Browsing by Subject "GENETIC-BASIS"

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  • Kurtelius, Arttu; Väntti, Nelli; Jahromi, Behnam Rezai; Tähtinen, Olli; Manninen, Hannu; Koskenvuo, Juha; Tulamo, Riikka; Kotikoski, Satu; Nurmonen, Heidi; Kämäräinen, Olli-Pekka; Huttunen, Terhi; Huttunen, Jukka; Fraunberg, Mikael von Und Zu; Koivisto, Timo; Jääskeläinen, Juha E.; Lindgren, Antti E. (2019)
    Background-Varying degrees of co-occurrence of intracranial aneurysms (IA) and aortic aneurysms (AA) have been reported. We sought to compare the risk for AA in fusiform intracranial aneurysms (fIA) and saccular intracranial aneurysms (sIA) disease and evaluate possible genetic connection between the fIA disease and AAs. Additionally, the characteristics and aneurysms of the fIA and sIA patients were compared. Methods and Results-The Kuopio Intracranial Aneurysm Database includes all 4253 sIA and 125 fIA patients from its Eastern Finnish catchment population, and 13 009 matched population controls and 18 455 first-degree relatives to the IA patients were identified, and the Finnish national registers were used to identify the individuals with AA. A total of 33 fIA patients were studied using an exomic gene panel of 37 genes associated with AAs. Seventeen (14.4%) fIA patients and 48 (1.2%) sIA patients had a diagnosis of AA. Both fIA and sIA patients had AAs significantly more often than their controls (1.2% and 0.5%) or relatives (0.9% and 0.3%). In a competing risks Cox regression model, the presence of fIA was the strongest risk factor for AA (subdistribution hazard ratio 7.6, 95% CI 3.9-14.9, P Conclusions-The prevalence of AAs is increased slightly in sIA patients and significantly in fIA patients. fIA patients are older and have more comorbid diseases than sIA patients but this alone does not explain their clinically significant AA risk.
  • Byers, Kelsey J. R. P.; Darragh, Kathy; Fernanda Garza, Sylvia; Abondano Almeida, Diana; Warren, Ian A.; Rastas, Pasi M. A.; Merrill, Richard M.; Schulz, Stefan; McMillan, W. Owen; Jiggins, Chris D. (2021)
    The degree to which loci promoting reproductive isolation cluster in the genome-that is, the genetic architecture of reproductive isolation-can influence the tempo and mode of speciation. Tight linkage between these loci can facilitate speciation in the face of gene flow. Pheromones play a role in reproductive isolation in many Lepidoptera species, and the role of endogenously produced compounds as secondary metabolites decreases the likelihood of pleiotropy associated with many barrier loci. Heliconius butterflies use male sex pheromones to both court females (aphrodisiac wing pheromones) and ward off male courtship (male-transferred antiaphrodisiac genital pheromones), and it is likely that these compounds play a role in reproductive isolation between Heliconius species. Using a set of backcross hybrids between H. melpomene and H. cydno, we investigated the genetic architecture of putative male pheromone compound production. We found a set of 40 significant quantitative trait loci (QTL) representing 33 potential pheromone compounds. QTL clustered significantly on two chromosomes, chromosome 8 for genital compounds and chromosome 20 for wing compounds, and chromosome 20 was enriched for potential pheromone biosynthesis genes. There was minimal overlap between pheromone QTL and known QTL for mate choice and color pattern. Nonetheless, we did detect linkage between a QTL for wing androconial area and optix, a color pattern locus known to play a role in reproductive isolation in these species. This tight clustering of putative pheromone loci might contribute to coincident reproductive isolating barriers, facilitating speciation despite ongoing gene flow.
