Genome-wide interaction studies reveal sex-specific asthma risk alleles.

Asthma is a complex disease with sex-specific differences in prevalence. Candidate gene studies have suggested that genotype-by-sex interaction effects on asthma risk exist, but this has not yet been explored at a genome-wide level. We aimed to identify sex-specific asthma risk alleles by performing a genome-wide scan for genotype-by-sex interactions in the ethnically diverse participants in the EVE Asthma Genetics Consortium. We performed male- and female-specific genome-wide association studies in 2653 male asthma cases, 2566 female asthma cases and 3830 non-asthma controls from European American, African American, African Caribbean and Latino populations. Association tests were conducted in each study sample, and the results were combined in ancestry-specific and cross-ancestry meta-analyses. Six sex-specific asthma risk loci had P-values < 1 × 10(-6), of which two were male specific and four were female specific; all were ancestry specific. The most significant sex-specific association in European Americans was at the interferon regulatory factor 1 (IRF1) locus on 5q31.1. We also identify a Latino female-specific association in RAP1GAP2. Both of these loci included single-nucleotide polymorphisms that are known expression quantitative trait loci and have been associated with asthma in independent studies. The IRF1 locus is a strong candidate region for male-specific asthma susceptibility due to the association and validation we demonstrate here, the known role of IRF1 in asthma-relevant immune pathways and prior reports of sex-specific differences in interferon responses.

Differential neural activity patterns for spatial relations in humans: a MEG study.

Children learn the words for above-below relations earlier than for left-right relations, despite treating these equally well in a simple visual categorization task. Even as adults--conflicts in congruency, such as when a stimulus is depicted in a spatially incongruent manner with respect to salient global cues--can be challenging. Here we investigated the neural correlates of encoding and maintaining in working memory above-below and left-right relational planes in 12 adults using magnetoencephalography in order to discover whether above-below relations are represented by the brain differently than left-right relations. Adults performed perfectly on the task behaviorally, so any differences in neural activity were attributed to the stimuli's cognitive attributes. In comparing above-below to left-right relations during stimulus encoding, we found the greatest differences in neural activity in areas associated with space and movement. In comparing congruent to incongruent trials, we found the greatest differential activity in premotor areas. For both contrasts, brain areas involved in the encoding phase were also involved in the maintenance phase, which provides evidence that those brain areas are particularly important in representing the relational planes or congruency types throughout the trial. When comparing neural activity associated with the relational planes during working memory, additional right posterior areas were implicated, whereas the congruent-incongruent contrast implicated additional bilateral frontal and temporal areas. These findings are consistent with the hypothesis left-right relations are represented differently than above-below relations.

Genome-wide association study identifies candidate genes for male fertility traits in humans.

Despite the fact that hundreds of genes are known to affect fertility in animal models, relatively little is known about genes that influence natural fertility in humans. To broadly survey genes contributing to variation in male fertility, we conducted a genome-wide association study (GWAS) of two fertility traits (family size and birth rate) in 269 married men who are members of a founder population of European descent that proscribes contraception and has large family sizes. Associations between ∼250,000 autosomal SNPs and the fertility traits were examined. A total of 41 SNPs with p ≤ 1 × 10(-4) for either trait were taken forward to a validation study of 123 ethnically diverse men from Chicago who had previously undergone semen analyses. Nine (22%) of the SNPs associated with reduced fertility in the GWAS were also associated with one or more of the ten measures of reduced sperm quantity and/or function, yielding 27 associations with p values < 0.05 and seven with p values < 0.01 in the validation study. On the basis of 5,000 permutations of our data, the probabilities of observing this many or more small p values were 0.0014 and 5.6 × 10(-4), respectively. Among the nine associated loci, outstanding candidates for male fertility genes include USP8, an essential deubiquitinating enzyme that has a role in acrosome assembly; UBD and EPSTI1, which have potential roles in innate immunity; and LRRC32, which encodes a latent transforming growth factor ß (TGF-ß) receptor on regulatory T cells. We suggest that mutations in these genes that are more severe may account for some of the unexplained infertility (or subfertility) in the general population.

