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OBJECTIVE: Metabolic dysfunction characterized by insulin resistance (IR) is an important risk factor for type-2 diabetes and coronary artery disease (CAD). The aim of this study was to determine if clinical lifestyle interventions differing in scope and intensity improve IR, defined by the lipoprotein IR (LPIR) score, in individuals differing in the severity of metabolic dysfunction. METHODS: Subjects with diagnosed type-2 diabetes, CAD or significant risk factors participated in one of two clinical lifestyle modification interventions: (i) intensive non-randomized programme with a strict vegetarian diet (n = 90 participants, 90 matched controls) or (ii) moderate randomized trial following a Mediterranean-style diet (n = 89 subjects, 58 controls). On-treatment and intention-to-treat analyses assessed changes over 1 year in LPIR, lipoprotein profiles and metabolic risk factors in intervention participants and controls in both programmes. RESULTS: In the on-treatment analysis, both interventions led to weight loss: [-8.9% (95% CI, -10.3 to -7.4), intensive programme; -2.8% (95% CI, -3.8 to -1.9), moderate programme; adjusted P < 0.001] and a decrease in the LPIR score [-13.3% (95% CI, -18.2 to -8.3), intensive; -8.8% (95% CI, -12.9 to -4.7), moderate; adjusted P < 0.01] compared with respective controls. Of the six lipoprotein parameters comprising LPIR, only large very-low-density lipoprotein particle concentrations decreased significantly in participants compared with controls in both programmes [-26.3% (95% CI, -43.0 to -9.6), intensive; -14.2% (95% CI, -27.4 to -1.0), moderate; P < 0.05]. Intention-to-treat analysis confirmed and strengthened the primary results. CONCLUSION: A stringent lifestyle modification intervention with a vegetarian diet and a moderate lifestyle modification intervention following a Mediterranean diet were both effective for improving IR defined by the LPIR score.
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BACKGROUND AND AIMS: Insulin and leptin are important markers of insulin resistance and vascular inflammation in metabolic and cardiovascular diseases. This study evaluated changes in circulating levels of insulin and leptin during a cardiovascular health program to improve our understanding of cardiometabolic risk reduction. METHODS AND RESULTS: Participants (n=76) completed a prospective, nonrandomized program designed to stabilize or reverse progression of coronary artery disease through dietary changes, exercise, stress management, and group support. Controls (n=76) were matched to participants based on age, gender, and disease status. Traditional cardiovascular risk factors were assessed at baseline, 12 weeks, and 52 weeks by standard methods. Dietary data were collected by 72-h recall and evaluated by Food Processor® v8.4.0. Ultrasensitive insulin and leptin levels were measured by radioimmunoassay. Participants successfully reduced their total caloric intake from >2000 calories per day to ≈ 1700 calories per day (p<0.05 compared to controls), lowered daily fat intake by >60% (p<0.001 compared to controls), and increased carbohydrate intake by >30% (p<0.001). Repeated-measures ANOVA indicated significant beneficial changes (p<0.001 compared to controls) in plasma insulin (-19%) and leptin (-33%) during the lifestyle program, as well as improvement in traditional cardiovascular risk factors. Response was similar between men and women for most risk factors and was not markedly influenced by medication use. CONCLUSION: Lifestyle changes focusing on diet, physical activity, and stress reduction can successfully modify both cardiovascular and metabolic risk factors, with the potential to mediate cardiometabolic risk through beneficial anti-inflammatory and anti-oxidative effects on the vasculature.
