IFI16 protein mediates the anti-inflammatory actions of the type-I interferons through suppression of activation of caspase-1 by inflammasomes

Background

Type-I interferons (IFNs) are used to treat certain inflammatory diseases. Moreover, activation of type-I IFN-signaling in immune cells inhibits the production of proinflammatory cytokines and activation of inflammasomes. However, the molecular mechanisms remain largely unknown. Upon sensing cytosolic double-stranded DNA, the AIM2 protein forms the AIM2-ASC inflammasome, resulting in activation of caspase-1. Given that the IFI16 and AIM2 proteins are IFN-inducible and can heterodimerize with each other, we investigated the regulation of IFI16, AIM2, and inflammasome proteins by type-I and type-II IFNs and explored whether the IFI16 protein could negatively regulate the activation of the AIM2 (or other) inflammasome.

Methodology/ Principal Findings

We found that basal levels of the IFI16 and AIM2 proteins were relatively low in peripheral blood monocytes (CD14⁺) and in the THP-1 monocytic cell line. However, treatment of THP-1 cells with type-I (IFN-α or β) or type-II (IFN-γ) IFN induced the expression levels of IFI16, AIM2, ASC and CASP1 proteins. The induced levels of IFI16 and AIM2 proteins were detected primarily in the cytoplasm. Accordingly, relatively more IFI16 protein bound with the AIM2 protein in the cytoplasmic fraction. Notably, increased expression of IFI16 protein in transfected HEK-293 cells inhibited activation of caspase-1 by the AIM2-ASC inflammasome. Moreover, the constitutive knockdown of the IFI16 expression in THP-1 cells increased the basal and induced [induced by poly(dA:dT) or alum] activation of the caspase-1 by the AIM2 and NLRP3 inflammasomes.

Conclusions/Significance

Our observations revealed that the type-I and type-II IFNs induce the expression of IFI16, AIM2, and inflammasome proteins to various extents in THP-1 cells and the expression of IFI16 protein in THP-1 cells suppresses the activation of caspase-1 by the AIM2 and NLRP3 inflammasomes. Thus, our observations identify the IFI16 protein as a mediator of the anti-inflammatory actions of the type-I IFNs.     

Multinucleate nature,and mating by use of isozyme analysis inPoria cocos

Double staining study of nuclei and cell walls inPoria cocos indicated that the hyphal cells were multinucleate and had no clamp connections. Isozyme analysis of alcohol dehydrogenase (ADH) in 52 natural isolates revealed that there were three types of banding patterns: type I, five bands; type II, one slow band; type III, one fast band. Regenerants expressing type-II or type-III ADH-isozyme pattern were obtained from type-I isolates via protoplast manipulation. When the type-II regenerants were mated with the type-III regenerants, hyphae of type-I phenotype appeared. These data indicated that these type-II and type-III regenerants derived from protoplasts of the type-I isolates were primary hyphae. These primary hyphal cells were also multinucleate. Inter-strain mating ofP. cocos was performed and confirmed by ADH-isozyme analysis. Confronting cultures of a type-III regenerant derived from protoplasts of a type-I isolate and a type-II regenerant derived from a type-II isolate resulted in type-I hyphae.     

Deregulation of phenylalanine biosynthesis evolved with the emergence of vascular plants

Phenylalanine (Phe) is the precursor of essential secondary products in plants. Here we show that a key, rate-limiting step in Phe biosynthesis, which is catalyzed by arogenate dehydratase, experienced feedback de-regulation during evolution. Enzymes from microorganisms and type-I ADTs from plants are strongly feedback-inhibited by Phe, while type-II isoforms remain active at high levels of Phe. We have found that type-II ADTs are widespread across seed plants and their overproduction resulted in a dramatic accumulation of Phe in planta, reaching levels up to 40 times higher than those observed following the expression of type-I enzymes. Punctual changes in the allosteric binding site of Phe and adjacent region are responsible for the observed relaxed regulation. The phylogeny of plant ADTs evidences that the emergence of type-II isoforms with relaxed regulation occurred at some point in the transition between nonvascular plants and tracheophytes, enabling the massive production of Phe-derived compounds, primarily lignin, a hallmark of vascular plants.

The appearance of arogenate dehydratase isoenzymes with reduced feedback inhibition during the early evolution of plants enabled the massive biosynthesis of phenylalanine-derived compounds.     

