Positionally biased gene loss after whole genome duplication: Evidence from human,yeast, and plant

Whole genome duplication (WGD) has made a significant contribution to many eukaryotic genomes including yeast, plants, and vertebrates. Following WGD, some ohnologs (WGD paralogs) remain in the genome arranged in blocks of conserved gene order and content (paralogons). However, the most common outcome is loss of one of the ohnolog pair. It is unclear what factors, if any, govern gene loss from paralogons. Recent studies have reported physical clustering (genetic linkage) of functionally linked (interacting) genes in the human genome and propose a biological significance for the clustering of interacting genes such as coexpression or preservation of epistatic interactions. Here we conduct a novel test of a hypothesis that functionally linked genes in the same paralogon are preferentially retained in cis after WGD. We compare the number of protein–protein interactions (PPIs) between linked singletons within a paralogon (defined as cis-PPIs) with that of PPIs between singletons across paralogon pairs (defined as trans-PPIs). We find that paralogons in which the number of cis-PPIs is greater than that of trans-PPIs are significantly enriched in human and yeast. The trend is similar in plants, but it is difficult to assess statistical significance due to multiple, overlapping WGD events. Interestingly, human singletons participating in cis-PPIs tend to be classified into “response to stimulus.” We uncover strong evidence of biased gene loss after WGD, which further supports the hypothesis of biologically significant gene clusters in eukaryotic genomes. These observations give us new insight for understanding the evolution of genome structure and of protein interaction networks.Well before genome sequences were available to test the hypothesis, Ohno proposed that two rounds (2R) of whole genome duplication (WGD) occurred in early vertebrate evolution (Ohno 1970). Ultimately, analysis of complete genome sequences verified the 2R hypothesis but did not reveal perfectly symmetric duplicate chromosomes. Instead, several studies uncovered complex fossils of the ancient genome duplication events where only some genes remained duplicated (termed “ohnologs”) (Wolfe 2000), and even these groups of duplicated genes had been broken up into “paralogons” by extensive genome rearrangements (Popovici et al. 2001; McLysaght et al. 2002; Panopoulou et al. 2003; Vandepoele et al. 2004; Dehal and Boore 2005; Nakatani et al. 2007; Putnam et al. 2008). The existence of biased gene loss following WGD due to structural or functional constraints is still considered an open question (Jaillon et al. 2009). Here we consider how functional interactions between genes may influence the patterns of gene loss following WGD.Large-scale linkage conservation between distantly related species has been shown by comparative analyses of vertebrate and invertebrate genomes (Putnam et al. 2007, 2008); however, the biological significance, if any, is unclear. Many functional gene clusters exist in the human genome (Popovici et al. 2001; Hurst et al. 2004; Makino and McLysaght 2008), and some of these, such as the HOX clusters, exist within paralogons (Popovici et al. 2001). We previously showed that interacting gene clusters in the human genome are more numerous than expected and have been conserved in vertebrate genomes more frequently than expected, indicating a functional role for clustering on the chromosome (Makino and McLysaght 2008). If we translate this observation to paralogons, we can consider the patterns of gene loss and test for preferential retention of interacting gene pairs in cis rather than in trans (Fig. 1). Following WGD, all interacting gene clusters will be perfectly duplicated, resulting in exactly equal numbers of cis- and trans-PPIs (protein–protein interactions). For interacting gene pairs that eventually revert to single-copy, the first gene loss is considered to be neutral if all losses are functionally equivalent. However, the second loss will result in either retention of a cis-PPI or of a trans-PPI. If there is no biological significance of the cis positioning of interacting genes, then this is a neutral “choice,” and each scenario should occur with equal frequency. However, if the relative proximity of interacting genes on the genome has biological relevance, then we expect to see non-random gene loss favoring the retention of the cis-PPI.Open in a separate windowFigure 1.Gene losses after whole genome duplication (WGD). Rectangles and horizontal lines represent genes and chromosomes, respectively. Red and green lines indicate cis- and trans-protein-protein interactions (PPIs) between proteins encoded by singletons or extant-paired ohnologs, respectively. (White rectangles) Genes prior to WGD. Blue and black rectangles show extant-paired ohnologs and singletons, respectively. Following WGD, all interacting gene clusters will be perfectly duplicated, resulting in exactly equal numbers of cis- and trans-PPIs. The first gene loss can occur at any locus. Gene loss that reverts the second gene to single copy will result in either retention of a cis- or a trans-PPI. If gene loss is neutral, then both scenarios should occur with equal frequency.Genome duplication has also been detected in other eukaryotic lineages including yeast (Wolfe and Shields 1997; Dietrich et al. 2004; Dujon et al. 2004; Kellis et al. 2004) and plants (Arabidopsis Genome Initiative 2000; Blanc et al. 2000). Additionally, there is evidence for interacting gene clusters in the yeast genome (Teichmann and Veitia 2004; Poyatos and Hurst 2006).Here we define protein–protein interactions (PPIs) between genes on the same “side” of a paralogon as cis-PPIs, and PPIs between genes across a paralogon pair as trans-PPIs (Fig. 1, red and green lines, respectively). Although the number of cis-PPIs must have been the same as that of trans-PPIs in a paralogon immediately after WGD, many of these interactions have been removed by gene losses during evolution. We test whether the number of cis-PPIs is greater than that of trans-PPIs in paralogons in human, yeast, and Arabidopsis.     

High-density lipoprotein levels and 10-year cardiovascular risk in HIV-1-infected patients

We aimed to determine the contribution of high-density lipoprotein cholesterol (HDL-c) to cardiovascular disease (CVD) risk in a cohort of HIV-infected patients. The contribution of CVD risk factors to the predicted CVD risk was assessed. We estimated the degree of reclassification of CVD risk if HDL-c concentration was increased in all patients by 20 and 40%, respectively. After age, HDL-c contributed most to the overall cardiovascular risk. Increasing HDL-c by 20% and 40% reclassified six and 12 patients to lower CVD risk groups, respectively. In this cohort, HDL-c contributed more to cardiovascular risk than smoking, total cholesterol, systolic blood pressure (SBP) and sex.     

