BackgroundEven though human sweat is odorless, bacterial growth and decomposition of specific odor precursors in it is believed to give rise to body odor in humans. While mechanisms of odor generation have been widely studied in adults, little is known for teenagers and pre-pubescent children who have distinct sweat composition from immature apocrine and sebaceous glands, but are arguably more susceptible to the social and psychological impact of malodor.ResultsWe integrated information from whole microbiome analysis of multiple skin sites (underarm, neck, and head) and multiple time points (1 h and 8 h after bath), analyzing 180 samples in total to perform the largest metagenome-wide association study to date on malodor. Significant positive correlations were observed between odor intensity and the relative abundance of Staphylococcus hominis, Staphylococcus epidermidis, and Cutibacterium avidum, as well as negative correlation with Acinetobacter schindleri and Cutibacterium species. Metabolic pathway analysis highlighted the association of isovaleric and acetic acid production (sour odor) from enriched S. epidermidis (teen underarm) and S. hominis (child neck) enzymes and sulfur production from Staphylococcus species (teen underarm) with odor intensity, in good agreement with observed odor characteristics in pre-pubescent children and teenagers. Experiments with cultures on human and artificial sweat confirmed the ability of S. hominis and S. epidermidis to independently produce malodor with distinct odor characteristics.ConclusionsThese results showcase the power of skin metagenomics to study host-microbial co-metabolic interactions, identifying distinct pathways for odor generation from sweat in pre-pubescent children and teenagers and highlighting key enzymatic targets for intervention.Electronic supplementary materialThe online version of this article (10.1186/s40168-018-0588-z) contains supplementary material, which is available to authorized users.
The tumor suppressor p53 has defined roles in varied cellular processes including apoptosis and DNA repair. While conventional genomic approaches have suggested a large number of p53 targets, there is a need for a systematic approach to validate these putative genes. We developed a method to identify and validate p53's transcriptional behavior by utilizing 16 non-synonymous p53 single-nucleotide polymorphism (SNP) variants. Five SNPs located within the DNA-binding domain of p53 were found to be functionally null, whereas the other 11 SNPs were p53WT-like in behavior. By integrating p53 ChIP-seq analysis with transcriptome data from the p53 SNP variants, 592 genes were identified as novel p53 targets. Many of these genes mapped to previously less well-characterized aspects of p53 function, such as cell signalling, metabolism, central nervous system, and immune system. These data provide pivotal insights into the involvement of p53 in diverse pathways of normal physiological processes and open new avenues for investigation of p53 function. Cell Death and Differentiation (2014) 21, 521-532; doi:10.1038/cdd.2013.132; published online 27 September 2013The tumor suppressor p53 acts as a master regulator of cellular stress responses through transcriptionally regulating specific target genes involved in diverse cellular functions including cell cycle arrest, apoptosis, and DNA repair. 1 With the aid of large-scale screening techniques, it has become clear that the scope of p53 functions is much broader than previously thought, 2,3 expanding to cellular and physiological processes such as metabolism 4 and development. 5 To have a better understanding of this important tumor suppressor, we must be able to study the full complexity of its downstream effects and this requires the efficient identification and validation of genes directly regulated by p53. To date, there are fewer than 150 validated p53 target genes 6-8 and at the same time validation studies have been slow, which is a limitation on the progress in this field.In order to be regulated by p53 a gene must possess the appropriate cognate response element (RE) within its regulatory region. However, our previous study has shown that simple sequence motif identification is not sufficient, as the p53RE exhibits variable binding kinetics that are dependent upon the dinucleotide core 'CWWG' combinations. 9 These variables often result in spurious outcomes and hence we are in need of more robust approaches to accurately identify p53 transcriptional networks.Here, we describe an unbiased method to review 135 reported p53 target genes and at the same time identify new p53 targets on a genome-wide scale. We utilized wild-type (WT) p53 together with 16 allelic replicates comprising all reported non-synonymous single-nucleotide polymorphism (SNP) variants of p53. As the transcriptional functions of these 16 SNPs have not been well studied, we first developed a customized luciferase assay with promoter reporter vectors encompassing all combinatorial forms of the dinucleotide ...
Genetic rearrangement by recombination is one of the major driving forces for genome evolution, and recombination is known to occur in non-random, discreet recombination sites within the genome. Mapping of recombination sites has proved to be difficult, particularly, in the human MHC region that is complicated by both population variation and highly polymorphic HLA genes. To overcome these problems, HLA-typed individuals from three representative populations: Asian, European and African were used to generate phased HLA haplotypes. Extended haplotype homozygosity (EHH) plots constructed from the phased haplotype data revealed discreet EHH drops corresponding to recombination events and these signatures were observed to be different for each population. Surprisingly, the majority of recombination sites detected are unique to each population, rather than being common. Unique recombination sites account for 56.8% (21/37 of total sites) in the Asian cohort, 50.0% (15/30 sites) in Europeans and 63.2% (24/38 sites) in Africans. Validation carried out at a known sperm typing recombination site of 45 kb (HLA-F-telomeric) showed that EHH was an efficient method to narrow the recombination region to 826 bp, and this was further refined to 660 bp by resequencing. This approach significantly enhanced mapping of the genomic architecture within the human MHC, and will be useful in studies to identify disease risk genes.
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