Genetics最新文献

Hybrid incompatibilities are a critical component of species barriers and may arise due to negative interactions between divergent regulatory elements in parental species. We used a comparative approach to identify common themes in the regulatory phenotypes associated with hybrid male sterility in two divergent rodent crosses, dwarf hamsters and house mice. We investigated three potential characteristic gene expression phenotypes in hybrids including the propensity of transgressive differentially expressed genes toward over or underexpression, the influence of developmental stage on patterns of misexpression, and the role of the sex chromosomes on misexpression phenotypes. In contrast to near pervasive overexpression in hybrid house mice, we found that misexpression in hybrid dwarf hamsters was dependent on developmental stage. In both house mouse and dwarf hamster hybrids, however, misexpression increased with the progression of spermatogenesis, although to varying extents and with potentially different consequences. In both systems, we detected sex chromosome-specific overexpression in stages of spermatogenesis where inactivated X chromosome expression was expected, but the hybrid overexpression phenotypes were fundamentally different. Importantly, misexpression phenotypes support the presence of multiple developmental blocks to spermatogenesis in dwarf hamster hybrids, including a potential role of meiotic stalling or breakdown early in spermatogenesis. Collectively, we demonstrate that while there are some similarities in hybrid expression phenotypes of house mice and dwarf hamsters, there are also clear differences that point toward unique mechanisms underlying hybrid male sterility. Our results highlight the potential of comparative approaches in helping to understand the causes and consequences of disrupted gene expression in speciation.

Transposable elements are DNA sequences that can move and replicate within genomes. Broadly, there are 2 types: autonomous elements, which encode the necessary enzymes for transposition, and nonautonomous elements, which rely on the enzymes produced by autonomous elements for their transposition. Nonautonomous elements have been proposed to regulate the numbers of transposable elements, which is a possible explanation for the persistence of transposition activity over long evolutionary times. However, previous modeling studies indicate that interactions between autonomous and nonautonomous elements usually result in the extinction of one type. Here, we study a stochastic model that allows for the stable coexistence of autonomous and nonautonomous retrotransposons. We determine the conditions for this coexistence and derive an analytical expression for the stationary distribution of their copy numbers, showing that nonautonomous elements regulate stochastic fluctuations and the number of autonomous elements in stationarity. We find that the stationary variances of each element can be expressed as a function of the average copy numbers and their covariance, enabling data comparison and model validation. These results suggest that continued transposition activity of transposable elements, regulated by nonautonomous elements, is a possible evolutionary outcome that could for example explain the long coevolutionary history of autonomous LINE1 and nonautonomous Alu element transposition in the human ancestry.

Hyphal elongation is the vegetative growth of filamentous fungi, and many species continuously elongate their hyphal tips over long periods. The details of the mechanisms for maintaining continuous growth are not yet clear. A novel short lifespan mutant of N. crassa that ceases hyphal elongation early was screened and analyzed to better understand the mechanisms for maintaining hyphal elongation in filamentous fungi. The mutant strain also exhibited high sensitivity to mutagens such as hydroxyurea and ultraviolet radiation. Based on these observations, we named the novel mutant "mutagen sensitive and short lifespan 1 (ms1)." The mutation responsible for the short lifespan and mutagen sensitivity in the ms1 strain was identified in DNA polymerase γ (mip-1:NCU00276). This mutation changed the amino acid at position 814 in the polymerase domain from leucine to arginine (MIP-1 L814R). A dosage analysis by next-generation sequencing reads suggested that mitochondrial DNA (mtDNA) sequences are decreased nonuniformly throughout the genome of the ms1 strain. This observation was confirmed by quantitative PCR for 3 representative loci and restriction fragment length polymorphisms in purified mtDNA. Direct repeat-mediated deletions, which had been reported previously, were not detected in the mitochondrial genome by our whole-genome sequencing analysis. These results imply the presence of novel mechanisms to induce the nonuniform decrease in the mitochondrial genome by DNA polymerase γ mutation. Some potential reasons for the nonuniform distribution of the mitochondrial genome are discussed in relation to the molecular functions of DNA polymerase γ.

We present a new hierarchical Bayesian method using multilocus genotypes to estimate recent seed and pollen migration rates in a spatially explicit framework that incorporates distance effects separately for each type of dispersal. The method additionally estimates population allelic frequencies, population divergence values, individual inbreeding coefficients, individual maternal and paternal ancestries, and allelic dropout rates. We conduct a numerical simulation analysis that indicates that the method can provide reliable estimates of seed and pollen migration rates and allow accurate inference of spatial effects on migration, at affordable sample sizes (25-50 individuals/population) when population genetic divergence is not low (FST≥0.05), or by increasing sampling (to at least 100 individuals/population) under weaker levels of divergence (FST=0.025). Simulations also show that the accuracy provided by assays with about one thousand unlinked polymorphic SNP loci may approach, for a given sample size, the theoretical maximum achievable under categorical origin discrimination. We apply our method to Taxus baccata data, revealing low but significant seed and pollen migration among nearby population remnants during the last generation, with a negative effect of interpopulation distance on migration that was detectable for pollen but not for seeds.

