Essay: On the close relationship between speciation, inbreeding and recessive mutations.

Whilst the principle of adaptive evolution is unanimously recognised as being caused by the process of natural selection favouring the survival and/or reproduction of individuals having acquired new advantageous traits, a consensus has proven much harder to find regarding the actual origin of species. Indeed, since speciation corresponds to the establishment of reproductive barriers, it is difficult to see how it could bring a selective advantage because it amounts to a restriction in the opportunities to breed with as many and/or as diverse partners as possible. In this regard, Darwin himself did not believe that reproductive barriers could be selected for, and today most evolutionary biologists still believe that speciation can only occur through a process of separation allowing two populations to diverge sufficiently to become infertile with one another. I do, however, take the view that, if so much speciation has occurred, and still occurs around us, it cannot be a consequence of passive drift but must result from a selection process, whereby it is advantageous for groups of individuals to reproduce preferentially with one another and reduce their breeding with the rest of the population.In this essay, I propose a model whereby new species arise by “budding” from an ancestral stock, via a process of inbreeding among small numbers of individuals, driven by the occurrence of advantageous recessive mutations. Since the phenotypes associated to such mutations can only be retained in the context of inbreeding, it is the pressure of the ancestral stock which will promote additional reproductive barriers, and ultimately result in complete separation of a new species. I thus contend that the phenomenon of speciation would be driven by mutations resulting in the advantageous loss of certain functions, whilst adaptive evolution would correspond to gains of function that would, most of the time be dominant.A very important further advantage of inbreeding is that it reduces the accumulation of recessive mutations in genomes. A consequence of the model proposed is that the existence of species would correspond to a metastable equilibrium between inbreeding and outbreeding, with excessive inbreeding promoting speciation, and excessive outbreeding resulting in irreversible accumulation of recessive mutations that could ultimately only lead to the species extinction.

Whilst the principle of adaptive evolution is unanimously recognised as being caused by the process of natural selection favouring the survival and/or reproduction of individuals having acquired new advantageous traits, a consensus has proven much harder to find regarding the actual origin of species. Indeed, since speciation corresponds to the establishment of reproductive barriers, it is difficult to see how it could bring a selective advantage because it amounts to a restriction in the opportunities to breed with as many and/or as diverse partners as possible. In this regard, Darwin himself did not believe that reproductive barriers could be selected for, and today most evolutionary biologists still believe that speciation can only occur through a process of separation allowing two populations to diverge sufficiently to become infertile with one another. I do, however, take the view that, if so much speciation has occurred, and still occurs around us, it cannot be a consequence of passive drift but must result from a selection process, whereby it is advantageous for groups of individuals to reproduce preferentially with one another and reduce their breeding with the rest of the population.In this essay, I propose a model whereby new species arise by “budding” from an ancestral stock, via a process of inbreeding among small numbers of individuals, driven by the occurrence of advantageous recessive mutations. Since the phenotypes associated to such mutations can only be retained in the context of inbreeding, it is the pressure of the ancestral stock which will promote additional reproductive barriers, and ultimately result in complete separation of a new species. I thus contend that the phenomenon of speciation would be driven by mutations resulting in the advantageous loss of certain functions, whilst adaptive evolution would correspond to gains of function that would, most of the time be dominant.A very important further advantage of inbreeding is that it reduces the accumulation of recessive mutations in genomes. A consequence of the model proposed is that the existence of species would correspond to a metastable equilibrium between inbreeding and outbreeding, with excessive inbreeding promoting speciation, and excessive outbreeding resulting in irreversible accumulation of recessive mutations that could ultimately only lead to the species extinction.

