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Proceedings of the National Academy of... Feb 2020Genome sequencing has established clinical utility for rare disease diagnosis. While increasing numbers of individuals have undergone elective genome sequencing, a...
Genome sequencing has established clinical utility for rare disease diagnosis. While increasing numbers of individuals have undergone elective genome sequencing, a comprehensive study surveying genome-wide disease-associated genes in adults with deep phenotyping has not been reported. Here we report the results of a 3-y precision medicine study with a goal to integrate whole-genome sequencing with deep phenotyping. A cohort of 1,190 adult participants (402 female [33.8%]; mean age, 54 y [range 20 to 89+]; 70.6% European) had whole-genome sequencing, and were deeply phenotyped using metabolomics, advanced imaging, and clinical laboratory tests in addition to family/medical history. Of 1,190 adults, 206 (17.3%) had at least 1 genetic variant with pathogenic (P) or likely pathogenic (LP) assessment that suggests a predisposition of genetic risk. A multidisciplinary clinical team reviewed all reportable findings for the assessment of genotype and phenotype associations, and 137 (11.5%) had genotype and phenotype associations. A high percentage of genotype and phenotype associations (>75%) was observed for dyslipidemia ( = 24), cardiomyopathy, arrhythmia, and other cardiac diseases ( = 42), and diabetes and endocrine diseases ( = 17). A lack of genotype and phenotype associations, a potential burden for patient care, was observed in 69 (5.8%) individuals with P/LP variants. Genomics and metabolomics associations identified 61 (5.1%) heterozygotes with phenotype manifestations affecting serum metabolite levels in amino acid, lipid and cofactor, and vitamin pathways. Our descriptive analysis provides results on the integration of whole-genome sequencing and deep phenotyping for clinical assessments in adults.
Topics: Adult; Aged; Aged, 80 and over; Cohort Studies; Diagnostic Imaging; Female; Genetic Predisposition to Disease; Genotype; Heart Diseases; Humans; Male; Metabolomics; Middle Aged; Phenotype; Precision Medicine; Whole Genome Sequencing; Young Adult
PubMed: 31980526
DOI: 10.1073/pnas.1909378117 -
Journal of the European Academy of... Nov 2017Pustular psoriasis (PP) is a group of inflammatory skin conditions characterized by infiltration of neutrophil granulocytes in the epidermis to such an extent that... (Review)
Review
Pustular psoriasis (PP) is a group of inflammatory skin conditions characterized by infiltration of neutrophil granulocytes in the epidermis to such an extent that clinically visible sterile pustules develop. Because of clinical co-incidence, PP is currently grouped with psoriasis vulgaris (PV). However, PP and PV are phenotypically different, respond differently to treatments and seem to be distinct on the genetic level. In contrast to PV, the phenotypes of PP are not well defined. Descriptions of each form of PP are discordant among standard dermatology textbooks [Saurat Dermatologie 2016, Rook's Dermatology 2016, Fitzpatrick's 2012 and Braun-Falco 2012], encumbering the collection of phenotypically well-matched groups of patients as well as clinical trials. The European Rare and Severe Psoriasis Expert Network (ERASPEN) was founded to define consensus criteria for diagnosis, deeply phenotype large groups of PP patients, analyse the genetics and pathophysiology and prepare for prospective clinical trials. This work reviews historical aspects of these conditions, new genetic findings and presents our initial considerations on the phenotypes of PP and a consensus classification of clinical phenotypes that will be used as a baseline for further, prospective studies of PP. Generalized pustular psoriasis (GPP) is defined as primary, sterile, macroscopically visible pustules on non-acral skin (excluding cases where pustulation is restricted to psoriatic plaques). GPP can occur with or without systemic inflammation, with or without PV and can either be a relapsing (>1 episode) or persistent (>3 months) condition. Acrodermatitis continua of Hallopeau (ACH) is characterized by primary, persistent (>3 months), sterile, macroscopically visible pustules affecting the nail apparatus. Palmoplantar pustulosis (PPP) has primary, persistent (>3 months), sterile, macroscopically visible pustules on palms and/or soles and can occur with or without PV.
Topics: Adult; Child; Consensus; Europe; Female; Humans; Male; Phenotype; Psoriasis
PubMed: 28585342
DOI: 10.1111/jdv.14386 -
The Journal of Animal Ecology Aug 2019Numerous studies have demonstrated that dispersal is dependent on both disperser phenotype and the local environment. However, there is substantial variability in the...