Victims of Bullying Among Students With a Disability or Chronic Illness and Their Peers: A Cross-National Study Between Ireland and France

PurposeTo explore bullying victimization among French and Irish students with a disability or chronic illness (D/CI), considering individual, social, and family factors. We investigated this issue in France and Ireland because of the documented differences between these two countries on relevant contextual factors.MethodsData from 12,048 students aged 11, 13, and 15 years (50.1% were boys) as part of the cross-national study 2006 Health Behaviour in School-aged Children were analyzed. Self-completion questionnaires were administered in classrooms; information on socio-demographic characteristics, bullying involvement, D/CI, school participation, social network, and family were collected. Multivariate logistic regressions were performed with individual, social, and family cofactors.ResultsOverall, the prevalence of bullying victimization was significantly higher in France compared with Ireland (34.2% [33.1–35.5] and 25.9% [24.5–27.4, respectively]). Youngest were more likely to report victimization; however, no gender differences were observed. In both countries, students with D/CI were significantly more likely to report that they have been bullied compared with students without D/CI, and a significant additional risk of being bullied was found when students reported D/CI with restriction in school participation. Regardless of country and D/CI status, being bullied was significantly associated with weaker social support and difficulty of communication with fathers, with even stronger associations found among students with D/CI.ConclusionAdolescents with D/CI are more likely to be victimized than their peers, with a similar risk in both countries. Besides individual, social and family factors are consistently associated to bullying victimization across countries. These results will guide future antibullying prevention programs.     

Sudden unexpected death in epilepsy: people with nocturnal seizures may be at highest risk

Purpose: Most people with epilepsy who die suddenly and whose death is attributed to sudden unexpected death in epilepsy (SUDEP) are found in or by the bed for unknown reasons. We assessed whether those with sleep‐related SUDEP were more likely to have nocturnal seizures, and whether seizure patterns (diurnal vs. nocturnal) differed from people dying suddenly and living controls with epilepsy. Methods: Seizure patterns in a cohort of 154 people with epilepsy who died suddenly and after autopsy conformed to the definition of SUDEP and 616 controls living with epilepsy were classified as having “exclusively diurnal” or “nocturnal seizures.” Comparisons were made between the groups. SUDEP was classified as sleep‐related or non–sleep‐related based on eyewitness accounts and the circumstances surrounding death. Key Findings: SUDEP was primarily a sleep‐related (58%) and unwitnessed (86%) event. If sleep‐related, SUDEP was more likely to be unwitnessed [odds ratio (OR) 4.4, 95% confidence interval (CI) 1.6–12]. Those with sleep‐related SUDEP were more likely to have a history of nocturnal seizures than those who had non–sleep‐related SUDEP (OR 3.6, 95% CI 1.4–9.4). Those who died were more likely to have a history of nocturnal seizures than living controls (OR 3.9, 95% CI 2.5–6.0). After correction for previously established SUDEP risk factors ( Langan et al., 2005 ), the presence of nocturnal seizures remained significant (OR 2.6, 95% CI 1.3–5.0). Significance: Nocturnal seizures seem to be an independent risk factor for SUDEP. These findings underscore the importance of preventive measures, which may include night supervision.     

Stress appraisals and cellular aging: a key role for anticipatory threat in the relationship between psychological stress and telomere length

Chronic psychological stress is a risk factor for multiple diseases of aging. Accelerated cellular aging as indexed by short telomere length has emerged as a potential common biological mechanism linking various forms of psychological stress and diseases of aging. Stress appraisals determine the degree and type of biological stress responses and altered stress appraisals may be a common psychological mechanism linking psychological stress and diseases of aging. However, no previous studies have examined the relationship between stress appraisals and telomere length. We exposed chronically stressed female caregivers and non-caregiving controls (N=50; M age=62.14±6.10) to a standardized acute laboratory stressor and measured their anticipatory and retrospective threat and challenge appraisals of the stressor. We hypothesized that threat and challenge appraisals would be associated with shorter and longer telomere length respectively, and that chronic caregiving stress would influence telomere length through altered stress appraisals. Higher anticipatory threat appraisals were associated with shorter age-adjusted telomere length (β=-.32, p=.03), but challenge appraisals and retrospective threat appraisals showed no independent association with telomere length. Caregivers reported significantly higher anticipatory (β=-.36, p=.006) and retrospective (β=-.29, p=.03) threat appraisals than controls, but similar challenge appraisals. Although there was no significant main effect of caregiver status on telomere length, caregiving had a significant indirect effect on telomere length through anticipatory threat appraisals. Exaggerated anticipatory threat appraisals may be a common and modifiable psychological mechanism of psychological stress effects on cellular aging.     

IL-1β inhibits axonal growth of developing sympathetic neurons

Several secreted proteins facilitate the growth and guidance of sympathetic axons to their target organs during development. Here we show that IL-1β, a key regulator of inflammation in the immune system, inhibits axonal growth and branching from cultured sympathetic neurons at a stage in development when their axons are ramifying within their targets in vivo. IL-1β is synthesised in sympathetic ganglia and its targets at this stage, and IL-1β protein is detectable in the axons and perikarya of the innervating neurons. It acts directly on developing axons to inhibit their growth via NF-κB signalling. These findings show that IL-1β is a novel locally, and target-derived factor that can regulate the extent of sympathetic axon growth during the late embryonic and early postnatal period in developing rat sympathetic neurons.