Person: Markianos, Kyriacos
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Markianos
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Kyriacos
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Markianos, Kyriacos
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Publication Biallelic Mutations In Human DCC Cause Developmental Split Brain Syndrome(2017) Jamuar, Saumya; Schmitz-Abe, Klaus; D’Gama, Alissa M.; Drottar, Marie; Chan, Wai-Man; Peeva, Maya; Servattalab, Sarah; Lam, Anh-Thu N.; Delgado, Mauricio R.; Clegg, Nancy J.; Al Zayed, Zayed; Dogar, Mohammad Asif; Alorainy, Ibrahim A.; Jamea, Abdullah Abu; Abu-Amero, Khaled; Griebel, May; Ward, Wendy; Lein, Ed S.; Markianos, Kyriacos; Barkovich, A. James; Robson, Caroline; Grant, P.; Bosley, Thomas M.; Engle, Elizabeth; Walsh, Christopher; Yu, Timothy W.Motor, sensory, and integrative activities of the brain are coordinated by a series of midline-bridging neuronal commissures whose development is tightly regulated. Here we report a novel human syndrome in which these commissures are widely disrupted, causing clinical manifestations of horizontal gaze palsy, scoliosis, and intellectual disability. Affected individuals were found to possess biallelic loss-of-function mutations in the axon guidance receptor Deleted in Colorectal Carcinoma (DCC), a gene previously implicated in congenital mirror movements when mutated in the heterozygous state, but whose biallelic loss-of-function human phenotype has not been reported. Structural MRI and diffusion tractography demonstrated broad disorganization of white matter tracts throughout the human CNS including loss of all commissural tracts at multiple levels of the neuraxis. Combined with data from animal models, these findings show that DCC is a master regulator of midline crossing and development of white matter projections throughout the human CNS.Publication Genetic Structure of a Local Population of the Anopheles gambiae Complex in Burkina Faso(Public Library of Science, 2016) Markianos, Kyriacos; Bischoff, Emmanuel; Mitri, Christian; Guelbeogo, Wamdaogo M.; Gneme, Awa; Eiglmeier, Karin; Holm, Inge; Sagnon, N’Fale; Vernick, Kenneth D.; Riehle, Michelle M.Members of the Anopheles gambiae species complex are primary vectors of human malaria in Africa. Population heterogeneities for ecological and behavioral attributes expand and stabilize malaria transmission over space and time, and populations may change in response to vector control, urbanization and other factors. There is a need for approaches to comprehensively describe the structure and characteristics of a sympatric local mosquito population, because incomplete knowledge of vector population composition may hinder control efforts. To this end, we used a genome-wide custom SNP typing array to analyze a population collection from a single geographic region in West Africa. The combination of sample depth (n = 456) and marker density (n = 1536) unambiguously resolved population subgroups, which were also compared for their relative susceptibility to natural genotypes of Plasmodium falciparum malaria. The population subgroups display fluctuating patterns of differentiation or sharing across the genome. Analysis of linkage disequilibrium identified 19 new candidate genes for association with underlying population divergence between sister taxa, A. coluzzii (M-form) and A. gambiae (S-form).Publication Mutations in the substrate binding glycine-rich loop of the mitochondrial processing peptidase-α protein (PMPCA) cause a severe mitochondrial disease(Cold Spring Harbor Laboratory Press, 2016) Joshi, Mugdha; Anselm, Irina; Shi, Jiahai; Bale, Tejus A.; Towne, Meghan; Schmitz-Abe, Klaus; Crowley, Laura; Giani, Felix C.; Kazerounian, Shideh; Markianos, Kyriacos; Lidov, Hart; Folkerth, Rebecca D.; Sankaran, Vijay; Agrawal, PankajWe describe a large Lebanese family with two affected members, a young female proband and her male cousin, who had multisystem involvement including profound global developmental delay, severe hypotonia and weakness, respiratory insufficiency, blindness, and lactic acidemia—findings consistent with an underlying mitochondrial disorder. Whole-exome sequencing was performed on DNA from the proband and both parents. The proband and her cousin carried compound heterozygous mutations in the PMPCA gene that encodes for α-mitochondrial processing peptidase (α-MPP), a protein likely involved in the processing of mitochondrial proteins. The variants were located close to and postulated to affect the substrate binding glycine-rich loop of the α-MPP protein. Functional assays including immunofluorescence and western blot analysis on patient's fibroblasts revealed that these variants reduced α-MPP levels and impaired frataxin production and processing. We further determined that those defects could be rescued through the expression of exogenous wild-type PMPCA cDNA. Our findings link defective α-MPP protein to a severe mitochondrial disease.Publication Association mapping by pooled sequencing identifies TOLL 11 as a protective factor against Plasmodium falciparum in Anopheles gambiae(BioMed Central, 2015) Redmond, Seth N.; Eiglmeier, Karin; Mitri, Christian; Markianos, Kyriacos; Guelbeogo, Wamdaogo M.; Gneme, Awa; Isaacs, Alison T.; Coulibaly, Boubacar; Brito-Fravallo, Emma; Maslen, Gareth; Mead, Daniel; Niare, Oumou; Traore, Sekou F.; Sagnon, N’Fale; Kwiatkowski, Dominic; Riehle, Michelle M.; Vernick, Kenneth D.Background: The genome-wide association study (GWAS) techniques that have been used for genetic mapping in other organisms have not been successfully applied to mosquitoes, which have genetic characteristics of high nucleotide diversity, low linkage disequilibrium, and complex population stratification that render population-based GWAS essentially unfeasible at realistic sample size and marker density. Methods: We designed a novel mapping strategy for the mosquito system that combines the power of linkage mapping with the resolution afforded by genetic association. We established founder colonies from West Africa, controlled for diversity, linkage disequilibrium and population stratification. Colonies were challenged by feeding on the infectious stage of the