Numerous studies have demonstrated that dispersal is dependent on both disperser phenotype and the local environment. However, there is substantial variability in the observed strength and direction of phenotype- and environment-dependent dispersal. This has been hypothesized to be the result of interactive effects among the multiple phenotypic and environmental factors that influence dispersal. Here, our goal was to test the hypothesis that these interactions are responsible for generating variation in dispersal behaviour. We achieved these goals by conducting a large, 2-year, mark-release-recapture study of the backswimmer Notonecta undulata in an array of 36 semi-natural ponds. We measured the effects of multiple phenotypic (sex and body size) and environmental (population density and sex ratio) factors, on both dispersal probability and dispersal distance. We found support for the hypothesis that interactive effects influence dispersal and produce variability in phenotype- and environment-dependent dispersal: dispersal probability was dependent on the three-way interaction between sex, body mass and population density. Small males displayed strong, positive density dependence in their dispersal behaviour, while large males and females overall did not respond strongly to density. Small notonectids, regardless of sex, were more likely to disperse, but this effect was strongest at high population densities. Finally, the distance dispersed by backswimmers was a negative function of population density, a pattern which we hypothesize could be related to: (a) individuals from high and low density patches having different dispersal strategies, or (b) the effect of density on dispersal capacity. These results suggest that phenotype-by-environment interactions strongly influence dispersal. Since phenotype- and environment-dependent dispersal has different consequences for ecological and evolutionary dynamics (e.g. metapopulation persistence and local adaptation) than random dispersal, interactive effects may have wide-reaching impacts on populations and communities. We therefore argue that more investment should be made into estimating the effects of multiple, interacting factors on dispersal and determining whether similar interactive effects are acting across systems.
Topics: Animals; Biological Evolution; Ecology; Female; Gene-Environment Interaction; Male; Phenotype; Population Density; Population Dynamics
PubMed: 31077361
DOI: 10.1111/1365-2656.13008 -
American Journal of Medical Genetics.... Jan 2014Two research groups have published reports on PIGA (phosphatidylinositol glycan class A) mutations that validate and extend our understanding of the range of phenotypes...
Two research groups have published reports on PIGA (phosphatidylinositol glycan class A) mutations that validate and extend our understanding of the range of phenotypes of this phenotypic spectrum. One report is primarily confirmatory of the discovery in 2012 that mutations in this gene cause a phenotype of dysmorphic features, neurologic manifestations, and biochemical perturbations. The second report describes an intriguing family with a phenotypically distinct neurological picture, distinguished primarily by CNS iron accumulation. These reports address important lessons in judging causality in the exome age and bear on the question of syndrome nomenclature.
Topics: Abnormalities, Multiple; Alkaline Phosphatase; Developmental Disabilities; Genetic Diseases, X-Linked; Germ-Line Mutation; Heredodegenerative Disorders, Nervous System; Humans; Iron Overload; Male; Membrane Proteins; Phenotype; Spasms, Infantile
PubMed: 24273085
DOI: 10.1002/ajmg.a.36213 -
Biological Reviews of the Cambridge... Aug 2001Mate choice by males has been recognized at least since Darwin's time, but its phylogenetic distribution and effect on the evolution of female phenotypes remain poorly... (Review)
Review
Mate choice by males has been recognized at least since Darwin's time, but its phylogenetic distribution and effect on the evolution of female phenotypes remain poorly known. Moreover, the relative importance of factors thought to underlie the evolution of male mate choice (especially parental investment and mate quality variance) is still unresolved. Here I synthesize the empirical evidence and theory pertaining to the evolution of male mate choice and sex role reversal in insects, and examine the potential for male mating preferences to generate sexual selection on female phenotypes. Although male mate choice has received relatively little empirical study, the available evidence suggests that it is widespread among insects (and other animals). In addition to 'precopulatory' male mate choice, some insects exhibit 'cryptic' male mate choice, varying the amount of resources allocated to mating on the basis of female mate quality. As predicted by theory, the most commonly observed male mating preferences are those that tend to maximize a male's expected fertilization success from each mating. Such preferences tend to favour female phenotypes associated with high fecundity or reduced sperm competition intensity. Among insect species