BackgroundSpeciation corresponds to the progressive establishment of reproductive barriers between groups of individuals derived from an ancestral stock. Since Darwin did not believe that reproductive barriers could be selected for, he proposed that most events of speciation would occur through a process of separation and divergence, and this point of view is still shared by most evolutionary biologists today.ResultsI do, however, contend that, if so much speciation occurs, the most likely explanation is that there must be conditions where reproductive barriers can be directly selected for. In other words, situations where it is advantageous for individuals to reproduce preferentially within a small group and reduce their breeding with the rest of the ancestral population. This leads me to propose a model whereby new species arise not by populations splitting into separate branches, but by small inbreeding groups "budding" from an ancestral stock. This would be driven by several advantages of inbreeding, and mainly by advantageous recessive phenotypes, which could only be retained in the context of inbreeding. Reproductive barriers would thus not arise as secondary consequences of divergent evolution in populations isolated from one another, but under the direct selective pressure of ancestral stocks. Many documented cases of speciation in natural populations appear to fit the model proposed, with more speciation occurring in populations with high inbreeding coefficients, and many recessive characters identified as central to the phenomenon of speciation, with these recessive mutations expected to be surrounded by patterns of limited genomic diversity.ConclusionsWhilst adaptive evolution would correspond to gains of function that would, most of the time, be dominant, this type of speciation by budding would thus be driven by mutations resulting in the advantageous loss of certain functions since recessive mutations very often correspond to the inactivation of a gene. A very important further advantage of inbreeding is that it reduces the accumulation of recessive mutations in genomes. A consequence of the model proposed is that the existence of species would correspond to a metastable equilibrium between inbreeding and outbreeding, with excessive inbreeding promoting speciation, and excessive outbreeding resulting in irreversible accumulation of recessive mutations that could ultimately only lead to extinction.Reviewer namesEugene V. Koonin, Patrick Nosil (nominated by Dr Jerzy Jurka), Pierre Pontarotti

Background: Speciation corresponds to the progressive establishment of reproductive barriers between groups of individuals derived from an ancestral stock. Since Darwin did not believe that reproductive barriers could be selected for, he proposed that most events of speciation would occur through a process of separation and divergence, and this point of view is still shared by most evolutionary biologists today. Results: I do, however, contend that, if so much speciation occurs, it must result from a process of natural selection, whereby it is advantageous for individuals to reproduce preferentially within a group and reduce their breeding with the rest of the population, leading to a model whereby new species arise not by populations splitting into separate branches, but by small inbreeding groups “budding” from an ancestral stock. This would be driven by several advantages of inbreeding, and mainly by advantageous recessive phenotypes, which could only be retained in the context of inbreeding. Reproductive barriers would thus not arise passively as a consequence of drift in isolated populations, but under the selective pressure of ancestral stocks. Most documented cases of speciation in natural populations appear to fit the model proposed, with more speciation occurring in populations with high inbreeding coefficients, many recessive characters identified as central to the phenomenon of speciation, with these recessive mutations expected to be surrounded by patterns of limited genomic diversity. Conclusions: Whilst adaptive evolution would correspond to gains of function that would, most of the time, be dominant, the phenomenon of speciation would thus be driven by mutations resulting in the advantageous loss of certain functions since recessive mutations very often correspond to the inactivation of a gene. A very important further advantage of inbreeding is that it reduces the accumulation of recessive mutations in genomes. A consequence of the model proposed is that the existence of species would correspond to a metastable equilibrium between inbreeding and outbreeding, with excessive inbreeding promoting speciation, and excessive outbreeding resulting in irreversible accumulation of recessive mutations that could ultimately only lead to the extinction.