  • Mancini, Alessandra; Howard, Sasha R.; Cabrera, Claudia P.; Barnes, Michael R.; David, Alessia; Wehkalampi, Karoliina; Heger, Sabine; Lomniczi, Alejandro; Guasti, Leonardo; Ojeda, Sergio R.; Dunkel, Leo (2019)
    The initiation of puberty is orchestrated by an augmentation of gonadotropin-releasing hormone (GnRH) secretion from a few thousand hypothalamic neurons. Recent findings have indicated that the neuroendocrine control of puberty may be regulated by a hierarchically organized network of transcriptional factors acting upstream of GnRH. These include enhanced at puberty 1 (EAP1), which contributes to the initiation of female puberty through transactivation of the GnRH promoter. However, no EAP1 mutations have been found in humans with disorders of pubertal timing. We performed whole-exome sequencing in 67 probands and 93 relatives from a large cohort of familial self-limited delayed puberty (DP). Variants were analyzed for rare, potentially pathogenic variants enriched in case versus controls and relevant to the biological control of puberty. We identified one in-frame deletion (Ala221del) and one rare missense variant (Asn770His) in EAP1 in two unrelated families; these variants were highly conserved and potentially pathogenic. Expression studies revealed Eap1 mRNA abundance in peri-pubertal mouse hypothalamus. EAP1 binding to the GnRH1 promoter increased in monkey hypothalamus at the onset of puberty as determined by chromatin immunoprecipitation. Using a luciferase reporter assay, EAP1 mutants showed a reduced ability to trans-activate the GnRH promoter compared to wild-type EAP1, due to reduced protein levels caused by the Ala221del mutation and subcellular mislocation caused by the Asn770His mutation, as revealed by western blot and immunofluorescence, respectively. In conclusion, we have identified the first EAP1 mutations leading to reduced GnRH transcriptional activity resulting in a phenotype of self-limited DP.
  • Lehtinen, Markku T.; Pulkkinen, Pertti (2017)
    In Scots pine (Pinus sylvestris L.), it has been shown that the parental conditions have a role in the phenological variation among first-year seedlings. For this reason, it is argued that they should be comprehensively controlled before estimating the parental genotype effects. This controlled-cross study examined the effects of a set of fathers of Scots pines on the timing of budset and autumn frost hardening of first-year seedlings. The paternal genotypes had either a northern or southern provenance, but had spent a period of over 25 years as grafts in a shared climatic environment in two closely located southern orchards. Pollen applied in the crosses was collected from these orchards in one year and all the maternal genotypes were pollinated in only one seed orchard. The results of freeze tests and budset observations of the consequent progeny were analysed and additionally compared with results obtained using seedlings from seed lots of natural forests in order to estimate the ability of northern paternal genotypes to maintain a northern effect under southern conditions. This environmentally controlled study demonstrated a significant effect of the paternal genotype on the budset and autumn frost hardening of first-year seedling of Scots pine. With the applied study design, no significant indication of an environmental influence on the effect of the paternal genotype was obtained. The accuracy of the observations is discussed. It is concluded that the results suggest a minor role of mutability in the effects of Scots pine paternal genotypes.
  • Howard, Sasha R.; Guasti, Leonardo; Ruiz-Babot, Gerard; Mancini, Alessandra; David, Alessia; Storr, HelenL; Metherell, Lousie A.; Sternberg, Michael J. E.; Cabrera, Claudia P.; Warren, Helen R.; Barnes, Michael R.; Quinton, Richard; de Roux, Nicolas; Young, Jacques; Guiochon-Mantel, Anne; Wehkalampi, Karoliina; Andre, Valentina; Gothilf, Yoav; Cariboni, Anna; Dunkel, Leo (2016)
    Early or late pubertal onset affects up to 5% of adolescents and is associated with adverse health and psychosocial outcomes. Self-limited delayed puberty (DP) segregates predominantly in an autosomal dominant pattern, but the underlying genetic background is unknown. Using exome and candidate gene sequencing, we have identified rare mutations in IGSF10 in 6 unrelated families, which resulted in intracellular retention with failure in the secretion of mutant proteins. IGSF10 mRNA was strongly expressed in embryonic nasal mesenchyme, during gonadotropin-releasing hormone (GnRH) neuronal migration to the hypothalamus. IGSF10 knockdown caused a reduced migration of immature GnRH neurons invitro, and perturbed migration andextension of GnRH neurons in a gnrh3:EGFP zebrafish model. Additionally, loss-of-function mutations in IGSF10 were identified in hypothalamic amenorrhea patients. Our evidence strongly suggests that mutations in IGSF10 cause DP in humans, and points to a common genetic basis for conditions of functional hypogonadotropic hypogonadism (HH). While dysregulation of GnRH neuronal migration is known to cause permanent HH, this is the first time that this has been demonstrated as a causal mechanism in DP. Synopsis Self-limited delayed puberty (DP) has strong familial inheritance, but the underlying genetic determinants are unknown. IGSF10 deficiency is found to affect embryonic GnRH neuronal migration and results in DP in humans. Pathogenic mutations in IGSF10 are found in patients with self-limited delayed puberty. IGSF10 is a gene of previously unclear function with no known human mutations. IGSF10 is expressed within the nasal mesenchyme during fetal development, in a pattern similar to known chemokines that direct migrational GnRH neurons to the hypothalamus. Knockdown of IGSF10 led to a reduced migration of GnRH neurons invitro and in a transgenic zebrafish model. IGSF10 loss-of-function mutations were also identified in patients with hypothalamic amenorrhea, suggesting an overlapping genetic and mechanistic basis between different types of functional hypogonadotropic hypogonadism, including DP and hypothalamic amenorrhea.