Type-II Myocardial Infarction – Patient Characteristics,Management and Outcomes

Background

Type-II MI is defined as myocardial infarction (MI) secondary to ischemia due to either increased oxygen demand or decreased supply. This categorization has been used for the last five years, yet, little is known about patient characteristics and clinical outcomes. In the current work we assessed the epidemiology, causes, management and outcomes of type II MI patients.

Methods

A comparative analysis was performed between patients with type-I and type-II MI who participated in two prospective national Acute Coronary Syndrome Israeli Surveys (ACSIS) performed in 2008 and 2010.

Results

The surveys included 2818 patients with acute MI of whom 127 (4.5%) had type-II MI. The main causes of type-II MI were anemia (31%), sepsis (24%), and arrhythmia (17%). Patients with type-II MI tended to be older (75.6±12 vs. 63.8±13, p<0.0001), female majority (43.3% vs. 22.3%, p<0.0001), had more frequently impaired functional level (45.7% vs. 17%, p<0.0001) and a higher GRACE risk score (150±32 vs. 110±35, p<0.0001). Patients with type-II MI were significantly less often referred for coronary interventions (36% vs. 89%, p<0.0001) and less frequently prescribed guideline-directed medical therapy. Mortality rates were substantially higher among patients with type-II MI both at thirty-day (13.6% vs. 4.9%, p<0.0001) and at one-year (23.9% vs. 8.6%, p<0.0001) follow-ups.

Conclusions

Patients with type-II compared to type-I MI have distinct demographics, increased prevalence of multiple comorbidities, a high-risk cardiovascular profile and an overall worse outcome. The complex medical condition of this cohort imposes a great therapeutic challenge and specific guidelines with recommended medical treatment and invasive strategies are warranted.     

Ultrastructure and innervation of the swimbladder of Tetractenos glaber (Tetraodontidae)

Summary The general structure, ultrastructure and innervation of the swimbladder of the smooth toadfish, Tetractenos glaber, were examined with light-microscopic, fluorescence-histochemical, and transmission electron-microscopic techniques. The structure of the swimbladder is similar to that of other euphysoclists. Fluorescence histochemistry showed adrenergic fibres in both the secretory and resorptive areas of the swimbladder. Transmission electron microscopy revealed two morphologically distinct axon profiles type-I profiles containing many small, flattened vesicles; type-II profiles containing both large, granular vesicles and rounded, small clear vesicles in varying proportions.The gas-gland cells and surrounding muscularis mucosae are innervated by both type-I and type-II fibres. Type-I fibres also innervate pre-rete arteries. The rete- and gas-gland capillaries do not appear to be innervated. Arteries running to the resorptive area are innervated by type-I fibres. Both type-I and type-II profiles make contact with the muscularis mucosae in the resorptive area. Only type-I fibres innervate the radial dilator muscle in the oval sphincter region, whereas only type II fibres innervate the circular muscle of the oval sphincter.Type-I fibres took up -methyl-noradrenaline, and could not be found after pre-treatment with 6-hydroxydopamine. They are, therefore, assumed to be adrenergic. Type-II fibres were tentatively identified, by exclusion, as cholinergic.     

Effects of human diabetic serum on the in vitro development of mouse preimplantation embryos

The effects of sera from different types of human diabetes (type I with and without ketoacidosis; type II treated with insulin or Daonil or untreated) on the in vitro development of early preimplantation mouse embryos were studied. In controls, 20% of blastocysts failed to develop successfully when grown for 72 h in RPMI medium supplemented with 10% fetal bovine serum and 50% nondiabetic human serum. In experiments using 50% diabetic serum, the highest embryotoxic effect was found in type-I diabetes with and without ketoacidosis: The percents of undeveloped embryos were 66 and 58, respectively. In type-II diabetes, embryotoxic effects were found among all studied types: The percent of undeveloped blastocysts varied from 36% in insulin-treated type-II diabetes to 44% in untreated type-II diabetes. A high correlation was found between the number of undeveloped embryos and the blood concentrations of metabolic diabetic factors: glucose (r = .53-.64 in type-I diabetes), B-HOB (r = .7-.77 in type-II diabetes untreated or treated with Daonil), acetoacetate (r = .66 in insulin-treated type-II diabetes), and HbA1c (r = .89 in insulin-treated type-II diabetes or .99 in Daonil-treated type-II diabetes). A concentration of 80% serum was embryo-toxic when obtained from nondiabetic or from diabetic human. The possible role of diabetic metabolic factors in causing increased risk of spontaneous abortions and infertility among diabetic women is discussed.     

