ABSTRACT
The human genome sequence will provide a reference for measuring DNA sequence variation in human populations. Sequence variants are responsible for the genetic component of individuality, including complex characteristics such as disease susceptibility and drug response. Most sequence variants are single nucleotide polymorphisms (SNPs), where two alternate bases occur at one position. Comparison of any two genomes reveals around 1 SNP per kilobase. A sufficiently dense map of SNPs would allow the detection of sequence variants responsible for particular characteristics on the basis that they are associated with a specific SNP allele. Here we have evaluated large-scale sequencing approaches to obtaining SNPs, and have constructed a map of 2,730 SNPs on human chromosome 22. Most of the SNPs are within 25 kilobases of a transcribed exon, and are valuable for association studies. We have scaled up the process, detecting over 65,000 SNPs in the genome as part of The SNP Consortium programme, which is on target to build a map of 1 SNP every 5 kilobases that is integrated with the human genome sequence and that is freely available in the public domain.
Subject(s)
Chromosomes, Human, Pair 22 , Polymorphism, Single Nucleotide , Sequence Analysis, DNA/methods , Cell Line , Chromosome Mapping/methods , Evaluation Studies as Topic , Gene Library , Genome, Human , Humans , Sequence AlignmentABSTRACT
X-linked lymphoproliferative syndrome (XLP or Duncan disease) is characterized by extreme sensitivity to Epstein-Barr virus (EBV), resulting in a complex phenotype manifested by severe or fatal infectious mononucleosis, acquired hypogammaglobulinemia and malignant lymphoma. We have identified a gene, SH2D1A, that is mutated in XLP patients and encodes a novel protein composed of a single SH2 domain. SH2D1A is expressed in many tissues involved in the immune system. The identification of SH2D1A will allow the determination of its mechanism of action as a possible regulator of the EBV-induced immune response.
Subject(s)
Carrier Proteins/genetics , Herpesviridae Infections/complications , Herpesvirus 4, Human , Intracellular Signaling Peptides and Proteins , Lymphoproliferative Disorders/genetics , Mutation , src Homology Domains/genetics , Antigens, CD , B-Lymphocytes/immunology , B-Lymphocytes/virology , Carrier Proteins/metabolism , Cloning, Molecular , Female , Genetic Linkage , Glycoproteins/metabolism , Herpesviridae Infections/immunology , Herpesviridae Infections/virology , Humans , Immunoglobulins/metabolism , Lymphoproliferative Disorders/complications , Lymphoproliferative Disorders/immunology , Lymphoproliferative Disorders/virology , Male , Molecular Sequence Data , Pedigree , Receptors, Cell Surface , Sequence Alignment , Sequence Deletion , Signaling Lymphocytic Activation Molecule Associated Protein , Signaling Lymphocytic Activation Molecule Family Member 1 , T-Lymphocytes/immunology , T-Lymphocytes/virology , X ChromosomeABSTRACT
Using exon trapping, we have identified a new human gene in Xp22 encoding a 3-kb mRNA. Expression of this RNA is detectable in a range of tissues but is most pronounced in skeletal muscle and heart. The gene, designated "sex comb on midleg-like-1" (SCML1), maps 14 kb centromeric of marker DXS418, between DXS418 and DXS7994, and is transcribed from telomere to centromere. SCML1 spans 18 kb of genomic DNA, consists of six exons, and has a 624-bp open reading frame. The predicted 27-kDa SCML1 protein contains two domains that each have a high homology to two Drosophila transcriptional repressors of the polycomb group (PcG) genes and their homologues in mouse and human. PcG genes are known to be involved in the regulation of homeotic genes, and the mammalian homologues of the PcG genes repress the expression of Hox genes. SCML1 appears to be a new human member of this gene group and may play an important role in the control of embryonal development.