopolyploids derived from a single polyploidization event 1–2 Million years ago, to investigate deleterious mutation accumulation. We use two methods of identifying deleterious mutations at the nucleotide and amino acid level, along with whole-genome resequencing of 43 individuals spanning six allopolyploid species and their two diploid progenitors, to demonstrate that deleterious mutations accumulate faster in allopolyploids than in their diploid progenitors. We find that, unlike what would be expected under models of demographic changes alone, strongly deleterious mutations show the biggest difference between ploidy levels, and this effect diminishes for moderately and mildly deleterious mutations. We further show that the proportion of nonsynonymous mutations that are deleterious differs between the two coresident subgenomes in the allopolyploids, suggesting that homoeologous masking acts unequally between subgenomes. Our results provide a genome-wide perspective on classic notions of the significance of gene duplication that likely are broadly applicable to allopolyploids, with implications for our understanding of the evolutionary fate of deleterious mutations. Finally, we note that some measures of selection (e.g. d N /d S , πN/ π S) may be biased when species of different ploidy levels are compared. [ABSTRACT FROM AUTHOR]

Population bottlenecks, inbreeding, and artificial selection can all, in principle, influence levels of deleterious genetic variation. However, the relative importance of each of these effects on genome-wide patterns of deleterious variation remains controversial. Domestic and wild canids offer a powerful system to address the role of these factors in influencing deleterious variation because their history is dominated by known bottlenecks and intense artificial selection. Here, we assess genome-wide patterns of deleterious variation in 90 whole-genome sequences from breed dogs, village dogs, and gray wolves. We find that the ratio of amino acid changing heterozygosity to silent heterozygosity is higher in dogs than in wolves and, on average, dogs have 2-3% higher genetic load than gray wolves. Multiple lines of evidence indicate this pattern is driven by less efficient natural selection due to bottlenecks associated with domestication and breed formation, rather than recent inbreeding. Further, we find regions of the genome implicated in selective sweeps are enriched for amino acid changing variants and Mendelian disease genes. To our knowledge, these results provide the first quantitative estimates of the increased burden of deleterious variants directly associated with domestication and have important implications for selective breeding programs and the conservation of rare and endangered species. Specifically, they highlight the costs associated with selective breeding and question the practice favoring the breeding of individuals that best fit breed standards. Our results also suggest that maintaining a large population size, rather than just avoiding inbreeding, is a critical factor for preventing the accumulation of deleterious variants.

Small, isolated populations present a challenge for conservation. The dueling effects of selection and drift in a limited pool of genetic diversity make the responses of small populations to environmental perturbations erratic and difficult to predict. This is particularly true at the edge of a species range, where populations often persist at the limits of their environmental tolerances. Populations of cisco, Coregonus artedi, in inland lakes have experienced numerous extirpations along the southern edge of their range in recent decades, which are thought to result from environmental degradation and loss of cold, well‐oxygenated habitat as lakes warm. Yet, cisco extirpations do not show a clear latitudinal pattern, suggesting that local environmental factors and potentially local adaptation may influence resilience. Here, we used genomic tools to investigate the nature of this pattern of resilience. We used restriction site‐associated DNA capture (Rapture) sequencing to survey genomic diversity and differentiation in southern inland lake cisco populations and compared the frequency of deleterious mutations that potentially influence fitness across lakes. We also examined haplotype diversity in a region of the major histocompatibility complex involved in stress and immune system response. We correlated these metrics to spatial and environmental factors including latitude, lake size, and measures of oxythermal habitat and found significant relationships between genetic metrics and broad and local factors. High levels of genetic differentiation among populations were punctuated by a phylogeographic break and residual patterns of isolation‐by‐distance. Although the prevalence of deleterious mutations and inbreeding coefficients was significantly correlated with latitude, neutral and non‐neutral genetic diversity were most strongly correlated with lake surface area. Notably, differences among lakes in the availability of estimated oxythermal habitat left no clear population genomic signature. Our results shed light on the complex dynamics influencing these isolated populations and provide valuable information for their conservation. [ABSTRACT FROM AUTHOR]

It has previously been shown that, conditional on its fixation, the time to fixation of a semi-dominant deleterious autosomal mutation in a randomly mating population is the same as that of an advantageous mutation. This result implies that deleterious mutations could generate selective sweep-like effects. Although their fixation probabilities greatly differ, the much larger input of deleterious relative to beneficial mutations suggests that this phenomenon could be important. We here examine how the fixation of mildly deleterious mutations affects levels and patterns of polymorphism at linked sites--both in the presence and absence of interference amongst deleterious mutations--and how this class of sites may contribute to divergence between-populations and species. We find that, while deleterious fixations are unlikely to represent a significant proportion of outliers in polymorphism-based genomic scans within populations, minor shifts in the frequencies of deleterious mutations can influence the proportions of private variants and the value of FST after a recent population split. As sites subject to deleterious mutations are necessarily found in functional genomic regions, interpretations in terms of recurrent positive selection may require reconsideration. [ABSTRACT FROM AUTHOR]