Molecular discrimination of type-I over type-II methionyl aminopeptidases

Two residues that are conserved in type-I methionyl aminopeptidases (MetAPs) but are absent in all type-II MetAPs are the cysteine residues (Escherichia coli MetAP-I: C59 and C70) that reside at the back of the substrate recognition pocket. These Cys residues are 4.4 A apart and do not form a disulfide bond. Since bacteria and fungi contain only type-I MetAPs while all human cells contain both type-I and type-II MetAPs, type-I MetAPs represent a novel antibiotic/antifungal target if type-I MetAPs can be specifically targeted over type-II. Based on reaction of the thiol-specific binding reagent 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB) with the type-I MetAP from E. coli and the type-II MetAP from Pyrococcus furiosus, the type-I MetAP can be selectively inhibited. Verification that DTNB covalently binds to C59 in EcMetAP-I was obtained by mass spectrometry (MS) from reaction of DTNB with the C59A and C70A mutant EcMetAP-I enzymes. In addition, two inhibitors of EcMetAP-I, 5-iodopentaphosphonic acid (1) and 6-phosphonohexanoic acid (2), were designed and synthesized. The first was designed as a selective-C59 binding reagent while the second was designed as a simple competitive inhibitor of EcMetAP. Indeed, inhibitor 1 forms a covalent interaction with C59 based on activity assays and MS measurements, while 2 does not. These data indicate that type-I MetAPs can be selectively targeted over type-II MetAPs, suggesting that type-I MetAPs represent a new enzymatic target for antibacterial or antifungal agents.     

Functional implications of the projections of neurons from individual labellar sensillum of Drosophila melanogaster as revealed by neuronal-marker horseradish peroxidase

Summary Earlier studies using Golgi silver impregnations from the labellar sensilla of adult Drosophila melanogaster revealed seven types of sensory axons projecting into the suboesophageal ganglion of the brain. These sensory terminals were designated as coiled fibres (type-I), shrubby fibres (type-II), ipsilateral ventral fibres (type-III), ipsilateral dorsal fibres (type-IV), contralateral ventral fibres (type-V), contralateral dorsal fibres (type-VI), and central fibres (type-VII). The present study identifies the projections of sensory neurons present in a single labellar taste-sensillum, using the neuronal marker horseradish peroxidase (HRP). Although the taste sensillum in question has five neurons, in a given experiment only one or at the most two neurons are labelled. The type of neuron labelled was usually specific to the stimulant solute (sucrose, sodium chloride or potassium chloride) present in the HRP solution. Although type-II fibres get labelled most of the time, irrespective of the stimulant present in HRP solution, type-IV fibres are labelled when attractants (0.1 M sucrose or 0.1 M sodium chloride) are used as stimulants in HRP solution. Type-VI fibres are labelled when the stimulant is 0.1 M potassium chloride, a repellent. HRP dissolved in distilled water revealed type-I coiled fibres. Besides revealing projections of sensillar neurons to the brain the present technique also inferred their possible function. Incubation of whole-brain tissue with 0.04% 3,3-diaminobenzidine tetrahydrochloride in presence of 0.06% hydrogen peroxide suggested that the glomerular organization is also present in the taste-sensory region as it is in olfactory neuropile.     

Glucan-phosphorylase forms in cotyledons of Pisum sativum L.: Localization,developmental change,in-vitro translation,and processing

The occurrence, location, and biosynthesis of glucan-phosphorylase (EC 2.4.1.1) isoenzymes were studied in cotyledons of developing or germinating seeds of Pisum sativum L. Type-I and type-II isoenzymes were detected, and were also localized by indirect immunofluorescence using polyclonal anti-type-I or anti-type-II phosphorylase antibodies. Type-I isoenzyme was found in the cytosol of parenchyma cells whereas the type-II enzyme form is a plastid protein which resides either in amyloplasts (in developing seeds) or in proplastids (in germinating seeds). During seed development, type-II phosphorylase was the predominant isoenzyme and the type-I isoenzyme represented a very minor compound. During germination, the latter increased whilst type-II phosphorylase remained at a constant level. In in-vitro translation experiments, type-I isoenzyme was observed as a final-size product with an apparent molecular weight of approx. 90 kDa. In contrast, type-II phosphorylase was translated as a high-molecular-weight precursor (116 kDa) which, when incubated with a stromal fraction of isolated intact pea chloroplasts, was processed to the size of the mature protein (105 kDa).Abbreviations IgG immunoglobulin G - kDa kilodalton - poly(A)⁺ RNA polyadenylated RNA - SDS-PAGE sodium dodecyl sulfate-polyacrylamide gel electrophoresis This work has been made possible by grants from the Deutsche Forschungsgemeinschaft. The authors are endebted to Mrs. Karin Niehüser for help in the immunocytochemical studies.     