Current challenges and future of agricultural genomes to phenomes in the USA.

Dramatic improvements in measuring genetic variation across agriculturally relevant populations (genomics) must be matched by improvements in identifying and measuring relevant trait variation in such populations across many environments (phenomics). Identifying the most critical opportunities and challenges in genome to phenome (G2P) research is the focus of this paper. Previously (Genome Biol, 23(1):1-11, 2022), we laid out how Agricultural Genome to Phenome Initiative (AG2PI) will coordinate activities with USA federal government agencies expand public-private partnerships, and engage with external stakeholders to achieve a shared vision of future the AG2PI. Acting on this latter step, AG2PI organized the "Thinking Big: Visualizing the Future of AG2PI" two-day workshop held September 9-10, 2022, in Ames, Iowa, co-hosted with the United State Department of Agriculture's National Institute of Food and Agriculture (USDA NIFA). During the meeting, attendees were asked to use their experience and curiosity to review the current status of agricultural genome to phenome (AG2P) work and envision the future of the AG2P field. The topic summaries composing this paper are distilled from two 1.5-h small group discussions. Challenges and solutions identified across multiple topics at the workshop were explored. We end our discussion with a vision for the future of agricultural progress, identifying two areas of innovation needed: (1) innovate in genetic improvement methods development and evaluation and (2) innovate in agricultural research processes to solve societal problems. To address these needs, we then provide six specific goals that we recommend be implemented immediately in support of advancing AG2P research.

Gesture use by chimpanzees (Pan troglodytes): differences between sexes in inter- and intra-sexual interactions.

Communication and social relationships are two of the most important aspects of primate life, but few studies have focused on linking these aspects in apes. There are some shared social pressures between the two sexes (e.g., kin selection, alliance formation, and protection against attack), but there are also differences (e.g., mate selection, dispersal, and social ranking systems). The aim of this study was to identify the communication strategies of the sexes with respect to their particular communication partner. I hypothesized the sexes use different strategies in their gestural communication based on their different social pressures. Specifically, males should have more positive intra-sexual relationships than females because of high focus on male-male alliance formation and maintaining high social rank, both of which directly affect their mating opportunities and relationships with all other members of the group. On the other hand, females should have more positive inter-sexual relationships due to the abuse they could receive from insubordination to males and because there is less focus on maintaining multiple, positive relationships with other females. Furthermore, because of differences in social pressures, males should have higher incidence of reassurance in same-sex interactions than females because it should be more important for males to mitigate negative interactions. I analyzed the characteristics of the gesture repertoire and frequency of gesture use for each sex in each of four contexts: (1) aggression, (2) submission, (3) greeting, and (4) reassurance. I looked at intra-sexual and inter-sexual interactions, separately. I found that, indeed, males and females utilize different strategies of gestural communication. I also found that females, but not males, have a distinct gesture strategy for communicating with the opposite sex than for the same sex. This study shows there are distinct strategies utilized by the two sexes and these differences may be explained by their differing social pressures.

How tufted capuchin monkeys (Cebus apella spp) and common chimpanzees (Pan troglodytes) align objects to surfaces: insights into spatial reasoning and implications for tool use.

This report addresses phylogenetic variation in a spatial skill that underlies tool use: aligning objects to a feature of a surface. Fragaszy and Cummins-Sebree's [Behavioral and Cognitive Neuroscience Reviews 4:282-306, 2005] model of relational spatial reasoning and Skill Development and Perception-Action theories guided the design of the study. We examined how capuchins and chimpanzees place stick objects of varying shapes into matching grooves on a flat surface. Although most individuals aligned the long axis of the object with the matching groove more often than expected by chance, all typically did so with poor precision. Some individuals managed to align a second feature, and only one (a capuchin monkey) achieved above-chance success at aligning three features with matching grooves. Our findings suggest that capuchins and chimpanzees do not reliably align objects along even one axis, and that neither species can reliably or easily master object placement tasks that require managing two or more spatial relations concurrently. Moreover, they did not systematically vary their behavior in a manner that would aid discovery of the affordances of the stick-surface combination beyond sliding the stick along the surface (which may have provided haptic information about the location of the groove). These limitations have profound consequences for the forms of tool use we can expect these individuals to master.

