RESUMO
BACKGROUND: In a previous work, we found linkage and association of type 1 diabetes (T1D) to a 12 known gene region at chromosome 2p25 in Colombian families. Here, we present further work on this candidate region. MATERIALS AND METHODS: Seventeen SNPs located on the 12 candidate genes, in 100 familial trios set, were tested by ARMS-tetraprimer-PCR or PCR-RFLP. Five extra SNPs in the vicinity of rs10186193 were typed. A replica phase included 97 novel familial trios, in whom diabetes-related auto-antibodies (AABs) were tested in sera of the patients. In addition to transmission disequilibrium tests, haplotype analyses were carried out using the unphased software. RESULTS: SNP rs10186193 (at RNASEH1 gene) showed association with T1D (P = 0.005). The additional five SNPs revealed that rs7607888 (P = 2.03 × 10-7), rs55981318 (P = 0.018), and rs1136545 (P = 1.93 × 10-9) were also associated with T1D. Haplotype analysis showed association for rs55981318-rs10186193 (P = 0.0005), rs7563960-rs7607888 (P = 0.0007), rs7607888-rs1136545 (P = 9.21 × 10-10), and rs1136545-rs11538545 (P = 6.67 × 10-8). In contrast, the new set of 97 familial trios tested for SNPs rs55981318, rs10186193, and rs7607888 did not support the previous finding; however, by combining the sample (197 trios), evidence of association of T1D with rs55981318 and rs7607888 was conclusive. In addition, a two-loci haplotype analysis of the combined sample showed significant association of RNASEH1 with T1D (P = 3.1 × 10-5). CONCLUSION: In conclusion, our analyses suggest that RNASEH1 gene variants associate with susceptibility/protection to T1D in Colombia.
Assuntos
Diabetes Mellitus Tipo 1/genética , Polimorfismo de Nucleotídeo Único , Ribonuclease H/genética , Adulto , Criança , Colômbia/epidemiologia , Diabetes Mellitus Tipo 1/epidemiologia , Família , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Fragmento de RestriçãoRESUMO
Congenital aniridia is a rare genetic disorder characterized by varying degrees of iris hypoplasia that are associated with additional ocular abnormalities. More than 90% of the causal mutations identified are found in the PAX6 gene, a transcription factor of critical importance in the process of neurogenesis and ocular development. Here, we investigate clinical, molecular, and craniofacial features of a large Brazilian family with congenital aniridia. Among the 56 eyes evaluated, phenotype variation encompassed bilateral total aniridia to mild iris defects with extensive variation between eyes of the same individual. PAX6 molecular screening indicated a heterozygous splice mutation (c.141 + 1G>A). Thus, we hypothesize that this splicing event may cause variation in the expression of the wild-type transcript, which may lead to the observed variation in phenotype. Affected individuals were more brachycephalic, even though their face height and cephalic circumference were not significantly different when compared to those of non-affected relatives. From this, we infer that the head shape of affected subjects may also be a result of the PAX6 splice-site mutation. Our data summarize the clinical variability associated with the ocular phenotype in a large family with aniridia, and help shed light on the role of PAX6 in neurocranial development.
Assuntos
Aniridia/genética , Aniridia/patologia , Anormalidades Craniofaciais/patologia , Anormalidades do Olho/patologia , Proteínas do Olho/genética , Proteínas de Homeodomínio/genética , Fatores de Transcrição Box Pareados/genética , Fenótipo , Proteínas Repressoras/genética , Adolescente , Adulto , Idoso , Análise de Variância , Sequência de Bases , Brasil , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação/genética , Fator de Transcrição PAX6 , Linhagem , Análise de Sequência de DNARESUMO
BACKGROUND/AIMS: Bipolar disorder (BP) is a severe psychiatric illness, characterised by alternating episodes of depression and mania, which ranks among the top ten causes of morbidity and life-long disability world-wide. We have previously performed a whole-genome linkage scan on 6 pedigrees segregating severe BP from the well-characterised population isolate of Antioquia, Colombia. We recently collected genotypes for the same set of 382 autosomal microsatellite markers in 9 additional Antioquian BP pedigrees. Here, we report the analysis of the combined pedigree set. METHODS: Linkage analysis using both parametric and nonparametric approaches was conducted for 3 different diagnostic models: severe BP only (BPI); mood disorders (BPI, BPII and major depression); and psychosis (operationally defined by the occurrence of at least 1 episode of hallucinations and/or delusions). RESULTS AND CONCLUSION: For BPI only, the most interesting result was obtained for chromosome 7p21.1-p22.2 under a recessive model of inheritance (heterogeneity LOD score = 2.80), a region that had previously been linked to BP in a study on Portuguese Island families. For both BPI and mood disorders, nonparametric analyses identified a locus on chromosome 12ct-q14 (nonparametric linkage = 2.55 and 2.35, respectively). This locus has not previously been reported as a candidate region for BP. Additional candidate regions were found on chromosomes 1p22-31 (mood disorders) and 21q21-22 (BPI), 2 loci that have repeatedly been implicated in BP susceptibility. Linkage analysis of psychosis as a phenotype identified candidate regions on chromosomes 2q24-31 and 16p12-q12. The finding on chromosome 16p is noteworthy because the same locus has been implicated by genome-wide association analyses of BP.
Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos Par 16 , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 21 , Cromossomos Humanos Par 7 , Adolescente , Adulto , Mapeamento Cromossômico , Colômbia , Feminino , Ligação Genética , Humanos , Masculino , Linhagem , Adulto JovemRESUMO
AIMS/HYPOTHESIS: Type 2 diabetes is more prevalent in US American minority populations of African or Native American descent than it is in European Americans. However, the proportion of this epidemiological difference that can be ascribed to genetic or environmental factors is unknown. To determine whether genetic ancestry is correlated with diabetes risk in Latinos, we estimated the proportion of European ancestry in case-control samples from Mexico and Colombia in whom socioeconomic status had been carefully ascertained. METHODS: We genotyped 67 ancestry-informative markers in 499 participants with type 2 diabetes and 197 controls from Medellín (Colombia), as well as in 163 participants with type 2 diabetes and 72 controls from central Mexico. Each participant was assigned a socioeconomic status scale via various measures. RESULTS: Although European ancestry was associated with lower diabetes risk in Mexicans (OR [95% CI] 0.06 [0.02-0.21], p = 2.0 x 10(-5)) and Colombians (OR 0.26 [0.08-0.78], p = 0.02), adjustment for socioeconomic status eliminated the association in the Colombian sample (OR 0.64 [0.19-2.12], p = 0.46) and significantly attenuated it in the Mexican sample (OR 0.17 [0.04-0.71], p = 0.02). Adjustment for BMI did not change the results. CONCLUSIONS/INTERPRETATION: The proportion of non-European ancestry is associated with both type 2 diabetes and lower socioeconomic status in admixed Latino populations from North and South America. We conclude that ancestry-directed search for genetic markers associated with type 2 diabetes in Latinos may benefit from information involving social factors, as these factors have a quantitatively important effect on type 2 diabetes risk relative to ancestry effects.
Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Hispânico ou Latino/estatística & dados numéricos , Fatores Socioeconômicos , Colômbia/epidemiologia , Diabetes Mellitus Tipo 2/economia , Diabetes Mellitus Tipo 2/genética , Humanos , México/epidemiologia , Grupos Raciais/estatística & dados numéricos , Estados Unidos/epidemiologia , População BrancaRESUMO
We previously reported linkage of bipolar disorder to 5q33-q34 in families from two closely related population isolates, the Central Valley of Costa Rica (CVCR) and Antioquia, Colombia (CO). Here we present follow up results from fine-scale mapping in large CVCR and CO families segregating severe bipolar disorder, BP-I, and in 343 population trios/duos from CVCR and CO. Employing densely spaced SNPs to fine map the prior linkage peak region increases linkage evidence and clarifies the position of the putative BP-I locus. We performed two-point linkage analysis with 1134 SNPs in an approximately 9 Mb region between markers D5S410 and D5S422. Combining pedigrees from CVCR and CO yields a LOD score of 4.9 at SNP rs10035961. Two other SNPs (rs7721142 and rs1422795) within the same 94 kb region also displayed LOD scores greater than 4. This linkage peak coincides with our prior microsatellite results and suggests a narrowed BP-I susceptibility regions in these families. To investigate if the locus implicated in the familial form of BP-I also contributes to disease risk in the population, we followed up the family results with association analysis in duo and trio samples, obtaining signals within 2 Mb of the peak linkage signal in the pedigrees; rs12523547 and rs267015 (P = 0.00004 and 0.00016, respectively) in the CO sample and rs244960 in the CVCR sample and the combined sample, with P = 0.00032 and 0.00016, respectively. It remains unclear whether these association results reflect the same locus contributing to BP susceptibility within the extended pedigrees.