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Enfermedades Cardiovasculares/prevención & control , Enfermedad de la Arteria Coronaria/terapia , Dieta con Restricción de Grasas , Dieta Vegetariana , Ejercicio Físico , Grupos de Autoayuda , Estrés Psicológico/prevención & control , Anciano , Índice de Masa Corporal , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Estudios de Cohortes , Terapia Combinada , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/prevención & control , Dieta Reductora , Femenino , Humanos , Estudios Longitudinales , Masculino , Síndrome Metabólico/epidemiología , Síndrome Metabólico/prevención & control , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/dietoterapia , Pennsylvania/epidemiología , Estudios Prospectivos , Factores de Riesgo , Caracteres Sexuales , Estrés Psicológico/terapiaAsunto(s)
ADN/aislamiento & purificación , Disección/instrumentación , Disección/métodos , Rayos Láser , Adhesión en Parafina/métodos , Algoritmos , Separación Celular/instrumentación , Separación Celular/métodos , ADN/ultraestructura , Terapia por Láser/instrumentación , Terapia por Láser/métodos , Micromanipulación/instrumentación , Micromanipulación/métodosRESUMEN
Breast cancer is a complex disease that still imposes a significant healthcare burden on women worldwide. The etiology of breast cancer is not known but significant advances have been made in the area of early detection and treatment. The advent of advanced molecular biology techniques, mapping of the human genome and availability of high throughput genomic and proteomic strategies opens up new opportunities and will potentially lead to the discovery of novel biomarkers for early detection and prognostication of breast cancer. Currently, many biomarkers, particularly the hormonal and epidermal growth factor receptors, are being utilized for breast cancer prognosis. Unfortunately, none of the biomarkers in use have sufficient diagnostic, prognostic and/or predictive power across all categories and stages of breast cancer. It is recognized that more useful information can be generated if tumors are interrogated with multiple markers. But choosing the right combination of biomarkers is challenging, because 1) multiple pathways are involved, 2) up to 62 genes and their protein products are potentially involved in breast cancer-related mechanisms and 3) the more markers evaluated, the more the time and cost involved. This review summarizes the current literature on selected biomarkers for breast cancer, discusses the functional relationships, and groups the selected genes based on a Gene Ontology classification.
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Biomarcadores de Tumor/clasificación , Biomarcadores de Tumor/genética , Neoplasias de la Mama Masculina/diagnóstico , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias de la Mama Masculina/genética , Ciclo Celular , Mapeo Cromosómico/métodos , Femenino , Hormonas , Humanos , MasculinoRESUMEN
BACKGROUND: The beta2-adrenergic receptor (ADRB2) plays a major role in regulating energy expenditure by stimulating lipid metabolism in human adipose tissue. Polymorphisms in the ADRB2 gene have been associated with obesity and various weight-related traits in cross-sectional studies of adults, but little is known about the effects of the ADRB2 gene on childhood obesity or the propensity to gain weight over time. OBJECTIVE: To assess the effects of a polymorphism in codon 16 (Arg16-->Gly) of the ADRB2 gene, which has been associated with a decrease in beta2-receptor density and efficiency, on longitudinal changes in obesity from childhood to young adulthood in a biracial cohort. DESIGN: Seven cross-sectional screenings of children and five cross-sectional screenings of young adults who were previously examined as children produced longitudinal data from childhood to young adulthood. METHODS: Height, weight and subscapular and triceps skinfolds were measured by trained examiners following identical protocols over the course of the study. Gender- and age-stratified analyses using random coefficients models were used to examine longitudinal genetic effects on obesity in 1151 African-American and Caucasian males and females who attended an average of six examinations over a 24 y period from childhood to young adulthood. RESULTS: Age-stratified analyses showed no clear genetic relationships with changes in obesity measures over time in females, but an age-dependent association was observed in males, where the relationship between the Arg16Gly polymorphism and obesity became stronger with age. In males who were 4-9 y of age at the beginning of the study in 1973, body mass index (BMI) was 4% higher in Gly/Gly and Arg/Gly males compared to those with Arg/Arg by 26 y of age. Subscapular skinfold measurements in Gly/Gly males became significantly different from Arg/Arg males (20% higher) by age 20. In the oldest male cohort (10-14 y of age in 1973), BMI increased at a significantly greater rate (0.4%/y) in males carrying the Gly16 form of the receptor relative to Arg/Arg males. BMI was significantly different between homozygous genotypes by approximately 26 y of age, and reached 8% higher in Gly/Gly males by age 32. Subscapular skinfolds also increased at a significantly greater rate (2%/y) in Gly/Gly males compared to Arg/Arg males, becoming significantly different (27%) by approximately 22 y of age and reaching a maximum difference of 50% by age 32. CONCLUSIONS: Our data suggest that the beta2-adrenergic receptor is associated with the propensity to gain weight from childhood to young adulthood in males. An increased understanding of genetic influences on the development of obesity may improve the effectiveness of interventions designed to reduce excess body weight and help define the role of genetic factors in diabetes and cardiovascular disease.