Language unifies relational coding: The roles of label acquisition and accessibility in making flexible relational judgments.

Language is likely structuring spatial judgments, but how it achieves this is not clear. We examined the development of relative, spatial judgments across verbal and nonverbal tasks of above, below, right and left in children between the ages of 5 and 10 years. We found that the verbal ability to make above/below judgments preceded verbal right/left judgments and all nonverbal judgments. We also found that only when the labels were accessed - as opposed to only having been acquired - did children's nonverbal performance improve. Our findings further indicate that accessing the correct term was not needed for enhanced performance. The results suggest that accessing language unifies different instantiations of a relation into a single representation.

An information theory analysis of spatial decisions in cognitive development.

Performance in a cognitive task can be considered as the outcome of a decision-making process operating across various knowledge domains or aspects of a single domain. Therefore, an analysis of these decisions in various tasks can shed light on the interplay and integration of these domains (or elements within a single domain) as they are associated with specific task characteristics. In this study, we applied an information theoretic approach to assess quantitatively the gain of knowledge across various elements of the cognitive domain of spatial, relational knowledge, as a function of development. Specifically, we examined changing spatial relational knowledge from ages 5 to 10 years. Our analyses consisted of a two-step process. First, we performed a hierarchical clustering analysis on the decisions made in 16 different tasks of spatial relational knowledge to determine which tasks were performed similarly at each age group as well as to discover how the tasks clustered together. We next used two measures of entropy to capture the gradual emergence of order in the development of relational knowledge. These measures of "cognitive entropy" were defined based on two independent aspects of chunking, namely (1) the number of clusters formed at each age group, and (2) the distribution of tasks across the clusters. We found that both measures of entropy decreased with age in a quadratic fashion and were positively and linearly correlated. The decrease in entropy and, therefore, gain of information during development was accompanied by improved performance. These results document, for the first time, the orderly and progressively structured "chunking" of decisions across the development of spatial relational reasoning and quantify this gain within a formal information-theoretic framework.

The microbial nitrogen cycling potential is impacted by polyaromatic hydrocarbon pollution of marine sediments.

During hydrocarbon exposure, the composition and functional dynamics of marine microbial communities are altered, favoring bacteria that can utilize this rich carbon source. Initial exposure of high levels of hydrocarbons in aerobic surface sediments can enrich growth of heterotrophic microorganisms having hydrocarbon degradation capacity. As a result, there can be a localized reduction in oxygen potential within the surface layer of marine sediments causing anaerobic zones. We hypothesized that increasing exposure to elevated hydrocarbon concentrations would positively correlate with an increase in denitrification processes and the net accumulation of dinitrogen. This hypothesis was tested by comparing the relative abundance of genes associated with nitrogen metabolism and nitrogen cycling identified in 6 metagenomes from sediments contaminated by polyaromatic hydrocarbons from the Deepwater Horizon (DWH) oil spill in the Gulf of Mexico, and 3 metagenomes from sediments associated with natural oil seeps in the Santa Barbara Channel. An additional 8 metagenomes from uncontaminated sediments from the Gulf of Mexico were analyzed for comparison. We predicted relative changes in metabolite turnover as a function of the differential microbial gene abundances, which showed predicted accumulation of metabolites associated with denitrification processes, including anammox, in the contaminated samples compared to uncontaminated sediments, with the magnitude of this change being positively correlated to the hydrocarbon concentration and exposure duration. These data highlight the potential impact of hydrocarbon inputs on N cycling processes in marine sediments and provide information relevant for system scale models of nitrogen metabolism in affected ecosystems.

Metagenomic analysis of microbial consortium from natural crude oil that seeps into the marine ecosystem offshore Southern California.

