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During the meiosis of many eukaryote species, crossovers tend to occur within narrow regions called recombination hotspots. In plants, it is generally thought that gene regulatory sequences, especially promoters and 5′ to 3′ untranslated regions, are enriched in hotspots, but this has been characterized in a handful of species only. We also lack a clear description of fine-scale variation in recombination rates within genic regions and little is known about hotspot position and intensity in plants. To address this question, we constructed fine-scale recombination maps from genetic polymorphism data and inferred recombination hotspots in 11 plant species. We detected gradients of recombination in genic regions in most species, yet gradients varied in intensity and shape depending on specific hotspot locations and gene structure. To further characterize recombination gradients, we decomposed them according to gene structure by rank and number of exons. We generalized the previously observed pattern that recombination hotspots are organized around the boundaries of coding sequences, especially 5′ promoters. However, our results also provided new insight into the relative importance of the 3′ end of genes in some species and the possible location of hotspots away from genic regions in some species. Variation among species seemed driven more by hotspot location among and within genes than by differences in size or intensity among species. Our results shed light on the variation in recombination rates at a very fine scale, revealing the diversity and complexity of genic recombination gradients emerging from the interaction between hotspot location and gene structure. [ABSTRACT FROM AUTHOR]

Abstract Background GGC and GCC short tandem repeats (STRs) are of various evolutionary, biological, and pathological implications. However, the fundamental two-repeats (dyads) of these STRs are widely unexplored. Results On a genome-wide scale, we mapped (GGC)2 and (GCC)2 dyads in human, and found monumental colonies (distance between each dyad

Background: GGC and GCC short tandem repeats (STRs) are of various evolutionary, biological, and pathological implications. However, the fundamental two-repeats (dyads) of these STRs are widely unexplored. Results: On a genome-wide scale, we mapped (GGC)2 and (GCC)2 dyads in human, and found monumental colonies (distance between each dyad < 500 bp) of extraordinary density, and in some instances periodicity. The largest (GCC)2 and (GGC)2 colonies were intergenic, homogeneous, and human-specific, consisting of 219 (GCC)2 on chromosome 2 (probability < 1.545E-219) and 70 (GGC)2 on chromosome 9 (probability = 1.809E-148). We also found that several colonies were shared in other great apes, and directionally increased in density and complexity in human, such as a colony of 99 (GCC)2 on chromosome 20, that specifically expanded in great apes, and reached maximum complexity in human (probability 1.545E-220). Numerous other colonies of evolutionary relevance in human were detected in other largely overlooked regions of the genome, such as chromosome Y and pseudogenes. Several of the genes containing or nearest to those colonies were divergently expressed in human. Conclusion: In conclusion, (GCC)2 and (GGC)2 form unprecedented genomic colonies that coincide with the evolution of human and other great apes. The extent of the genomic rearrangements leading to those colonies support overlooked recombination hotspots, shared across great apes. The identified colonies deserve to be studied in mechanistic, evolutionary, and functional platforms. [ABSTRACT FROM AUTHOR]

Meiotic recombination is an important evolutionary force and an essential meiotic process. In many species, recombination events concentrate into hotspots defined by the site-specific binding of PRMD9. Rapid evolution of Prdm9 's zinc finger DNA-binding array leads to remarkably abrupt shifts in the genomic distribution of hotspots between species, but the question of how Prdm9 allelic variation shapes the landscape of recombination between populations remains less well understood. Wild house mice (Mus musculus) harbor exceptional Prdm9 diversity, with >150 alleles identified to date, and pose a particularly powerful system for addressing this open question. We employed a coalescent-based approach to construct broad- and fine-scale sex-averaged recombination maps from contemporary patterns of linkage disequilibrium in nine geographically isolated wild house mouse populations, including multiple populations from each of three subspecies. Comparing maps between wild mouse populations and subspecies reveals several themes. First, we report weak fine- and broad-scale recombination map conservation across subspecies and populations, with genetic divergence offering no clear prediction for recombination map divergence. Second, most hotspots are unique to one population, an outcome consistent with minimal sharing of Prdm9 alleles between surveyed populations. Finally, by contrasting aggregate hotspot activity on the X versus autosomes, we uncover evidence for population-specific differences in the degree and direction of sex dimorphism for recombination. Overall, our findings illuminate the variability of both the broad- and fine-scale recombination landscape in M. musculus and underscore the functional impact of Prdm9 allelic variation in wild mouse populations. [ABSTRACT FROM AUTHOR]

