RESUMEN
Infection with the malaria parasite Plasmodium falciparum leads to widely different clinical conditions in children, ranging from mild flu-like symptoms to coma and death. Despite the immense medical implications, the genetic and molecular basis of this diversity remains largely unknown. Studies of in vitro gene expression have found few transcriptional differences between different parasite strains. Here we present a large study of in vivo expression profiles of parasites derived directly from blood samples from infected patients. The in vivo expression profiles define three distinct transcriptional states. The biological basis of these states can be interpreted by comparison with an extensive compendium of expression data in the yeast Saccharomyces cerevisiae. The three states in vivo closely resemble, first, active growth based on glycolytic metabolism, second, a starvation response accompanied by metabolism of alternative carbon sources, and third, an environmental stress response. The glycolytic state is highly similar to the known profile of the ring stage in vitro, but the other states have not been observed in vitro. The results reveal a previously unknown physiological diversity in the in vivo biology of the malaria parasite, in particular evidence for a functional mitochondrion in the asexual-stage parasite, and indicate in vivo and in vitro studies to determine how this variation may affect disease manifestations and treatment.
Asunto(s)
Malaria Falciparum/parasitología , Plasmodium falciparum/metabolismo , Animales , Análisis por Conglomerados , Ácidos Grasos/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Glucólisis/genética , Humanos , Malaria Falciparum/sangre , Análisis de Secuencia por Matrices de Oligonucleótidos , Plasmodium falciparum/genética , Plasmodium falciparum/crecimiento & desarrollo , Plasmodium falciparum/patogenicidad , Transcripción Genética , Ácidos Tricarboxílicos/metabolismoRESUMEN
Genetic studies are under way for many complex traits, spurred by the recent feasibility of whole genome scans. Clear guidelines for the interpretation of linkage results are needed to avoid a flood of false positive claims. At the same time, an overly cautious approach runs the risk of causing true hints of linkage to be missed. We address this problem by proposing specific standards designed to maintain rigor while also promoting communication.
Asunto(s)
Ligamiento Genético , Genética/normas , Genoma , Escala de Lod , Modelos Genéticos , Proyectos de Investigación/normas , Estadística como AsuntoRESUMEN
Many valuable animal models of human disease are known and new models are continually being generated in existing inbred strains,. Some disease models are simple mendelian traits, but most have a polygenic basis. The current approach to identifying quantitative trait loci (QTLs) that underlie such traits is to localize them in crosses, construct congenic strains carrying individual QTLs, and finally map and clone the genes. This process is time-consuming and expensive, requiring the genotyping of large crosses and many generations of breeding. Here we describe a different approach in which a panel of chromosome substitution strains (CSSs) is used for QTL mapping. Each of these strains has a single chromosome from the donor strain substituting for the corresponding chromosome in the host strain. We discuss the construction, applications and advantages of CSSs compared with conventional crosses for detecting and analysing QTLs, including those that have weak phenotypic effects.
Asunto(s)
Mapeo Cromosómico , Cromosomas , Endogamia , Carácter Cuantitativo Heredable , Animales , Cruzamientos Genéticos , Marcadores Genéticos , Genoma , Genotipo , Humanos , Ratones , Ratones Endogámicos , Muridae , FenotipoRESUMEN
The BB rat is among the best models of insulin-dependent diabetes mellitus--with onset and pathogenesis closely resembling the human disease. One unusual feature is a severe T-cell lymphopenia, which appears to be inherited as a recessive trait controlled by a single gene, Lyp. Based on genetic analysis of several crosses, we show that development of diabetes involves at least three genes: Lyp, which is tightly linked to the neuropeptide Y (Npy) gene on chromosome 4, a gene linked to the major histocompatibility complex (MHC) on chromosome 20, and a third unmapped gene for which the Fischer rat strain carries an allele conferring resistance.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Animales , Secuencia de Bases , Mapeo Cromosómico , Cruzamientos Genéticos , ADN/genética , Femenino , Genes Recesivos , Ligamiento Genético , Marcadores Genéticos , Linfopenia/genética , Complejo Mayor de Histocompatibilidad , Masculino , Datos de Secuencia Molecular , Neuropéptido Y/genética , Ratas , Ratas Endogámicas BB , Ratas Endogámicas F344 , Ratas Endogámicas Lew , Linfocitos TRESUMEN
Linkage disequilibrium mapping in isolated populations provides a powerful tool for fine structure localization of disease genes. Here, Luria and Delbrück's classical methods for analysing bacterial cultures are adapted to the study of human isolated founder populations in order to estimate (i) the recombination fraction between a disease locus and a marker; (ii) the expected degree of allelic homogeneity in a population; and (iii) the mutation rate of marker loci. Using these methods, we report striking linkage disequilibrium for diastrophic dysplasia (DTD) in Finland indicating that the DTD gene should lie within 0.06 centimorgans (or about 60 kilobases) of the CSF1R gene. Predictions about allelic homogeneity in Finland and mutation rates in simple sequence repeats are confirmed by independent observations.