Crude oils can be major contaminants of the marine ecosystem and microorganisms play a significant role in the degradation of its main constituents. To increase our understanding of the microbial hydrocarbon degradation process in the marine ecosystem, we collected crude oil from an active seep area located in the Santa Barbara Channel (SBC) and generated a total of about 52 Gb of raw metagenomic sequence data. The assembled data comprised ~500 Mb, representing ~1.1 million genes derived primarily from chemolithoautotrophic bacteria. Members of Oceanospirillales, a bacterial order belonging to the Deltaproteobacteria, recruited less than 2% of the assembled genes within the SBC metagenome. In contrast, the microbial community associated with the oil plume that developed in the aftermath of the Deepwater Horizon (DWH) blowout in 2010, was dominated by Oceanospirillales, which comprised more than 60% of the metagenomic data generated from the DWH oil plume. This suggests that Oceanospirillales might play a less significant role in the microbially mediated hydrocarbon conversion within the SBC seep oil compared to the DWH plume oil. We hypothesize that this difference results from the SBC oil seep being mostly anaerobic, while the DWH oil plume is aerobic. Within the Archaea, the phylum Euryarchaeota, recruited more than 95% of the assembled archaeal sequences from the SBC oil seep metagenome, with more than 50% of the sequences assigned to members of the orders Methanomicrobiales and Methanosarcinales. These orders contain organisms capable of anaerobic methanogenesis and methane oxidation (AOM) and we hypothesize that these orders - and their metabolic capabilities - may be fundamental to the ecology of the SBC oil seep.

Longitudinal analysis of microbial interaction between humans and the indoor environment.

The bacteria that colonize humans and our built environments have the potential to influence our health. Microbial communities associated with seven families and their homes over 6 weeks were assessed, including three families that moved their home. Microbial communities differed substantially among homes, and the home microbiome was largely sourced from humans. The microbiota in each home were identifiable by family. Network analysis identified humans as the primary bacterial vector, and a Bayesian method significantly matched individuals to their dwellings. Draft genomes of potential human pathogens observed on a kitchen counter could be matched to the hands of occupants. After a house move, the microbial community in the new house rapidly converged on the microbial community of the occupants' former house, suggesting rapid colonization by the family's microbiota.

Metagenomics reveals sediment microbial community response to Deepwater Horizon oil spill.

The Deepwater Horizon (DWH) oil spill in the spring of 2010 resulted in an input of ∼4.1 million barrels of oil to the Gulf of Mexico; >22% of this oil is unaccounted for, with unknown environmental consequences. Here we investigated the impact of oil deposition on microbial communities in surface sediments collected at 64 sites by targeted sequencing of 16S rRNA genes, shotgun metagenomic sequencing of 14 of these samples and mineralization experiments using (14)C-labeled model substrates. The 16S rRNA gene data indicated that the most heavily oil-impacted sediments were enriched in an uncultured Gammaproteobacterium and a Colwellia species, both of which were highly similar to sequences in the DWH deep-sea hydrocarbon plume. The primary drivers in structuring the microbial community were nitrogen and hydrocarbons. Annotation of unassembled metagenomic data revealed the most abundant hydrocarbon degradation pathway encoded genes involved in degrading aliphatic and simple aromatics via butane monooxygenase. The activity of key hydrocarbon degradation pathways by sediment microbes was confirmed by determining the mineralization of (14)C-labeled model substrates in the following order: propylene glycol, dodecane, toluene and phenanthrene. Further, analysis of metagenomic sequence data revealed an increase in abundance of genes involved in denitrification pathways in samples that exceeded the Environmental Protection Agency (EPA)'s benchmarks for polycyclic aromatic hydrocarbons (PAHs) compared with those that did not. Importantly, these data demonstrate that the indigenous sediment microbiota contributed an important ecosystem service for remediation of oil in the Gulf. However, PAHs were more recalcitrant to degradation, and their persistence could have deleterious impacts on the sediment ecosystem.

Increased protein-coding mutations in the mitochondrial genome of African American women with preeclampsia.

