Identifying candidate genes underlying isolated congenital anosmia.

An estimated 1 in 10 000 people are born without the ability to smell, a condition known as congenital anosmia, and about one third of those people have non-syndromic, or isolated congenital anosmia (ICA). Despite the significant impact of olfaction for our quality of life, the underlying causes of ICA remain largely unknown. Using whole exome sequencing (WES) in 10 families and 141 individuals with ICA, we identified a candidate list of 162 rare, segregating, deleterious variants in 158 genes. We confirmed the involvement of CNGA2, a previously implicated ICA gene that is an essential component of the olfactory transduction pathway. Furthermore, we found a loss-of-function variant in SREK1IP1 from the family gene candidate list, which was also observed in 5% of individuals in an additional non-family cohort with ICA. Although SREK1IP1 has not been previously associated with olfaction, its role in zinc ion binding suggests a potential influence on olfactory signaling. This study provides a more comprehensive understanding of the spectrum of genetic alterations and their etiology in ICA patients, which may improve the diagnosis, prognosis, and treatment of this disorder and lead to better understanding of the mechanisms governing basic olfactory function.

Odor coding in the mammalian olfactory epithelium.

Noses are extremely sophisticated chemical detectors allowing animals to use scents to interpret and navigate their environments. Odor detection starts with the activation of odorant receptors (ORs), expressed in mature olfactory sensory neurons (OSNs) populating the olfactory mucosa. Different odorants, or different concentrations of the same odorant, activate unique ensembles of ORs. This mechanism of combinatorial receptor coding provided a possible explanation as to why different odorants are perceived as having distinct odors. Aided by new technologies, several recent studies have found that antagonist interactions also play an important role in the formation of the combinatorial receptor code. These findings mark the start of a new era in the study of odorant-receptor interactions and add a new level of complexity to odor coding in mammals.

Interspecific variation of olfactory preferences in flies, mice, and humans.

Aiming to unravel interspecific differences in olfactory preferences, we performed comparative studies of odor valence in flies, mice, and humans. Our analysis suggests a model where flies and mice share similar olfactory preferences, but neither species share odor preferences with humans. This model contrasts with a previous study by Mandairon et al., which suggested that the olfactory preferences of mice and humans are similar. A probabilistic examination revealed that underpowered studies can result in spurious significant correlations, which can account for the differences between both studies. Future analyses aimed at dissecting the olfactory preferences across species need to test large numbers of odorants to stress-test the model proposed here and identify robust associations.

Predicted mechanistic impacts of human protein missense variants.

Genome sequencing efforts have led to the discovery of tens of millions of protein missense variants found in the human population with the majority of these having no annotated role and some likely contributing to trait variation and disease. Sequence-based artificial intelligence approaches have become highly accurate at predicting variants that are detrimental to the function of proteins but they do not inform on mechanisms of disruption. Here we combined sequence and structure-based methods to perform proteome-wide prediction of deleterious variants with information on their impact on protein stability, protein-protein interactions and small-molecule binding pockets. AlphaFold2 structures were used to predict approximately 100,000 small-molecule binding pockets and stability changes for over 200 million variants. To inform on protein-protein interfaces we used AlphaFold2 to predict structures for nearly 500,000 protein complexes. We illustrate the value of mechanism-aware variant effect predictions to study the relation between protein stability and abundance and the structural properties of interfaces underlying trans protein quantitative trait loci (pQTLs). We characterised the distribution of mechanistic impacts of protein variants found in patients and experimentally studied example disease linked variants in FGFR1.

Short-term consumption of highly processed diets varying in macronutrient content impair the sense of smell and brain metabolism in mice.

OBJECTIVE: Food processing greatly contributed to increased food safety, diversity, and accessibility. However, the prevalence of highly palatable and highly processed food in our modern diet has exacerbated obesity rates and contributed to a global health crisis. While accumulating evidence suggests that chronic consumption of such foods is detrimental to sensory and neural physiology, it is unclear whether its short-term intake has adverse effects. Here, we assessed how short-term consumption (<2 months) of three diets varying in composition and macronutrient content influence olfaction and brain metabolism in mice. METHODS: The diets tested included a grain-based standard chow diet (CHOW; 54% carbohydrate, 32% protein, 14% fat; #8604 Teklad Rodent diet , Envigo Inc.), a highly processed control diet (hpCTR; 70% carbohydrate, 20% protein, 10% fat; #D12450B, Research Diets Inc.), and a highly processed high-fat diet (hpHFD; 20% carbohydrate, 20% protein, 60% fat; #D12492, Research Diets Inc.). We performed behavioral and metabolic phenotyping, electro-olfactogram (EOG) recordings, brain glucose metabolism imaging, and mitochondrial respirometry in different brain regions. We also performed RNA-sequencing (RNA-seq) in the nose and across several brain regions, and conducted differential expression analysis, gene ontology, and network analysis. RESULTS: We show that short-term consumption of the two highly processed diets, but not the grain-based diet, regardless of macronutrient content, adversely affects odor-guided behaviors, physiological responses to odorants, transcriptional profiles in the olfactory mucosa and brain regions, and brain glucose metabolism and mitochondrial respiration. CONCLUSIONS: Even short periods of highly processed food consumption are sufficient to cause early olfactory and brain abnormalities, which has the potential to alter food choices and influence the risk of developing metabolic disease.