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Obesidad/genética , Polimorfismo Genético , Grupos Raciales , Receptores Adrenérgicos beta 2/genética , Alelos , Población Negra , Estatura , Índice de Masa Corporal , Peso Corporal , Niño , Preescolar , Estudios de Cohortes , Estudios Transversales , Metabolismo Energético , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Estudios Longitudinales , Masculino , Mutación , Obesidad/prevención & control , Receptores Adrenérgicos beta 2/fisiología , Caracteres Sexuales , Grosor de los Pliegues Cutáneos , Aumento de Peso/genética , Población BlancaRESUMEN
The effects of the lipoprotein lipase (LPL) Serine 447 Stop (S447X) polymorphism on high-density lipoprotein cholesterol (HDLC) and triglycerides (TG) have been demonstrated. However, little is known about its effect on the tracking of HDLC and TG over time and familial risk of coronary artery disease (CAD). This aspect was examined in black and white individuals (n=829) aged 5-18 year at baseline, followed on average 18.8 yr. The frequency of the X447 allele was lower in Blacks than Whites (0.043 vs. 0.087, P=0.002). Carriers vs. noncarriers of the X447 allele had lower TG (99.3 vs 122.1 mg/dl, P<0.01) and higher HDLC (51.1 vs. 49.7 mg/dl, P<0.05) in adulthood, but not in childhood. The trends in genotype-specific means of childhood and adulthood levels of HDLC and TG in sex or race subgroups were similar to those in the total sample. With respect to tracking over time, of those in the bottom quartile of HDLC in childhood, 46.1% of the noncarriers vs. 23.1% of the carriers remained in this lowest quartile into adulthood (P=0.03); corresponding values for the top quartile of HDLC were 37.5% for the noncarriers vs. 57.1% for the carriers (P=0.03). Although TG tended to track better among the carriers in the bottom quartile and among the noncarriers in the top quartile, this trend was not significant. Carriers showed lower prevalence of parental history of CAD than noncarriers (6.9% vs. 14.1%, P=0.02) independently of lipoprotein variables, adiposity, blood pressure, age, sex and race. Thus, the X447 allele of the LPL gene is associated with an increase in HDLC and a decrease in TG in adults, tracking of HDLC since childhood, and a lower family history of CAD.
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HDL-Colesterol/análisis , Enfermedad de la Arteria Coronaria/genética , Lipoproteína Lipasa/genética , Serina/genética , Triglicéridos/análisis , Adolescente , Adulto , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/epidemiología , Estudios Transversales , Recolección de Datos , Femenino , Predisposición Genética a la Enfermedad , Variación Genética , Humanos , Masculino , Probabilidad , Regiones Promotoras Genéticas , Sensibilidad y EspecificidadRESUMEN
Impaired endothelial function with decreased nitric oxide production is shared by insulin resistance and essential hypertension. Although there are limited data on the association between the endothelial nitric oxide synthase (eNOS) G894T polymorphism and hypertension, information is absent on the combined effects of eNOS G894T genotype and insulin resistance status on blood pressure (BP) levels and the familial risk of hypertension. This aspect was examined in a community-based sample of 1021 unrelated African American and white young adults aged 19 to 38 years. African Americans displayed a lower frequency of the T894 allele than whites (0.105 v 0.324, P < .001). After adjusting for sex, age, and body mass index (BMI), noncarriers versus carriers of the T894 allele had significantly higher systolic (SBP), diastolic (DBP) BP and mean arterial pressure (MAP) levels (111.7 v 109.2 mm Hg for SBP; 73.6 v 72.3 mm Hg for DBP; 86.3 v 84.6 mm Hg for MAP), with both African Americans and whites showing similar trends. This association was modulated by insulin resistance status, measured by the homeostasis model assessment of insulin resistance (HOMA IR) using fasting insulin and glucose. Subjects with high insulin resistance (above the median HOMA IR) showed significantly greater differences in BP levels between noncarriers and carriers of the T894 allele. Furthermore, the G894T genotype and insulin resistance also showed a combined effect on the prevalence of parental hypertension, a measure of familial risk, with noncarriers versus carriers in the high insulin resistance group showing higher prevalence (70.5% v 51.3%, P = .006, adjusted for race). Thus, the allelic variation (G894T) in the eNOS gene locus in conjunction with insulin resistance may be one factor contributing to the predisposition to hypertension.
