5,184 research outputs found

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

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    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. 
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    The existence of species rests on a metastable equilibrium between inbreeding and outbreeding

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

    Get PDF
    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. 
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    Inbreeding depression maintained by recessive lethal mutations interacting with stabilizing selection on quantitative characters in a partially self-fertilizing population

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    International audienceThe bimodal distribution of fitness effects of new mutations and standing genetic variation, due to early-acting strongly deleterious recessive mutations and late-acting mildly deleterious mutations, is analyzed using the Kondrashov model for lethals (K), with either the infinitesimal model for selfing (IMS) or the Gaussian allele model (GAM) for quantitative genetic variance under stabilizing selection. In the combined models (KIMS and KGAM) high genomic mutation rates to lethals and weak stabilizing selection on many characters create strong interactions between early and late inbreeding depression, by changing the distribution of lineages selfed consecutively for different numbers of generations. Alternative stable equilibria can exist at intermediate selfing rates for a given set of parameters. Evolution of quantitative genetic variance under multivariate stabilizing selection can strongly influence the purging of nearly recessive lethals, and sometimes vice versa. If the selfing rate at the purging threshold for quantitative genetic variance in IMS or GAM alone exceeds that for nearly recessive lethals in K alone, then in KIMS and KGAM stabilizing selection causes selective interference with purging of lethals, increasing the mean number of lethals compared to K; otherwise, stabilizing selection causes selective facilitation in purging of lethals, decreasing the mean number of lethals

    The Biochemical Characterization of Human Histidyl-tRNA Synthetase and Disease Associated Variants

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    Human histidyl-tRNA synthetase (HARS) is an aminoacyl-tRNA synthetase (AARS) that catalyzes the attachment of the amino acid histidine to histidyl-tRNA (tRNAHis) in a two-step reaction that is essential for protein translation. Currently, two human diseases, Usher Syndrome IIIB (USH3B) and an inherited peripheral neuropathy, Charcot Marie Tooth Syndrome (CMT), have been linked genetically to single point mutations in the HARS gene. The recessive HARS USH3B mutation encodes an Y454S substitution localized at the interface between the anticodon-binding domain and the catalytic domain of the opposing subunit. Patients with Usher Syndrome IIIB lose their sight and hearing during their second decade of life, and clinicians have observed that the onset of deafness and blindness may be episodic and correlate with febrile illness. Furthermore, some young USH3B patients present with a fatal form of acute respiratory distress. In addition to the single HARS mutation linked to Usher Syndrome, eight other mutations in the HARS gene are associated with CMT, an inherited peripheral neuropathy. Peripheral neuropathies are associated with progressive and length-dependent damage of the motor and sensory neurons that transmit information to the spinal cord. The age of onset and phenotypic severity of CMT linked to HARS is highly variable. When expressed in a yeast model system, the HARS variants are dominantly lethal, and confer defects in axonal guidance and locomotor deficiencies when expressed in C.elegans. Here, the biochemical characterization of the HARS USH3B and three peripheral neuropathy variants are described. The approaches included enzyme kinetic analysis with purified HARS enzymes to monitor catalytic deficiencies, differential scanning fluorimetry (DSF) to evaluate structural instability, and cellular models to detect physiological effects of axonal outgrowth by CMT variants. The results suggest that Usher Syndrome IIIB is unlikely to be a consequence of a simple loss of aminoacylation function, while HARS-linked peripheral neuropathy variants all share common catalytic defects in aminoacylation. The HARS system represents a notable example in which two different complex human diseases arise from distinct mutations in the same parent gene. By understanding the biochemical basis of these inherited mutations and their link to Usher Syndrome and CMT, it may be possible to develop mechanism-based therapies to improve the quality of life of patients afflicted with them

    Dynamics of statistical associations between many genes

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    A Human-Derived Monoclonal Antibody Targeting Extracellular Connexin Domain Selectively Modulates Hemichannel Function

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    Connexin hemichannels, which are plasma membrane hexameric channels (connexons) composed of connexin protein protomers, have been implicated in a host of physiological processes and pathological conditions. A number of single point pathological mutations impart a "leaky" character to the affected hemichannels, i.e., make them more active or hyperactive, suggesting that normal physiological condition could be recovered using selective hemichannel inhibitors. Recently, a human-derived monoclonal antibody named abEC1.1 has been shown to inhibit both wild type and hyperactive hemichannels composed of human (h) connexin 26 (hCx26) subunits. The aims of this work were (1) to characterize further the ability of abEC1.1 to selectively modulate connexin hemichannel function and (2) to assess its in vitro stability in view of future translational applications. In silico analysis of abEC1.1 interaction with the hCx26 hemichannel identified critically important extracellular domain amino acids that are conserved in connexin 30 (hCx30) and connexin 32 (hCx32). Patch clamp experiments performed in HeLa DH cells confirmed the inhibition efficiency of abEC1.1 was comparable for hCx26, hCx30 and hCx32 hemichannels. Of note, even a single amino acid difference in the putative binding region reduced drastically the inhibitory effects of the antibody on all the other tested hemichannels, namely hCx30.2/31.3, hCx30.3, hCx31, hCx31.1, hCx37, hCx43 and hCx45. Plasma membrane channels composed of pannexin 1 were not affected by abEC1.1. Finally, size exclusion chromatography assays showed the antibody does not aggregate appreciably in vitro. Altogether, these results indicate abEC1.1 is a promising tool for further translational studies

    Human Pathogenic Mutations in Protein Domains

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    Polymorphism

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