Meiosis is an essential component of the sexual life cycle in eukaryotes. The independent assortment of chromosomes in meiosis increases genetic diversity at the level of whole chromosomes and meiotic recombination increases genetic diversity within chromosomes. The resulting variability fuels evolution. Interestingly, global mapping of recombination in diverse taxa revealed dramatic changes in its frequency distribution between closely related species, subspecies, and even isolated populations of the same species. New insight into mechanisms for these evolutionarily rapid changes has come from analyses of environmentally induced plasticity of recombination in fission yeast. Many different DNA sites, and where identified their binding/activator proteins, control the positioning of recombination at hotspots. Each different class of hotspots functions as an independently controlled rheostat that modulates rates of recombination over a broad dynamic range in response to changing conditions. Together, this independent modulation can rapidly and dramatically alter the global frequency distribution of recombination. This process likely contributes substantially to (i.e., can largely explain) evolutionarily rapid, Prdm9-independent changes in the recombination landscape. Moreover, the precise control mechanisms allow cells to dynamically favor or disfavor newly arising combinations of linked alleles in response to changing extracellular and intracellular conditions, which has striking implications for the impacts of meiotic recombination on evolution. [ABSTRACT FROM AUTHOR]

Meiosis is an essential component of the sexual life cycle in eukaryotes. The independent assortment of chromosomes in meiosis increases genetic diversity at the level of whole chromosomes and meiotic recombination increases genetic diversity within chromosomes. The resulting variability fuels evolution. Interestingly, global mapping of recombination in diverse taxa revealed dramatic changes in its frequency distribution between closely related species, subspecies, and even isolated populations of the same species. New insight into mechanisms for these evolutionarily rapid changes has come from analyses of environmentally induced plasticity of recombination in fission yeast. Many different DNA sites, and where identified their binding/activator proteins, control the positioning of recombination at hotspots. Each different class of hotspots functions as an independently controlled rheostat that modulates rates of recombination over a broad dynamic range in response to changing conditions. Together, this independent modulation can rapidly and dramatically alter the global frequency distribution of recombination. This process likely contributes substantially to (i.e., can largely explain) evolutionarily rapid, Prdm9-independent changes in the recombination landscape. Moreover, the precise control mechanisms allow cells to dynamically favor or disfavor newly arising combinations of linked alleles in response to changing extracellular and intracellular conditions, which has striking implications for the impacts of meiotic recombination on evolution.

• Co-infection or co-colonisation of Staphylococcus aureus (S. aureus) and vancomycin-resistant enterococci (VRE) are sources of vanA dissemination. • Three main mechanisms of acquisition of the vanA operon in S. aureus are conjugation, transposition of Tn1546 and enterococcal plasmid integration. • There is a worldwide occurrence of hotspots for vanA -containing plasmid integration via homologous recombination in S. aureus strains. • It is necessary to screen for S. aureus in patients with VRE infections and people in direct contact with them, and test antimicrobial susceptibility of S. aureus for methicillin and vancomycin. Vancomycin is frequently used as a last line of defence against infections due to multidrug-resistant Staphylococcus aureus (S. aureus). A recent finding described the acquisition of vancomycin-resistant S. aureus strains by the integration of an enterococcal plasmid containing the vanA operon into the S. aureus chromosome via homologous recombination involving a specific integration site called locus L2. To characterise all mechanisms of acquisition of vanA , this study analysed the 15 706 S. aureus genomes to look for vanA and described its genetic environment. A complete vanA operon was found in 25 S. aureus strains isolated from 12 patients, including nine co-isolated with vancomycin-resistant Enterococcus strains. VanA was found within transposon Tn1546-like elements on 17 plasmids and eight chromosomes. VanA might be acquired through conjugation of enterococcal and staphylococcal plasmids, transposition of Tn1546 carrying vanA and plasmid integration into the chromosome. Further, L2 was detected in 2087 genomes (13.3%) of S. aureus strains across different continents. Six potential chromosomal hotspots for integration of the entire vanA -containing enterococcal plasmid were identified by homologous recombination via L2. These findings suggest that the recently described scenario in a New York patient could be reproduced anywhere. Surveillance of this possibility is mandatory, especially in patients with vancomycin-resistant Enterococcus infection or colonisation. [Display omitted] [ABSTRACT FROM AUTHOR]