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Presión Sanguínea , Endotelio Vascular/enzimología , Hipertensión/genética , Resistencia a la Insulina , Óxido Nítrico Sintasa/genética , Polimorfismo Genético , Adolescente , Adulto , Población Negra , Estudios Transversales , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Hipertensión/epidemiología , Masculino , Padres , Prevalencia , Riesgo , Estados Unidos , Población BlancaRESUMEN
Development and progression of atherosclerosis involves recruitment and binding of circulating leukocytes to areas of inflammation within the vascular endothelium mediated by a diverse array of cellular adhesion molecules. A polymorphism in the endothelial-leukocyte adhesion molecule 1 (E-selectin) gene has been implicated in early-onset, angiographically defined, severe atherosclerotic disease because it profoundly affects ligand recognition and binding specificity, resulting in a significant increase in cellular adhesion. Relationships between the E-selectin S128R polymorphism and coronary artery calcification (CAC), a marker of atherosclerosis detected with noninvasive electron beam computed tomography, were examined in 294 asymptomatic women aged 40--88 years and 314 asymptomatic men aged 30--80 years from the Epidemiology of Coronary Artery Calcification Study. The E-selectin polymorphism was not associated with presence of CAC in men of any age or in women over age 50. In women 50 years of age or younger the E-selectin polymorphism was significantly associated with presence of CAC after adjustment for age, body mass index, systolic blood pressure, ratio of total cholesterol to high-density lipoprotein cholesterol, and smoking. The significant association between E-selectin and CAC in women 50 years of age or younger may suggest that the 128R allele is a risk factor for coronary atherosclerosis in younger asymptomatic women, who typically have lower levels of traditional risk factors and reduced adhesion molecule expression due to the presence of higher levels of endogenous hormones.
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Calcinosis/genética , Cardiomiopatías/genética , Vasos Coronarios/patología , Selectina E/genética , Polimorfismo Genético , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento , Arterias/patología , Calcinosis/fisiopatología , Cardiomiopatías/fisiopatología , Selectina E/metabolismo , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Caracteres Sexuales , Estadística como AsuntoRESUMEN
PURPOSE: To outline potential benefits of integrating recent developments in bioinformatics and statistical genetics with traditional epidemiologic studies to localize genes influencing complex phenotypes and examine genetic effects on disease susceptibility. METHODS: An overview of bioinformatic and statistical approaches for localizing disease-susceptibility genes as well as challenges associated with identifying functional DNA variants and context-dependent genetic effects concludes this three-part series on the importance of genetics in epidemiologic research. RESULTS: Rapidly evolving bioinformatic and statistical methods are providing invaluable information on newly-discovered genes and molecular variation influencing human diseases that is readily available to epidemiologic researchers. CONCLUSIONS: Integrating bioinformatics and molecular biotechnology with epidemiologic methods of assessing disease risk is rapidly expanding our ability to identify genetic influences on complex human diseases. These technological advances are likely to have a profound impact on current knowledge of complex disease etiology, and may reveal novel approaches to disease treatment and prevention.
