Negative selection on human genes underlying inborn errors depends on disease outcome and both the mode and mechanism of inheritance

Genetic variants underlying life-threatening diseases, being unlikely to be transmitted to the next generation, are gradually and selectively eliminated from the population through negative selection. We study the determinants of this evolutionary process in human genes underlying monogenic diseases by comparing various negative selection scores and an integrative approach, CoNeS, at 366 loci underlying inborn errors of immunity (IEI). We find that genes underlying autosomal dominant (AD) or X-linked IEI have stronger negative selection scores than those underlying autosomal recessive (AR) IEI, whose scores are not different from those of genes not known to be disease causing. Nevertheless, genes underlying AR IEI that are lethal before reproductive maturity with complete penetrance have stronger negative selection scores than other genes underlying AR IEI. We also show that genes underlying AD IEI by loss of function have stronger negative selection scores than genes underlying AD IEI by gain of function, while genes underlying AD IEI by haploinsufficiency are under stronger negative selection than other genes underlying AD IEI. These results are replicated in 1,140 genes underlying inborn errors of neurodevelopment. Finally, we propose a supervised classifier, SCoNeS, which predicts better than state-of-the-art approaches whether a gene is more likely to underlie an AD or AR disease. The clinical outcomes of monogenic inborn errors, together with their mode and mechanisms of inheritance, determine the levels of negative selection at their corresponding loci. Integrating scores of negative selection may facilitate the prioritization of candidate genes and variants in patients suspected to carry an inborn error.

Negative (or purifying) selection is the natural process by which deleterious alleles are selectively purged from the population (1). In diploid species, the strength of negative selection at a given locus is predicted to increase with decreasing fitness and increasing dominance of the genetic variants controlling traits: Variation causing early death in the heterozygous state are the least likely to be transmitted to the next generation, as their carriers have fewer offspring than noncarriers (2). Human genetic variants that cause severe diseases are, thus, expected to be the primary targets of negative selection, particularly for diseases affecting heterozygous individuals. In humans, several studies have ranked protein-coding genes according to their levels of negative selection (3–5). Nevertheless, the extent to which negative selection affects human disease-causing genes, and the factors determining its strength, remain largely unknown, particularly because our knowledge of the severity, mode, and mechanism of inheritance of the corresponding human diseases remains incomplete (3, 6–8).The strength of negative selection at a given gene has been traditionally approximated by comparing the coding sequence of the gene in a given species with that of one or several closely related species; it depends on the proportion of amino acid changes that have accumulated during evolution (9–11). With the advent of high-throughput sequencing, intraspecies metrics have been developed, based on the comparison of the probability of predicted loss-of-function (pLOF) mutations for a gene under a random model with the frequency of pLOF mutations observed in population databases (5, 12, 13), which capture the species-specific evolution of genes. Using an interspecies-based method and a hand-curated version of the Online Mendelian Inheritance in Man (hOMIM) database, a previous study elegantly showed that most human genes for which mutations cause highly penetrant diseases, including autosomal dominant (AD) diseases in particular, evolve under stronger negative selection than genes associated with complex disorders (6). However, other studies based on OMIM genes have reported conflicting results (3, 14–17), probably due to the incompleteness and heterogeneity of the datasets used. Moreover, no study has yet addressed this problem with intraspecies metrics, even though it has been suggested that the choice of the reference species for interspecies metrics contributes to discrepancies across studies (6).We aimed to improve the identification of the drivers of negative selection acting on human disease-causing genes, by developing a negative selection score combining several informative intraspecies and interspecies statistics, focusing on inborn errors of immunity (IEI). IEI, previously known as primary immunodeficiencies (18), are genetic diseases that disrupt the development or function of human immunity. They form a large and expanding group of genetic diseases that has been widely studied, and they are well characterized physiologically (immunologically) and phenotypically (clinically) (19–21). IEI are often symptomatic in early childhood, and at least until the turn of the 20th century and the introduction of antibiotics, most individuals with IEI probably died before reaching reproductive maturity. Accordingly, IEI genes have probably been under strong negative selection from the dawn of humankind until very recently. In this study, we investigated whether the severity of IEI and their mode and mechanism of inheritance have left signatures of negative selection of various intensities in the corresponding human genes. Furthermore, we validated our model on genes underlying inborn errors of neurodevelopment (IEND), another group of well-characterized severe genetic diseases.     

Early mitochondrial adaptations in skeletal muscle to diet-induced obesity are strain dependent and determine oxidative stress and energy expenditure but not insulin sensitivity

This study sought to elucidate the relationship between skeletal muscle mitochondrial dysfunction, oxidative stress, and insulin resistance in two mouse models with differential susceptibility to diet-induced obesity. We examined the time course of mitochondrial dysfunction and insulin resistance in obesity-prone C57B and obesity-resistant FVB mouse strains in response to high-fat feeding. After 5 wk, impaired insulin-mediated glucose uptake in skeletal muscle developed in both strains in the absence of any impairment in proximal insulin signaling. Impaired mitochondrial oxidative capacity preceded the development of insulin resistant glucose uptake in C57B mice in concert with increased oxidative stress in skeletal muscle. By contrast, mitochondrial uncoupling in FVB mice, which prevented oxidative stress and increased energy expenditure, did not prevent insulin resistant glucose uptake in skeletal muscle. Preventing oxidative stress in C57B mice treated systemically with an antioxidant normalized skeletal muscle mitochondrial function but failed to normalize glucose tolerance and insulin sensitivity. Furthermore, high fat-fed uncoupling protein 3 knockout mice developed increased oxidative stress that did not worsen glucose tolerance. In the evolution of diet-induced obesity and insulin resistance, initial but divergent strain-dependent mitochondrial adaptations modulate oxidative stress and energy expenditure without influencing the onset of impaired insulin-mediated glucose uptake.     