there is wide variation in mechanisms used by males to assess female mate quality, some of which (e.g. probing, antennating or repeatedly mounting the female) may be difficult to distinguish from copulatory courtship. According to theory, selection for male choosiness is an increasing function of mate quality variance and those reproductive costs that reduce, with each mating, the number of subsequent matings that a male can perform ('mating investment') Conversely, choosiness is constrained by the costs of mate search and assessment, in combination with the accuracy of assessment of potential mates and of the distribution of mate qualities. Stronger selection for male choosiness may also be expected in systems where female fitness increases with each copulation than in systems where female fitness peaks at a small number of matings. This theoretical framework is consistent with most of the empirical evidence. Furthermore, a variety of observed male mating preferences have the potential to exert sexual selection on female phenotypes. However, because male insects typically choose females based on phenotypic indicators of fecundity such as body size, and these are usually amenable to direct visual or tactile assessment, male mate choice often tends to reinforce stronger vectors of fecundity or viability selection, and seldom results in the evolution of female display traits. Research on orthopterans has shown that complete sex role reversal (i.e. males choosy, females competitive) can occur when male parental investment limits female fecundity and reduces the potential rate of reproduction of males sufficiently to produce a female-biased operational sex ratio. By contrast, many systems exhibiting partial sex role reversal (i.e. males choosy and competitive) are not associated with elevated levels of male parental investment, reduced male reproductive rates, or reduced male bias in the operational sex ratio. Instead, large female mate quality variance resulting from factors such as strong last-male sperm precedence or large variance in female fecundity may select for both male choosiness and competitiveness in such systems. Thus, partial and complete sex role reversal do not merely represent different points along a continuum of increasing male parental investment, but may evolve via different evolutionary pathways.
Topics: Animals; Female; Insecta; Male; Phenotype; Sex Characteristics; Sexual Behavior, Animal
PubMed: 11569787
DOI: 10.1017/s1464793101005693 -
Proceedings. Biological Sciences Sep 2003Genetic models of sexual selection are concerned with a dynamic process in which female preference and male trait values coevolve. We present a rigorous method for...
Genetic models of sexual selection are concerned with a dynamic process in which female preference and male trait values coevolve. We present a rigorous method for characterizing evolutionary endpoints of this process in phenotypic terms. In our phenotypic characterization the mate-choice strategy of female population members determines how attractive females should find each male, and a population is evolutionarily stable if population members are actually behaving in this way. This provides a justification of phenotypic explanations of sexual selection and the insights into sexual selection that they provide. Furthermore, the phenotypic approach also has enormous advantages over a genetic approach when computing evolutionarily stable mate-choice strategies, especially when strategies are allowed to be complex time-dependent preference rules. For simplicity and clarity our analysis deals with haploid mate-choice genetics and a male trait that is inherited phenotypically, for example by vertical cultural transmission. The method is, however, easily extendible to other cases. An example illustrates that the sexy son phenomenon can occur when there is phenotypic inheritance of the male trait.
Topics: Animals; Biological Evolution; Computer Simulation; Female; Male; Models, Genetic; Phenotype; Selection, Genetic; Sexual Behavior, Animal
PubMed: 14561306
DOI: 10.1098/rspb.2003.2396 -
Nature Genetics Mar 2024Available genetically defined cancer models are limited in genotypic and phenotypic complexity and underrepresent the heterogeneity of human cancer. Here, we describe a...
Available genetically defined cancer models are limited in genotypic and phenotypic complexity and underrepresent the heterogeneity of human cancer. Here, we describe a combinatorial genetic strategy applied to an organoid transformation assay to rapidly generate diverse, clinically relevant bladder and prostate cancer models. Importantly, the clonal architecture of the resultant tumors can be resolved using single-cell or spatially resolved next-generation sequencing to uncover polygenic drivers of cancer phenotypes.
Topics: Male; Humans; Genotype; Phenotype; Neoplasms; Genetic Association Studies
PubMed: 38424461
DOI: 10.1038/s41588-024-01674-1 -
Nature Communications Nov 2022Identical genetic variations can have different phenotypic effects depending on their parent of origin. Yet, studies focusing on parent-of-origin effects have been...
