Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations

X-linked recessive ectodermal dysplasia with immunodeficiency is a rare primary immunodeficiency caused by hypomorphic mutations of the IKBKG gene encoding the nuclear factor kappa B essential modulator (NEMO) protein. This condition displays enormous allelic, immunological, and clinical heterogeneity, and therapeutic decisions are difficult because NEMO operates in both hematopoietic and nonhematopoietic cells. Hematopoietic stem cell transplantation (HSCT) is potentially life-saving, but the small number of case reports available suggests it has been reserved for only the most severe cases. Here, we report the health status before HSCT, transplantation outcome, and clinical follow-up for a series of 29 patients from unrelated kindreds from 11 countries. Between them, these patients carry 23 different hypomorphic IKBKG mutations. HSCT was performed from HLA-identical related donors (n = 7), HLA-matched unrelated donors (n = 12), HLA-mismatched unrelated donors (n = 8), and HLA-haploidentical related donors (n = 2). Engraftmentwas documented in 24 patients, and graft-versus-host disease in 13 patients. Up to 7 patients died 0.2 to 12 months after HSCT. The global survival rate after HSCT among NEMO-deficient children was 74% at a median follow-up after HSCT of 57months (range, 4-108 months). Preexisting mycobacterial infection and colitis were associated with poor HSCT outcome. The underlyingmutation does not appear to have any influence, as patients with the same mutation had different outcomes. Transplantation did not appear to cure colitis, possibly as a result of cell-intrinsic disorders of the epithelial barrier. Overall, HSCT can cure most clinical features of patients with a variety of IKBKG mutations.St. Giles FoundationRockefeller UniversityINSERMParis Descartes UniversityCentre de Reference des Deficits Immunitaires Hereditaires (CEREDIH)German Ministry for Education and ResearchNational Institute for Health Research and GOSH Biomedical Research CentreRobert A. Good/Jeffrey Modell FellowshipNecker Hosp Sick Children, AP HP, Study Ctr Immunodeficiencies, Paris, FranceTokyo Med & Dent Univ, Dept Pediat & Dev Biol, Tokyo, JapanNiigata Univ, Grad Sch Med & Dent Sci, Dept Pediat, Niigata, JapanAnn & Robert H Lurie Childrens Hosp Chicago, Div Pediat Dermatol, Chicago, IL 60611 USANorthwestern Univ, Dept Pediat, Feinberg Sch Med, Chicago, IL 60611 USACincinnati Childrens Hosp, Med Ctr, Bone Marrow Transplantat & Immune Deficiency, Cincinnati, OH USAKyoto Univ, Grad Sch Med, Dept Pediat, Kyoto, JapanHirosaki Univ, Grad Sch Med, Dept Pediat, Hirosaki, Aomori, JapanUniv Hosp, Pediat Oncohematoimmunol Unit, Angers, FranceUniv Lyon 1, Sch Med, Genet Unit, Hosp Civils Lyon, Bron, FranceEmory Univ, Dept Pediat, Div Bone Marrow Transplant, Aflac Canc & Blood Disorders Ctr Childrens Hlth, Atlanta, GA 30322 USAUniv Zurich, Univ Childrens Hosp Zurich, Div Stem Cell Transplantat, Zurich, SwitzerlandUniv Hosp, Dept Biochem & Genet, Angers, FranceNatl Inst Pediat, Clin Immunol Dept, Mexico City, DF, MexicoNatl Inst Pediat, Program Hematopoiet Stem Cell Transplantat, Mexico City, DF, MexicoUCL, Great Ormond St Inst Child Hlth, London, EnglandNatl Jewish Hlth, Dept Pediat, Immunodeficiency Diag & Treatment Program, Denver, CO USAOregon Hlth & Sci Univ, Dept Pediat Dermatol, Portland, OR 97201 USAStarship Hosp, Starship Blood & Canc Ctr, Paediat Haematol, Auckland, New ZealandUniv Wales Hosp, Immunodeficiency Ctr Wales, Cardiff, S Glam, WalesUniv Freiburg, Ctr Chron Immunodeficiency, Freiburg, GermanyNewcastle Univ, Inst Cellular Med, Primary Immunodeficiency Grp, Newcastle Upon Tyne, Tyne & Wear, EnglandNewcastle Tyne Hosp NHS Fdn Trust, Great North Childrens Hosp, Paediat Immunol Dept, Newcastle Upon Tyne, Tyne & Wear, EnglandUniv Fed Sao Paulo, Inst Biomed Sci, Dept Pediat, Sao Paulo, BrazilUniv Fed Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo, BrazilGreat Ormond St Hosp Children NHS Fdn Trust, Blood & Marrow Transplant Unit, London, EnglandNIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USANIH, Dept Lab Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USAParis Descartes Univ, Imagine Inst, Paris, FranceNecker Hosp Sick Children, AP HP, Pediat Hematol Immunol & Rheumatol Unit, Paris, FranceCambridge Biomed Res Ctr, Natl Inst Hlth Res, Cambridge, EnglandOxford Univ Hosp NHS Fdn Trust, Natl Inst Hlth Res, Oxford Biomed Res Ctr, Oxford, EnglandNecker Hosp Sick Children, INSERM, UMR1163, Lab Human Genet Infect Dis,Necker Branch, Paris, FranceRockefeller Univ, St Giles Lab Human Genet Infect Dis, Rockefeller Branch, 1230 York Ave, New York, NY 10021 USAHoward Hughes Med Inst, New York, NY USATexas Childrens Hosp, Baylor Coll Med, Sect Immunol Allergy & Rheumatol, Ctr Human Immunobiol, Houston, TX 77030 USAUniv Fed Sao Paulo, Inst Biomed Sci, Dept Pediat, Sao Paulo, BrazilUniv Fed Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo, BrazilWeb of Scienc