It has long been known (circa 1917) that environmental conditions, as well as speciation, can affect dramatically the frequency distribution of Spo11/Rec12-dependent meiotic recombination. Here, by analyzing DNA sequence-dependent meiotic recombination hotspots in the fission yeast Schizosaccharomyces pombe, we reveal a molecular basis for these phenomena. The impacts of changing environmental conditions (temperature, nutrients, and osmolarity) on local rates of recombination are mediated directly by DNA site-dependent hotspots (M26, CCAAT, and Oligo-C). This control is exerted through environmental condition-responsive signal transduction networks (involving Atf1, Pcr1, Php2, Php3, Php5, and Rst2). Strikingly, individual hotspots modulate rates of recombination over a very broad dynamic range in response to changing conditions. They can range from being quiescent to being highly proficient at promoting activity of the basal recombination machinery (Spo11/Rec12 complex). Moreover, each different class of hotspot functions as an independently controlled rheostat; a condition that increases the activity of one class can decrease the activity of another class. Together, the independent modulation of recombination rates by each different class of DNA site-dependent hotspots (of which there are many) provides a molecular mechanism for highly dynamic, large-scale changes in the global frequency distribution of meiotic recombination. Because hotspot-activating DNA sites discovered in fission yeast are conserved functionally in other species, this process can also explain the previously enigmatic, Prdm9-independent, evolutionarily rapid changes in hotspot usage between closely related species, subspecies, and isolated populations of the same species. [ABSTRACT FROM AUTHOR]

Meiotic recombination plays a pivotal role in genetic evolution. Genetic variation induced by recombination is a crucial factor in generating biodiversity and a driving force for evolution. At present, the development of recombination hotspot prediction methods has encountered challenges related to insufficient feature extraction and limited generalization capabilities. This paper focused on the research of recombination hotspot prediction methods. We explored deep learning-based recombination hotspot prediction and scrutinized the shortcomings of prevalent models in addressing the challenge of recombination hotspot prediction. To addressing these deficiencies, an automated machine learning approach was utilized to construct recombination hotspot prediction model. The model combined sequence information with physicochemical properties by employing TF-IDF-Kmer and DNA composition components to acquire more effective feature data. Experimental results validate the effectiveness of the feature extraction method and automated machine learning technology used in this study. The final model was validated on three distinct datasets and yielded accuracy rates of 97.14%, 79.71%, and 98.73%, surpassing the current leading models by 2%, 2.56%, and 4%, respectively. In addition, we incorporated tools such as SHAP and AutoGluon to analyze the interpretability of black-box models, delved into the impact of individual features on the results, and investigated the reasons behind misclassification of samples. Finally, an application of recombination hotspot prediction was established to facilitate easy access to necessary information and tools for researchers. The research outcomes of this paper underscore the enormous potential of automated machine learning methods in gene sequence prediction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

A salmon louse (Lepeophtheirus salmonis salmonis) genetic linkage map was constructed to serve as a genomic resource for future investigations into the biology of this important marine parasitic copepod species, and to provide insights into the inheritance patterns of genetic markers in this species. SNP genotyping of 8 families confirmed the presence of 15 linkage groups based upon the assignment of 93,773 markers. Progeny sample size weight adjusted map sizes in males (with the exception of SL12 and SL15) ranged in size from 96.50 cM (SL11) to 134.61 cM (SL06), and total combined map steps or bins ranged from 143 (SL09) to 203 (SL13). The SL12 male map was the smallest linkage group with a weight-averaged size of 3.05 cM with 6 recombination bins. Male:female specific recombination rate differences are 10.49:1 and represent one of the largest reported sex-specific differences for any animal species. Recombination ratio differences (M:F) ranged from 1.0 (SL12) to 29:1 (SL15). The number of markers exhibiting normal Mendelian segregation within the sex linkage group SL15 was extremely low (N = 80) in comparison to other linkage groups genotyped [range: 1459 (SL12)—10206 markers (SL05)]. Re-evaluation of Mendelian inheritance patterns of markers unassigned to any mapping parent according to hemizygous segregation patterns (models presented) identified matches for many of these markers to hemizygous patterns. The greatest proportion of these markers assigned to SL15 (N increased to 574). Inclusion of the hemizygous markers revised SL15 sex-specific recombination rate differences to 28:1. Recombination hot- and coldspots were identified across all linkage groups with all linkage groups possessing multiple peaks. Nine of 13 linkage groups evaluated possessed adjacent domains with hot-coldspot transitional zones. The most common pattern was for one end of the linkage to show elevated recombination in addition to internal regions. For SL01 and SL06, however, a terminal region with high recombination was not evident while a central domain possessing extremely high-recombination levels was present. High levels of recombination were weakly coupled to higher levels of SNP variation within domains, but this association was very strong for the central domains of SL01 and SL06. From the pooled paternal half-sib lots (several virgin females placed with 1 male), only 1 or two surviving family lots were obtained. Surviving families possessed parents where both the male and female possessed either inherently low or high recombination rates. This study provides insight into the organization of the sea louse genome, and describes large differences in recombination rate that exist among individuals of the same sex, and between the sexes. These differences in recombination rate may be coupled to the capabilities of this species to adapt to environmental and pharmaceutical treatments, given that family survivorship appears to be enhanced when parents have similar recombination levels. [ABSTRACT FROM AUTHOR]

