There is considerable interest in understanding patterns of linkage disequilibrium (LD) in the human genome, to aid investigations of human evolution and facilitate association studies in complex ...disease. The relative influences of meiotic crossover distribution and population history on LD remain unclear, however. In particular, it is uncertain to what extent crossovers are clustered into 'hot spots, that might influence LD patterns. As a first step to investigating the relationship between LD and recombination, we have analyzed a 216-kb segment of the class II region of the major histocompatibility complex (MHC) already characterized for familial crossovers. High-resolution LD analysis shows the existence of extended domains of strong association interrupted by patchwork areas of LD breakdown. Sperm typing shows that these areas correspond precisely to meiotic crossover hot spots. All six hot spots defined share a remarkably similar symmetrical morphology but vary considerably in intensity, and are not obviously associated with any primary DNA sequence determinants of hot-spot activity. These hot spots occur in clusters and together account for almost all crossovers in this region of the MHC. These data show that, within the MHC at least, crossovers are far from randomly distributed at the molecular level and that recombination hot spots can profoundly affect LD patterns.
Little is known about the nature of recombination hotspots in the human genome and the relationship between crossover activity and patterns of linkage disequilibrium. We have therefore used both ...haplotype analysis and direct detection of crossovers in sperm to characterize a putative recombination hotspot in the TAP2 gene within the class II region of the MHC. Haplotype diversity provided evidence for a localized hotspot within intron 2 of this gene. Sperm DNA typing using allele-specific PCR primers to selectively amplify recombinant TAP2 molecules revealed a highly localized meiotic crossover hotspot approximately 1.2 kb long, unusually abundant in sequence polymorphisms and flanked by DNA much less active in recombination. Sperm crossover appeared to be fully reciprocal, and almost all crossover products were simple, involving a single exchange between adjacent heterozygous markers. This hotspot appears to be much more active in female than male meiosis. No primary sequence similarities could be found between any of the very few well defined crossover hotspots in the human genome, all of which show recombinationally active domains 1-2 kb long. Direct comparison of recombination frequency and haplotype diversity in TAP2 showed that linkage disequilibrium measures were a poor predictor of crossover frequency in this region, with non-recombining markers sometimes in free association and with examples of pairs of markers spanning the recombination hotspot showing substantial or even absolute linkage disequilibrium.
Meiotic gene conversion has an important role in allele diversification and in the homogenization of gene and other repeat DNA sequence families, sometimes with pathological consequences. But little ...is known about the dynamics of gene conversion in humans and its relationship to meiotic crossover. We therefore developed screening and selection methods to characterize sperm conversions in two meiotic crossover hot spots in the major histocompatibility complex (MHC) and one in the sex chromosomal pseudoautosomal pairing region PAR1 (ref. 9). All three hot spots are active in gene conversion and crossover. Conversion tracts are short and define a steep bidirectional gradient centered at the peak of crossover activity, consistent with crossovers and conversions being produced by the same recombination-initiating events. These initiations seem to be spread over a narrow zone, rather than occurring at a single site, and seem preferentially to yield conversions rather than crossovers. Crossover breakpoints are more broadly diffused than conversion breakpoints, suggesting either differences between conversion and crossover processing after initiation or the existence of a quality control checkpoint at which short interactions between homologous chromosomes are preferentially aborted as conversions.
Human DNA diversity arises ultimately from germline mutation that creates new haplotypes that can be reshuffled by meiotic recombination. Reciprocal crossover generates recombinant haplotypes but ...should not influence the frequencies of alleles in a population. We demonstrate crossover asymmetry at a recombination hot spot in the major histocompatibility complex, whereby reciprocal exchanges in sperm map to different locations in the hot spot. We identify a single-nucleotide polymorphism at the center of the hot spot and show that, when heterozygous, it seems sufficient to cause this asymmetry, apparently by influencing the efficiency of highly localized crossover initiation. As a consequence, crossovers in heterozygotes are accompanied by biased gene conversion, most likely occurring by gap repair, that can also affect nearby polymorphisms through repair of an extended gap. The result is substantial over-transmission of the recombination-suppressing allele and neighboring markers to crossover products. Computer simulations show that this meiotic drive, although weak at the population level, is sufficient to favor eventual fixation of the recombination-suppressing variant. These findings provide an explanation for the relatively uniform widths of human crossover hot spots and suggest that hot spots may be generally prone to extinction by meiotic drive.