Assuntos
Indígena Americano ou Nativo do Alasca/genética , Transtorno Bipolar/genética , Cromossomos Humanos Par 5/genética , Ligação Genética , Linhagem , Colômbia , Costa Rica , Família , Feminino , Frequência do Gene , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , América Latina , Escore Lod , Masculino , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
INTRODUCTION: Gilles de la Tourette Syndrome (GTS) is a chronic neuropsychiatric disorder characterized by phonic and motor tics. Although its physiopathologic bases are unknown, the cortical-striatal-thalamic-cortical circuit has been studied. The association of GTS with attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), motors tics (MT) or phonics tics (PT), the high family aggregation, and the concordance studies in twins, support the genetics bases of this disorder. Currently, GTS is accepted as a complex disorder and the associated disorders could be alternative expressions of the same syndrome. AIM: To evaluate genetic linkage to 2p11, 6p24, 11q23, 20q13 and 21q22 regions in an Antioquian family with enough power to detect linkage. PATIENTS AND METHODS: With the Linkage program and using autosomic dominant, recessive and additive inheritance models, the genetic linkage was calculated; two phenotypic spectra was considered: one broad spectrum including affected individuals with GTS, ADHD, OCD, MT, and PT, and a narrow spectrum with only GTS. RESULTS: The most probable inheritance pattern for a susceptibility locus in GTS and its associated disorders in this family is autosomic additive. The presence of a locus involved in GTS in the 2p11 region has been rejected. CONCLUSION: The linkage values for D20S1085 and D6S477 markers are suggestive and therefore it is not possible reject that these markers will be in linkage disequilibrium with genes involved in the GTS, ADHD, OCD, MT, and PT etiology.
Assuntos
Família , Síndrome de Tourette/genética , Adolescente , Criança , Pré-Escolar , Colômbia , Feminino , Ligação Genética , Genótipo , Humanos , Escore Lod , Masculino , Linhagem , Fenótipo , Síndrome de Tourette/fisiopatologiaRESUMO
Three related patients from Colombia presented with a juvenile-onset neuronal ceroid lipofuscinosis. Electron microscopy of one case showed condensed fingerprint profiles, and genetic analyses identified a novel missense mutation in CLN5. The authors demonstrate the existence of pathogenic CLN5 mutations outside northern Europe and that mutations in this gene can lead to an atypical late-onset neuronal ceroid lipofuscinosis disease, in addition to the late infantile form first described in Finland.
Assuntos
Proteínas de Membrana/genética , Mutação de Sentido Incorreto , Lipofuscinoses Ceroides Neuronais/genética , Mutação Puntual , Sequência de Aminoácidos , Animais , Cegueira/genética , Criança , Códon/genética , Colômbia/epidemiologia , Consanguinidade , Progressão da Doença , Éxons/genética , Feminino , Heterogeneidade Genética , Humanos , Proteínas de Membrana Lisossomal , Masculino , Proteínas de Membrana/química , Proteínas de Membrana/deficiência , Microscopia Eletrônica , Dados de Sequência Molecular , Lipofuscinoses Ceroides Neuronais/epidemiologia , Linhagem , Fenótipo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Vertebrados/genéticaRESUMO
Generalized epilepsy with febrile seizures plus (GEFS+) is an inherited epileptic syndrome with a marked clinical and genetic heterogeneity. Here we report the molecular characterization of a large pedigree with a severe clinical form of GEFS+. Genetic linkage analysis implied the involvement of the FEB3 in the disease phenotype of this family (parametric two-point lod-score of 2.2). Sequencing of the SCN1A gene revealed a novel aspartic acid for glycine substitution at position 1742 of this sodium channel subunit. The amino-acid replacement lies in the pore-forming region of domain IV of SCN1A. Our observations are consistent with the genotype-phenotype correlation studies suggesting that mutations in the pore-forming loop of SCN1A can lead to a clinically more severe epileptic syndrome.