The results of the bioinformatic search for the potential sites of the recombination in the genome-wide structures of the tick-borne encephalitis virus (TBEV) through a series of software techniques were presented in this work. The genomes of the 55 TBEV strains were assayed, 21 of them showed the presence of the recombination sites. Recombinant strains belonged to the Far Eastern (19 strains) and European (2 strains) genotypes. 22 sites of the recombination attributed were identified to five types based on position, strain, and regional characteristics. The parental strains were identified based on the genotypic and geographical parameters, which do not contradict the possibility of the formation of the recombinants. Nearly two-thirds of the sites are located in the regions of NS4a and Ns4b genes, which are the "hot spots" of the recombination, most of them being concentrated in the gene NS4. it was shown that the recombination processes did not occur at the level of the genotypes (European genotype) or certain groups within the genotype (Far East) and were typical of the peripheral populations.

Traditional plant breeding relies on meiotic recombination for mixing of parental alleles to create novel allele combinations. Detailed analysis of recombination patterns in model organisms shows that recombination is tightly regulated within the genome, but frequencies vary extensively along chromosomes. Despite being a model organism for fruit developmental studies, high-resolution recombination patterns are lacking in tomato. In this study, we developed a novel methodology to use low-coverage resequencing to identify genome-wide recombination patterns and applied this methodology on 60 tomato Recombinant Inbred Lines (RILs). Our methodology identifies polymorphic markers from the low-coverage resequencing population data and utilizes the same data to locate the recombination breakpoints in individuals by using a variable sliding window. We identified 1,445 recombination sites comprising 112 recombination prone regions enriched for AT-rich DNA motifs. Furthermore, the recombination prone regions in tomato preferably occurred in gene promoters over intergenic regions, an observation consistent with Arabidopsis thaliana, Zea mays and Mimulus guttatus. Overall, our cost effective method and findings enhance the understanding of meiotic recombination in tomato and suggest evolutionarily conserved recombination associated genomic features. [ABSTRACT FROM AUTHOR]

The aim of this study was to decipher the molecular epidemiological and antigenic characteristics of infectious bronchitis virus strains (IBVs) isolated in recent years in southwestern China. A total of 24 field strains were isolated from diseased chickens between 2012 and 2016. Phylogenetic analysis based on S1 nucleotide sequences showed that 16 of the 24 isolates were clustered into four distinct genotypes: QX (37.5%), TW (16.7%, TWI and TWII), Mass (8.3%), and J2 (4.2%). The QX genotype was still the prevalent genotype in southwestern China. Recombination analysis of the S1 subunit gene showed that eight of the 24 field strains were recombinant variants that originated from field strains and vaccine strains. A new potential recombination hotspot [ATTTT(T/A)] was identified, implying that recombination events may become more and more common. The antigenicity of ten IBVs, including seven field strains and commonly used vaccine strains, were assayed with a viral cross-neutralization assay in chicken embryonated kidney cells (CEK). The results showed that the ten IBVs could be divided into four serotypes (Massachusetts, 793B, Sczy3, and SCYB). Sczy3 and 793B were the predominant serotypes. Six of the seven field isolates (all except for cK/CH/SCYB/140913) cross-reacted well with anti-sera against other field strains. In conclusion, the genetic and antigenic features of IBVs from southwestern China in recent years have changed when compared to the previous reports. The results could provide a reference for vaccine development and the prevention of infectious bronchitis in southwestern China. [ABSTRACT FROM AUTHOR]

Abstract We have studied the recombination rate behaviour of a set of 140 genes which were investigated for their potential importance in inflammatory disease. Each gene was extensively sequenced in 24 individuals of African descent and 23 individuals of European descent, and the recombination process was studied separately in the two population samples. The results obtained from the two populations were highly correlated, suggesting that demographic bias does not affect our population genetic estimation procedure. We found evidence that levels of recombination correlate with levels of nucleotide diversity. High marker density allowed us to study recombination rate variation on a very fine spatial scale. We found that about 40 per cent of genes showed evidence of uniform recombination, while approximately 12 per cent of genes carried distinct signatures of recombination hotspots. On studying the locations of these hotspots, we found that they are not always confined to introns but can also stretch across exons. An investigation of the protein products of these genes suggested that recombination hotspots can sometimes separate exons belonging to different protein domains; however, this occurs much less frequently than might be expected based on evolutionary studies into the origins of recombination. This suggests that evolutionary analysis of the recombination process is greatly aided by considering nucleotide sequences and protein products jointly.

