Inheritable variable sizes of DNA stretches in the human MHC: conserved extended haplotypes and their fragments or blocks

Wiley - Tập 62 Số 1 - Trang 1-20 - 2003
Edmond J. Yunis1,2,3, Charles E. Larsen4,5,3, Marcelo Fernández-Viña6, Zuheir L. Awdeh5, Tatiana Romero1,2, John A. Hansen7, Chester A. Alper8,5
1Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA
2Department of Pathology, Harvard Medical School, Boston, MA
3these authors contributed equally to this work
4Department of Medicine, Harvard Medical School, Boston, MA
5The Center for Blood Research, Boston, MA,
6Department of Oncology, Georgetown University, Naval Medical Research Institute, Kensington, MD
7Fred Hutchinson Cancer Research Center, Department of Medicine, University of Washington, Seattle, WA
8Department of Pediatrics, Harvard Medical School, Boston, MA

Tóm tắt

Abstract:  The difference in sizes of conserved stretches of DNA sequence within the major histocompatibility complex (MHC) in human individuals constitutes an underappreciated genetic diversity that has many practical implications. We developed a model to describe the variable sizes of stretches of conserved DNA in the MHC using the known frequencies of four different kinds of small (< 0.2 Mb) blocks of relatively conserved DNA sequence: HLA‐Cw/B; TNF; complotype; and HLA‐DR/DQ. Each of these small blocks is composed of two or more alleles of closely linked loci inherited as one genetic unit. We updated the concept of the conserved extended haplotype (CEH) using HLA allele identification and TNF microsatellites to show that specific combinations of the four blocks form single genetic units (≥ 1.5 Mb) with a total haplotype frequency in the Caucasian population of 0.30. Some CEHs extend to the HLA‐A and ‐DPB1 loci forming fixed genetic units of up to at least 3.2 Mb of DNA. Finally, intermediate fragments of CEHs also exist, which are, nevertheless, larger than any of the four small blocks. This complexity of genetic fixity at various levels should be taken into account in studies of genetic disease association, immune response control, and human diversity. This knowledge could also be used for matching CEHs and their fragments for patients undergoing allotransplantation.

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Wiley

Tập 62 Số 1

1-20

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