Research

LIke ThisLIke ThisLIke This

Kyriacos  Markianos, PhD

Kyriacos Markianos
Department:
Medicine Research
Division
Genetics and Genomics Research
Hospital Title:
Associate Scientist, Program in Genomics
Academic Title:
Assistant Professor of Pediatrics, Harvard Medical School
Research Focus Area:
Genetic studies in human and model organisms
Contact Via Email
Send an email to SendYour Name*Your Email Address*Subject*Comments*

Research Overview

Our laboratory focuses on the development of computational methods for the design and analysis of genetic studies in humans and model organisms. In addition to developing widely applicable methods, we work closely with other groups at Boston Children's Hospital on study design and bioinformatics tools suitable for their ongoing research studies.

Current projects:
Mapping and identification of genetic changes associated with disease
We use both traditional, family-based linkage approaches and more recent methods like copy number variation (CNV) analysis, next-generation transcriptome and exome sequencing to identify genetic changes when only limited family history or just population samples are available. Typically our lab is responsible for informatics and study design; we work closely with other labs responsible for patient data collection and functional studies of putative causative mutations.

Transcriptome sequencing
Most complex diseases have proven refractory to genetic analysis. Even for simple single-gene disorders, the mechanism of action is often not understood. The emergence of whole-transcriptome sequencing allows us to investigate transcriptome levels, alternative splicing and mutation changes simultaneously throughout the genome with unprecedented precision.

Sideroblastic anemia 
In collaboration with pathologist Mark Fleming, MD, DPhil, we used high-density Affymetrix 6.0 chips to map a new locus associated with sideroblastic anemia (a rare group of blood disorders in which the bone marrow cannot make red blood cells) in a large multiplex pedigree. We used the same Affymetrix 6.0 chips to identify another locus through haplotype sharing among unrelated affected individuals. We are now pursuing CNV analysis and whole-exosome sequencing to identify the causative genetic changes.

Autism
In collaboration with Christopher Walsh, MD, PhD, we are using homozygosity mapping to identify autism susceptibility genes in Middle Eastern pedigrees with shared ancestry. We have identified a number of genetic changes associated with the disease, including disruption of three genes implicated in synaptic development (c3orf58, NHE9, and PCDH10). These findings contribute to our growing understanding that autism results from miswiring or missing connections in the brain.

Malaria
The malarial parasite Plasmodium falciparum is rapidly evolving resistance to existing antimalarial drugs. We are hoping to facilitate the design of new strategies by uncovering the underlying genetics behind natural mosquito resistance to the malarial parasite. We have traced the resistance in African mosquito field populations to a single region of the genome. We are now conducting a follow-up association study to pinpoint the specific variants responsible for resistance or susceptibility.

Facioscapulohumeral muscular dystrophy (FSHD)
In collaboration with Louis Kunkel,PhD, we are developing expertise and analytic tools for transcriptome sequencing of tissue samples from patients with FSHD, an inherited disease that is linked to a contraction of transcriptional repeats, and whose clinical manifestations vary widely. By characterizing the widespread changes in transcriptional regulation, we hope to uncover the mechanism of action and further understand what lies behind the variability of the disease.

Other diseases
We are creating an analysis pipeline to routinely employ for the analysis of disease-associated CNVs. In collaboration with Christopher Walsh, MD, PhD, we are working to identify copy number changes associated with sporadic cases of intellectual disability. We are also analyzing samples collected by Patricia Donahoe, MD, at Massachusetts General Hospital and Cynthia Morton, MD, at Brigham and Women’s Hospital, to identify CNVs associated with hearing loss and congenital diaphragmatic hernia. In the future, we plan to use the same pipeline to identify CNVs associated with sideroblastic anemia and Sudden Infant Death Syndrome.

About Kyriacos Markianos

Kyriacos Markianos received his PhD in physics from the University of Massachusetts. He studied statistical genetics and computational biology at the Kruglyak laboratory at the Fred Hutchinson Cancer Research Center in Seattle.