Plant height is a very important trait affecting rice production. The introduction of the Green Revolution gene, sd-1, into rice cultivars to create semi-dwarfism has increased grain production. In the development of modern rice breeding, there is an urgent need for a somewhat higher plant for not only maintenance of strong lodging resistance, but also more biomass. In this study, the plant height quantitative trait locus (QTL) qPH3 with moderate effect and the yield per plant QTL qYD3 were identified on chromosome 3 in a population derived from two semi-dwarf cultivars. The 02428 alleles of both QTLs contributed to increasing phenotypic values. In the near-isogenic background, both QTLs exhibited the characteristics of a single Mendelian gene. qPH3 and qYD3 were tightly linked, no more than 130 kb apart, with additive effects of 5.2 cm and 4.4 g, respectively. They were further fine-mapped to a 19-kb region and a 65-kb region, respectively, where the recombination hotspot occurred. The gene encoding gibberellin 20-oxidase associated with plant height was regarded as the candidate of qPH3. Both linked QTLs are in coupling phase, which is convenient for simultaneously selecting both genes for breeding high-yield varieties maintaining strong lodging resistance. Isolation of qYD3 is very promising due to its location in a recombination hotspot region. [ABSTRACT FROM AUTHOR]

The genetic variability of SARS-CoV-2 (genus Betacoronavirus , family Coronaviridae ) has been scrutinized since its first detection in December 2019. Although the role of structural variants, particularly deletions, in virus evolution is little explored, these genome changes are extremely frequent. They are associated with relevant processes, including immune escape and attenuation. Deletions commonly occur in accessory ORFs and might even lead to the complete loss of one or more ORFs. This scenario poses an interesting question about the origin and spreading of extreme structural rearrangements that persist without compromising virus viability. Here, we analyze the genome of SARS-CoV-2 in late 2021 in Uruguay and identify a Delta lineage (AY.20) that experienced a large deletion (872 nucleotides according to the reference Wuhan strain) that removes the 7a, 7b, and 8 ORFs. Deleted viruses coexist with wild-type (without deletion) AY.20 and AY.43 strains. The Uruguayan deletion is like those identified in Delta strains from Poland and Japan but occurs in a different Delta clade. Besides providing proof of the circulation of this large deletion in America, we infer that the 872-deletion arises by the consecutive occurrence of a 6-nucleotide deletion, characteristic of delta strains, and an 866-nucleotide deletion that arose independently in the AY.20 Uruguayan lineage. The largest deletion occurs adjacent to transcription regulatory sequences needed to synthesize the nested set of subgenomic mRNAs that serve as templates for transcription. Our findings support the role of transcription sequences as a hotspot for copy-choice recombination and highlight the remarkable dynamic of SARS-CoV-2 genomes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Elsevier Inc. All rights reserved.)

Human adenovirus species D (HAdV-D), which is composed of clinically and epidemiologically important pathogens worldwide, contains more taxonomic "types" than any other species of the genus Mastadenovirus, although the mechanisms accounting for the high level of diversity remain to be disclosed. Recent studies of known and new types of HAdV-D have indicated that intertypic recombination between distant types contributes to the increasing diversity of the species. However, such findings raise the question as to how homologous recombination events occur between diversified types since homologous recombination is suppressed as nucleotide sequences diverge. In order to address this question, we investigated the distribution of the recombination boundaries in comparison with the landscape of intergenomic sequence conservation assessed according to the synonymous substitution rate (dS). The results revealed that specific genomic segments are conserved between even the most distantly related genomes; we call these segments "universally conserved segments" (UCSs). These findings suggest that UCSs facilitate homologous recombination, resulting in intergenomic segmental exchanges of UCS-flanking genomic regions as recombination modules. With the aid of such a mechanism, the haploid genomes of HAdV-Ds may have been reshuffled, resulting in chimeric genomes out of diversified repertoires in the HAdV-D population analogous to the MHC region reshuffled via crossing over in vertebrates. In addition, some HAdVs with chimeric genomes may have had the opportunity to avoid host immune responses thereby causing epidemics. [ABSTRACT FROM AUTHOR]

