The asexual genome of Drosophila

AbstractThe rate of recombination affects the mode of molecular evolution. In high-recombining sequence, the targets of selection are individual genetic loci; under low recombination, selection collectively acts on large, genetically linked genomic segments. Selection under linkage can induce clonal interference, a specific mode of evolution by competition of genetic clades within a population. This mode is well known in asexually evolving microbes, but has not been traced systematically in an obligate sexual organism. Here we show that the Drosophila genome is partitioned into two modes of evolution: a local interference regime with limited effects of genetic linkage, and an interference condensate with clonal competition. We map these modes by differences in mutation frequency spectra, and we show that the transition between them occurs at a threshold recombination rate that is predictable from genomic summary statistics. We find the interference condensate in segments of low-recombining sequence that are located primarily in chromosomal regions flanking the centromeres and cover about 20% of the Drosophila genome. Condensate regions have characteristics of asexual evolution that impact gene function: the efficacy of selection and the speed of evolution are lower and the genetic load is higher than in regions of local interference. Our results suggest that multicellular eukaryotes can harbor heterogeneous modes and tempi of evolution within one genome. We argue that this variation generates selection on genome architecture.Author SummaryThe Drosophila genome is an ideal system to study how the rate of recombination affects molecular evolution. It harbors a wide range of local recombination rates, and its high-recombining parts show broad signatures of adaptive evolution. The low-recombining parts, however, have remained dark genomic matter that has been omitted from most studies on the inference of selection. Here we show that these genomic regions evolve in a different way, which involves clonal competition and is akin to the evolution of asexual systems. This regime shows a lower efficacy of selection, a lower speed of evolution, and a higher genetic load than high-recombining regions. We argue these evolutionary differences have functional consequences: protein stability and protein expression are gene traits likely to be partially compromised by low recombination rates.

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Inbreeding depression and genetic load at partially linked loci in a metapopulation

Genetics Research ◽

10.1017/s0016672310000133 ◽

2010 ◽

Vol 92 (2) ◽

pp. 127-140 ◽

Cited By ~ 2

Author(s):

SHU-RONG ZHOU ◽

JOHN R. PANNELL

Keyword(s):

Inbreeding Depression ◽

Random Mating ◽

Genetic Load ◽

Minor Effect ◽

Deleterious Mutations ◽

Recombination Rates ◽

Sexual Systems ◽

Biological Phenomena ◽

Population Turnover ◽

Wide Range

SummaryInbreeding depression has important implications for a wide range of biological phenomena, such as inbreeding avoidance, the evolution and maintenance of sexual systems and extinction rates of small populations. Previous investigations have asked how inbreeding depression evolves in single and subdivided populations through the fixation of deleterious mutations as a result of drift, as well as through the expression of deleterious mutations segregating in a population. These studies have focused on the effects of mutation and selection at single loci, or at unlinked loci. Here, we used simulations to investigate the evolution of genetic load and inbreeding depression due to multiple partially linked loci in metapopulations. Our results indicate that the effect of linkage depends largely on the kinds of deleterious alleles involved. For weakly deleterious and partially recessive mutations, the speed of mutation accumulation at segregating loci in a random-mating subdivided population of a given structure tends to be retarded by increased recombination between adjacent loci – although the highest numbers of fixation of slightly recessive mutant alleles were for low but finite recombination rates. Although linkage had a relatively minor effect on the evolution of metapopulations unless very low values of recombination were assumed, close linkage between adjacent loci tended to enhance population structure and population turnover. Finally, within-deme inbreeding depression, between-deme inbreeding depression and heterosis generally increased with decreased recombination rates. Moreover, increased selfing reduced the effective amount of recombination, and hence the effects of tight linkage on metapopulation genetic structure were decreased with increasing selfing. In contrast, linkage had little effect on the fate of lethal and highly recessive alleles. We compare our simulation results with predictions made by models that ignore the complexities of recombination.

