Browsing by Subject "INHERITANCE"

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  • Bodea, Corneliu A.; Neale, Benjamin M.; Ripke, Stephan; Daly, Mark J.; Devlin, Bernie; Roeder, Kathryn; Int IBD Genetics Consortium; Palotie, A. (2016)
    One goal of human genetics is to understand the genetic basis of disease, a challenge for diseases of complex inheritance because risk alleles are few relative to the vast set of benign variants. Risk variants are often sought by association studies in which allele frequencies in case subjects are contrasted with those from population-based samples used as control subjects. In an ideal world we would know population-level allele frequencies, releasing researchers to focus on case subjects. We argue this ideal is possible, at least theoretically, and we outline a path to achieving it in reality. If such a resource were to exist, it would yield ample savings and would facilitate the effective use of data repositories by removing administrative and technical barriers. We call this concept the Universal Control Repository Network (UNICORN), a means to perform association analyses without necessitating direct access to individual-level control data. Our approach to UNICORN uses existing genetic resources and various statistical tools to analyze these data, including hierarchical clustering with spectral analysis of ancestry; and empirical Bayesian analysis along with Gaussian spatial processes to estimate ancestry-specific allele frequencies. We demonstrate our approach using tens of thousands of control subjects from studies of Crohn disease, showing how it controls false positives, provides power similar to that achieved when all control data are directly accessible, and enhances power when control data are limiting or even imperfectly matched ancestrally. These results highlight how UNICORN can enable reliable, powerful, and convenient genetic association analyses without access to the individual-level data.
  • Nováková, Eliška; Zablatzká , Lenka; Brus , Jan; Nesrstová , Viktorie; Hanáček, Pavel; Kalendar, Ruslan; Cvrčková , Fatima; Majeský , Ľuboš; Smýkal, Petr (2019)
    Reproductive isolation is an important component of species differentiation. The plastid accD gene coding for the acetyl-CoA carboxylase subunit and the nuclear bccp gene coding for the biotin carboxyl carrier protein were identified as candidate genes governing nuclear-cytoplasmic incompatibility in peas. We examined the allelic diversity in a set of 195 geographically diverse samples of both cultivated (Pisum sativum, P. abyssinicum) and wild (P. fulvum and P. elatius) peas. Based on deduced protein sequences, we identified 34 accD and 31 bccp alleles that are partially geographically and genetically structured. The accD is highly variable due to insertions of tandem repeats. P. fulvum and P. abyssinicum have unique alleles and combinations of both genes. On the other hand, partial overlap was observed between P. sativum and P. elatius. Mapping of protein sequence polymorphisms to 3D structures revealed that most of the repeat and indel polymorphisms map to sequence regions that could not be modeled, consistent with this part of the protein being less constrained by requirements for precise folding than the enzymatically active domains. The results of this study are important not only from an evolutionary point of view but are also relevant for pea breeding when using more distant wild relatives.
  • Katajisto, Pekka; Doehla, Julia; Chaffer, Christine L.; Pentinmikko, Nalle; Marjanovic, Nemanja; Iqbal, Md Sharif; Zoncu, Roberto; Chen, Walter; Weinberg, Robert A.; Sabatini, David M. (2015)
    By dividing asymmetrically, stem cells can generate two daughter cells with distinct fates. However, evidence is limited in mammalian systems for the selective apportioning of subcellular contents between daughters. We followed the fates of old and young organelles during the division of human mammary stemlike cells and found that such cells apportion aged mitochondria asymmetrically between daughter cells. Daughter cells that received fewer old mitochondria maintained stem cell traits. Inhibition of mitochondrial fission disrupted both the age-dependent subcellular localization and segregation of mitochondria and caused loss of stem cell properties in the progeny cells. Hence, mechanisms exist for mammalian stemlike cells to asymmetrically sort aged and young mitochondria, and these are important for maintaining stemness properties.