There is growing understanding that the environment plays an important role both in the transmission of antibiotic resistant pathogens and in their evolution. Accordingly, researchers and ...stakeholders world-wide seek to further explore the mechanisms and drivers involved, quantify risks and identify suitable interventions. There is a clear value in establishing research needs and coordinating efforts within and across nations in order to best tackle this global challenge. At an international workshop in late September 2017, scientists from 14 countries with expertise on the environmental dimensions of antibiotic resistance gathered to define critical knowledge gaps. Four key areas were identified where research is urgently needed: 1) the relative contributions of different sources of antibiotics and antibiotic resistant bacteria into the environment; 2) the role of the environment, and particularly anthropogenic inputs, in the evolution of resistance; 3) the overall human and animal health impacts caused by exposure to environmental resistant bacteria; and 4) the efficacy and feasibility of different technological, social, economic and behavioral interventions to mitigate environmental antibiotic resistance.11The recommendations from the workshop have also been communicated in a separate report published on the website of the JPIAMR (www.jpiamr.org).
•The environment plays important roles in the development of antibiotic resistance.•Critical knowledge gaps and research needs in this area were identified.•These include aspects on evolution, transmission and interventions.•The analysis provided may be useful for guiding future research efforts.
The Pakistan Margin is characterised by a strong mid-water oxygen minimum zone (OMZ) that intercepts the seabed at bathyal depths (150–1300
m). We investigated whether faunal abundance and diversity ...trends were similar among protists (foraminiferans and gromiids), metazoan macrofauna and megafauna along a transect (140–1850
m water depth) across the OMZ during the 2003 intermonsoon (March–May) and late/post-monsoon (August–October) seasons. All groups exhibited some drop in abundance in the OMZ core (250–500
m water depth; O
2: 0.10–0.13
mL
L
−1=4.46–5.80
μM) but to differing degrees. Densities of foraminiferans >63
μm were slightly depressed at 300
m, peaked at 738
m, and were much lower at deeper stations. Foraminiferans >300
μm were the overwhelmingly dominant macrofaunal organisms in the OMZ core. Macrofaunal metazoans reached maximum densities at 140
m depth, with additional peaks at 850, 940 and 1850
m where foraminiferans were less abundant. The polychaete
Linopherus sp. was responsible for a macrofaunal biomass peak at 950
m. Apart from large swimming animals (fish and natant decapods), metazoan megafauna were absent between 300 and 900
m (O
2 <0.14–0.15
mL
L
−1=6.25–6.69
μM) but were represented by a huge, ophiuroid-dominated abundance peak at 1000
m (O
2 ∼0.15–0.18
mL
L
−1=6.69–8.03
μM). Gromiid protists were confined largely to depths below 1150
m (O
2 >0.2
mL
L
−1=8.92
μM). The progressively deeper abundance peaks for foraminiferans (>63
μm),
Linopherus sp. and ophiuroids probably represent lower OMZ boundary edge effects and suggest a link between body size and tolerance of hypoxia. Macro- and megafaunal organisms collected between 800 and 1100
m were dominated by a succession of different taxa, indicating that the lower part of the OMZ is also a region of rapid faunal change. Species diversity was depressed in all groups in the OMZ core, but this was much more pronounced for macrofauna and megafauna than for foraminiferans. Oxygen levels strongly influenced the taxonomic composition of all faunal groups. Calcareous foraminiferans dominated the seasonally and permanently hypoxic sites (136–300
m); agglutinated foraminiferans were relatively more abundant at deeper stations where oxygen concentrations were >0.13
mL
L
−1(=5.80
μM). Polychaetes were the main macrofaunal taxon within the OMZ; calcareous macrofauna and megafauna (molluscs and echinoderms) were rare or absent where oxygen levels were lowest. The rarity of larger animals between 300 and 700
m on the Pakistan Margin, compared with the abundant macrofauna in the OMZ core off Oman, is the most notable contrast between the two sides of the Arabian Sea. This difference probably reflects the slightly higher oxygen levels and better food quality on the western side.
The finding of a previously undescribed cold-water coral reef (Banana Reef) in the Scottish Mingulay reef complex, with denser coverage of livingLophelia pertusathan the principal Mingulay 1 Reef, ...was the incentive for a comparative study of the food supply to the 2 reefs. Suspended particulate matter (SPM) samples from the surface and bottom water covering a tidal cycle were compared with respect to lipids, pigments, and δ13C and δ15N. Lipid profiles and stable isotope signatures of SPM were compared with those of coral tissue samples. Concurrently, hydrographic measurements were conducted to track the movement of the water masses across both reefs. Between-reef differences in SPM lipid concentrations were small compared to those in coral tissue. Corals at Banana Reef had lower lipid concentrations, pointing to less favourable food conditions than at Mingulay 1. Stable isotopes signatures and lipid profiles showed that corals on both reefs feed primarily on surface algal matter, within the timeframe of our study. At Mingulay 1, fresh microalgae are supplied to the coral reef by local downwelling. This downwelling pulse is tidally advected to Banana Reef. Food conditions observed during this study at both reefs do not explain the between-reef difference in coral coverage. A speculative explanation for the denser coral coverage at the deeper Banana Reef encompasses the slightly lower temperature that exhibits lower metabolic stress on corals, in combination with a higher current speed and particle encounter rate.