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Mating system and recombination affect molecular evolution in four Triticeae species

Genetics Research ◽

10.1017/s0016672307009032 ◽

2008 ◽

Vol 90 (1) ◽

pp. 97-109 ◽

Cited By ~ 54

Author(s):

A. HAUDRY ◽

A. CENCI ◽

C. GUILHAUMON ◽

E. PAUX ◽

S. POIRIER ◽

...

Keyword(s):

Molecular Evolution ◽

Mating System ◽

Mating Systems ◽

Genetic Load ◽

Gc Content ◽

Aegilops Speltoides ◽

Effective Population ◽

Recombination Rates ◽

Biased Gene Conversion ◽

Evolution Of Genomes

SummaryMating systems and recombination are thought to have a deep impact on the organization and evolution of genomes. Because of the decline in effective population size and the interference between linked loci, the efficacy of selection is expected to be reduced in regions with low recombination rates and in the whole genome of self-fertilizing species. At the molecular level, relaxed selection is expected to result in changes in the rate of protein evolution and the pattern of codon bias. It is increasingly recognized that recombination also affects non-selective processes such as the biased gene conversion towards GC alleles (bGC). Like selection, this kind of meiotic drive in favour of GC over AT alleles is expected to be reduced in weakly recombining regions and genomes. Here, we investigated the effect of mating system and recombination on molecular evolution in four Triticeae species: two outcrossers (Secale cereale and Aegilops speltoides) and two selfers (Triticum urartu and Triticum monococcum). We found that GC content, possibly driven by bGC, is affected by mating system and recombination as theoretically predicted. Selection efficacy, however, is only weakly affected by mating system and recombination. We investigated the possible reasons for this discrepancy. A surprising one is that, in outcrossing lineages, selection efficacy could be reduced because of high substitution rates in favour of GC alleles. Outcrossers, but not selfers, would thus suffer from a ‘GC-induced’ genetic load. This result sheds new light on the evolution of mating systems.

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Zebrafish Models to Study New Pathways in Tauopathies

International Journal of Molecular Sciences ◽

10.3390/ijms22094626 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4626

Author(s):

Clément Barbereau ◽

Nicolas Cubedo ◽

Tangui Maurice ◽

Mireille Rossel

Keyword(s):

Cognitive Deficits ◽

Tau Protein ◽

Common Point ◽

Transgenic Models ◽

Synaptic Loss ◽

Wide Range ◽

Transgenic Lines ◽

Functional Consequences ◽

The Common

Tauopathies represent a vast family of neurodegenerative diseases, the most well-known of which is Alzheimer’s disease. The symptoms observed in patients include cognitive deficits and locomotor problems and can lead ultimately to dementia. The common point found in all these pathologies is the accumulation in neural and/or glial cells of abnormal forms of Tau protein, leading to its aggregation and neurofibrillary tangles. Zebrafish transgenic models have been generated with different overexpression strategies of human Tau protein. These transgenic lines have made it possible to highlight Tau interacting factors or factors which may limit the neurotoxicity induced by mutations and hyperphosphorylation of the Tau protein in neurons. Several studies have tested neuroprotective pharmacological approaches. On few-days-old larvae, modulation of various signaling or degradation pathways reversed the deleterious effects of Tau mutations, mainly hTauP301L and hTauA152T. Live imaging and live tracking techniques as well as behavioral follow-up enable the analysis of the wide range of Tau-related phenotypes from synaptic loss to cognitive functional consequences.