Asunto(s)
Mapeo Cromosómico/métodos , Cromosomas Humanos Par 5 , Genética de Población , Desequilibrio de Ligamiento/genética , Osteocondrodisplasias/genética , Secuencia de Bases , Niño , Femenino , Finlandia , Marcadores Genéticos/genética , Haplotipos/genética , Humanos , Masculino , Modelos Genéticos , Datos de Secuencia Molecular , Mutación/genética , Osteocondrodisplasias/etnología , Linaje , Polimorfismo Genético/genética , Receptor de Factor Estimulante de Colonias de Macrófagos/genéticaRESUMEN
Linkage disequilibrium (LD) analysis is traditionally based on individual genetic markers and often yields an erratic, non-monotonic picture, because the power to detect allelic associations depends on specific properties of each marker, such as frequency and population history. Ideally, LD analysis should be based directly on the underlying haplotype structure of the human genome, but this structure has remained poorly understood. Here we report a high-resolution analysis of the haplotype structure across 500 kilobases on chromosome 5q31 using 103 single-nucleotide polymorphisms (SNPs) in a European-derived population. The results show a picture of discrete haplotype blocks (of tens to hundreds of kilobases), each with limited diversity punctuated by apparent sites of recombination. In addition, we develop an analytical model for LD mapping based on such haplotype blocks. If our observed structure is general (and published data suggest that it may be), it offers a coherent framework for creating a haplotype map of the human genome.
Asunto(s)
Genoma Humano , Haplotipos , Secuencia de Bases , Cromosomas Humanos Par 5 , ADN , Humanos , Desequilibrio de Ligamiento , Cadenas de Markov , Datos de Secuencia Molecular , Polimorfismo de Nucleótido SimpleRESUMEN
Hypertension, diabetes and hyperlipidemia are risk factors for life-threatening complications such as end-stage renal disease, coronary artery disease and stroke. Why some patients develop complications is unclear, but only susceptibility genes may be involved. To test this notion, we studied crosses involving the fawn-hooded rat, an animal model of hypertension that develops chronic renal failure. Here, we report the localization of two genes, Rf-1 and Rf-2, responsible for about half of the genetic variation in key indices of renal impairment. In addition, we localize a gene, Bpfh-1, responsible for about 26% of the genetic variation in blood pressure. Rf-1 strongly affects the risk of renal impairment, but has no significant effect on blood pressure. Our results show that susceptibility to a complication of hypertension is under at least partially independent genetic control from susceptibility to hypertension itself.
Asunto(s)
Hipertensión/genética , Ratas Mutantes/genética , Insuficiencia Renal/genética , Animales , Secuencia de Bases , Mapeo Cromosómico , Cartilla de ADN/química , Femenino , Ligamiento Genético , Masculino , Datos de Secuencia Molecular , Proteinuria/genética , Ratas , Ratas EndogámicasRESUMEN
The neuronal ceroid lipofuscinoses (NCLs) represent a group of common recessive inherited neurodegenerative disorders of childhood, with an incidence of 1:12,500 live births. They are characterized by accumulation of autofluorescent lipopigments in various tissues. Several forms of NCLs have been identified, based on age at onset, progression of disease, neurophysiological and histopathological findings and separate genetic loci. All types of NCL cause progressive visual and mental decline, motor disturbance, epilepsy and behavioral changes, and lead to premature death. One of the subtypes, Finnish variant late infantile neuronal ceroid lipofuscinosis (vLINCL; MIM256731) affects children at 4-7 years of age. The first symptom is motor clumsiness, followed by progressive visual failure, mental and motor deterioration and later by myoclonia and seizures. We have previously reported linkage for vLINCL on chromosome 13 (ref. 5) and constructed a long-range physical map over the region. Here, we report the positional cloning of a novel gene, CLN5, underlying this severe neurological disorder. The gene encodes a putative transmembrane protein which shows no homology to previously reported proteins. Sequence analysis of DNA samples from patients with three different haplotypes revealed three mutations; one deletion, one nonsense and one missense mutation, suggesting that mutations in this gene are responsible for vLINCL.