A computational method for estimating the PCR duplication rate in DNA and RNA-seq experiments

Background

PCR amplification is an important step in the preparation of DNA sequencing libraries prior to high-throughput sequencing. PCR amplification introduces redundant reads in the sequence data and estimating the PCR duplication rate is important to assess the frequency of such reads. Existing computational methods do not distinguish PCR duplicates from “natural” read duplicates that represent independent DNA fragments and therefore, over-estimate the PCR duplication rate for DNA-seq and RNA-seq experiments.

Results

In this paper, we present a computational method to estimate the average PCR duplication rate of high-throughput sequence datasets that accounts for natural read duplicates by leveraging heterozygous variants in an individual genome. Analysis of simulated data and exome sequence data from the 1000 Genomes project demonstrated that our method can accurately estimate the PCR duplication rate on paired-end as well as single-end read datasets which contain a high proportion of natural read duplicates. Further, analysis of exome datasets prepared using the Nextera library preparation method indicated that 45–50% of read duplicates correspond to natural read duplicates likely due to fragmentation bias. Finally, analysis of RNA-seq datasets from individuals in the 1000 Genomes project demonstrated that 70–95% of read duplicates observed in such datasets correspond to natural duplicates sampled from genes with high expression and identified outlier samples with a 2-fold greater PCR duplication rate than other samples.

Conclusions

The method described here is a useful tool for estimating the PCR duplication rate of high-throughput sequence datasets and for assessing the fraction of read duplicates that correspond to natural read duplicates. An implementation of the method is available at https://github.com/vibansal/PCRduplicates.

     

Development of bovine embryos in a cell-free culture medium: Effects of type of serum, timing of its inclusion and heat inactivation

Bovine embryos, derived from in vitro matured (IVM)/in vitro fertilized (IVF) ova, were used to investigate the effects of timing of serum inclusion in the culture medium and different types of blood sera and heat inactivation of the serum on embryo development. In Experiment 1, oocytes at 18 h post insemination were allocated to 1 of the following 4 treatments: 1) TCM-199 + 0.1 mg/ml polyvinylalcohol (PVA), 2) TCM-199 supplemented with 10% bovine calf serum (BCS), 3) PVA medium followed by BCS medium at 47 h, or 4) PVA medium followed by BCS medium at 82 h. Supplementation with BCS at 18 h post insemination suppressed (P<0.05) development of morulae/blastocysts (17.6%) when compared with PVA (30.5%) or with serum supplementation at 47 or 82 h post insemination (32.4 and 27.6%, respectively). However, inclusion of BCS at 18, 47 or 82 h post insemination produced more blastocysts (16.8, 29.3 and 22.1%, respectively; P<0.05) than medium +PVA (8.8%). In Experiment 2, ova were cultured from 18 h to 42 h post insemination in PVA-medium, then >/=2-cell embryos were transferred into serum-supplemented medium for another 168 h. Fetal bovine serum (FBS) +/- heat-inactivation (56 degrees C for 30 min, = heated FBS) suppressed morula/blastocyst development compared with medium + PVA, medium + BCS or medium + heated BCS (P<0.05). Bovine calf serum was superior to FBS in supporting blastocyst development (35.1 and 15.2%, respectively), but there was no difference between BCS and heated BCS. However, heated FBS increased the proportion of blastocysts/>/=8-cell embryos compared with that of FBS (51.0 and 31.4%, respectively; P<0.05). These results indicate that the type of serum supplementation and the timing of its inclusion in the culture medium markedly affect bovine embryo development in vitro, and that heat inactivation of serum with high embryotrophic properties is not necessary.     

Polymorphism of 2-μm plasmids in industrial strains of Saccharomyces cerevisiae

Restriction fragment length polymorphism (RFLP) analyses of industrial Saccharomyces yeast DNA have identified eight 2-m plasmidsvariants that fall into two distinct types. Type-I plasmids are of unique form, whereas type-II plasmids exist in seven distinct RFLP forms. Only two different 2-m variants were observed in 35 bakers' strains analysed. One variant was the unique type-I whereas the second variant represents an ancestral form of the type-II plasmid. Sixteen of nineteen wine yeasts carried a distinctive type-II plasmid with a homeologous STB repeat whereas ale and lager yeasts had a wide range of type-II variants. Relative to nuclear and mtDNA, 2-m polymorphism is less diverse and not diagnostic for a specific strain. This 2-m DNA polymorphism is a convenient and useful addendum to nuclear and mtDNA RFLP analyses but cannot serve as the sole marker for strain identification. A tentative phylogeny of industrial S. cerevisiae yeasts is suggested with origins in bakers' yeast carrying the ancestral type-II form. Correspondence to: G. H. Rank     