Assuntos
Epilepsia Generalizada/genética , Proteínas do Tecido Nervoso/genética , Mutação Puntual/genética , Convulsões Febris , Canais de Sódio/genética , Adulto , Idade de Início , Substituição de Aminoácidos , Ácido Aspártico/genética , Criança , Pré-Escolar , Análise Mutacional de DNA , Epilepsia Generalizada/complicações , Epilepsia Generalizada/etnologia , Ligação Genética/genética , Genótipo , Glicina/genética , Humanos , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Canal de Sódio Disparado por Voltagem NAV1.1 , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Convulsões Febris/complicações , Convulsões Febris/etnologia , Convulsões Febris/genética , Índice de Gravidade de Doença , América do SulRESUMO
It has been proposed that women had a higher migration rate than men throughout human evolutionary history. However, in a recent study of South American natives using mtDNA restriction fragment polymorphisms and Y-chromosome microsatellites we failed to detect a significant difference in estimates of migration rates between the sexes. As the high mutation rate of microsatellites might affect estimates of population structure, we now examine biallelic polymorphisms in both mtDNA and the Y-chromosome. Analyses of these markers in Amerinds from North, Central and South America agree with our previous findings in not supporting a higher migration rate for women in these populations. Furthermore, they underline the importance of genetic drift in the evolution of Amerinds and suggest the existence of a North to South gradient of increasing drift in the Americas.
Assuntos
Cromossomos Humanos Y , DNA Mitocondrial/genética , Genética Populacional , Indígenas Norte-Americanos/genética , Polimorfismo Genético , Emigração e Imigração , Evolução Molecular , Frequência do Gene/genética , Haplótipos/genética , Humanos , Masculino , Polimorfismo de Fragmento de RestriçãoRESUMO
We report the genetic characterization of one family with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) type 1 and two families with BPES type 2 from a historically isolated population in northwest Colombia. Linkage and haplotype analyses indicate that BPES in these families is linked to 3q23. Mutation screening of FOXL2 in the family with BPES type 1 revealed a novel 394C --> T nonsense mutation which deletes the forkhead DNA binding domain. The two families with BPES type 2 both carry an in-frame 30 bp duplication that leads to the elongation of a polyalanine tract. This duplication has been previously reported in Europe, where recurrent mutation has been demonstrated in unrelated familial and sporadic BPES cases. The recurrent nature of this duplication seems to relate to the secondary structure of this DNA region. The genotype-phenotype correlation seen in the Colombian families is consistent with the recent proposal that BPES type 1 is caused by truncating mutations leading to haploinsufficiency, while BPES type 2 is due to mutations generating elongated protein products.
Assuntos
Blefarofimose/genética , Blefaroptose/genética , Cromossomos Humanos Par 3 , Proteínas de Ligação a DNA/genética , Pálpebras/anormalidades , Mutação , Fatores de Transcrição/genética , Colômbia/etnologia , Feminino , Proteína Forkhead Box L2 , Fatores de Transcrição Forkhead , Ligação Genética , Marcadores Genéticos , Haplótipos , Humanos , Masculino , LinhagemRESUMO
Objetivos: Caracterizar una muestra de familias y tríos de una población colombiana aislada para mapear loci involucrados en la vulnerabilidad al Trastorno Afectivo Bipolar tipo I (TAB- I). Métodos: Se recolectan tríos y genealogías utilizando las entrevistas FIGS-DIGS en miembros de las familias y posibles afectados. El poder para detectar ligamiento (PDL) se estima por simulación. El modelo utilizado asume una frecuencia para el alelo afectado de 0.003, penetrancias de 0.01,0.81 y 0.9 y un marcador de cuatro alelos a 5cM del locus. Resultados: Se identificaron 28 familias con TAB-I, con 3.603 individuos y 160 afectados, y 246 tríos. Asumiendo homogeneidad genética y teniendo en cuenta la evidencia genética del mestizaje, las simulaciones mostraron PDL significativos de 100 por ciento para un LOD-score>3. Estamos examinando el desequilibrio promedio en tríos y tamizando en familias los cromosomas 12,18 y 21. Conclusión: Tenemos un grupo significativo de familias y trios pertenecientes a una población aislada con un poder para detectar ligamiento al Trastorno Afectivo Bipolar. Esto permite realizar estudios de ligamiento buscando genes involucrados en la vulnerabilidad al TAB-I en población Colombiana
Assuntos
Transtorno BipolarRESUMO
We report the molecular characterization of three multiplex families and a sporadic case of juvenile Parkinsonism identified in the province of Antioquia (Colombia). Linkage and haplotype analysis using markers in 6q25.2-27 indicated that Parkinsonism in the pedigrees is linked to the parkin gene (maximum LOD-score of 3.85) but that they carry two different mutant haplotypes. Sequence analysis revealed a novel G to A transition in exon 6 at position 736 (G736A) of parkin. This change results in a non-conservative cysteine for tyrosine substitution. All affected individuals from two families were homozygous for this mutation, which was not detected in 100 normal controls. Patients from the family carrying the second haplotype and the sporadic case were homozygous for a GT insertion in exon 3. This mutation has been previously identified in French families with juvenile Parkinsonism. The concomitant presence of founder effects and allelic heterogeneity in Antioquia might relate to the founding admixture at the origin of this population.