Mitochondrial membrane phospholipid cardiolipin is essential for the stability of several inner mitochondrial membrane protein complexes. We recently showed that the abundance of mitochondrial magnesium channel MRS2 is reduced in models of Barth syndrome, an X-linked genetic disorder caused by a remodeling defect in cardiolipin. However, the mechanism underlying the reduced abundance of MRS2 in cardiolipin-depleted mitochondria remained unknown. In this study, we utilized yeast mutants of mitochondrial proteases to identify an evolutionarily conserved m-AAA protease, Yta10/Yta12, responsible for degrading Mrs2. The activity of m-AAA protease is regulated by the inner mitochondrial membrane scaffolding complex prohibitin, and consistent with this role, we find that Mrs2 turnover is increased in yeast prohibitin mutants. Importantly, we find that deleting Yta10 in cardiolipin-deficient yeast cells restores the steady-state levels of Mrs2 to the wild-type cells, and the knockdown of AFG3L2, a mammalian homolog of Yta12, increases the abundance of MRS2 in a murine muscle cell line. Thus, our work has identified the m-AAA protease/prohibitin complex as an evolutionarily conserved regulator of Mrs2 that can be targeted to restore Mrs2 abundance in cardiolipin-depleted cells.

The CAP (cysteine-rich secretory proteins, antigen-5, and pathogenesis-related) proteins are widely expressed and have been implicated to play diverse roles ranging from mammalian reproduction to plant immune response. Increasing evidence supports a role of CAP proteins in lipid binding. The Caenorhabditis elegans CAP protein LON-1 is known to regulate body size and bone morphogenetic protein (BMP) signaling. LON-1 is a secreted protein with a conserved CAP domain and a C-terminal unstructured domain with no homology to other proteins. In this study, we report that the C-terminal domain of LON-1 is dispensable for its function. Instead, key conserved residues located in the CAP domain are critical for LON-1 function in vivo. We further showed that LON-1 is capable of binding sterol, but not fatty acid, in vitro, and that certain key residues implicated in LON-1 function in vivo are also important for LON-1 sterol binding in vitro. These findings suggest a role of LON-1 in regulating body size and BMP signaling via sterol binding.

A major obstacle to predictive understanding of evolution stems from the complexity of biological systems, which prevents detailed characterization of key evolutionary properties. Here, we highlight some of the major sources of complexity that arise when relating molecular mechanisms to their evolutionary consequences and ask whether accounting for every mechanistic detail is important to accurately predict evolutionary outcomes. To do this, we developed a mechanistic model of a bacterial promoter regulated by 2 proteins, allowing us to connect any promoter genotype to 6 phenotypes that capture the dynamics of gene expression following an environmental switch. Accounting for the mechanisms that govern how this system works enabled us to provide an in-depth picture of how regulated bacterial promoters might evolve. More importantly, we used the model to explore which factors that contribute to the complexity of this system are essential for understanding its evolution, and which can be simplified without information loss. We found that several key evolutionary properties-the distribution of phenotypic and fitness effects of mutations, the evolutionary trajectories during selection for regulation-can be accurately captured without accounting for all, or even most, parameters of the system. Our findings point to the need for a mechanistic approach to studying evolution, as it enables tackling biological complexity and in doing so improves the ability to predict evolutionary outcomes.

Metaxins are a family of evolutionarily conserved proteins that reside on the mitochondria outer membrane (MOM) and participate in the protein import into the mitochondria. Metaxin-2 (Mtx2), a member of this family, has been identified as a key component in the machinery for mitochondrial transport in both C. elegans and human neurons. To deepen our understanding of Mtx2's role in neurons, we examined the homologous genes CG5662 and CG8004 in Drosophila. The CG5662 is a non-essential gene while CG8004 null mutants die at late pupal stages. The CG8004 protein is widely expressed throughout the Drosophila nervous system and is targeted to mitochondria. However, neuronal CG8004 is dispensable for animal survival and is partially required for mitochondrial distribution in certain neuropil regions. Conditional knockout of CG8004 in adult gustatory receptor neurons (GRNs) impairs mitochondrial trafficking along GRN axons and diminishes the mitochondrial quantities in axon terminals. The absence of CG8004 also leads to mitochondrial fragmentation within GRN axons, a phenomenon that may be linked to mitochondrial transport through its genetic interaction with the fusion proteins Marf and Opa1. While the removal of neuronal CG8004 is not lethal during the developmental stage, it does have consequences for the lifespan and healthspan of adult Drosophila. At last, double knockout (KO) of CG5662 and CG8004 shows similar phenotypes as the CG8004 single KO, suggesting that CG5662 does not compensate for the loss of CG8004. In summary, our findings suggest that CG8004 plays a conserved and context-dependent role in axonal mitochondrial transport, as well it is important for sustaining neuronal function. Therefore, we refer to CG8004 as the Drosophila Metaxin-2 (dMtx2).

Spinal muscular atrophy and amyotrophic lateral sclerosis are devastating neurodegenerative diseases characterized by motor neuron loss. Although these 2 disorders have distinct genetic origins, recent studies suggest that they share common etiological mechanisms rooted in proteostatic dysfunction. At the heart of this emerging understanding is the survival motor neuron (SMN) complex.

Trioecy, a rare reproductive system where hermaphrodites, females, and males coexist, is found in certain algae, plants, and animals. Though it has evolved independently multiple times, its rarity suggests it may be an unstable or transitory evolutionary strategy. In the well-studied Caenorhabditis elegans, attempts to engineer a trioecious strain have reverted to the hermaphrodite/male system, reinforcing this view. However, these studies did not consider the sex-determination systems of naturally stable trioecious species. The discovery of free-living nematodes of the Auanema genus, which have naturally stable trioecy, provides an opportunity to study these systems. In Auanema, females produce only oocytes, while hermaphrodites produce both oocytes and sperm for self-fertilization. Crosses between males and females primarily produce daughters (XX hermaphrodites and females), while male-hermaphrodite crosses result in sons only. These skewed sex ratios are due to X-chromosome drive during spermatogenesis, where males produce only X-bearing sperm through asymmetric cell division. The stability of trioecy in Auanema is influenced by maternal control over sex determination and environmental cues. These factors offer insights into the genetic and environmental dynamics that maintain trioecy, potentially explaining its evolutionary stability in certain species.