Time-lapse tracking of barley androgenesis reveals position-determined cell death within pro-embryos

Following abiotic stress to induce barley (Hordeum vulgare L.) androgenesis, the development of 794 enlarged microspores in culture was monitored by time-lapse tracking. In total, 11% of the microspores tracked developed into embryo-like structures (type-I pathway), 36% formed multicellular structures (type-II pathway) and 53% of the microspores followed gametophytic divisions, accumulated starch and died in the first days of tracking (type-III pathway). Despite the microspore fate, enlarged microspores showed similar morphologies directly after stress treatment. Ultrastructural analysis, however, revealed two morphologically distinct cell types. Cells with a thin intine layer and an undifferentiated cytoplasm after stress treatment were associated with type-I and type-II pathways, whereas the presence of differentiated amyloplasts and a thick intine layer were associated with the type-III pathway. Tracking revealed that the first morphological change associated with embryogenic potential was a star-like morphology, which was a transitory stage between uninucleate vacuolated microspores after stress and the initiation of cell division. The difference between type-I and type-II pathways was observed during the time they displayed the star-like morphology. During the transition phase, embryo-like structures in the type-I pathway were always released out of the exine wall at the opposite side of the pollen germ pore, whereas in the type-II pathway multicellular structures were unable to break the exine and to release embryo-like structures. Moreover, by combining viability studies with cell tracking, we show that release of embryo-like structures was preceded by a decrease in viability of the cells positioned at the site of exine wall rupture. These cells were also positively stained by Sytox orange, a cell death indicator. Thereby, we demonstrate, for the first time, that a position-determined cell death process marks the transition from a multicellular structure into an embryo-like structure during barley androgenesis.     

Sequential targeting of interferon pathways for increased host resistance to bacterial superinfection during influenza

Bacterial co-infections represent a major clinical complication of influenza. Host-derived interferon (IFN) increases susceptibility to bacterial infections following influenza, but the relative roles of type-I versus type-II IFN remain poorly understood. We have used novel mouse models of co-infection in which colonizing pneumococci were inoculated into the upper respiratory tract; subsequent sublethal influenza virus infection caused the bacteria to enter the lungs and mediate lethal disease. Compared to wild-type mice or mice deficient in only one pathway, mice lacking both IFN pathways demonstrated the least amount of lung tissue damage and mortality following pneumococcal-influenza virus superinfection. Therapeutic neutralization of both type-I and type-II IFN pathways similarly provided optimal protection to co-infected wild-type mice. The most effective treatment regimen was staggered neutralization of the type-I IFN pathway early during co-infection combined with later neutralization of type-II IFN, which was consistent with the expression and reported activities of these IFNs during superinfection. These results are the first to directly compare the activities of type-I and type-II IFN during superinfection and provide new insights into potential host-directed targets for treatment of secondary bacterial infections during influenza.     

The hair-peg organs of the shore crab,Carcinus maenas (Crustacea,Decapoda): Ultrastructure and functional properties of sensilla sensitive to changes in seawater concentration

Summary The hair-peg organs of the shore crab, Carcinus maenas, are modified hair-sensilla. A small hair shaft (peg) is surrounded by a tuft of solid cuticular bristles (hairs). Each hair-peg organ is innervated by 6 sensory neurons, 2 of which have scolopidial (type-I) dendrites. The outer segments of all dendrites pass through a cuticular canal extending to the articulated hair base in which the 2 type-I dendrites terminate. The other 4 (type-II) dendrites reach the clavate tip of the hair shaft and have access to a terminal pore and a large sickle-shaped aperture. Three inner and 8–12 outer enveloping cells belong to a hair-peg organ. The innermost enveloping cell contains a scolopale, which has desmosomal connections to the ciliary rootlets of the type-I dendrites. An inner and an outer sensillum lymph space are present. The ultrastructural features of the dendrites and the cuticular apparatus indicate that the hair-peg organs are bimodal sensilla, comprising 2 mechano- and 4 chemosensitive sensory neurons. Extracellular recordings from the leg nerve indicate that the chemosensitive neurons of the hair-peg organs respond to changes in seawater concentration in the physiological range of Carcinus maenas.Supported by the Deutsche Forschungsgemeinschaft (SFB 45/A1; W. Gnatzy)     