Deconstructing the mouse olfactory percept through an ethological atlas.

Odor perception in non-humans is poorly understood. Here, we generated the most comprehensive mouse olfactory ethological atlas to date, consisting of behavioral responses to a diverse panel of 73 odorants, including 12 at multiple concentrations. These data revealed that mouse behavior is incredibly diverse and changes in response to odorant identity and concentration. Using only behavioral responses observed in other mice, we could predict which of two odorants was presented to a held-out mouse 82% of the time. Considering all 73 possible odorants, we could uniquely identify the target odorant from behavior on the first try 20% of the time and 46% within five attempts. Although mouse behavior is difficult to predict from human perception, they share three fundamental properties: first, odor valence parameters explained the highest variance of olfactory perception. Second, physicochemical properties of odorants can be used to predict the olfactory percept. Third, odorant concentration quantitatively and qualitatively impacts olfactory perception. These results increase our understanding of mouse olfactory behavior and how it compares to human odor perception and provide a template for future comparative studies of olfactory percepts among species.

Selection against males in Caenorhabditis elegans under two mutational treatments.

Within populations with mixed mating systems, selfing is expected to be favoured over outcrossing unless a countervailing process such as severe inbreeding depression is present. In this study, we consider the relationship between the expression of deleterious alleles and the maintenance of outcrossing in the nematode species, Caenorhabditis elegans. This species is characterized by an androdioecious breeding system composed of males at low frequency and self-fertilizing hermaphrodites that can only outcross via males. Here, we find that experimentally increasing the mutational load in four different isogenic wild isolates using 10 generations of Ethylmethane sulphonate (EMS) and UV irradiation mutagenesis significantly diminishes the cost of males. Males are maintained at higher frequencies in mutagenized versus non-mutagenized populations. Nevertheless, males still tend to be driven to low frequencies within isolates that are known to be prone to lose males. Further, we determine the viability effects of a single round of mutagen exposure and find that, for EMS, outcrossing overcomes the almost completely recessive and nearly lethal effects generated. We briefly interpret our results in light of current evolutionary theory of outcrossing rates.

Genetic variation for outcrossing among Caenorhabditis elegans isolates.

The evolution of breeding systems results from the existence of genetic variation and selective forces favoring different outcrossing rates. In this study we determine the extent of genetic variation for characters directly related to outcrossing, such as male frequency, male mating ability, and male reproductive success, in several wild isolates of the nematode Caenorhabditis elegans. This species is characterized by an androdioecious breeding system in which males occur with hermaphrodites that can either self-fertilize or outcross with males. We find genetic variation for all characters measured, but also find that environmental variation is a large fraction of the total phenotypic variance. We further determine the existence of substantial genetic variation for population competitive performance in several laboratory environments. However, these measures are uncorrelated with outcrossing characters. The data presented here contribute to an understanding of male maintenance in natural populations through their role in outcrossing.

Emergence and diversification of fly pigmentation through evolution of a gene regulatory module.

The typical pattern of morphological evolution associated with the radiation of a group of related species is the emergence of a novel trait and its subsequent diversification. Yet the genetic mechanisms associated with these two evolutionary steps are poorly characterized. Here, we show that a spot of dark pigment on fly wings emerged from the assembly of a novel gene regulatory module in which a set of pigmentation genes evolved to respond to a common transcriptional regulator determining their spatial distribution. The primitive wing spot pattern subsequently diversified through changes in the expression pattern of this regulator. These results suggest that the genetic changes underlying the emergence and diversification of wing pigmentation patterns are partitioned within genetic networks.

Evolution of outcrossing in experimental populations of Caenorhabditis elegans.

Caenorhabditis elegans can reproduce exclusively by self-fertilization. Yet, males can be maintained in laboratory populations, a phenomenon that continues to puzzle biologists. In this study we evaluated the role of males in facilitating adaptation to novel environments. For this, we contrasted the evolution of a fitness component exclusive to outcrossing in experimental populations of different mating systems. We introgressed a modifier of outcrossing into a hybrid population derived from several wild isolates to transform the wild-type androdioecious mating system into a dioecious mating system. By genotyping 375 single-nucleotide polymorphisms we show that the two populations had similar standing genetic diversity available for adaptation, despite the occurrence of selection during their derivation. We then performed replicated experimental evolution under the two mating systems from starting conditions of either high or low levels of diversity, under defined environmental conditions of discrete non-overlapping generations, constant density at high population sizes (N = 10(4)), no obvious spatial structure and abundant food resources. During 100 generations measurements of sex ratios and male competitive performance showed: 1) adaptation to the novel environment; 2) directional selection on male frequency under androdioecy; 3) optimal outcrossing rates of 0.5 under androdioecy; 4) the existence of initial inbreeding depression; and finally 5) that the strength of directional selection on male competitive performance does not depend on male frequencies. Taken together, these results suggest that androdioecious males are maintained at intermediate frequencies because outcrossing is adaptive.