RESUMEN
Helicobacter pylori produces acute superficial gastritis in nearly all of its human hosts. However, a subset of individuals develops chronic atrophic gastritis (ChAG), a condition characterized in part by diminished numbers of acid-producing parietal cells and increased risk for development of gastric adenocarcinoma. Previously, we used a gnotobiotic transgenic mouse model with an engineered ablation of parietal cells to show that loss of parietal cells provides an opportunity for a H. pylori isolate from a patient with ChAG (HPAG1) to bind to, enter, and persist within gastric stem cells. This finding raises the question of how ChAG influences H. pylori genome evolution, physiology, and tumorigenesis. Here we describe the 1,596,366-bp HPAG1 genome. Custom HPAG1 Affymetrix GeneChips, representing 99.6% of its predicted ORFs, were used for whole-genome genotyping of additional H. pylori ChAG isolates obtained from Swedish patients enrolled in a case-control study of gastric cancer, as well as ChAG- and cancer-associated isolates from an individual who progressed from ChAG to gastric adenocarcinoma. The results reveal a shared gene signature among ChAG strains, as well as genes that may have been lost or gained during progression to adenocarcinoma. Whole-genome transcriptional profiling of HPAG1's response to acid during in vitro growth indicates that genes encoding components of metal uptake and utilization pathways, outer membrane proteins, and virulence factors are among those associated with H. pylori's adaptation to ChAG.
Asunto(s)
Gastritis Atrófica/microbiología , Genoma Bacteriano/genética , Helicobacter pylori/genética , Adenocarcinoma/microbiología , Emparejamiento Base , Enfermedad Crónica , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Regulación Bacteriana de la Expresión Génica , Inestabilidad Genómica , Genotipo , Helicobacter pylori/efectos de los fármacos , Helicobacter pylori/crecimiento & desarrollo , Humanos , Concentración de Iones de Hidrógeno , Datos de Secuencia Molecular , Análisis de Secuencia por Matrices de Oligonucleótidos , Análisis de Secuencia de ADN , Neoplasias Gástricas/microbiologíaRESUMEN
Eight palindromes comprise one-quarter of the euchromatic DNA of the male-specific region of the human Y chromosome, the MSY. They contain many testis-specific genes and typically exhibit 99.97% intra-palindromic (arm-to-arm) sequence identity. This high degree of identity could be interpreted as evidence that the palindromes arose through duplication events that occurred about 100,000 years ago. Using comparative sequencing in great apes, we demonstrate here that at least six of these MSY palindromes predate the divergence of the human and chimpanzee lineages, which occurred about 5 million years ago. The arms of these palindromes must have subsequently engaged in gene conversion, driving the paired arms to evolve in concert. Indeed, analysis of MSY palindrome sequence variation in existing human populations provides evidence of recurrent arm-to-arm gene conversion in our species. We conclude that during recent evolution, an average of approximately 600 nucleotides per newborn male have undergone Y-Y gene conversion, which has had an important role in the evolution of multi-copy testis gene families in the MSY.
Asunto(s)
Cromosomas Humanos Y/genética , Cromosomas de los Mamíferos/genética , Evolución Molecular , Conversión Génica/genética , Hominidae/genética , Cromosoma Y/genética , Animales , Secuencia de Bases , Eucromatina/genética , Amplificación de Genes/genética , Duplicación de Gen , Gorilla gorilla/genética , Humanos , Masculino , Datos de Secuencia Molecular , Familia de Multigenes/genética , Mutagénesis/genética , Especificidad de Órganos , Pan paniscus/genética , Pan troglodytes/genética , Caracteres Sexuales , Procesos de Determinación del Sexo , Testículo/metabolismoRESUMEN
The male-specific region of the Y chromosome, the MSY, differentiates the sexes and comprises 95% of the chromosome's length. Here, we report that the MSY is a mosaic of heterochromatic sequences and three classes of euchromatic sequences: X-transposed, X-degenerate and ampliconic. These classes contain all 156 known transcription units, which include 78 protein-coding genes that collectively encode 27 distinct proteins. The X-transposed sequences exhibit 99% identity to the X chromosome. The X-degenerate sequences are remnants of ancient autosomes from which the modern X and Y chromosomes evolved. The ampliconic class includes large regions (about 30% of the MSY euchromatin) where sequence pairs show greater than 99.9% identity, which is maintained by frequent gene conversion (non-reciprocal transfer). The most prominent features here are eight massive palindromes, at least six of which contain testis genes.