  • Scala, Giovanni; Federico, Antonio; Palumbo, Domenico; Cocozza, Sergio; Greco, Dario (2020)
    DNA methylation alterations are related to multiple molecular mechanisms. The DNA context of CpG sites plays a crucial role in the maintenance and stability of methylation patterns. The quantitative relationship between DNA composition and DNA methylation has been studied in normal as well as pathological conditions, showing that DNA methylation status is highly dependent on the local sequence context. In this work, we describe this relationship by analyzing the DNA sequence context associated to methylation profiles in both physiological and pathological conditions. In particular, we used DNA motifs to describe methylation stability patterns in normal tissues and aberrant methylation events in cancer lesions. In this manuscript, we show how different groups of DNA sequences can be related to specific epigenetic events, across normal and cancer tissues, and provide a thorough structural and functional characterization of these sequences.
  • DoGA consortium; Bannasch, Danika L.; Kaelin, Christopher B.; Letko, Anna; Loechel, Robert; Hug, Petra; Jagannathan, Vidhya; Henkel, Jan; Roosje, Petra; Hytönen, Marjo K.; Lohi, Hannes; Arumilli, Meharji; Minor, Katie M.; Mickelson, James R.; Drogemuller, Cord; Barsh, Gregory S.; Leeb, Tosso; Iivanainen, Antti (2021)
    Distinctive colour patterns in dogs are an integral component of canine diversity. Colour pattern differences are thought to have arisen from mutation and artificial selection during and after domestication from wolves but important gaps remain in understanding how these patterns evolved and are genetically controlled. In other mammals, variation at the ASIP gene controls both the temporal and spatial distribution of yellow and black pigments. Here, we identify independent regulatory modules for ventral and hair cycle ASIP expression, and we characterize their action and evolutionary origin. Structural variants define multiple alleles for each regulatory module and are combined in different ways to explain five distinctive dog colour patterns. Phylogenetic analysis reveals that the haplotype combination for one of these patterns is shared with Arctic white wolves and that its hair cycle-specific module probably originated from an extinct canid that diverged from grey wolves more than 2 million years ago. Natural selection for a lighter coat during the Pleistocene provided the genetic framework for widespread colour variation in dogs and wolves. Dogs exhibit remarkable variation in colour patterns. Here, the authors identify structural variants of independent regulatory modules for ventral and hair cycle expression of the ASIP gene that explain five distinctive dog colour patterns and trace back the origin of one colour pattern to an extinct canid.
  • 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.
  • Howard, Sasha R.; Oleari, Roberto; Poliandri, Ariel; Chantzara, Vasiliki; Fantin, Alessandro; Ruiz-Babot, Gerard; Metherell, Louise A.; Cabrera, Claudia P.; Barnes, Michael R.; Wehkalampi, Karoliina; Guasti, Leonardo; Ruhrberg, Christiana; Cariboni, Anna; Dunkel, Leo (2018)
    Context: Self-limited delayed puberty (DP) segregates in an autosomal-dominant pattern, but the genetic basis is largely unknown. Although DP is sometimes seen in relatives of patients with hypogonadotropic hypogonadism (HH), mutations in genes known to cause HH that segregate with the trait of familial self-limited DP have not yet been identified. Objective: To assess the contribution of mutations in genes known to cause HH to the phenotype of self-limited DP. Design, Patients, and Setting: We performed whole-exome sequencing in 67 probands and 93 relatives from a large cohort of familial self-limited DP, validated the pathogenicity of the identified gene variant in vitro, and examined the tissue expression and functional requirement of the mouse homolog in vivo. Results: A potentially pathogenic gene variant segregating with DP was identified in 1 of 28 known HH genes examined. This pathogenic variant occurred in HS6ST1 in one pedigree and segregated with the trait in the six affected members with heterozygous transmission (P = 3.01 x 10 -5 ). Biochemical analysis showed that this mutation reduced sulfotransferase activity in vitro. Hs6st1 mRNA was expressed in peripubertal wild-type mouse hypothalamus. GnRH neuron counts were similar in Hs6st1 (+/-) and Hs6st1(+/+) mice, but vaginal opening was delayed in Hs6st1(+/-) mice despite normal postnatal growth. Conclusions: We have linked a deleterious mutation in HS6ST1 to familial self-limited DP and show that heterozygous Hs6st1 loss causes DP in mice. In this study, the observed overlap in potentially pathogenic mutations contributing to the phenotypes of self-limited DP and HH was limited to this one gene.
