Meiotic recombination events cluster into narrow segments of the genome, defined as hotspots. Here, we demonstrate that a major player for hotspot specification is the Prdm9 gene. First, two mouse strains that differ in hotspot usage are polymorphic for the zinc finger DNA binding array of PRDM9. Second, the human consensus PRDM9 allele is predicted to recognize the 13-mer motif enriched at human hotspots; this DNA binding specificity is verified by in vitro studies. Third, allelic variants of PRDM9 zinc fingers are significantly associated with variability in genome-wide hotspot usage among humans. Our results provide a molecular basis for the distribution of meiotic recombination in mammals, where the binding of PRDM9 to specific DNA sequences targets the initiation of recombination at specific locations in the genome.
Summary Studies in mice and humans have revealed intriguing associations between host genetics and the microbiome. Here we report a 16S rRNA-based analysis of the gut microbiome in 1,126 twin pairs, a subset of which was previously reported. Tripling the sample narrowed the confidence intervals around heritability estimates and uncovered additional heritable taxa, some of which are validated in other studies. Repeat sampling of subjects showed heritable taxa to be temporally stable. A candidate gene approach uncovered associations between heritable taxa and genes related to diet, metabolism and olfaction. We replicate an association between Bifidobacterium and the lactase (LCT) gene locus and identify an association between the host gene ALDH1L1 and SHA-98 bacteria, suggesting a link between formate production and blood pressure. Additional genes detected are involved in barrier defense and self/non-self recognition. Our results indicate that diet-sensing, metabolism, and immune defense are important drivers of human-microbiome co-evolution.
BACKGROUND The Amish and Hutterites are U.S. agricultural populations whose lifestyles are remarkably similar in many respects but whose farming practices, in particular, are distinct; the former follow traditional farming practices whereas the latter use industrialized farming practices. The populations also show striking disparities in the prevalence of asthma, and little is known about the immune responses underlying these disparities. METHODS We studied environmental exposures, genetic ancestry, and immune profiles among 60 Amish and Hutterite children, measuring levels of allergens and endotoxins and assessing the microbiome composition of indoor dust samples. Whole blood was collected to measure serum IgE levels, cytokine responses, and gene expression, and peripheral-blood leukocytes were phenotyped with flow cytometry. The effects of dust extracts obtained from Amish and Hutterite homes on immune and airway responses were assessed in a murine model of experimental allergic asthma. RESULTS Despite the similar genetic ancestries and lifestyles of Amish and Hutterite children, the prevalence of asthma and allergic sensitization was 4 and 6 times as low in the Amish, whereas median endotoxin levels in Amish house dust was 6.8 times as high. Differences in microbial composition were also observed in dust samples from Amish and Hutterite homes. Profound differences in the proportions, phenotypes, and functions of innate immune cells were also found between the two groups of children. In a mouse model of experimental allergic asthma, the intranasal instillation of dust extracts from Amish but not Hutterite homes significantly inhibited airway hyperreactivity and eosinophilia. These protective effects were abrogated in mice that were deficient in MyD88 and Trif, molecules that are critical in innate immune signaling. CONCLUSIONS The results of our studies in humans and mice indicate that the Amish environment provides protection against asthma by engaging and shaping the innate immune response. (Funded by the National Institutes of Health and others.)
With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10(-11)). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of approximately 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry.