Assuntos
Efeito Fundador , Ligases/genética , Transtornos Parkinsonianos/genética , Mutação Puntual , Adolescente , Adulto , Idade de Início , Alelos , Colômbia , Cisteína/genética , Saúde da Família , Feminino , Heterogeneidade Genética , Humanos , Masculino , Linhagem , Tirosina/genética , Ubiquitina-Proteína LigasesRESUMO
The short variant of a functional length polymorphism in the promoter region of the serotonin transporter has been associated with several behavioural and psychiatric traits, including bipolar mood disorder. The same short allele has also been implicated as a modifier of the bipolar phenotype. Here we evaluate the etiologic/modifier role of this polymorphism in a case (N=103) / control (N=112) sample for bipolar mood disorder (type I) collected from an isolated South American population. We did not detect an association between bipolar disorder and the 5-HTT promoter polymorphism in this sample. However, an excess of the short allele was seen in younger cases and in cases with psychotic symptoms. When combined with data from the literature, the increased frequency of the short allele in patients with psychotic symptoms was statistically significant.
Assuntos
Transtorno Bipolar/genética , Proteínas de Transporte/genética , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Polimorfismo Genético/genética , Idade de Início , Alelos , Transtorno Bipolar/epidemiologia , Colômbia/epidemiologia , Frequência do Gene , Ligação Genética , Genética Populacional , Humanos , Razão de Chances , Regiões Promotoras Genéticas/genética , Proteínas da Membrana Plasmática de Transporte de SerotoninaRESUMO
To evaluate sex-specific differences in gene flow between Native American populations from South America and between those populations and recent immigrants to the New World, we examined the genetic diversity at uni- and biparental genetic markers of five Native American populations from Colombia and in published surveys from native South Americans. The Colombian populations were typed for five polymorphisms in mtDNA, five restriction sites in the beta-globin gene cluster, the DQA1 gene, and nine autosomal microsatellites. Elsewhere, we published results for seven Y-chromosome microsatellites in the same populations. Autosomal polymorphisms showed a mean G(ST) of 6.8%, in agreement with extensive classical marker studies of South American populations. MtDNA and Y-chromosome markers resulted in G(ST) values of 0.18 and 0.165, respectively. When only Y chromosomes of confirmed Amerind origin were used in the calculations (as defined by the presence of allele T at locus DYS199), G(ST) increased to 0.22. G(ST) values calculated from published data for other South American natives were 0.3 and 0.29 for mtDNA and Amerind Y chromosomes, respectively. The concordance of these estimates does not support an important difference in migration rates between the sexes throughout the history of South Amerinds. Admixture analysis of the Colombian populations suggests an asymmetric pattern of mating involving mostly immigrant men and native women.
Assuntos
DNA Mitocondrial/genética , Variação Genética/genética , Indígenas Sul-Americanos/genética , Filogenia , Caracteres Sexuais , Cromossomo Y/genética , África , Censos , Colômbia , Emigração e Imigração , Europa (Continente) , Feminino , Frequência do Gene/genética , Pool Gênico , Globinas/genética , Antígenos HLA-DQ/genética , Cadeias alfa de HLA-DQ , Haplótipos/genética , Humanos , Linguística , Masculino , Repetições de Microssatélites/genética , Família Multigênica/genética , Polimorfismo de Fragmento de Restrição , América do SulRESUMO
Historical and genetic evidences suggest that the recently founded population of Antioquia (Colombia) is potentially useful for the genetic mapping of complex traits. This population was established in the 16th-17th centuries through the admixture of Amerinds, Europeans, and Africans and grew in relative isolation until the late 19th century. To examine the origin of the founders of Antioquia, we typed 11 markers on the nonrecombining portion of the Y chromosome and four markers on mtDNA in a sample of individuals with confirmed Antioquian ancestry. The polymorphisms on the Y chromosome (five biallelic markers and six microsatellites) allow an approximation to the origin of founder men, and those on mtDNA identify the four major founder Native American lineages. These data indicate that approximately 94% of the Y chromosomes are European, 5% are African, and 1% are Amerind. Y-chromosome data are consistent with an origin of founders predominantly in southern Spain but also suggest that a fraction came from northern Iberia and that some possibly had a Sephardic origin. In stark contrast with the Y-chromosome, approximately 90% of the mtDNA gene pool of Antioquia is Amerind, with the frequency of the four Amerind founder lineages being closest to Native Americans currently living in the area. These results indicate a highly asymmetric pattern of mating in early Antioquia, involving mostly immigrant men and local native women. The discordance of our data with blood-group estimates of admixture suggests that the number of founder men was larger than that of women.