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Restriction Fragment Length Polymorphism and Divergence in the Genomic Regions of High and Low Recombination in Self-Fertilizing and Cross-Fertilizing Aegilops Species

Genetics ◽

10.1093/genetics/148.1.423 ◽

1998 ◽

Vol 148 (1) ◽

pp. 423-434

Author(s):

Jan Dvorřák ◽

Ming-Cheng Luo ◽

Zu-Li Yang

Keyword(s):

Related Species ◽

Gene Diversity ◽

Single Copy ◽

Species Variation ◽

Recombination Rates ◽

Distal Chromosome ◽

Phylogenetic Status ◽

Average Gene ◽

Genomic Regions ◽

Chromosome Regions

Abstract RFLP was investigated at 52 single-copy gene loci among six species of Aegilops, including both cross-fertilizing and self-fertilizing species. Average gene diversity (H) was found to correlate with the level of outcrossing. No relationship was found between H and the phylogenetic status of a species. In all six species, the level of RFLP at a locus was a function of the position of the locus on the chromosome and the recombination rate in the neighborhood of the locus. Loci in the proximal chromosome regions, which show greatly reduced recombination rates relative to the distal regions, were significantly less variable than loci in the distal chromosome regions in all six species. Variation in recombination rates was also reflected in the haplotype divergence between closely related species; loci in the chromosome regions with low recombination rates were found to be diverged less than those in the chromosome regions with high recombination rates. This relationship was not found among the more distantly related species.

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Modeling Linkage Disequilibrium and Identifying Recombination Hotspots Using Single-Nucleotide Polymorphism Data

Genetics ◽

10.1093/genetics/165.4.2213 ◽

2003 ◽

Vol 165 (4) ◽

pp. 2213-2233 ◽

Cited By ~ 41

Author(s):

Na Li ◽

Matthew Stephens

Keyword(s):

Linkage Disequilibrium ◽

Recombination Rate ◽

Population Sample ◽

Simulated Data ◽

Region Of Interest ◽

Population Data ◽

Recombination Rates ◽

Single Nucleotide ◽

Recombination Hotspots ◽

Genomic Regions

AbstractWe introduce a new statistical model for patterns of linkage disequilibrium (LD) among multiple SNPs in a population sample. The model overcomes limitations of existing approaches to understanding, summarizing, and interpreting LD by (i) relating patterns of LD directly to the underlying recombination process; (ii) considering all loci simultaneously, rather than pairwise; (iii) avoiding the assumption that LD necessarily has a “block-like” structure; and (iv) being computationally tractable for huge genomic regions (up to complete chromosomes). We examine in detail one natural application of the model: estimation of underlying recombination rates from population data. Using simulation, we show that in the case where recombination is assumed constant across the region of interest, recombination rate estimates based on our model are competitive with the very best of current available methods. More importantly, we demonstrate, on real and simulated data, the potential of the model to help identify and quantify fine-scale variation in recombination rate from population data. We also outline how the model could be useful in other contexts, such as in the development of more efficient haplotype-based methods for LD mapping.

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Role of CxxC-finger protein 1 in establishing mouse oocyte epigenetic landscapes

Nucleic Acids Research ◽

10.1093/nar/gkab107 ◽

2021 ◽

Author(s):

Qian-Qian Sha ◽

Ye-Zhang Zhu ◽

Yunlong Xiang ◽

Jia-Li Yu ◽

Xiao-Ying Fan ◽

...

Keyword(s):

Dna Methylation ◽

Histone H3 ◽

Finger Protein ◽

Maternal Genome ◽

Wide Range ◽

Transcriptional Changes ◽

Nuclear Events ◽

Genomic Regions ◽

Cxxc Finger Protein 1

Abstract During oogenesis, oocytes gain competence and subsequently undergo meiotic maturation and prepare for embryonic development; trimethylated histone H3 on lysine-4 (H3K4me3) mediates a wide range of nuclear events during these processes. Oocyte-specific knockout of CxxC-finger protein 1 (CXXC1, also known as CFP1) impairs H3K4me3 accumulation and causes changes in chromatin configurations. This study investigated the changes in genomic H3K4me3 landscapes in oocytes with Cxxc1 knockout and the effects on other epigenetic factors such as the DNA methylation, H3K27me3, H2AK119ub1 and H3K36me3. H3K4me3 is overall decreased after knocking out Cxxc1, including both the promoter region and the gene body. CXXC1 and MLL2, which is another histone H3 methyltransferase, have nonoverlapping roles in mediating H3K4 trimethylation during oogenesis. Cxxc1 deletion caused a decrease in DNA methylation levels and affected H3K27me3 and H2AK119ub1 distributions, particularly at regions with high DNA methylation levels. The changes in epigenetic networks implicated by Cxxc1 deletion were correlated with the transcriptional changes in genes in the corresponding genomic regions. This study elucidates the epigenetic changes underlying the phenotypes and molecular defects in oocytes with deleted Cxxc1 and highlights the role of CXXC1 in orchestrating multiple factors that are involved in establishing the appropriate epigenetic states of maternal genome.