Oligomerization of plant FtsZ1 and FtsZ2 plastid division proteins

FtsZ was identified in bacteria as the first protein to localize mid-cell prior to division and homologs have been found in many plant species. Bacterial studies demonstrated that FtsZ forms a ring structure that is dynamically exchanged with a soluble pool of FtsZ. Our previous work established that Arabidopsis FtsZ1 and FtsZ2-1 are capable of in vitro self-assembly into two distinct filament types, termed type-I and type-II and noted the presence of filament precursor molecules which prompted this investigation. Using a combination of electron microscopy, gel chromatography and native PAGE revealed that (i) prior to FtsZ assembly initiation the pool consists solely of dimers and (ii) during assembly of the Arabidopsis FtsZ type-II filaments the most common intermediate between the dimer and filament state is a tetramer. Three-dimensional reconstructions of the observed dimer and tetramer suggest these oligomeric forms may represent consecutive steps in type-II filament assembly and a mechanism is proposed, which is expanded to include FtsZ assembly into type-I filaments. Finally, the results permit a discussion of the oligomeric nature of the soluble pool in plants.     

Bile salt activation of cerebroside sulphate sulphohydrolase.

The cholate and taurodeoxycholate activations of cerebroside sulphate sulphohydrolase (cerebroside-3-sulphate 3-sulphohydrolase, EC 3.1.6.8) activity of arylsulphatase A (aryl-sulphate sulphohydrolase, EC 3.1.6.1) were compared. Taurodeoxycholate caused a sharp peak of response at a concentration of 1.25 mg/ml (type-I activation). Cholate also showed type-I activation but, in addition, it evoked a second, higher, response plateau at concentrations between 5 and 10 mg/ml (type-II activation). At the pH of the reaction, cholate is converted largely to the sparingly soluble free aicd, so at the high concentrations associated with type-II activation, copious precipitates were formed. It was found that the precipitated material was essential for the type-II activation. Type-I activation appears to involve bile salt interaction with substrate, while type-II activation appears to involve enzyme interaction with solid-phase cholic acid. the putative mutant arylsulphatase A in an unusual form of metachromatic leukodystrophy hydolysed cerebroside sulphate only in the presence of high levels of cholate. The type-II activation may thus be simulating a physiological desulphation reaction.     

Early evolutionary history and genomic features of gene duplicates in the human genome

Background

Human gene duplicates have been the focus of intense research since the development of array-based and targeted next-generation sequencing approaches in the last decade. These studies have primarily concentrated on determining the extant copy-number variation from a population-genomic perspective but lack a robust evolutionary framework to elucidate the early structural and genomic characteristics of gene duplicates at emergence and their subsequent evolution with increasing age.

Results

We analyzed 184 gene duplicate pairs comprising small gene families in the draft human genome with 10 % or less synonymous sequence divergence. Human gene duplicates primarily originate from DNA-mediated events, taking up genomic residence as intrachromosomal copies in direct or inverse orientation. The distribution of paralogs on autosomes follows random expectations in contrast to their significant enrichment on the sex chromosomes. Furthermore, human gene duplicates exhibit a skewed gradient of distribution along the chromosomal length with significant clustering in pericentromeric regions. Surprisingly, despite the large average length of human genes, the majority of extant duplicates (83 %) are complete duplicates, wherein the entire ORF of the ancestral copy was duplicated. The preponderance of complete duplicates is in accord with an extremely large median duplication span of 36 kb, which enhances the probability of capturing ancestral ORFs in their entirety. With increasing evolutionary age, human paralogs exhibit declines in (i) the frequency of intrachromosomal paralogs, and (ii) the proportion of complete duplicates. These changes may reflect lower survival rates of certain classes of duplicates and/or the role of purifying selection. Duplications arising from RNA-mediated events comprise a small fraction (11.4 %) of all human paralogs and are more numerous in older evolutionary cohorts of duplicates.

Conclusions

The degree of structural resemblance, genomic location and duplication span appear to influence the long-term maintenance of paralogs in the human genome. The median duplication span in the human genome far exceeds that in C. elegans and yeast and likely contributes to the high prevalence of complete duplicates relative to structurally heterogeneous duplicates (partial and chimeric). The relative roles of regulatory sequence versus exon-intron structure changes in the acquisition of novel function by human paralogs remains to be determined.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1827-3) contains supplementary material, which is available to authorized users.