Asunto(s)
Proteínas de la Membrana/genética , Mutación , Lipofuscinosis Ceroideas Neuronales/genética , Secuencia de Aminoácidos , Secuencia de Bases , ADN Complementario , Exones , Finlandia , Humanos , Proteínas de Membrana de los Lisosomas , Datos de Secuencia Molecular , Eliminación de Secuencia , Distribución TisularRESUMEN
Cytosine methylation of mammalian DNA is essential for the proper epigenetic regulation of gene expression and maintenance of genomic integrity. To define the mechanism through which demethylated cells die, and to establish a paradigm for identifying genes regulated by DNA methylation, we have generated mice with a conditional allele for the maintenance DNA methyltransferase gene Dnmt1. Cre-mediated deletion of Dnmt1 causes demethylation of cultured fibroblasts and a uniform p53-dependent cell death. Mutational inactivation of Trp53 partially rescues the demethylated fibroblasts for up to five population doublings in culture. Oligonucleotide microarray analysis showed that up to 10% of genes are aberrantly expressed in demethylated fibroblasts. Our results demonstrate that loss of Dnmt1 causes cell-type-specific changes in gene expression that impinge on several pathways, including expression of imprinted genes, cell-cycle control, growth factor/receptor signal transduction and mobilization of retroelements.
Asunto(s)
Apoptosis , Metilación de ADN , Regulación de la Expresión Génica , Genoma , Impresión Genómica , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Virales , Alelos , Animales , Sitios de Ligazón Microbiológica/genética , División Celular , Línea Celular Transformada , Células Cultivadas , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Evolución Molecular , Fibroblastos , Eliminación de Gen , Perfilación de la Expresión Génica , Genes de Partícula A Intracisternal/genética , Integrasas/genética , Integrasas/metabolismo , Ratones , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/análisis , ARN Mensajero/genética , Recombinación Genética/genética , Células Madre/enzimología , Células Madre/metabolismoRESUMEN
Individuals inheriting the same mutation predisposing to cancer may show very different outcomes, ranging from early aggressive cancer to disease-free survival. Experimental mouse models can provide a powerful tool to identify factors in the environment and genetic background that account for such modifications. The Min mouse strain, in which the ApcMin mutation disrupts the mouse homologue of the human familial polyposis gene, develops intestinal neoplasms whose multiplicity is strongly affected by genetic background. We previously mapped a strong modifier locus, Mom1 (modifier of Min-1), to a 4-cM region on mouse chromosome 4 containing a candidate gene Pla2g2a encoding a secretory phospholipase. Here, we report that a cosmid transgene overexpressing Pla2g2a caused a reduction in tumour multiplicity and size, comparable to that conferred by a single copy of the resistance allele of Mom1. These results offer strong evidence that this secretory phospholipase can provide active tumour resistance. The association of Pla2g2a with Mom1 thus withstands a strong functional test and is likely to represent the successful identification of a polymorphic quantitative trait locus in mammals.
Asunto(s)
Mapeo Cromosómico , Genes Supresores de Tumor , Neoplasias Intestinales/genética , Fosfolipasas A/genética , Poliposis Adenomatosa del Colon/genética , Animales , Secuencia de Bases , Cartilla de ADN , Genes APC , Genotipo , Humanos , Inmunidad Innata , Ratones , Ratones Endogámicos AKR , Ratones Transgénicos , Datos de Secuencia Molecular , Fosfolipasas A/análisis , Fosfolipasas A/biosíntesis , Reacción en Cadena de la PolimerasaRESUMEN
We describe a technique, genetically directed representational difference analysis (GDRDA), for specifically generating genetic markers linked to a trait of interest. GDRDA is applicable, in principle, to virtually any organism, because it requires neither prior knowledge of the chromosomal location of the gene controlling the trait nor the availability of a pre-existing genetic map. Based on a subtraction technique described recently called representational difference analysis, GDRDA uses the principles of transmission genetics to create appropriate Tester and Driver samples for subtraction. We demonstrate the usefulness of GDRDA by, for example, successfully targeting three polymorphisms to an interval of less than 1 cM of the mouse nude locus of chromosome 11.