Identical genetic variations can have different phenotypic effects depending on their parent of origin. Yet, studies focusing on parent-of-origin effects have been limited in terms of sample size due to the lack of parental genomes or known genealogies. We propose a probabilistic approach to infer the parent-of-origin of individual alleles that does not require parental genomes nor prior knowledge of genealogy. Our model uses Identity-By-Descent sharing with second- and third-degree relatives to assign alleles to parental groups and leverages chromosome X data in males to distinguish maternal from paternal groups. We combine this with robust haplotype inference and haploid imputation to infer the parent-of-origin for 26,393 UK Biobank individuals. We screen 99 phenotypes for parent-of-origin effects and replicate the discoveries of 6 GWAS studies, confirming signals on body mass index, type 2 diabetes, standing height and multiple blood biomarkers, including the known maternal effect at the MEG3/DLK1 locus on platelet phenotypes. We also report a novel maternal effect at the TERT gene on telomere length, thereby providing new insights on the heritability of this phenotype. All our summary statistics are publicly available to help the community to better characterize the molecular mechanisms leading to parent-of-origin effects and their implications for human health.
Topics: Humans; Male; Alleles; Biological Specimen Banks; Diabetes Mellitus, Type 2; Genome-Wide Association Study; Phenotype; Female
PubMed: 36335127
DOI: 10.1038/s41467-022-34383-6 -
Nature Communications Nov 2022Current concepts regarding the biology of aging are primarily based on studies aimed at identifying factors regulating lifespan. However, lifespan as a sole proxy...
Current concepts regarding the biology of aging are primarily based on studies aimed at identifying factors regulating lifespan. However, lifespan as a sole proxy measure for aging can be of limited value because it may be restricted by specific pathologies. Here, we employ large-scale phenotyping to analyze hundreds of markers in aging male C57BL/6J mice. For each phenotype, we establish lifetime profiles to determine when age-dependent change is first detectable relative to the young adult baseline. We examine key lifespan regulators (putative anti-aging interventions; PAAIs) for a possible countering of aging. Importantly, unlike most previous studies, we include in our study design young treated groups of animals, subjected to PAAIs prior to the onset of detectable age-dependent phenotypic change. Many PAAI effects influence phenotypes long before the onset of detectable age-dependent change, but, importantly, do not alter the rate of phenotypic change. Hence, these PAAIs have limited effects on aging.
Topics: Mice; Animals; Male; Longevity; Mice, Inbred C57BL; Aging; Phenotype
PubMed: 36369285
DOI: 10.1038/s41467-022-34515-y -
Philosophical Transactions of the Royal... Jul 1988Sexual selection by female choice is expected to give rise to a frequency-dependent sexual advantage in favour of preferred male phenotypes: the rarer the preferred...
Sexual selection by female choice is expected to give rise to a frequency-dependent sexual advantage in favour of preferred male phenotypes: the rarer the preferred phenotypes, the more often they are chosen as mates. This 'rare-male advantage' can maintain a polymorphism when two or more phenotypes are mated preferentially: each phenotype gains an advantage when it is rarer than the others; no preferred phenotype can then be lost from the population. Expression of preference may be complete or partial. In models of complete preference, females with a preference always mate preferentially. Models of partial preference are more realistic: in these models, the probability that a female mates preferentially depends on the frequency with which she encounters the males she prefers. Two different 'encounter models' of partial preference have been derived: the O'Donald model and the Charlesworth model. The encounter models contain the complete preference model as a limiting case. In this paper, the Charlesworth model is generalized to allow for female preference of more than one male phenotype. Levels of frequency dependence can then be compared in the O'Donald and Charlesworth models. The complete preference model and both encounter models are formulated in the same genetical terms of preferences for dominant and recessive male phenotypes. Polymorphic equilibria and conditions for stability are derived for each of the three models. The models are then fitted to data of frequencies of matings observed in experiments with the two-spot ladybird. The complete preference model gives as good a fit as the encounter models to the data of these and other experiments. The O'Donald and Charlesworth encounter models are shown to produce a very similar frequency-dependent relation. Generally, as females become less choosy, they express their preference with more dependence on male frequency, whereas the resulting selection of the males becomes less frequency dependent. More choosy females are more constant in expressing their preference, producing greater frequency dependence in the selection of the males.
Topics: Animals; Female; Gene Frequency; Male; Mathematics; Models, Genetic; Phenotype; Selection, Genetic; Sexual Behavior, Animal
PubMed: 2905493
DOI: 10.1098/rstb.1988.0066