Publications

Publications powered by Harvard Catalyst Profiles
  1. Joshi M, Anselm I, Shi J, Bale TA, Towne M, Schmitz-Abe K, Crowley L, Giani FC, Kazerounian S, Markianos K, Lidov HG, Folkerth R, Sankaran VG, Agrawal PB. Mutations in the substrate binding glycine-rich loop of the mitochondrial processing peptidase-a protein (PMPCA) cause a severe mitochondrial disease. Cold Spring Harb Mol Case Stud. 2016 May; 2(3):a000786.
  2. Crawford JE, Riehle MM, Markianos K, Bischoff E, Guelbeogo WM, Gneme A, Sagnon N, Vernick KD, Nielsen R, Lazzaro BP. Evolution of GOUNDRY, a cryptic subgroup of Anopheles gambiae s.l., and its impact on susceptibility to Plasmodium infection. Mol Ecol. 2016 Apr; 25(7):1494-510.
  3. Markianos K, Bischoff E, Mitri C, Guelbeogo WM, Gneme A, Eiglmeier K, Holm I, Sagnon N, Vernick KD, Riehle MM. Genetic Structure of a Local Population of the Anopheles gambiae Complex in Burkina Faso. PLoS One. 2016; 11(1):e0145308.
  4. Schmitz-Abe K, Ciesielski SJ, Schmidt PJ, Campagna DR, Rahimov F, Schilke BA, Cuijpers M, Rieneck K, Lausen B, Linenberger ML, Sendamarai AK, Guo C, Hofmann I, Newburger PE, Matthews D, Shimamura A, Snijders PJ, Towne MC, Niemeyer CM, Watson HG, Dziegiel MH, Heeney MM, May A, Bottomley SS, Swinkels DW, Markianos K, Craig EA, Fleming MD. Congenital sideroblastic anemia due to mutations in the mitochondrial HSP70 homologue HSPA9. Blood. 2015 Dec 17; 126(25):2734-8.
  5. Mitri C, Markianos K, Guelbeogo WM, Bischoff E, Gneme A, Eiglmeier K, Holm I, Sagnon N, Vernick KD, Riehle MM. The kdr-bearing haplotype and susceptibility to Plasmodium falciparum in Anopheles gambiae: genetic correlation and functional testing. Malar J. 2015 Oct 06; 14:391.
  6. Agrawal PB, Joshi M, Marinakis NS, Schmitz-Abe K, Ciarlini PD, Sargent JC, Markianos K, De Girolami U, Chad DA, Beggs AH. Expanding the phenotype associated with the NEFL mutation: neuromuscular disease in a family with overlapping myopathic and neurogenic findings. JAMA Neurol. 2014 Nov; 71(11):1413-20.
  7. Chakraborty PK, Schmitz-Abe K, Kennedy EK, Mamady H, Naas T, Durie D, Campagna DR, Lau A, Sendamarai AK, Wiseman DH, May A, Jolles S, Connor P, Powell C, Heeney MM, Giardina PJ, Klaassen RJ, Kannengiesser C, Thuret I, Thompson AA, Marques L, Hughes S, Bonney DK, Bottomley SS, Wynn RF, Laxer RM, Minniti CP, Moppett J, Bordon V, Geraghty M, Joyce PB, Markianos K, Rudner AD, Holcik M, Fleming MD. Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD). Blood. 2014 Oct 30; 124(18):2867-71.
  8. Sankaran VG, Joshi M, Agrawal A, Schmitz-Abe K, Towne MC, Marinakis N, Markianos K, Berry GT, Agrawal PB. Rare complete loss of function provides insight into a pleiotropic genome-wide association study locus. Blood. 2013 Nov 28; 122(23):3845-7.
  9. Campagna DR, de Bie CI, Schmitz-Abe K, Sweeney M, Sendamarai AK, Schmidt PJ, Heeney MM, Yntema HG, Kannengiesser C, Grandchamp B, Niemeyer CM, Knoers NV, Swart S, Marron G, van Wijk R, Raymakers RA, May A, Markianos K, Bottomley SS, Swinkels DW, Fleming MD. X-linked sideroblastic anemia due to ALAS2 intron 1 enhancer element GATA-binding site mutations. Am J Hematol. 2014 Mar; 89(3):315-9.
  10. Ceyhan-Birsoy O, Agrawal PB, Hidalgo C, Schmitz-Abe K, DeChene ET, Swanson LC, Soemedi R, Vasli N, Iannaccone ST, Shieh PB, Shur N, Dennison JM, Lawlor MW, Laporte J, Markianos K, Fairbrother WG, Granzier H, Beggs AH. Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy. Neurology. 2013 Oct 1; 81(14):1205-14.
  11. Show all