Asunto(s)
Ligamiento Genético , Marcadores Genéticos , Técnicas Genéticas , Polimorfismo Genético , Animales , Secuencia de Bases , Mapeo Cromosómico , Clonación Molecular , Cruzamientos Genéticos , Cartilla de ADN/genética , Femenino , Masculino , Ratones , Ratones Endogámicos/genética , Ratones Desnudos/genética , Técnicas de Sonda Molecular , Datos de Secuencia MolecularRESUMEN
Airway hyperresponsiveness is a key characteristic of human asthma and a marker for asthma-like conditions in animals. F1 mice derived from A/J and C57BL/6J display a phenotype which resembles the asthma-like phenotype of the A/J mice. Since airway responsiveness failed to segregate as a mendelian trait, we show significant linkage at two loci, Bhr1 (lod = 3.0) and Bhr2 (lod = 3.7) on chromosomes 2 and 15. A third locus, Bhr3 (lod = 2.83), maps to chromosome 17. Each of these loci maps near candidate loci implicated in the pathobiology of asthma. Our study represents the first linkages established through a genome-wide survey of airway hyperresponsiveness in any mammal.
Asunto(s)
Asma/genética , Asma/fisiopatología , Mapeo Cromosómico , Pulmón/fisiología , Pruebas de Función Respiratoria , Análisis de Varianza , Animales , Cruzamientos Genéticos , ADN/análisis , ADN/aislamiento & purificación , Femenino , Ligamiento Genético , Genotipo , Humanos , Riñón/metabolismo , Escala de Lod , Pulmón/efectos de los fármacos , Masculino , Mamíferos , Cloruro de Metacolina/farmacología , Ratones , Ratones Endogámicos A , Ratones Endogámicos C57BL , Parasimpaticomiméticos/farmacología , Fenotipo , Pletismografía , Reacción en Cadena de la PolimerasaRESUMEN
Non-insulin dependent diabetes mellitus (NIDDM) is a major public health problem, but its aetiology remains poorly understood. We have performed a comprehensive study of the genetic basis of diabetes in the Goto-Kakizaki (GK) rat, the most widely used animal model of non-obese NIDDM. The genetic dissection of NIDDM using this model has allowed us to map three independent loci involved in the disease. In addition, we identify a major factor affecting body weight, but not glucose tolerance, on chromosome 7 and map a further 10 regions that are suggestive for linkage. We conclude that NIDDM is polygenic and fasting hyperglycaemia and postprandial hyperglycaemia clearly have distinct genetic bases.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Ratas Mutantes/genética , Animales , Secuencia de Bases , Peso Corporal , Mapeo Cromosómico , Cartilla de ADN/química , Modelos Animales de Enfermedad , Ayuno , Femenino , Ligamiento Genético , Glucosa/metabolismo , Hiperglucemia/genética , Insulina/genética , Masculino , Datos de Secuencia Molecular , Ratas , Ratas Endogámicas F344RESUMEN
Early outgrowth of the vertebrate embryonic limb requires signalling by the apical ectodermal ridge (AER) to the progress zone (PZ), which in response proliferates and lays down the pattern of the presumptive limb in a proximal to distal progression. Signals from the PZ maintain the AER until the anlagen for the distal phalanges have been formed. The semidominant mouse mutant dactylaplasia (Dac) disrupts the maintenance of the AER, leading to truncation of distal structures of the developing footplate, or autopod. Adult Dac homozygotes thus lack hands and feet except for malformed single digits, whereas heterozygotes lack phalanges of the three middle digits. Dac resembles the human autosomal dominant split hand/foot malformation (SHFM) diseases. One of these, SHFM3, maps to chromosome 10q24 (Refs 6,7), which is syntenic to the Dac region on chromosome 19, and may disrupt the orthologue of Dac. We report here the positional cloning of Dac and show that it belongs to the F-box/WD40 gene family, which encodes adapters that target specific proteins for destruction by presenting them to the ubiquitination machinery. In conjuction with recent biochemical studies, this report demonstrates the importance of this gene family in vertebrate embryonic development.