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Computación en Informática Médica , Epidemiología Molecular/métodos , Interpretación Estadística de Datos , Bases de Datos Factuales , Ligamiento Genético , Predisposición Genética a la Enfermedad , Humanos , MutaciónRESUMEN
BACKGROUND: Susceptibility to common chronic diseases such as coronary heart disease (CHD) appears to be influenced by "context-dependent effects," which include interactions among genes (genetic epistasis) and among genes and environmental factors (gene-environment interactions). METHODS: A synthesis of current knowledge and research findings demonstrates the importance of integrating genetic research on cardiovascular disease with preventive medicine and public health initiatives. RESULTS: A variety of candidate genes have been implicated in risk for CHD, but only limited examples of context-dependent effects have been described. Interactions between genetic and environmental factors appear to influence lipid metabolism, plasma homocysteine levels, and pharmacologic response to many commonly prescribed medications. Quantification of genetic effects associated with increased disease risk that are modifiable by interventions such as diet, exercise, and smoking cessation is an important interface between molecular genetics and preventive medicine. CONCLUSIONS: As a primary focus of preventive medicine expands to encompass early detection and treatment of asymptomatic individuals at risk for disease, the ability to quantify the influence of context-dependent effects on disease risk will be critical for determining drug safety and effectiveness in diverse patient populations and for implementing effective prevention and treatment programs.
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Enfermedad Coronaria/genética , Enfermedad Coronaria/prevención & control , Ambiente , Predisposición Genética a la Enfermedad/genética , Genética Médica , Estilo de Vida , Biología Molecular , Medicina Preventiva , Enfermedad Coronaria/tratamiento farmacológico , Pruebas Genéticas , Variación Genética/genética , Humanos , Mutación/genética , Prevención Primaria , Factores de RiesgoRESUMEN
PURPOSE: To provide a synthesis of current approaches to the discovery of genes associated with complex human diseases by examining the joint potential of traditional epidemiologic methods and current molecular techniques for gene discovery. METHODS: A discussion of optimal approaches for defining complex disease phenotypes in genetic epidemiology, ascertainment strategies for estimating genetic influences on disease risk, genomic approaches for localizing complex-disease-susceptibility genes, and the potential synergistic effects of integrating genetic and traditional epidemiologic expertise is provided in the second part of a three-part series on the importance of genetics in epidemiologic research. RESULTS: The ability to quantify genetic influences on disease risk appears highly dependent on the measurement of specific risk factor traits, ascertainment strategies for recruiting study subjects, and a variety of genomic approaches that are rapidly facilitating our ability to identify genes influencing inherited human diseases and to quantify genetic influences on disease risk. CONCLUSIONS: Integrating population-based methods of assessing disease risk with human genetics and genome technology is critical for identifying genetic polymorphisms that influence risk of disease and for defining genetic effects on complex disease etiology.
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Mapeo Cromosómico/métodos , Biología Molecular/tendencias , Epidemiología Molecular/tendencias , Proyectos de Investigación/normas , Salud de la Familia , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Genética de Población , Humanos , Fenotipo , Vigilancia de la Población/métodos , Terminología como AsuntoRESUMEN
PURPOSE: To define a general framework of current approaches to the discovery of disease-associated genes and the role of genetic factors in influencing disease risk through the integration of genome technology and traditional epidemiologic methods. METHODS: An overview of basic concepts in human genetics, laboratory methodology for measuring genetic variation believed to influence common diseases, and issues concerning preparation and utilization of genetic materials is provided as a foundation for genetic epidemiologic research. RESULTS: Identification and characterization of human genetic variation is providing new risk factors for disease in the form of DNA sequence variation. The availability of genetic material from participants in large epidemiologic studies and appropriate informed consent represents an invaluable resource for exploring genetic and environmental influences on disease risk. CONCLUSIONS: Advances in genome technology coupled with vast amounts of genetic data resulting from the Human Genome Project are broadening the scope of epidemiologic research and providing tools to identify individuals at increased risk of disease. Combining diverse expertise from the fields of epidemiology and human genetics provides unique opportunities to localize disease-susceptibility genes and examine molecular mechanisms of complex disease etiology.