Leptin signaling in adipose tissue: role in lipid accumulation and weight gain

Rationale: The link between obesity, hyperleptinemia, and development of cardiovascular disease is not completely understood. Increases in leptin have been shown to impair leptin signaling via caveolin-1-dependent mechanisms. However, the role of hyperleptinemia versus impaired leptin signaling in adipose tissue is not known. Objective: To determine the presence and significance of leptin-dependent increases in adipose tissue caveolin-1 expression in humans. Methods and Results: We designed a longitudinal study to investigate the effects of increases in leptin on adipose tissue caveolin-1 expression during weight gain in humans. Ten volunteers underwent 8 weeks of overfeeding, during which they gained an average weight of 4.1±1.4 kg, with leptin increases from 7±3.8 to 12±5.7 ng/mL. Weight gain also resulted in changes in adipose tissue caveolin-1 expression, which correlated with increases in leptin (rho=0.79, P=0.01). In cultured human white preadipocytes, leptin increased caveolin-1 expression, which in turn impaired leptin cellular signaling. Functionally, leptin decreased lipid accumulation in differentiating human white preadipocytes, which was prevented by caveolin-1 overexpression. Further, leptin decreased perilipin and fatty acid synthase expression, which play an important role in lipid storage and biogenesis. Conclusions: In healthy humans, increases in leptin, as seen with modest weight gain, may increase caveolin-1 expression in adipose tissue. Increased caveolin-1 expression in turn impairs leptin signaling and attenuates leptin-dependent lowering of intracellular lipid accumulation. Our study suggests a leptin-dependent feedback mechanism that may be essential to facilitate adipocyte lipid storage during weight gain.     

Prevalence of neuropathic pain among black African patients suffering from common low back pain

To study the prevalence and semiotic characteristics of neuropathic pain in the common low back pain to the Black African subject. This was a prospective cross-sectional survey carried on from April 1 2009 to August 31 2009 in consultations of rheumatology, neurology, and neurosurgery at the University Hospital Yalgado Ouédraogo in Ouagadougou (Burkina Faso). All patients with a low back pain or a common lomboradiculalgie were included. DN4 questionnaire was used for the diagnosis of neuropathic pain. One hundred and seven patients have been recruited during the study period; Sixty-four (59.80%) were female (sex ratio M/F: 0.67). The average age was 34.11?±?13.46?years of age with extremes of 20 and 79. The average duration of disease was 48.53?months with extremes of 10?days and 50?years. Eighty-seven patients (81.31%) had a disease duration, which was 3?months longer. Sixty-six patients (61.70%) had a predominant lomboradiculalgie; among the remaining 41, low back pain predominated. Average intensity of pain was 62.81?±?22.43 (on a scale of 100). A sign of Lasèque was present in the 41 (38.30%) patients. Fifty-three (49.5%) patients had a neuropathic pain. The prevalence of neuropathy signs according to the DN4 questionnaire was as follows: burning (n?=?37; 34.58%), painful cold (n?=?13; 12.15%), electric shocks (n?=?31; 38.97%), pins and needles (n?=?34; 31.77%), tingling (n?=?35; 32.71%), numbness (n?=?45; 42.05%), itching (n?=?18; 16.82%), touch hypoesthesia (n?=?35; 32.71%), pinprick (n?=?33; 30.84%), and tactile allodynia (n?=?21; 19.62%). Among the studied variables, the presence of a radiculalgy was statistically associated with neuropathic pain. The lomboradiculalgie of the Black African subject associates neuropathic pain observed in half of patients. Treatment must therefore always take account of this association. However, further studies are needed before any definitive conclusion.     

Tratamiento quirúrgico de la mediastinitis necrosante descendente

Introduction

Descending necrotizing mediastinitis (DNM) is a serious infection which occurs as a complication of oropharyngeal infection. Its surgical management and the routine transthoracic approach remain controversial. In this article we report our experience in the management of this disease, and review the different surgical approaches that have been reported in the medical literature.

Material and methods

A retrospective review was made of the clinical records of 29 patients treated between 1988 and 2009. Several demographic variables were analyzed, origin of the initial infection, stage of the disease according to Endo's classification, surgical technique and outcome.

Results

Surgical treatment consisted of both cervical and mediastinal drainage and radical debridement. The mediastinal drainage was made through a transcervical approach in 10 cases and transthoracic in 19, depending on the extent of the mediastinitis. The outcome was satisfactory in 24 patients and 5 died (mortality 17.2%).

Conclusions

According to our results and the conclusions of the main authors, we recommend a prompt and aggressive surgery with a transthoracic approach in cases of widespread DNM.