The Arabian Sea is a region of elevated productivity with the highest globally recorded fluxes of particulate organic matter (POM) to the deep ocean, providing an abundant food source for fauna at ...the seafloor. However, benthic communities are also strongly influenced by an intense oxygen minimum zone (OMZ), which impinges on the continental slope from 100 to 1000 m water depth. We compared the trophic ecology of foraminifera on the Oman and Pakistan margins of the Arabian Sea (140–3185 m water depth). These two margins are contrasting both in terms of the abundance of sedimentary organic matter and the intensity of the OMZ. Organic carbon concentrations of surficial sediments were higher on the Oman margin (3.32 ± 1.4%) compared to the Pakistan margin (2.45 ± 1.1%) and sedimentary organic matter (SOM) quality estimated from the Hydrogen Index was also higher on the Oman margin (300–400 mg HC mg TOC−1) compared to the Pakistan margin (< 250 mg HC mg TOC−1). The δ13C and δ15N values of sediments were similar on both margins (−20 and 8‰, respectively). Stable isotope analysis (SIA) showed that foraminiferal cells had a wide range of δ13C values (−25.5 to −11.5‰), implying that they utilise multiple food sources; indeed δ13C values varied between depths, foraminiferal types and between the two margins. Foraminifera had broad ranges in δ15N values (−7.8 to 27.3‰). The enriched values suggest that some species may store nitrate to utilise in respiration; this was most notable on the Pakistan margin. Depleted foraminiferal δ15N values, particularly at the Oman margin, may reflect feeding on chemosynthetic bacteria. We suggest that differences in productivity regimes may be responsible for the differences observed in foraminiferal isotopic composition. In addition, at the time of sampling, whole jellyfish carcasses (Crambionella orsini) and a carpet of jelly detritus were observed across the Oman margin transect. Associated chemosynthetic bacteria may have provided an organic-rich food source for foraminifera at these sites. Our data suggest that foraminifera in OMZ settings can utilise a variety of food sources and metabolic pathways to meet their energetic demands.
The risk of adverse reactions to 3,4-methylenedioxymethamphetamine (MDMA), more commonly known as "ecstasy", is now widely known in both the USA and UK, but the patterns of illness remain varied. We ...report our experience during 1990 and 1991. There has been a recent increase in cases of severe toxicity following recreational misuse of small amounts of MDMA. Among 7 fatalities, the pattern of toxicity included fulminant hyperthermia, convulsions, disseminated intravascular coagulation, rhabdomyolysis, and acute renal failure. Until now, there have been few reports of this type of toxicity from MDMA, which may be related both to the potential of the drug to alter thermoregulation and to the circumstances of misuse. In addition, we have monitored 7 cases of hepatotoxicity and suspect that the frequency of this complication is increasing; a history of MDMA misuse should be sought in young people presenting with unexplained jaundice or hepatomegaly. We also describe 5 subjects involved in road traffic accidents in whom MDMA was identified. Misuse of MDMA can have severe acute toxic effects; few data are available concerning long-term morbidity, and this deserves close monitoring in future.
Recombination, demographic history, drift and selection influence the extent of linkage disequilibrium (LD) in the human genome, but their relative contributions remain unclear. To investigate the ...effect of meiotic recombination versus population history on LD, three populations with different demographic histories (UK north Europeans, Saami and Zimbabweans) were genotyped for high-frequency single-nucleotide polymorphisms (SNPs) across a 75 kb DNA segment of the MHC class II region. This region spans three well-characterized recombination hotspots and a 60 kb long LD block. Despite a high level of underlying haplotype diversity and considerable divergence in haplotype composition between populations, all three populations showed very similar patterns of LD. Surprisingly, the entire 60 kb LD block was present even in Africans, although it was relatively difficult to detect owing to a systematic deficiency of high frequency SNPs. In contrast, DNA within recombination hotspots did not show this low nucleotide diversity in Africans. Thus, while population history has some influence on LD, our findings suggest that recombination hotspots play a major global role in shaping LD patterns as well as helping to maintain localized SNP diversity in this region of the MHC.