The Relationship between the Aging- and Photo-Dependent T414G Mitochondrial DNA Mutation with Cellular Senescence and Reactive Oxygen Species Production in Cultured Skin Fibroblasts

Chronic exposure of organisms to endo- or exogenous genotoxic products results in the accumulation of mutations in the genome and eventually to the development of cancers. Early detection of these mutations would allow the identification of at risk individuals who present a high load of mutations either because of an occupational or environmental exposure, or because of less efficient DNA repair processes. However, highly specific and sensitive assays are required to allow the detection of point mutations in a whole genome. We review a long-term study on the mutagenesis induced in E.coli by an aromatic amide, the N-2-acetylaminofluorene. A major contribution of this work was to reveal the presence of specific mutation hot spot sequences. Taking advantage of this observation, we designed a specific, sensitive and semi-quantitative in vitro assay allowing the detection of carcinogen induced mutations. This assay has been validated in vivo and demonstrate the sensitivity of the technique in early detection of mutations and its usefullness in molecular epidemiology, early diagnostic and prognosis.

In a genetic study of postzygotic reproductive isolation among species of the Drosophila virilis group, we find that the X chromosome has the largest effect on male and female hybrid sterility and inviability. The X alone has a discernible effect on postzygotic isolation between closely related species. Hybridizations involving more distantly related species also show large X-effects, although the autosomes may also play a role. In the only hybridization yet subjected to such analysis, we show that hybrid male and female sterility result from the action of different X-linked loci. Our results accord with genetic studies of other taxa, and support the view that both Haldane's rule (heterogametic F1 sterility or inviability) and the large effect of the X chromosome on reproductive isolation result from the accumulation by natural selection of partially recessive or underdominant mutations. We also describe a method that allows genetic analysis of reproductive isolation between species that produce completely sterile or inviable hybrids. Such species pairs, which represent the final stage of speciation, cannot be analyzed by traditional methods. The X chromosome also plays an important role in postzygotic isolation between these species.

Mitochondrial dysfunction plays an important role in the aging process. However, the mechanism by which this dysfunction causes aging is not fully understood. The accumulation of mutations in the mitochondrial genome (or “mtDNA”) has been proposed as a contributor. One compelling piece of evidence in support of this hypothesis comes from the PolgD257A/D257A mutator mouse (Polgmut/mut). These mice express an error‐prone mitochondrial DNA polymerase that results in the accumulation of mtDNA mutations, accelerated aging, and premature death. In this paper, we have used the Polgmut/mut model to investigate whether the age‐related biological effects observed in these mice are triggered by oxidative damage to the DNA that compromises the integrity of the genome. Our results show that mutator mouse has significantly higher levels of 8‐oxoguanine (8‐oxoGua) that are correlated with increased nuclear DNA (nDNA) strand breakage and oxidative nDNA damage, shorter average telomere length, and reduced mtDNA integrity. Based on these results, we propose a model whereby the increased level of reactive oxygen species (ROS) associated with the accumulation of mtDNA mutations in Polgmut/mut mice results in higher levels of 8‐oxoGua, which in turn lead to compromised DNA integrity and accelerated aging via increased DNA fragmentation and telomere shortening. These results suggest that mitochondrial play a central role in aging and may guide future research to develop potential therapeutics for mitigating aging process.

Negative natural selection on deleterious mutations plays a key role in shaping human genetic variation. Understanding the dominance of deleterious mutations is critical as it can fundamentally impact the rate and efficiency of natural selection, the magnitude of inbreeding depression, and the prevalence and evolution of genetic diseases. Despite its inarguable importance, the dominance effects of mutations remain poorly understood in humans, primarily because existing statistical methods cannot distinguish them from the overall selective effects of mutations. In this work, we take a fundamentally different approach to infer dominance by leveraging the distribution of Neanderthal ancestry across the human genome. We show through simulations that recessive deleterious mutations lead to an increase in archaic introgressed ancestry in the absence of positive selection, contrary to what is expected when deleterious mutations are additive. Leveraging this unique pattern, we develop a machine learning classifier to infer dominance in genomic windows at a megabase resolution, trained on simulations of a human demographic model with Neanderthal introgression using fully recessive or additive mutations. Our method demonstrates robust accuracy at detecting genomic windows containing recessive deleterious mutations, with particularly high power in exon-dense regions. When applied to the non-African populations from the 1000 Genomes Project, we find that approximately 3-9% of the human genome is enriched for recessive mutations with most recessive regions shared across human populations. Furthermore, our method reveals that recessive deleterious mutations are not evenly distributed across the genome: regions enriched for recessive mutations are significantly depleted of haploinsufficient genes and runs of homozygosity, and are enriched with non-additive variants associated with complex traits. Overall, our Neanderthal ancestry-based approach reveals the presence of recessive deleterious mutations in the human genome and suggests that these mutations are found in regions containing genes associated with metabolism and immune-related traits.