  • Dastani, Zari; Hivert, Marie-France; Timpson, Nicholas; Perry, John R. B.; Yuan, Xin; Scott, Robert A.; Henneman, Peter; Heid, Iris M.; Kizer, Jorge R.; Lyytikainen, Leo-Pekka; Fuchsberger, Christian; Tanaka, Toshiko; Morris, Andrew P.; Small, Kerrin; Isaacs, Aaron; Beekman, Marian; Coassin, Stefan; Lohman, Kurt; Qi, Lu; Kanoni, Stavroula; Pankow, James S.; Uh, Hae-Won; Wu, Ying; Bidulescu, Aurelian; Rasmussen-Torvik, Laura J.; Greenwood, Celia M. T.; Ladouceur, Martin; Grimsby, Jonna; Manning, Alisa K.; Liu, Ching-Ti; Kooner, Jaspal; Mooser, Vincent E.; Vollenweider, Peter; Kapur, Karen A.; Chambers, John; Wareham, Nicholas J.; Langenberg, Claudia; Frants, Rune; Willems-vanDijk, Ko; Oostra, Ben A.; Willems, Sara M.; Lamina, Claudia; Winkler, Thomas W.; Psaty, Bruce M.; Nuotio, Marja-Liisa; Perola, Markus; Eriksson, Johan G.; GLGC Investigators, DIAGRAM Consortium, MAGIC Consortium, MuTHER Consortium; Ripatti, Samuli; Kaprio, Jaakko; Lokki, Marja-Liisa (2012)
  • Tringali, Angela; Bowman, Reed; Husby, Arild (2015)
    Sexually dimorphic plumage coloration is widespread in birds and is generally thought to be a result of sexual selection for more ornamented males. Although many studies find an association between coloration and fitness related traits, few of these simultaneously examine selection and inheritance. Theory predicts that sex-linked genetic variation can facilitate the evolution of dimorphism, and some empirical work supports this, but we still know very little about the extent of sex linkage of sexually dimorphic traits. We used a longitudinal study on juvenile Florida scrub-jays (Aphelocoma coerulescens) to estimate strength of selection and autosomal and Z-linked heritability of mean brightness, UV chroma, and hue. Although plumage coloration signals dominance in juveniles, there was no indication that plumage coloration was related to whether or not an individual bred or its lifetime reproductive success. While mean brightness and UV chroma are moderately heritable, hue is not. There was no evidence for sex-linked inheritance of any trait with most of the variation explained by maternal effects. The genetic correlation between the sexes was high and not significantly different from unity. These results indicate that evolution of sexual dimorphism in this species is constrained by low sex-linked heritability and high intersexual genetic correlation.
  • Class, Barbara; Kluen, Edward; Brommer, Jon E. (2019)
    Indirect sexual selection arises when reproductive individuals choose their mates based on heritable ornaments that are genetically correlated to fitness. Evidence for genetic associations between ornamental colouration and fitness remains scarce. In this study, we investigate the quantitative genetic relationship between different aspects of tail structural colouration (brightness, hue and UV chroma) and performance (cell-mediated immunity, body mass and wing length) in blue tit (Cyanistes caeruleus) nestlings. In line with previous studies, we find low heritability for structural colouration and moderate heritability for performance measures. Multivariate animal models show positive genetic correlations between the three measures of performance, indicating quantitative genetic variation for overall performance, and tail brightness and UV chroma, two genetically independent colour measures, are genetically correlated with performance (positively and negatively, respectively). Our results suggest that mate choice based on independent aspects of tail colouration can have fitness payoffs in blue tits and provide support for the indirect benefits hypothesis. However, low heritability of tail structural colouration implies that indirect sexual selection on mate choice for this ornament will be a weak evolutionary force.