Asunto(s)
Extremidades/embriología , Deformidades Congénitas de las Extremidades/genética , Proteínas/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Mapeo Cromosómico , Proteínas F-Box , Heterocigoto , Humanos , Mesodermo/metabolismo , Ratones , Ratones Endogámicos BALB C , Modelos Genéticos , Datos de Secuencia Molecular , Familia de Multigenes , Mutación , Homología de Secuencia de Aminoácido , Factores de Tiempo , Distribución TisularRESUMEN
The genetics of asthma and atopy have been difficult to determine because these diseases are genetically heterogeneous and modified by environment. The pedigrees in our study (n=86) originate in eastern central Finland (Kainuu province). According to census records, this region had only 200 households (2,000 inhabitants) in the mid sixteenth to mid seventeenth centuries. The current population of 100,000 represents the expansion of these founders within the past 400 years. Because this population is relatively homogeneous, we hypothesized that the molecular genetic mechanisms underlying asthma might also have reduced heterogeneity and therefore be easier to dissect than in mixed populations. A recent twin family study supported a strong genetic component for asthma in Finland. We carried out a genome-wide scan for susceptibility loci in asthma in the Kainuu subpopulation. We identified two regions of suggestive linkage and studied them further with higher-density mapping. We obtained evidence for linkage in a 20-cM region of chromosome 7p14-p15 for three phenotypes: asthma, a high level of immunoglobulin E (IgE; atopy) and the combination of the phenotypes. The strongest linkage was seen for high serum IgE (non-parametric linkage (NPL) score 3.9, P=0.0001), exceeding the threshold for genome-wide significance based on simulations. We also observed linkage between this locus and asthma or atopy in two independent data sets.
Asunto(s)
Asma/genética , Cromosomas Humanos Par 7/genética , Efecto Fundador , Hipersensibilidad Inmediata/genética , Asma/epidemiología , Mapeo Cromosómico , Femenino , Finlandia/epidemiología , Ligamiento Genético , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Genoma Humano , Humanos , Hipersensibilidad Inmediata/epidemiología , Inmunoglobulina E , Masculino , LinajeRESUMEN
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS or SACS) is an early onset neurodegenerative disease with high prevalence (carrier frequency 1/22) in the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region of Quebec. We previously mapped the gene responsible for ARSACS to chromosome 13q11 and identified two ancestral haplotypes. Here we report the cloning of this gene, SACS, which encodes the protein sacsin. The ORF of SACS is 11,487 bp and is encoded by a single gigantic exon spanning 12,794 bp. This exon is the largest to be identified in any vertebrate organism. The ORF is conserved in human and mouse. The putative protein contains three large segments with sequence similarity to each other and to the predicted protein of an Arabidopsis thaliana ORF. The presence of heat-shock domains suggests a function for sacsin in chaperone-mediated protein folding. SACS is expressed in a variety of tissues, including the central nervous system. We identified two SACSmutations in ARSACS families that lead to protein truncation, consistent with haplotype analysis.
Asunto(s)
Ataxia/genética , Cromosomas Humanos Par 13 , Proteínas de Choque Térmico/genética , Mutación , Sistemas de Lectura Abierta , Degeneraciones Espinocerebelosas/genética , Secuencia de Aminoácidos , Animales , Arabidopsis/genética , Secuencia de Bases , Mapeo Cromosómico , Exones , Proteínas de Choque Térmico/química , Humanos , Desequilibrio de Ligamiento , Ratones , Datos de Secuencia Molecular , Prevalencia , Quebec/epidemiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Alineación de Secuencia , Homología de Secuencia de AminoácidoRESUMEN
Spondylocostal dysostosis (SD, MIM 277300) is a group of vertebral malsegmentation syndromes with reduced stature resulting from axial skeletal defects. SD is characterized by multiple hemivertebrae, rib fusions and deletions with a non-progressive kyphoscoliosis. Cases may be sporadic or familial, with both autosomal dominant and autosomal recessive modes of inheritance reported. Autosomal recessive SD maps to a 7.8-cM interval on chromosome 19q13.1-q13.3 that is homologous with a mouse region containing a gene encoding the Notch ligand delta-like 3 (Dll3). Dll3 is mutated in the X-ray-induced mouse mutant pudgy (pu), causing a variety of vertebrocostal defects similar to SD phenotypes. Here we have cloned and sequenced human DLL3 to evaluate it as a candidate gene for SD and identified mutations in three autosomal recessive SD families. Two of the mutations predict truncations within conserved extracellular domains. The third is a missense mutation in a highly conserved glycine residue of the fifth epidermal growth factor (EGF) repeat, which has revealed an important functional role for this domain. These represent the first mutations in a human Delta homologue, thus highlighting the critical role of the Notch signalling pathway and its components in patterning the mammalian axial