In eukaryotes, detailed surveys of recombination rates have shown variation at multiple genomic scales and the presence of “hotspots” of highly elevated recombination. In bacteria, studies of recombination rate variation are less developed, in part because there are few analysis methods that take into account the clonal context within which bacterial evolution occurs. Here, we focus in particular on identifying “hot regions” of the genome where DNA is transferred frequently between isolates. We present a computationally efficient algorithm based on the recently developed “chromosome painting” algorithm, which characterizes patterns of haplotype sharing across a genome. We compare the average genome wide painting, which principally reflects clonal descent, with the painting for each site which additionally reflects the specific deviations at the site due to recombination. Using simulated data, we show that hot regions have consistently higher deviations from the genome wide average than normal regions. We applied our approach to previously analyzed Escherichia coli genomes and revealed that the new method is highly correlated with the number of recombination events affecting each site inferred by ClonalOrigin, a method that is only applicable to small numbers of genomes. Furthermore, we analyzed recombination hot regions in Campylobacter jejuni by using 200 genomes. We identified three recombination hot regions, which are enriched for genes related to membrane proteins. Our approach and its implementation, which is downloadable from https://github.com/bioprojects/orderedPainting, will help to develop a new phase of population genomic studies of recombination in prokaryotes. [ABSTRACT FROM PUBLISHER]

Genetic recombination is an essential event during the process of meiosis resulting in an exchange of segments between paired chromosomes. Estimating recombination rate is crucial for understanding the process of recombination. Experimental methods are normally difficult and limited to small scale estimations. Thus statistical methods using population genetics data are important for large-scale analysis. LDhat is an extensively used statistical method using rjMCMC algorithm to predict recombination rates. Due to the complexity of rjMCMC scheme, LDhat may take a long time for large SNP data sets. In addition, rjMCMC parameters should be manually defined in the original program which directly impact results. To address these issues, we designed an improved algorithm based on LDhat implementing MCMC convergence diagnostic algorithms to automatically predict values of parameters and monitor the mixing process. Then parallel computation methods were employed to further accelerate the new program. The new algorithms have been tested on ten samples from HapMap phase 2 data set. The results were compared with previous code and showed nearly identical output. However, our new methods achieved significant acceleration proving that they are more efficient and reliable for the estimation of recombination rates. The stand-alone package is freely available for download http://www.ntu.edu.sg/home/zhengjie/software/CPLDhat. [ABSTRACT FROM PUBLISHER]

The extraordinary heterogeneous nature of the deleterious mutations in the F8 gene that lead to functional deficiency of clotting factor VIII in haemophilia A makes routine direct mutation profiling difficult. When direct mutation analysis cannot be performed or a causative/candidate mutation is not found, a second-line approach to track the defective F8 gene within at-risk families is linkage genetic analysis with, tried-and-tested, F8-intragenic and/or extragenic non-recombining multiallelic short tandem repeats (STR). Although several typing STR loci within and around F8 have been described, there is need for improving assessment, because the combined informativeness of available assays rarely reaches 100%. Here, we characterized a newly identified 0.28 cM-resolution marker-set, consisting of a dinucleotide STR located on F8 intron 21 ( F8Int21; [AC]) and three extragenic tetranucleotide STR located on GAB3 intron 1 ( GAB3Int1; [TAAA]) and TMLHE intron 1 ( TMLHEInt1.1; [GAAA] and TMLHEInt1.3; [ATTC]). Heterozygosity rates determined in 100 unrelated females ranged from 0.25 ( GAB3Int1) to 0.63 ( F8Int21). The set rendered a combined informativeness of 0.91 for at least one marker and 0.60 for a minimum of two loci, with at least one F8-intragenic. Multiallelic interlocus non-random association analysis revealed that GAB3Int1 is not in significant gametic disequilibrium (GD) with F8Int21, F8Int9.2, TMLHEInt1.3 or TMLHEInt1.1. Gametic disequilibrium breakdown attests historical recombination between GAB3Int1 and the F8 gene. Through computational analysis of reference assembly sequence data, we note in the GD breakdown region and in the F8 gene a higher than average density of the 13-mer CCNCCNTNNCCNC consensus motif, commonly associated with recombination hotspots. [ABSTRACT FROM AUTHOR]

Synapsis of homologs during meiotic prophase I is associated with a protein complex built along the bivalents—the synaptonemal complex (SC). Mutations in the SC-component gene ZIP1 diminish SC formation, leading to reduced recombination levels and low spore viability. Here we show that in SK1 strains heterozygous for a deletion of ZIP1 in certain regions meiotic interference are impaired with no decrease in recombination levels. The extent of synapsis is over all reduced and NDJ levels of a large endogenous chromosome and of artificial chromosomes (YACs) rise to twice the level of wild type strains. A substantial proportion of mis-segregating YACs had undergone crossing over. This demonstrates that different functions of Zip1 display differential sensitivities to changes in expression levels. [ABSTRACT FROM AUTHOR]