The accumulation of somatic mutations during aging is not uniform across tissue types and, in addition, shows significant variability in the source of mutation that can be modified by small molecule interventions.

The accumulation of somatic mutations during aging is not uniform across tissue types and, in addition, shows significant variability in the source of mutation that can be modified by small molecule interventions.

The accumulation of somatic mutations during aging is not uniform across tissue types and, in addition, shows significant variability in the source of mutation that can be modified by small molecule interventions.

The objective of this study is to increase our understanding of mutation accumulation in multicellular genomes with deficiencies in the DNA damage response regulators employing the model organism Arabidopsis thaliana. We compare and quantify genomic mutations between wild‐type cells and cells defective in global regulator ATR of the DNA damage response mechanism. We have established mutation accumulation (MA) lines for whole genome mutation analysis. Assembly and analysis of the MA line genomes show a spectrum of genome rearrangements as compared to point mutations. Defects in ATR and related repair pathways generate a unique spectrum of mutational events that can be used to predict similar genomic deficiencies in other organisms. A combination of bioinformatics, genomic analysis and a model organism that tolerates mutation accumulation of DNA damage response genes sheds light on how global regulators of the DNA damage response affect overall genomic stability and how defects in these genes contribute to genomic instability. Understanding how global regulators of the DNA damage response affect genomic stability in healthy human cells and how defects in these genes contribute to genomic instability seen in cancer cells requires the knowledge of how and why specific mutation occurs. This study bridges a critical gap in knowledge, how genomes of multicellular organisms respond to genome instability when essential genes involved in the DNA repair pathway are mutated.Support or Funding InformationNational Science Foundation

The intricate relationship between genomic mutations and proteomic network topology represents a frontier in understanding cellular resilience and disease mechanisms. This study presents a novel approach to analyzing how proteomic topological structures evolve and potentially break down in response to accumulating genomic mutations, offering insights into the complex interplay between genetic alterations and protein interaction networks. We developed a computational model simulating a network of ten key proteins (A-J) over 20 discrete time points, each representing a state of increasing genomic mutation load. Our model incorporates dynamic protein interaction strengths that fluctuate in response to simulated genomic alterations and a topological representation of the protein network, allowing for visualization of structural changes. Not forgetting a quantitative measure of network integrity, correlating with the system's ability to maintain function under mutational stress. Our Key findings include: visualization of proteomic network evolution through a series of topological graphs, revealing how genomic mutations progressively alter protein interaction patterns and identification of a critical "breakage point" in the network topology, signifying a threshold where genomic mutations overwhelm the protein network's ability to maintain its functional structure. And also quantification of network properties, including interaction strengths and overall network density, demonstrating the non-linear relationship between genomic mutations and proteomic topological integrity.The observed breakage point may represent a critical threshold in disease progression, where the accumulation of genomic mutations leads to a collapse in the proteomic interaction network, potentially triggering pathological states. This methodology offers a new perspective on the genotype-phenotype relationship, viewing it through the lens of protein network topology. Our approach provides a framework for future studies to analyze how specific genomic mutations might impact proteomic structures, potentially leading to new insights in cancer research, neurodegenerative disorders, and other mutation-driven diseases. It also suggests that maintaining proteomic topological integrity could be a key factor in cellular resilience against genomic instability.

Genomic divergence and mutation load in the Begonia masoniana complex from limestone karsts