RESUMO
Interactions of killer cell immunoglobulin-like receptors (KIRs) with major histocompatibility complex (MHC) class I ligands diversify natural killer cell responses to infection. By analyzing sequence variation in diverse human populations, we show that the KIR3DL1/S1 locus encodes two lineages of polymorphic inhibitory KIR3DL1 allotypes that recognize Bw4 epitopes of protein">HLA-A and HLA-B and one lineage of conserved activating KIR3DS1 allotypes, also implicated in Bw4 recognition. Balancing selection has maintained these three lineages for over 3 million years. Variation was selected at D1 and D2 domain residues that contact HLA class I and at two sites on D0, the domain that enhances the binding of KIR3D to HLA class I. HLA-B variants that gained Bw4 through interallelic microconversion are also products of selection. A worldwide comparison uncovers unusual KIR3DL1/S1 evolution in modern sub-Saharan Africans. Balancing selection is weak and confined to D0, KIR3DS1 is rare and KIR3DL1 allotypes with similar binding sites predominate. Natural killer cells express the dominant KIR3DL1 at a high frequency and with high surface density, providing strong responses to cells perturbed in Bw4 expression.
Assuntos
População Negra/genética , Receptores KIR3DL1/genética , Receptores KIR3DS1/genética , Seleção Genética , Alelos , Sequência de Aminoácidos , Sítios de Ligação/genética , Frequência do Gene , Genética Populacional , Antígenos HLA-B/química , Antígenos HLA-B/genética , Humanos , Desequilíbrio de Ligação , Dados de Sequência Molecular , Filogenia , Polimorfismo Genético , Estrutura Terciária de Proteína , Receptores KIR3DL1/química , Receptores KIR3DS1/química , Homologia de Sequência de AminoácidosRESUMO
Cryptococcus neoformans is a basidiomycetous yeast ubiquitous in the environment, a model for fungal pathogenesis, and an opportunistic human pathogen of global importance. We have sequenced its approximately 20-megabase genome, which contains approximately 6500 intron-rich gene structures and encodes a transcriptome abundant in alternatively spliced and antisense messages. The genome is rich in transposons, many of which cluster at candidate centromeric regions. The presence of these transposons may drive karyotype instability and phenotypic variation. C. neoformans encodes unique genes that may contribute to its unusual virulence properties, and comparison of two phenotypically distinct strains reveals variation in gene content in addition to sequence polymorphisms between the genomes.
Assuntos
Cryptococcus neoformans/genética , Genoma Fúngico , Processamento Alternativo , Parede Celular/metabolismo , Cromossomos Fúngicos/genética , Biologia Computacional , Cryptococcus neoformans/patogenicidade , Cryptococcus neoformans/fisiologia , Elementos de DNA Transponíveis , Proteínas Fúngicas/metabolismo , Biblioteca Gênica , Genes Fúngicos , Humanos , Íntrons , Dados de Sequência Molecular , Fenótipo , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Polissacarídeos/metabolismo , RNA Antissenso , Análise de Sequência de DNA , Transcrição Gênica , Virulência , Fatores de Virulência/metabolismoRESUMO
The human malaria parasite Plasmodium falciparum is responsible for the death of more than a million people every year. To stimulate basic research on the disease, and to promote the development of effective drugs and vaccines against the parasite, the complete genome of P. falciparum clone 3D7 has been sequenced, using a chromosome-by-chromosome shotgun strategy. Here we report the nucleotide sequence of the third largest of the parasite's 14 chromosomes, chromosome 12, which comprises about 10% of the 23-megabase genome. As the most (A + T)-rich (80.6%) genome sequenced to date, the P. falciparum genome presented severe problems during the assembly of primary sequence reads. We discuss the methodology that yielded a finished and fully contiguous sequence for chromosome 12. The biological implications of the sequence data are more thoroughly discussed in an accompanying Article (ref. 3).