Asunto(s)
Disostosis/genética , Proteínas de la Membrana/genética , Costillas/anomalías , Escoliosis/genética , Columna Vertebral/anomalías , Adulto , Animales , Niño , Cromosomas Humanos Par 19/genética , Clonación Molecular , Secuencia Conservada , Análisis Mutacional de ADN , Disostosis/diagnóstico por imagen , Disostosis/etiología , Femenino , Ligamiento Genético , Humanos , Lactante , Recién Nacido , Péptidos y Proteínas de Señalización Intracelular , Masculino , Ratones , Datos de Secuencia Molecular , Mutación , Linaje , Estructura Terciaria de Proteína/genética , Radiografía , Receptores Notch , Costillas/diagnóstico por imagen , Escoliosis/diagnóstico por imagen , Escoliosis/etiología , Homología de Secuencia de Aminoácido , Transducción de Señal/genética , Columna Vertebral/diagnóstico por imagenRESUMEN
Pudgy (pu) homozygous mice exhibit clear patterning defects at the earliest stages of somitogenesis, resulting in adult mice with severe vertebral and rib deformities. By positional cloning and complementation, we have determined that the pu phenotype is caused by a mutation in the delta-like 3 gene (Dll3), which is homologous to the Notch-ligand Delta in Drosophila. Histological and molecular marker analyses show that the pu mutation disrupts the proper formation of morphological borders in early somite formation and of rostral-caudal compartment boundaries within somites. Viability analysis also indicates an important role in early development. The results point to a key role for a Notch-signalling pathway in the initiation of patterning of vertebrate paraxial mesoderm.
Asunto(s)
Glicosiltransferasas , Proteínas de la Membrana/genética , Proteínas de la Membrana/fisiología , Mutación , Somitos/fisiología , Empalme Alternativo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Mapeo Cromosómico , ADN Complementario , Péptidos y Proteínas de Señalización Intracelular , Ratones , Datos de Secuencia Molecular , Proteínas/metabolismoRESUMEN
Radiation hybrid (RH) maps are a useful tool for genome analysis, providing a direct method for localizing genes and anchoring physical maps and genomic sequence along chromosomes. The construction of a comprehensive RH map for the human genome has resulted in gene maps reflecting the location of more than 30,000 human genes. Here we report the first comprehensive RH map of the mouse genome. The map contains 2,486 loci screened against an RH panel of 93 cell lines. Most loci (93%) are simple sequence length polymorphisms (SSLPs) taken from the mouse genetic map, thereby providing direct integration between these two key maps. We performed RH mapping by a new and efficient approach in which we replaced traditional gel- or hybridization-based assays by a homogeneous 5'-nuclease assays involving a single common probe for all genetic markers. The map provides essentially complete connectivity and coverage across the genome, and good resolution for ordering loci, with 1 centiRay (cR) corresponding to an average of approximately 100 kb. The RH map, together with an accompanying World-Wide Web server, makes it possible for any investigator to rapidly localize sequences in the mouse genome. Together with the previously constructed genetic map and a YAC-based physical map reported in a companion paper, the fundamental maps required for mouse genomics are now available.
Asunto(s)
Técnicas Genéticas , Genoma , Ratones/genética , Mapeo Físico de Cromosoma , Animales , Escala de Lod , Modelos Genéticos , Modelos Estadísticos , Polimorfismo GenéticoRESUMEN
Genetic association studies are viewed as problematic and plagued by irreproducibility. Many associations have been reported for type 2 diabetes, but none have been confirmed in multiple samples and with comprehensive controls. We evaluated 16 published genetic associations to type 2 diabetes and related sub-phenotypes using a family-based design to control for population stratification, and replication samples to increase power. We were able to confirm only one association, that of the common Pro12Ala polymorphism in peroxisome proliferator-activated receptor-gamma(PPARgamma) with type 2 diabetes. By analysing over 3,000 individuals, we found a modest (1.25-fold) but significant (P=0.002) increase in diabetes risk associated with the more common proline allele (85% frequency). Moreover, our results resolve a controversy about common variation in PPARgamma. An initial study found a threefold effect, but four of five subsequent publications failed to confirm the association. All six studies are consistent with the odds ratio we describe. The data implicate inherited variation in PPARgamma in the pathogenesis of type 2 diabetes. Because the risk allele occurs at such high frequency, its modest effect translates into a large population attributable risk-influencing as much as 25% of type 2 diabetes in the general population.