  12. Bartnikas TB, Wildt SJ, Wineinger AE, Schmitz-Abe K, Markianos K, Cooper DM, Fleming MD. A novel rat model of hereditary hemochromatosis due to a mutation in transferrin receptor 2. Comp Med. 2013 Apr; 63(2):143-55.
  13. Yu TW, Chahrour MH, Coulter ME, Jiralerspong S, Okamura-Ikeda K, Ataman B, Schmitz-Abe K, Harmin DA, Adli M, Malik AN, D'Gama AM, Lim ET, Sanders SJ, Mochida GH, Partlow JN, Sunu CM, Felie JM, Rodriguez J, Nasir RH, Ware J, Joseph RM, Hill RS, Kwan BY, Al-Saffar M, Mukaddes NM, Hashmi A, Balkhy S, Gascon GG, Hisama FM, LeClair E, Poduri A, Oner O, Al-Saad S, Al-Awadi SA, Bastaki L, Ben-Omran T, Teebi AS, Al-Gazali L, Eapen V, Stevens CR, Rappaport L, Gabriel SB, Markianos K, State MW, Greenberg ME, Taniguchi H, Braverman NE, Morrow EM, Walsh CA. Using whole-exome sequencing to identify inherited causes of autism. Neuron. 2013 Jan 23; 77(2):259-73.
  14. Paterson DS, Rivera KD, Broadbelt KG, Trachtenberg FL, Belliveau RA, Holm IA, Haas EA, Stanley C, Krous HF, Kinney HC, Markianos K. Lack of association of the serotonin transporter polymorphism with the sudden infant death syndrome in the San Diego Dataset. Pediatr Res. 2010 Nov; 68(5):409-13.
  15. Riehle MM, Markianos K, Lambrechts L, Xia A, Sharakhov I, Koella JC, Vernick KD. A major genetic locus controlling natural Plasmodium falciparum infection is shared by East and West African Anopheles gambiae. Malar J. 2007; 6:87.
  16. Riehle MM, Markianos K, Niaré O, Xu J, Li J, Touré AM, Podiougou B, Oduol F, Diawara S, Diallo M, Coulibaly B, Ouatara A, Kruglyak L, Traoré SF, Vernick KD. Natural malaria infection in Anopheles gambiae is regulated by a single genomic control region. Science. 2006 Apr 28; 312(5773):577-9.
  17. Abecasis G, Cox N, Daly MJ, Kruglyak L, Laird N, Markianos K, Patterson N. No bias in linkage analysis. Am J Hum Genet. 2004 Oct; 75(4):722-3; author reply 723-7.
  18. Furman I, Rieder MJ, Da Ponte S, Carrington DP, Nickerson DA, Kruglyak L, Markianos K. Sequence-based linkage analysis. Am J Hum Genet. 2004 Oct; 75(4):647-53.
  19. Ostrander EA, Markianos K, Stanford JL. Finding prostate cancer susceptibility genes. Annu Rev Genomics Hum Genet. 2004; 5:151-75.
  20. Matise TC, Sachidanandam R, Clark AG, Kruglyak L, Wijsman E, Kakol J, Buyske S, Chui B, Cohen P, de Toma C, Ehm M, Glanowski S, He C, Heil J, Markianos K, McMullen I, Pericak-Vance MA, Silbergleit A, Stein L, Wagner M, Wilson AF, Winick JD, Winn-Deen ES, Yamashiro CT, Cann HM, Lai E, Holden AL. A 3.9-centimorgan-resolution human single-nucleotide polymorphism linkage map and screening set. Am J Hum Genet. 2003 Aug; 73(2):271-84.
  21. Niaré O, Markianos K, Volz J, Oduol F, Touré A, Bagayoko M, Sangaré D, Traoré SF, Wang R, Blass C, Dolo G, Bouaré M, Kafatos FC, Kruglyak L, Touré YT, Vernick KD. Genetic loci affecting resistance to human malaria parasites in a West African mosquito vector population. Science. 2002 Oct 4; 298(5591):213-6.
  22. Félix J, Berisso MC, Christian DC, Gara A, Gottschalk EE, Gutiérrez G, Hartouni EP, Knapp BC, Kreisler MN, Lee S, Markianos K, Moreno G, Reyes MA, Sosa M, Wang MH, Wehmann A, Wesson D. Lambda(0) polarization in 800-GeV/cpp --&gt p(f)(Lambda0K+). Phys Rev Lett. 2002 Feb 11; 88(6):061801.
  23. Wang MH, Berisso MC, Christian DC, Félix J, Gara A, Gottschalk E, Gutiérrez G, Hartouni EP, Knapp BC, Kreisler MN, Lee S, Markianos K, Moreno G, Reyes MA, Sosa M, Wehmann A, Wesson D. Diffractively produced charm final states in 800-GeV/c pp collisions. Phys Rev Lett. 2001 Aug 20; 87(8):082002.
  24. Markianos K, Daly MJ, Kruglyak L. Efficient multipoint linkage analysis through reduction of inheritance space. Am J Hum Genet. 2001 Apr; 68(4):963-77.