Sexual dimorphism in anatomical, physiological, and behavioural traits characterize many vertebrate species. In humans, sexual dimorphism is also observed in the prevalence, course, and severity of many common diseases, including cardiovascular diseases, autoimmune diseases, and asthma. Although sex differences in the endocrine and immune systems probably contribute to these observations, recent studies suggest that sex-specific genetic architecture also influences human phenotypes, including reproductive, physiological, and disease traits. It is likely that an underlying mechanism is differential gene regulation in males and females, particularly in sex steroid responsive genes. Genetic studies that ignore sex-specific effects in their design and interpretation could fail to identify a significant proportion of the genes that contribute to risk for complex diseases.Differences between males and females in anatomical, physiological, and behavioral traits characterize many vertebrate species, including humans. Although some may be apparent at birth, striking differences between the sexes most often emerge at or around the time of sexual maturation. It is thought that these are, in large part, due to sex hormone levels that differ in males and females beginning in utero and continuing throughout life 1 (Figure 1). The genetic contribution to sexual dimorphism was, until recently, less studied. Indeed, whereas genes on sex chromosomes contribute to many sexually dimorphic traits, the autosomal genome is generally assumed to be similar among the males and females of a species. Mechanisms for dosage compensation in HETEROGAMETIC species further assure that genetic contributions from the shared sex chromosome (X chromosome in mammals) is equivalent among males and females, at least for most genes 2 .Recent studies have challenged this paradigm, however, suggesting that natural variation within the autosomal genomes of many species also affects anatomical, physiological, and behavioral traits differently in males and females 3-5 . In this context, sex can be considered an 'environmental' variable that includes the cellular, metabolic, physiological, anatomical, and even behavioral differences between boys and girls (in childhood) or between men and women (in adulthood). Sex, then, may interact with genotype in a manner similar to other environmental factors (Figure 2). However, unlike most other environmental factors, sex is easily observable and (usually) unambiguous. Such sex-specific genetic architecture suggests new models of susceptibility for common diseases and sheds light on potential mechanisms of sexual dimorphism [Box 1] in human phenotypes.In this review, we argue that sex-specific genetic architecture is common in humans and that genotype-sex interactions contribute to differences in the prevalence, course, and severity of diseases as well as to other quantitative phenotypes. We provide recent examples of genotypesex interactions as evidence to support this argument and illustrate how patterns of t...
Prostate cancer is the most prevalent noncutaneous cancer in males in developed regions, with African American men having among the highest worldwide incidence and mortality rates. Here we report a second genetic variant in the 8q24 region that, in conjunction with another variant we recently discovered, accounts for about 11%-13% of prostate cancer cases in individuals of European descent and 31% of cases in African Americans. We made the current discovery through a genome-wide association scan of 1,453 affected Icelandic individuals and 3,064 controls using the Illumina HumanHap300 BeadChip followed by four replication studies. A key step in the discovery was the construction of a 14-SNP haplotype that efficiently tags a relatively uncommon (2%-4%) susceptibility variant in individuals of European descent that happens to be very common (approximately 42%) in African Americans. The newly identified variant shows a stronger association with affected individuals who have an earlier age at diagnosis.
Asthma and atopy are complex phenotypes that are influenced by both genetic and environmental factors. A review of nearly 500 papers on disease association studies identified 25 genes that have been associated with an asthma or atopy phenotype in six or more populations. An additional 54 genes have been associated in 2-5 populations. Here, we discuss the methods that have been used to identify susceptibility genes for common diseases and overview the status of asthma genetic research. Finally, current challenges and future directions are discussed.
Summary Asthma and allergy are common conditions with complex etiologies involving both genetic and environmental contributions. Recent genome-wide association studies (GWAS) and meta-analyses of GWAS have begun to shed light on both common and distinct pathways that contribute to asthma and allergic diseases. Associations with variation in genes encoding the epithelial cell-derived cytokines, interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP), and the IL1RL1 gene encoding the IL-33 receptor, ST2, highlight the central roles for innate immune response pathways that promote the activation and differentiation of T-helper 2 (Th2) cells in the pathogenesis of both asthma and allergic diseases. In contrast, variation at the 17q21 asthma locus, encoding the ORMDL3 and GSDML genes, is specifically associated with risk for childhood onset asthma. These and other genetic findings are providing a list of well-validated asthma and allergy susceptibility genes that are expanding our understanding of the common and unique biological pathways that are dysregulated in these related conditions. Ongoing studies will continue to broaden our understanding of asthma and allergy and unravel the mechanisms for the development of these complex traits.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.