As more human genomic data become available, fine-scale recombination rate variation can be inferred on a genome-wide scale. Current statistical methods to infer recombination rates that can be applied to moderate, or large, genomic regions are limited to approximated likelihoods. Here, we develop a Bayesian fulllikelihood method using Markov Chain Monte Carlo (MCMC) to estimate background recombination rates and hotspots. The probability model is inspired by the observed patterns of recombination at several genomic regions analyzed in sperm-typing studies. Posterior probabilities and Bayes factors of recombination hotspots along chromosomes are inferred. For moderate-size genomic regions (e.g., with <100 SNPs), the full-likelihood method is used. Larger regions are split into subintervals (typically each having between 20 and 50 markers). The likelihood is approximated based on the genealogies for each subinterval. The background recombination rates, hotspots. and parameters are evaluated by using a parallel computing approach and assuming shared parameters across the subintervals. Simulation analyses show that our method can accurately estimate the variation in recombination rates across genomic regions. In particular, clusters of hotspots can be distinguished even though weaker hotspots are present. The method is applied to SNP data from the HLA region, the MS32, and chromosome 19. [ABSTRACT FROM AUTHOR]

Channels and developmental genes belong to the molecular key players in the human central nervous system (CNS). Mutations in these genes often cause monogenic neurological disease and interspecies comparisons had shown reduced divergence. On the other hand, accelerated evolution of genes with roles in neurotransmission and development had indicated widespread positive selection in hominids. In the present study, we hypothesized that recombination hotspots could be enriched at genes with particularly important role in the CNS, because at those loci beneficial mutations may occur on a highly constrained background and consequently increased recombination could promote their fixation. To test this hypothesis, we retrieved CNS genes based on keyword search, expression data and expert knowledge. Consistent with our hypothesis, we find an enrichment of hotspot predictions around genes that are retrieved by all three strategies. Moreover, when comparing human genes based on their Gene Ontology annotations, we find hotspot predictions preferentially located around channels and neurodevelopmental genes. Taken together with the distinct sequence evolution that was reported by comparative genomic studies, this finding indicates continued positive selection at many CNS gene loci. In support of this interpretation, we also find an enrichment of recombination hotspot predictions around conserved noncoding regions that were reported to display a signature of accelerated evolution in the human lineage. Widespread positive selection acting on CNS gene loci could relate to the high prevalence of human nervous system disorders with genetically complex inheritance, potentially under an ancestral susceptibility allele model.European Journal of Human Genetics (2007) 15, 1071–1078; doi:10.1038/sj.ejhg.5201876; published online 13 June 2007 [ABSTRACT FROM AUTHOR]

Recently, haplotype-based association studies have become popular for detecting disease-related or drug-response-associated genes. In these studies, it has been gradually recognized that a haplotype block structure is important. A rational and automatic method for identifying the haplotype block structure from SNP data has been desired. We have developed a new method using an ancestor-derived model and the minimum description length principle. The proposed method was applied to real data on the TAP2 gene in which a recombination hotspot was previously reported in human sperm data. The proposed method could identify an appropriate haplotype block structure, while existing methods failed. The performance of the proposed method was also investigated in a simulation study. The proposed method presented a better performance in real data analysis and the simulation study than existing methods. The proposed method was powerful from the viewpoint of hotspot sensitivity and was robust to mutation except at the edge of a sequence. [ABSTRACT FROM AUTHOR]

Abstract: In Escherichia coli, homologous recombination initiated at double-stranded DNA breaks requires the RecBCD enzyme, a multifunctional heterotrimeric complex that possesses processive helicase and exonuclease activities. Upon encountering the DNA regulatory sequence, χ, the enzymatic properties of RecBCD enzyme are altered. Its helicase activity is reduced, the 3′→5′nuclease activity is attenuated, the 5′→3′ nuclease activity is up-regulated, and it manifests an ability to load RecA protein onto single-stranded DNA. The net result of these changes is the production of a highly recombinogenic structure known as the presynaptic filament. Previously, we found that the recC1004 mutation alters χ-recognition so that this mutant enzyme recognizes an altered χ sequence, χ*, which comprises seven of the original nucleotides in χ, plus four novel nucleotides. Although some consequences of this mutant enzyme–mutant χ interaction could be detected in vivo and in vitro, stimulation of recombination in vivo could not. To resolve this seemingly contradictory observation, we examined the behavior of a RecA mutant, RecA730, that displays enhanced biochemical activity in vitro and possesses suppressor function in vivo. We show that the recombination deficiency of the RecBC1004D–χ* interaction can be overcome by the enhanced ability of RecA730 to assemble on single-stranded DNA in vitro and in vivo. These data are consistent with findings showing that the loading of RecA protein by RecBCD is necessary in vivo, and they show that RecA proteins with enhanced single-stranded DNA-binding capacity can partially bypass the need for RecBCD-mediated loading. [Copyright &y& Elsevier]