  25. Markianos K, Carlson S, Gibbs M, Kruglyak L. A joint analysis of asthma affection status and IgE levels in multiple data sets collected for asthma. Genet Epidemiol. 2001; 21 Suppl 1:S148-53.
  26. Finberg KE, Heeney MM, Campagna DR, Aydinok Y, Pearson HA, Hartman KR, Mayo MM, Samuel SM, Strouse JJ, Markianos K, Andrews NC, Fleming MD. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet. 2008 May; 40(5):569-71.
  27. Broadbelt KG, Barger MA, Paterson DS, Holm IA, Haas EA, Krous HF, Kinney HC, Markianos K, Beggs AH. Serotonin-related FEV gene variant in the sudden infant death syndrome is a common polymorphism in the African-American population. Pediatr Res. 2009 Dec; 66(6):631-5.
  28. Riehle MM, Guelbeogo WM, Gneme A, Eiglmeier K, Holm I, Bischoff E, Garnier T, Snyder GM, Li X, Markianos K, Sagnon N, Vernick KD. A cryptic subgroup of Anopheles gambiae is highly susceptible to human malaria parasites. Science. 2011 Feb 4; 331(6017):596-8.
  29. Morrow EM, Yoo SY, Flavell SW, Kim TK, Lin Y, Hill RS, Mukaddes NM, Balkhy S, Gascon G, Hashmi A, Al-Saad S, Ware J, Joseph RM, Greenblatt R, Gleason D, Ertelt JA, Apse KA, Bodell A, Partlow JN, Barry B, Yao H, Markianos K, Ferland RJ, Greenberg ME, Walsh CA. Identifying autism loci and genes by tracing recent shared ancestry. Science. 2008 Jul 11; 321(5886):218-23.
  30. Eran A, Li JB, Vatalaro K, McCarthy J, Rahimov F, Collins C, Markianos K, Margulies DM, Brown EN, Calvo SE, Kohane IS, Kunkel LM. Comparative RNA editing in autistic and neurotypical cerebella. Mol Psychiatry. 2013 Sep; 18(9):1041-8.
  31. Nakayama T, Al-Maawali A, El-Quessny M, Rajab A, Khalil S, Stoler JM, Tan WH, Nasir R, Schmitz-Abe K, Hill RS, Partlow JN, Al-Saffar M, Servattalab S, LaCoursiere CM, Tambunan DE, Coulter ME, Elhosary PC, Gorski G, Barkovich AJ, Markianos K, Poduri A, Mochida GH. Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination. Am J Hum Genet. 2015 May 7; 96(5):709-19.
  32. Ahmed MY, Chioza BA, Rajab A, Schmitz-Abe K, Al-Khayat A, Al-Turki S, Baple EL, Patton MA, Al-Memar AY, Hurles ME, Partlow JN, Hill RS, Evrony GD, Servattalab S, Markianos K, Walsh CA, Crosby AH, Mochida GH. Loss of PCLO function underlies pontocerebellar hypoplasia type III. Neurology. 2015 Apr 28; 84(17):1745-50.
  33. Redmond SN, Eiglmeier K, Mitri C, Markianos K, Guelbeogo WM, Gneme A, Isaacs AT, Coulibaly B, Brito-Fravallo E, Maslen G, Mead D, Niare O, Traore SF, Sagnon N, Kwiatkowski D, Riehle MM, Vernick KD. Association mapping by pooled sequencing identifies TOLL 11 as a protective factor against Plasmodium falciparum in Anopheles gambiae. BMC Genomics. 2015 Oct 13; 16:779.
  34. Lichtenstein DA, Crispin AW, Sendamarai AK, Campagna DR, Schmitz-Abe K, Sousa CM, Kafina MD, Schmidt PJ, Niemeyer CM, Porter J, May A, Patnaik MM, Heeney MM, Kimmelman A, Bottomley SS, Paw BH, Markianos K, Fleming MD. A recurring mutation in the respiratory complex 1 protein NDUFB11 is responsible for a novel form of X-linked sideroblastic anemia. Blood. 2016 Oct 13; 128(15):1913-1917.
  35. Cattivelli K, Campagna DR, Schmitz-Abe K, Heeney MM, Yaish HM, Caruso Brown AE, Kearney S, Walkovich K, Markianos K, Fleming MD, Neufeld EJ. Ringed sideroblasts in ß-thalassemia. Pediatr Blood Cancer. 2016 Nov 3.
  36. Morton SU, Neilan EG, Peake RW, Shi J, Schmitz-Abe K, Towne M, Markianos K, Prabhu SP, Agrawal PB. Hyperammonemia as a Presenting Feature in Two Siblings with FBXL4 Variants. JIMD Rep. 2016 Nov 18.
LIke ThisLIke ThisLIke This
Close