  • Mancini, Alessandra; Howard, Sasha R.; Marelli, Federica; Cabrera, Claudia P.; Barnes, Michael R.; Sternberg, Michael J. E.; Leprovots, Morgane; Hadjidemetriou, Irene; Monti, Elena; David, Alessia; Wehkalampi, Karoliina; Oleari, Roberto; Lettieri, Antonella; Vezzoli, Valeria; Vassart, Gilbert; Cariboni, Anna; Bonomi, Marco; Garcia, Marie Isabelle; Guasti, Leonardo; Dunkel, Leo (2020)
    The initiation of puberty is driven by an upsurge in hypothalamic gonadotropin-releasing hormone (GnRH) secretion. In turn, GnRH secretion upsurge depends on the development of a complex GnRH neuroendocrine network during embryonic life. Although delayed puberty (DP) affects up to 2% of the population, is highly heritable, and is associated with adverse health outcomes, the genes underlying DP remain largely unknown. We aimed to discover regulators by whole-exome sequencing of 160 individuals of 67 multigenerational families in our large, accurately phenotyped DP cohort. LGR4 was the only gene remaining after analysis that was significantly enriched for potentially pathogenic, rare variants in 6 probands, Expression analysis identified specific Lgr4 expression at the site of GnRH neuron development. LGR4 mutant proteins showed impaired Wnt/beta-catenin signaling, owing to defective protein expression, trafficking, and degradation. Mice deficient in Lgr4 had significantly delayed onset of puberty and fewer GnRH neurons compared with WT, whereas lgr4 knockdown in zebrafish embryos prevented formation and migration of GnRH neurons. Further, genetic lineage tracing showed strong Lgr4-mediated Wnt/beta-catenin signaling pathway activation during GnRH neuron development. In conclusion, our results show that LGR4 deficiency impairs Wnt/beta-catenin signaling with observed defects in GnRH neuron development, resulting in a DP phenotype.
  • Hagstrom, Erik; Freyer, Christoph; Battersby, Brendan J.; Stewart, James B.; Larsson, Nils-Goran (2014)
  • Sharapova, Svetlana O.; Haapaniemi, Emma; Sakovich, Inga S.; Rojas, Jessica; Gamez-Diaz, Laura; Mareika, Yuliya E.; Guryanova, Irina E.; Migas, Alexandr A.; Mikhaleuskaya, Taisiya M.; Grimbacher, Bodo; Aleinikova, Olga V. (2018)
  • Chasman, Daniel I.; Anttila, Verneri; Buring, Julie E.; Ridker, Paul M.; Schuerks, Markus; Kurth, Tobias; Int Headache Genetics Consortium (2014)
  • Erola, Jani; Lehti, Hannu; Baier, Tina; Karhula, Aleksi (2022)
    To what extent are differences in education, occupational standing, and income attributable to genes, and do genetic influences differ by parents' socioeconomic standing? When in a children's life course does parents' socioeconomic standing matter for genetic influences, and for which of the outcomes, fixed at the different stages of the attainment process, do they matter most? We studied these research questions using Finnish register-based data on 6,529 pairs of twins born between 1975 and 1986. We applied genetically sensitive variance decompositions and took gene-environment interactions into account. Since zygosity was unknown, we compared same-sex and opposite-sex twins to estimate the proportion of genetic variation. Genetic influences were strongest in education and weakest in income, and always strongest among those with the most advantaged socioeconomic background, independent of the socioeconomic indicator used. We found that the shared environment influences were negligible for all outcomes. Parental social background measured early during childhood was associated with weaker interactions with genetic influences. Genetic influences on children's occupation were largely mediated through their education, whereas for genetic influences on income, mediation through education and occupational standing made little difference. Interestingly, we found that non-shared environment influences were greater among the advantaged families and that this pattern was consistent across outcomes. Stratification scholars should therefore emphasize the importance of the non-shared environment as one of the drivers of the intergenerational transmission of social inequalities.