Preeclampsia occurs more frequently in women of African ancestry. The cause of this hypertensive complication is unclear, but placental oxidative stress may play a role. Because mitochondria are the major sites of oxidative phosphorylation, we hypothesized that placentas of preeclamptic pregnancies harbor mitochondrial DNA (mtDNA) mutations. Next-generation sequencing of placental mtDNA in African American preeclamptics (N = 30) and controls (N = 38) from Chicago revealed significant excesses in preeclamptics of nonsynonymous substitutions in protein-coding genes and mitochondrially encoded nicotinamide adenine dinucleotide dehydrogenase 5 gene and an increase in the substitution rate (P = .0001). Moreover, 88% of preeclamptics and 53% of controls carried at least one nonsynonymous substitution (P = .005; odds ratio [OR] = 6.36, 95% confidence interval [CI]: 1.5-39.1). These results were not replicated in a sample of African American preeclamptics (N = 162) and controls (N = 171) from Detroit. Differences in study design and heterogeneity may account for this lack of replication. Nonsynonymous substitutions in mtDNA may be risk factors for preeclampsia in some African American women, but additional studies are required to establish this relationship.

Impacts of gene essentiality, expression pattern, and gene compactness on the evolutionary rate of mammalian proteins.

Understanding the determinants of the rate of protein sequence evolution is of fundamental importance in evolutionary biology. Many recent studies have focused on the yeast because of the availability of many genome-wide expressional and functional data. Yeast studies revealed a predominant role of gene expression level and a minor role of gene essentiality in determining the rate of protein sequence evolution. Whether these rules apply to complex organisms such as mammals is unclear. Here we assemble a list of 1,138 essential and 2,341 nonessential mouse genes based on targeted gene deletion experiments and report a significant impact of gene essentiality on the rate of mammalian protein evolution. Gene expression level has virtually no effect, although tissue specificity in expression pattern has a strong influence. Unexpectedly, gene compactness, measured by average intron size and untranslated region length, has the greatest influence. Hence, the relative importance of the various factors in determining the rate of mammalian protein evolution is gene compactness > gene essentiality approximately tissue specificity > expression level. Our results suggest a considerable variation in rate determinants between unicellular organisms such as the yeast and multicellular organisms such as mammals.

Characterization of dermatoglyphics in PHOX2B-confirmed congenital central hypoventilation syndrome.

OBJECTIVE: Individuals with congenital central hypoventilation syndrome have characteristic variants in the PHOX2B gene (primarily polyalanine expansion mutations). The PHOX2B gene acts as a transcriptional activator in the promotion of pan-neuronal differentiation in the autonomic nervous system during early embryologic development, with a primary role in the sympathetic noradrenergic phenotype in vertebrates. Because sympathetic innervation has been hypothesized to affect the development of dermatoglyphic pattern types, we hypothesized that individuals with PHOX2B-confirmed congenital central hypoventilation syndrome would have characteristic dermatoglyphic patterning and that the dermatoglyphic phenotype would be related to the disease-defining PHOX2B genotype. METHODS: Dermatoglyphic pattern type frequency, left/right symmetry, and genotype/phenotype correlation were assessed for 33 individuals with PHOX2B-confirmed congenital central hypoventilation syndrome and compared with published control data. RESULTS: Dermatoglyphic pattern type frequencies were altered in congenital central hypoventilation syndrome cases versus controls. In particular, there was an increase of arches in females and ulnar loops in males, with the largest differences for the left hand and for individuals with both congenital central hypoventilation syndrome and Hirschsprung disease. Dissimilarity scores between the congenital central hypoventilation syndrome and congenital central hypoventilation syndrome + Hirschsprung disease cases were not significantly different, nor were dissimilarity scores between all of the female and all of the male cases. No significant association was found between the number of polyalanine repeats in the PHOX2B genotypic category and dermatoglyphic pattern frequencies in the congenital central hypoventilation syndrome study groups. CONCLUSIONS: These results represent the first report describing specific dermatoglyphic patterning in congenital central hypoventilation syndrome and suggest a relationship between PHOX2B and the expression of dermatoglyphic pattern types. An expanded congenital central hypoventilation syndrome data set to include the full spectrum of PHOX2B mutations is necessary to further delineate the role of PHOX2B in dermatoglyphic patterning.