The NK gene complex (NKC) controls murine cytomegalovirus (MCMV) immunity through Cmv1-dependent natural killer (NK) cell responses. Ly49H expression correlates with Cmv1 phenotypes in different inbred strains, is required for MCMV resistance in C57BL/6 (B6) mice, and its interaction with the MCMV encoded m157 protein leads to NK cell-mediated destruction of virus-infected cells. However, genetic mapping studies have previously indicated that Cmv1 should reside in the D6Wum9–16 NKC interval, distal to Ly49h. Since these data suggested that multiple NKC-linked loci could regulate viral immunity, a putative MCMV resistance control (Mrc) locus was pinpointed to within the D6Wum9–16 interval on a NKC-aligned bacterial artificial chromosome (BAC). Sequence analysis of BAC 151 revealed several novel G-protein coupled receptor genes, an HMG-1 remnant and many additional polymorphic microsatellites that were useful in determining the minimal genetic interval for the Mrc locus. Moreover, comparison of B6, BALB/c, A/J and recombinant Mrc alleles restricted the genetic interval to approximately 470 bp and showed that it was also a hotspot for recombination. MCMV challenge of novel NKC recombinant mice demonstrated that MrcB6 was not required for MCMV resistance nor could it directly complement the Ly49BALB haplotype to rescue MCMV susceptibility. Taken together, these data show that while Mrc apparently guides recombination, Ly49H expression is sufficient for MCMV resistance in B6 mice. A direct role for MrcB6 in virus resistance is excluded in the novel mice. [ABSTRACT FROM AUTHOR]

Interleukin-4 (IL-4) is a pleiotropic cytokine produced primarily by activated CD4+ T lymphocytes, mast cells, and basophils. It modulates the functions of a variety of cell types involved with the immune response. This cytokine differentially regulates two major HIV-1 coreceptors and activates viral expression, and is thus a reasonable candidate gene for analyses in HIV-1/AIDS cohort studies. Population genetic variation in five single nucleotide polymorphisms (SNPs) in the 5′ region of the IL-4 gene was assessed in five racial groups. Neutrality tests reveal that the populations are evolving in accord with the infinite-sites model. However, coalescent simulations suggest greater haplotype diversity among African Americans than expected. This increased variation is presumably attributable to recombination or gene conversion. Genetic epidemiological analyses were conducted among European American and African American participants enrolled in five USA-based HIV-1/AIDS cohorts. One SNP, -589T, known to influence IL-4 transcription was previously shown to be associated with HIV-1/AIDS in both Japanese and French populations. Present analyses failed to identify any significant associations with HIV-1 infection or progression to AIDS. [ABSTRACT FROM AUTHOR]

Susceptibility to chemically induced lung tumorigenesis has previously been mapped to a genomic interval of 27 kb in the MHC class III region of the mouse using two H2a/b intra-H2 recombinants, B10.A(1R) and B10.A(2R). Three genes are located within this interval, G7e (encoding a viral envelope protein), G7a/Vars2 (encoding valyl-tRNA synthetase), and G7c (a gene with unknown function). A 70 kb contig, spanning the 27 kb region and extending 20 kb either side, was constructed from lambda phage libraries with genomic inserts derived from mouse strains B10.A(1R) and B10.A(2R). The region was analyzed for single-nucleotide polymorphisms, which would facilitate further fine mapping of the interval. Analysis of the expression levels of the candidate genes did not reveal any difference between B10.A(1R) and B10.A(2R). In addition, no differences were found at the sequence level in the 27 kb interval except for an A to T transition in intron 7 of G7c. A database comparison of the sequence surrounding this polymorphism did not identify any DNA-binding or enhancer consensus sequence. In conclusion, the previously observed phenotype could not be associated with or assigned to any of the candidate genes G7e, G7a/Vars2, or G7c, nor could any of the other susceptibility loci, which have been reported to map to this region (Cps1, Acp, Orch1, and Igis1) [ABSTRACT FROM AUTHOR]