human malaria parasite, Plasmodium falciparum, mosquitoes were phenotyped for parasite load, and DNA pools for phenotypically similar mosquitoes were Illumina sequenced. Phenotype-genotype mapping was carried out in two stages, coarse and fine. Results: In the first mapping stage, pooled sequences were analysed genome-wide for intervals displaying relativereduction in diversity between phenotype pools, and candidate genomic loci were identified for influence upon parasite infection levels. In the second mapping stage, focused genotyping of SNPs from the first mapping stage was carried out in unpooled individual mosquitoes and replicates. The second stage confirmed significant SNPs in a locus encoding two Toll-family proteins. RNAi-mediated gene silencing and infection challenge revealed that TOLL 11 protects mosquitoes against P. falciparum infection. Conclusions: We present an efficient and cost-effective method for genetic mapping using natural variation segregating in defined recent Anopheles founder colonies, and demonstrate its applicability for mapping in a complex non-model genome. This approach is a practical and preferred alternative to population-based GWAS for first-pass mapping of phenotypes in Anopheles. This design should facilitate mapping of other traits involved in physiology, epidemiology, and behaviour. Electronic supplementary material The online version of this article (doi:10.1186/s12864-015-2009-z) contains supplementary material, which is available to authorized users.Publication The kdr-bearing haplotype and susceptibility to Plasmodium falciparum in Anopheles gambiae: genetic correlation and functional testing(BioMed Central, 2015) Mitri, Christian; Markianos, Kyriacos; Guelbeogo, Wamdaogo M.; Bischoff, Emmanuel; Gneme, Awa; Eiglmeier, Karin; Holm, Inge; Sagnon, N’Fale; Vernick, Kenneth D.; Riehle, Michelle M.Background: Members of the Anophelesgambiae species complex are primary vectors of human malaria in Africa. It is known that a large haplotype shared between An. gambiae and Anophelescoluzzii by introgression carries point mutations of the voltage-gated sodium channel gene para, including the L1014F kdr mutation associated with insensitivity to pyrethroid insecticides. Carriage of L1014F kdr is also correlated with higher susceptibility to infection with Plasmodium falciparum. However, the genetic mechanism and causative gene(s) underlying the parasite susceptibility phenotype are not known. Methods: Mosquitoes from the wild Burkina Faso population were challenged by feeding on natural P. falciparum gametocytes. Oocyst infection phenotypes were determined and were tested for association with SNP genotypes. Candidate genes in the detected locus were prioritized and RNAi-mediated gene silencing was used to functionally test for gene effects on P. falciparum susceptibility. Results: A genetic locus, Pfin6, was identified that influences infection levels of P. falciparum in mosquitoes. The locus segregates as a ~3 Mb haplotype carrying 65 predicted genes including the para gene. The haplotype carrying the kdr allele of para is linked to increased parasite infection prevalence, but many single nucleotide polymorphisms on the haplotype are also equally linked to the infection phenotype. Candidate genes in the haplotype were prioritized and functionally tested. Silencing of para did not influence P. falciparum infection, while silencing of a predicted immune gene, serine protease ClipC9, allowed development of significantly increased parasite numbers. Conclusions: Genetic variation influencing Plasmodium infection in wild Anopheles is linked to a natural ~3 megabase haplotype on chromosome 2L that carries the kdr allele of the para gene. Evidence suggests that para gene function does not directly influence parasite susceptibility, and the association of kdr with infection may be due to tight linkage of kdr with other gene(s) on the haplotype. Further work will be required to determine if ClipC9 influences the outcome of P. falciparum infection in nature, as well as to confirm the absence of a direct influence by para. Electronic supplementary material The online version of this article (doi:10.1186/s12936-015-0924-8) contains supplementary material, which is available to authorized users.Publication A Major Genetic Locus Controlling Natural Plasmodium falciparum Infection is Shared by East and West African Anopheles gambiae(BioMed Central, 2007) Riehle, Michelle M; Markianos, Kyriacos; Lambrechts, Louis; Xia, Ai; Sharakhov, Igor; Koella, Jacob C; Vernick, Kenneth DBackground: Genetic linkage mapping identified a region of chromosome 2L in the Anopheles gambiae genome that exerts major control over natural infection by Plasmodium falciparum. This 2L Plasmodium-resistance interval was mapped in mosquitoes from a natural population in Mali, West Africa, and controls the numbers of P. falciparum oocysts that develop on the vector midgut. An important question is whether genetic variation with respect to Plasmodium-resistance exists across Africa, and if so whether the same or multiple geographically distinct resistance mechanisms are responsible for the trait. Methods: To identify P falciparum resistance loci in pedigrees generated and infected in Kenya, East Africa, 28 microsatellite loci were typed across the mosquito genome. Genetic linkage mapping was used to detect significant linkage between genotype and numbers of midgut oocysts surviving to 7–8 days post-infection. Results: A major malaria-control locus was identified on chromosome 2L in East African mosquitoes, in the same apparent position originally identified from the West African population. Presence of this resistance locus explains 75% of parasite free mosquitoes. The Kenyan resistance locus is named EA_Pfin1 (East Africa_ Plasmodium falciparum Infection Intensity). Conclusion: Detection of a malaria-control locus at the same chromosomal location in both East and West African mosquitoes indicates that, to the level of genetic resolution of the analysis, the same mechanism of Plasmodium-resistance, or a mechanism controlled by the same genomic region, is found across Africa, and thus probably operates in A. gambiae throughout its entire range.