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Effects of Selection at Linked Sites on Patterns of Genetic Variability

Annual Review of Ecology Evolution and Systematics ◽

10.1146/annurev-ecolsys-010621-044528 ◽

2021 ◽

Vol 52 (1) ◽

pp. 177-197

Author(s):

Brian Charlesworth ◽

Jeffrey D. Jensen

Keyword(s):

Genetic Variability ◽

Population Genetic ◽

Selective Sweeps ◽

Recombination Rates ◽

Frequency Distributions ◽

A Genome ◽

Demographic Processes ◽

Dna Sequence Variants ◽

Genomic Regions ◽

Functional Components

Patterns of variation and evolution at a given site in a genome can be strongly influenced by the effects of selection at genetically linked sites. In particular, the recombination rates of genomic regions correlate with their amount of within-population genetic variability, the degree to which the frequency distributions of DNA sequence variants differ from their neutral expectations, and the levels of adaptation of their functional components. We review the major population genetic processes that are thought to lead to these patterns, focusing on their effects on patterns of variability: selective sweeps, background selection, associative overdominance, and Hill–Robertson interference among deleterious mutations. We emphasize the difficulties in distinguishing among the footprints of these processes and disentangling them from the effects of purely demographic factors such as population size changes. We also discuss how interactions between selective and demographic processes can significantly affect patterns of variability within genomes.

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Functional consequences of the first reported mutations of the proto-oncogene PTTG1IP/PBF

Endocrine Related Cancer ◽

10.1530/erc-16-0340 ◽

2017 ◽

Vol 24 (9) ◽

pp. 459-474 ◽

Cited By ~ 2

Author(s):

W Imruetaicharoenchoke ◽

A Fletcher ◽

W Lu ◽

R J Watkins ◽

B Modasia ◽

...

Keyword(s):

Colony Formation ◽

Human Cancer ◽

Soft Agar ◽

Cellular Migration ◽

3T3 Fibroblasts ◽

Wide Range ◽

Functional Consequences ◽

Altered Cell ◽

Proliferation Assays ◽

Nih 3T3

Pituitary tumor-transforming gene 1-binding factor (PTTG1IP; PBF) is a multifunctional glycoprotein, which is overexpressed in a wide range of tumours, and significantly associated with poorer oncological outcomes, such as early tumour recurrence, distant metastasis, extramural vascular invasion and decreased disease-specific survival. PBF transforms NIH 3T3 fibroblasts and induces tumours in nude mice, while mice harbouring transgenic thyroidal PBF expression show hyperplasia and macrofollicular lesions. Our assumption that PBF becomes an oncogene purely through increased expression has been challenged by the recent report of mutations in PBF within the Catalogue of Somatic Mutations in Cancer (COSMIC) database. We therefore sought to determine whether the first 10 PBF missense substitutions in human cancer might be oncogenic. Anisomycin half-life studies revealed that most mutations were associated with reduced protein stability compared to wild-type (WT) PBF. Proliferation assays narrowed our interest to two mutational events which significantly altered cell turnover: C51R and R140W. C51R was mainly confined to the endoplasmic reticulum while R140W was apparent in the Golgi apparatus. Both C51R and R140W lost the capacity to induce cellular migration and significantly reduced cell invasion. Colony formation and soft agar assays demonstrated that, in contrast to WT PBF, both mutants were unable to elicit significant colony formation or anchorage-independent growth. However, C51R and R140W retained the ability to repress radioiodide uptake, a functional hallmark of PBF. Our data reveal new insight into PBF function and confirm that, rather than being oncogenic, mutations in PBF are likely to be passenger effects, with overexpression of PBF the more important aetiological event in human cancer.