Abstract Background In order for aging to evolve in response to a declining strength of selection with age, a genetic architecture that allows for mutations with age-specific effects on organismal performance is required. Our understanding of how selective effects of individual mutations are distributed across ages is however poor. Established evolutionary theories assume that mutations causing aging have negative late-life effects, coupled to either positive or neutral effects early in life. New theory now suggests evolution of aging may also result from deleterious mutations with increasing negative effects with age, a possibility that has not yet been empirically explored. Results To directly test how the effects of deleterious mutations are distributed across ages, we separately measure age-specific effects on fecundity for each of 20 mutations in Drosophila melanogaster. We find that deleterious mutations in general have a negative effect that increases with age and that the rate of increase depends on how deleterious a mutation is early in life. Conclusions Our findings suggest that aging does not exclusively depend on genetic variants assumed by the established evolutionary theories of aging. Instead, aging can result from deleterious mutations with negative effects that amplify with age. If increasing negative effect with age is a general property of deleterious mutations, the proportion of mutations with the capacity to contribute towards aging may be considerably larger than previously believed.

Serum and glucocorticoid-regulated kinase 1 (SGK1) is a Ser/Thr protein kinase involved in regulating cell survival, growth, proliferation, and migration. Its elevated expression and dysfunction are reported in breast, prostate, hepatocellular, lung adenoma, and renal carcinomas. We have analyzed the SGK1 mutations to explore their impact at the sequence and structure level by utilizing state-of-the-art computational approaches. Several pathogenic and destabilizing mutations were identified based on their impact on SGK1 and analyzed in detail. Three amino acid substitutions, K127M, T256A, and Y298A, in the kinase domain of SGK1 were identified and incorporated structurally into original coordinates of SGK1 to explore their time evolution impact using all-atom molecular dynamic (MD) simulations for 200 ns. MD results indicate substantial conformational alterations in SGK1, thus its functional loss, particularly upon T256A mutation. This study provides meaningful insights into SGK1 dysfunction upon mutation, leading to disease progression, including cancer, and neurodegeneration.

Whether freshwater fish colonize remote islands following tectonic or transoceanic dispersal remains an evolutionary puzzle. Integrating dating of known tectonic events with phylogenomics and current species distribution, we find that killifish species distribution is not explained by species dispersal by tectonic drift only. Investigating the colonization of a nonannual killifish (golden panchax, Pachypanchax playfairii) on the Seychelle islands, we found genetic support for transoceanic dispersal and experimentally discovered an adaptation to complete tolerance to seawater. At the macroevolutionary scale, despite their long‐lasting isolation, nonannual golden panchax show stronger genome‐wide purifying selection than annual killifishes from continental Africa. However, progressive decline in effective population size over a more recent timescale has probably led to the segregation of slightly deleterious mutations across golden panchax populations, which represents a potential threat for species preservation in the long term. [ABSTRACT FROM AUTHOR]

Objective: Domestication of wild animals results in a reduction in the effective population size, and this could affect the deleterious mutation load of domesticated breeds. Furthermore, artificial selection will also contribute to the accumulation of deleterious mutations due to the increased rate of inbreeding among these animals. The process of domestication, founder population size, and artificial selection differ between cattle breeds, which could lead to a variation in their deleterious mutation loads. We investigated this using mitochondrial genome data from 364 animals belonging to 18 cattle breeds of the world. Results: Our analysis revealed more than a fivefold difference in the deleterious mutation load among cattle breeds. We also observed a negative correlation between the breed age and the proportion of deleterious amino acid-changing polymorphisms. This suggests a proportionally higher deleterious SNPs in young breeds compared to older breeds. Our results highlight the magnitude of difference in the deleterious mutations present in the mitochondrial genomes of various breeds. The results of this study could be useful in predicting the rate of incidence of genetic diseases in different breeds. [ABSTRACT FROM AUTHOR]

During range expansion, edge populations are expected to face increased genetic drift, which in turn can alter and potentially compromise adaptive dynamics, preventing the removal of deleterious mutations and slowing down adaptation. Here, we contrast populations of the European subspecies Arabidopsis lyrata ssp. petraea , which expanded its Northern range after the last glaciation. We document a sharp decline in effective population size in the range-edge population and observe that nonsynonymous variants segregate at higher frequencies. We detect a 4.9% excess of derived nonsynonymous variants per individual in the range-edge population, suggesting an increase of the genomic burden of deleterious mutations. Inference of the fitness effects of mutations and modeling of allele frequencies under the explicit demographic history of each population predicts a depletion of rare deleterious variants in the range-edge population, but an enrichment for fixed ones, consistent with the bottleneck effect. However, the demographic history of the range-edge population predicts a small net decrease in per-individual fitness. Consistent with this prediction, the range-edge population is not impaired in its growth and survival measured in a common garden experiment. We further observe that the allelic diversity at the self-incompatibility locus, which ensures strict outcrossing and evolves under negative frequency-dependent selection, has remained unchanged. Genomic footprints indicative of selective sweeps are broader in the Northern population but not less frequent. We conclude that the outcrossing species A. lyrata ssp. petraea shows a strong resilience to the effect of range expansion. [ABSTRACT FROM AUTHOR]