Intraobserver error associated with measurements of the hand.

Measurements of the hand are common in studies that use anthropometric data. However, despite widespread usage, relatively few studies have formally assessed the degree of measurement error associated with standard measurements of the hand. This is significant because high amounts of measurement error can invalidate statistical results. In this paper, intraobserver precision estimates for measures of total hand length and total 3rd-digit length were evaluated from repeated measures on 90 subjects (180 separate hands and fingers). From this replicate data, three precision estimates were calculated: the technical error of measurement (TEM), the relative technical error of measurement (rTEM), and the coefficient of reliability (R). For both measurements, all three estimates yielded a very high degree of precision (TEM < 2 mm, rTEM < 1%, and R > or = 0.95). These results suggest that both total hand length and 3rd-digit length are sufficiently precise for anthropometric research applications.

Hair whorls and handedness: informative phenotypic markers in nonsyndromic cleft lip with or without cleft palate (NS CL/P) cases and their unaffected relatives.

Cleft lip with or without cleft palate (CL/P) is a complex disorder with a range of phenotypic manifestations and a birth prevalence that varies by population (1/500-1/2,000). Investigators have postulated that CL/P cases may have abnormal brain development, citing structural brain differences, and cognitive impairments in affected individuals. Previously, increased levels of non-right handedness (NRH), a marker for abnormal brain lateralization, have also been demonstrated in CL/P cases. Atypical hair whorls, more direct markers of altered brain development, may be related to NRH. To date, neither hair whorl patterns nor their relationship to NRH have been studied in a CL/P population. In the current study, we investigate the hypothesis that altered brain development is part of the phenotypic spectrum of NS CL/P by assessing NRH and atypical hair whorls in CL/P families. The study population included 49 nonsyndromic CL/P cases and 116 of their unaffected relatives; 21.8% of the study population was NRH compared to the 10% population estimate (P < 0.0001). Counter-clockwise hair whorls (CCW) were found in 12.7% of all subjects compared to a population rate of 9.9 %. Of all subjects, 11% of the NRH individuals had CCW, which was similar to the frequency of CCW in right-handed individuals. Approximately 80% of the whorls were placed on either the right or center of the scalp. No significant associations were found between the type of cleft and handedness, hair whorl rotation, or placement. These results suggest that certain phenotypic markers of abnormal brain development may comprise part of the extended phenotype of orofacial clefting.

Dermatoglyphic fingerprint heterogeneity among individuals with nonsyndromic cleft lip with or without cleft palate and their unaffected relatives in China and the Philippines.

Cleft lip with or without cleft palate (CL/P) is a common birth defect (birth prevalence ranging from 1/500 to 1/2,000) with a complex etiology. Traits potentially related to CL/P, such as dermatoglyphics, may reflect the genetic and epidemiologic heterogeneity observed in CL/P. Such phenotypic heterogeneity in dermatoglyphic patterns may account for some of the variability in previously reported associations of dermatoglyphics and CL/P. To test this hypothesis, we took dermatoglyphic prints from individuals with nonsyndromic CL/P (n = 460) and their unaffected relatives (n = 254) from the Philippines and China. For both samples three raters designated the patterns as arch, ulnar loop, radial loop, whorl, or "other." Chi-square analysis and standard ANOVA were used to investigate heterogeneity between Filipino and Chinese study subjects. The significant associations between particular pattern types and CL/P were not the same in both populations, demonstrating population-specific association of CL/P and dermatoglyphic pattern types. The ANOVA of pattern type included both CL/P cases and their relatives, with affection status, sex, and population group as variables. For each pattern type except arches, population was significant (p < 0.0001); for radial loops, affection status was additionally significant (p < 0.0001). When only CL/P cases were considered, population was again significant for the ulnar loop (p < 0.0001), whorl (p < 0.0001), and "other" (p = 0.0002) patterns. The ANOVAs demonstrate between-population heterogeneity in dermatoglyphic pattern types. These results support our hypothesis that population-specific associations and population heterogeneity in dermatoglyphic patterns exist for CL/P cases and their relatives.