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Brain-wide quantification of the supraspinal connectome

10.1101/2021.06.10.447885 ◽

2021 ◽

Author(s):

Zimei Wang ◽

Adam Romanski ◽

Vatsal Mehra ◽

Yunfang Wang ◽

Benjamin C. Campbell ◽

...

Keyword(s):

Spinal Cord ◽

Web Based ◽

Locomotor Recovery ◽

Adult Mice ◽

Comprehensive Information ◽

Normal Behavior ◽

Wide Range ◽

Cord Injury ◽

Functional Consequences ◽

Intuitive Manner

The supraspinal connectome is essential for normal behavior and homeostasis and consists of a wide range of sensory, motor, and autonomic projections from brain to spinal cord. Extensive work spanning a century has largely mapped the cell bodies of origin, yet their broad distribution and complex spatial relationships present significant challenges to the dissemination and application of this knowledge. Fields that study disruptions of supraspinal projections, for example spinal cord injury, have focused mostly on a handful of major populations that carry motor commands, with only limited consideration of dozens more that provide autonomic or crucial motor modulation. More comprehensive information is essential to understand the functional consequences of different injuries and to better evaluate the efficacy of treatments. Using viral retrograde labeling, 3D imaging, and registration to standard neuro-anatomical atlases we now provide a platform to profile the entire supraspinal connectome by rapidly visualizing and quantifying tens of thousands of supraspinal neurons, each assigned to more than 60 identified regions and nuclei throughout the brains of adult mice. We then use this tool to compare the lumbar versus cervically-projecting connectomes, to profile brain-wide the sensitivity of supraspinal populations to graded spinal injuries, and to correlate locomotor recovery with connectome measurements. To share these insights in an intuitive manner, we present an interactive web-based resource, which aims to spur progress by broadening understanding and analyses of essential but understudied supraspinal populations.

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Possible role of natural selection in the formation of tandem-repetitive noncoding DNA.

Genetics ◽

10.1093/genetics/136.1.333 ◽

1994 ◽

Vol 136 (1) ◽

pp. 333-341

Author(s):

W Stephan ◽

S Cho

Keyword(s):

Natural Selection ◽

Satellite Dna ◽

Repeat Length ◽

Crossing Over ◽

Recombination Rates ◽

Noncoding Dna ◽

Satellite Dnas ◽

Unequal Crossing Over ◽

Wide Range ◽

Long Range Ordering

Abstract A simulation model of sequence-dependent amplification, unequal crossing over and mutation is analyzed. This model predicts the spontaneous formation of tandem-repetitive patterns of noncoding DNA from arbitrary sequences for a wide range of parameter values. Natural selection is found to play an essential role in this self-organizing process. Natural selection which is modeled as a mechanism for controlling the length of a nucleotide string but not the sequence itself favors the formation of tandem-repetitive structures. Two measures of sequence heterogeneity, inter-repeat variability and repeat length, are analyzed in detail. For fixed mutation rate, both inter-repeat variability and repeat length are found to increase with decreasing rates of (unequal) crossing over. The results are compared with data on micro-, mini- and satellite DNAs. The properties of minisatellites and satellite DNAs resemble the simulated structures very closely. This suggests that unequal crossing over is a dominant long-range ordering force which keeps these arrays homogeneous even in regions of very low recombination rates, such as at satellite DNA loci. Our analysis also indicates that in regions of low rates of (unequal) crossing over, inter-repeat variability is maintained at a low level at the expense of much larger repeat units (multimeric repeats), which are characteristic of satellite DNA. In contrast, the microsatellite data do not fit the proposed model well, suggesting that unequal crossing over does not act on these very short tandem arrays.

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