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Epidemiología , Técnicas Genéticas , Genética Médica , Biología Molecular , ADN/aislamiento & purificación , Epidemiología/legislación & jurisprudencia , Ética , Marcadores Genéticos , Genética Médica/legislación & jurisprudencia , Humanos , Polimorfismo GenéticoRESUMEN
Non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is a common disorder of middle-aged individuals characterized by high blood glucose levels which, if untreated, can cause serious medical complications and lead to early death. Genetic factors play an important role in determining susceptibility to this disorder. However, the number of genes involved, their chromosomal location and the magnitude of their effect on NIDDM susceptibility are unknown. We have screened the human genome for susceptibility genes for NIDDM using non-and quasi-parametric linkage analysis methods in a group of Mexican American affected sib pairs. One marker, D2S125, showed significant evidence of linkage to NIDDM and appears to be a major factor affecting the development of diabetes mellitus in Mexican Americans. We propose that this locus be designated NIDDM1.
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Cromosomas Humanos Par 2 , Diabetes Mellitus Tipo 2/genética , Americanos Mexicanos/genética , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/etnología , Ligamiento Genético , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Japón , Población BlancaRESUMEN
DNA sequence data from introns, flanking regions, and the eta globin pseudogene region all show a significantly higher rate of nucleotide substitution in the Old World monkey lineage than in the human lineage after the separation of the two lineages, or, in other words, the data support the hominoid rate-slowdown hypothesis. Data from both protein sequences and DNA sequences show that the rate of evolution is significantly higher in the rodent lineage than in the primate lineage. Furthermore, DNA sequences from introns show that the rate of nucleotide substitution is at least two times higher in rodents than in higher primates. The male-to-female ratio of mutation rate is estimated to be between 3 and 6 in higher primates, whereas it is only 2 in mice and rats. These ratios are similar to the corresponding male-to-female ratios of germ cell divisions in higher primates and in rodents, suggesting that errors in DNA replication during germ cell division are the primary source of mutation, or, in other words, mutation is largely DNA replication-dependent. This conclusion provides further support for the generation-time effect hypothesis.
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Evolución Molecular , Primates/genética , Roedores/genética , Animales , ADN/genética , Femenino , Globinas/genética , Hominidae/genética , Humanos , Intrones , Masculino , Ratones , Modelos Genéticos , Mutación , Seudogenes , Ratas , Cromosomas Sexuales/genética , Factores de TiempoRESUMEN
Rapid discoveries of novel and unexpected disease-associated genes for atherosclerotic coronary artery disease (CAD) are anticipated as genomic maps become more detailed and methods for mapping complex disease phenotypes become more refined. Although establishing association or linkage of a marker locus to a CAD susceptibility gene is an important first step, the long-term goal should be to define the underlying functional mutations and explore possible disease mechanisms, including the gene-environment interactions that culminate in clinically apparent disease. This review will define a contemporary research paradigm for study of the genetics of CAD and other common chronic diseases using the tools of modern molecular biology and human genetics.
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Arteriosclerosis/genética , Enfermedad Coronaria/genética , Animales , Enfermedad Crónica , HumanosRESUMEN
Variable number of tandem repeat (VNTR) loci typically exhibit high rates of germline mutations that alter allele length and thus are ideal models for examining processes governing repeat sequence instability. We have characterized by nucleotide sequencing the internal structure of the apolipoprotein B (Apo B) 3' VNTR in a sample of same- and different-sized alleles previously associated with flanking marker haplotypes. Significant linkage disequilibrium between flanking polymorphisms and minisatellite alleles excludes unequal recombination as the predominant mechanism of mutation at the Apo B VNTR and is consistent with intra-allelic mutational processes such as replication slippage and/or unequal sister chromatid exchange. Diversity among different length alleles was distinctly polar and was usually attributable to changes in copy number at one particular repeat sequence. Analysis of predicted secondary structures for the dimeric repeats demonstrated a relationship between variability and the potential to form self-complementary intermediates. Preferential instability of the variable repeat: (i) was a function of its location within the tandem array; (ii) was not solely dependent on copy number; and (iii) may be related to the base composition of the VNTR and the degree of self-complementarity between the dimeric repeat sequences. The data suggest that polarized variability may be independent of the mutational process(es) generating length variation at minisatellite loci and suggest a possible alternative mechanism of mutation that involves the formation of secondary structures.
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Apolipoproteínas B/genética , Repeticiones de Minisatélite , Alelos , Secuencia de Bases , ADN/química , ADN/genética , Cartilla de ADN/genética , Haplotipos , Humanos , Desequilibrio de Ligamiento , Datos de Secuencia Molecular , Conformación de Ácido Nucleico , Reacción en Cadena de la PolimerasaRESUMEN
The genomes of homeothermic (warm-blooded) vertebrates are mosaic interspersions of homogeneously GC-rich and GC-poor regions (isochores). Evolution of genome compartmentalization and GC-rich isochores is hypothesized to reflect either selective advantages of an elevated GC content or chromosome location and mutational pressure associated with the timing of DNA replication in germ cells. To address the present controversy regarding the origins and maintenance of isochores in homeothermic vertebrates, newly obtained as well as published nucleotide sequences of the insulin and insulin-like growth factor (IGF) genes, members of a well-characterized gene family believed to have evolved by repeated duplication and divergence, were utilized to examine the evolution of base composition in nonconstrained (flanking) and weakly constrained (introns and fourfold degenerate sites) regions. A phylogeny derived from amino acid sequences supports a common evolutionary history for the insulin/IGF family genes. In cold-blooded vertebrates, insulin and the IGFs were similar in base composition. In contrast, insulin and IGF-II demonstrate dramatic increases in GC richness in mammals, but no such trend occurred in IGF-I. Base composition of the coding portions of the insulin and IGF genes across vertebrates correlated (r = 0.90) with that of the introns and flanking regions. The GC content of homologous introns differed dramatically between insulin/IGF-II and IGF-I genes in mammals but was similar to the GC level of noncoding regions in neighboring genes. Our findings suggest that the base composition of introns and flanking regions is determined by chromosomal location and the mutational pressure of the isochore in which the sequences are embedded. An elevated GC content at codon third positions in the insulin and the IGF genes may reflect selective constraints on the usage of synonymous codons.
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Composición de Base/genética , Evolución Biológica , Factor II del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/genética , Insulina/genética , Animales , Secuencia de Bases , Variación Genética , Humanos , Intrones , Mamíferos/genética , Datos de Secuencia Molecular , Familia de Multigenes , Filogenia , Relaxina/genética , Secuencias Repetitivas de Ácidos Nucleicos , Mapeo Restrictivo , Vertebrados/genéticaRESUMEN
Nucleotide sequences were obtained from the approximately 1.7 kb intron 7 of the insulin-like growth factor II gene in human and representatives of both Old World and New World monkeys and analyzed with additional published noncoding regions (both introns and flanking regions) that differ substantially in base composition (GC content). Relative rate tests, utilized to examine differential rates of molecular evolution between humans and Old World monkeys, support the hypothesis that the rate of nucleotide substitution is slower in humans than in Old World monkeys. Comparisons of approximately 4,300 nucleotide positions revealed a significantly higher evolutionary rate in the Old World monkey lineage than in the human lineage for both intron sequences and flanking regions. The data indicate that the molecular clock hypothesis is not applicable to the human and Old World monkey lineages and that the hominoid rate slowdown is a general phenomenon--it is not unique to a particular gene region and is not influenced by regional differences in base composition.