Assuntos
Efeito Fundador , Indígenas Sul-Americanos/genética , Filogenia , Caracteres Sexuais , População Branca/genética , África do Norte , Alelos , Viés , Colômbia , DNA Mitocondrial/genética , Feminino , Frequência do Gene/genética , Haplótipos/genética , Humanos , Masculino , Repetições de Microssatélites/genética , Polimorfismo Genético/genética , Espanha , Cromossomo Y/genéticaRESUMO
We studied 46 unrelated sickle cell anemia patients from the western region of Colombia which has the largest Black population of the country. Twenty-three children and 23 adults were studied. The distribution of haplotypes in the children was 58% Bantu, 38% Benin, and 4% Senegal, and in the adults it was 59.4% Bantu, 35.1% Benin, and 5.5% Senegal (p = 0.920). All 92 chromosomes had typical African haplotypes, Bantu 55.5%, Benin 34.8%, Senegal, 4.3%, and Cameroon, 5.4%. Our results suggest a lack of differential survival among patients with sickle cell anemia and typical beta-globin gene cluster haplotypes. They also agree closely with historical data that indicate that most African slaves brought to Colombia originated from Angola (Bantu population) and the Sao Thomó Island in the Bight of Benin (Central West Africa).
Assuntos
Anemia Falciforme/genética , Globinas/genética , Haplótipos/genética , Adolescente , Adulto , África/etnologia , Fatores Etários , Anemia Falciforme/epidemiologia , Criança , Pré-Escolar , Colômbia/epidemiologia , Etnicidade/genética , Frequência do Gene , Humanos , Família MultigênicaRESUMO
Recently, Y chromosome markers have begun to be used to study Native American origins. Available data have been interpreted as indicating that the colonizers of the New World carried a single founder haplotype. However, these early studies have been based on a few, mostly complex polymorphisms of insufficient resolution to determine whether observed diversity stems from admixture or diversity among the colonizers. Because the interpretation of Y chromosomal variation in the New World depends on founding diversity, it is important to develop marker systems with finer resolution. Here we evaluate the hypothesis of a single-founder Y haplotype for Amerinds by using 11 Y-specific markers in five Colombian Amerind populations. Two of these markers (DYS271, DYS287) are reliable indicators of admixture and detected three non-Amerind chromosomes in our sample. Two other markers (DYS199, M19) are single-nucleotide polymorphisms mostly restricted to Native Americans. The relatedness of chromosomes defined by these two markers was evaluated by constructing haplotypes with seven microsatellite loci (DYS388 to 394). The microsatellite backgrounds found on the two haplogroups defined by marker DYS199 demonstrate the existence of at least two Amerind founder haplotypes, one of them (carrying allele DYS199 T) largely restricted to Native Americans. The estimated age and distribution of these haplogroups places them among the founders of the New World.
Assuntos
Variação Genética , Indígenas Sul-Americanos/genética , Repetições de Microssatélites , Filogenia , Cromossomo Y/genética , Colômbia , Marcadores Genéticos , Haplótipos , Humanos , MasculinoRESUMO
OBJECTIVE AND METHODS: We have analyzed a set of multigenerational extended pedigrees ascertained from affected cases of idiopathic epilepsy in the Antioquian Neurologic Institute. All pedigrees show familial aggregation of several forms of non myoclonic idiopathic epilepsy. In a recent paper, we have demonstrated that generalized idiopathic epilepsy of the awakening type is better explained by the existence of a major gene. In this paper, we have explored by simulation techniques the usefulness of the bigger pedigrees for linkage analysis. By using simlink and taking into account the parameters of the major gene, we have estimated that total power of three families is approximately 100 million times favoring the linkage detection. RESULTS AND CONCLUSIONS: These analyses suggest that the major gene accounting by the susceptibility to develop generalized idiopathic epilepsy of the awakening type could be localized by typifying affected families belonging to the Paisa community from Antioquia, Colombia (Acta Neurol Colomb 1997; 13: 69-75).
Assuntos
Epilepsia Generalizada/epidemiologia , Epilepsia Generalizada/genética , Triagem de Portadores Genéticos , Ligação Genética/genética , Modelos Genéticos , Família Multigênica/genética , Adolescente , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Colômbia/epidemiologia , Eletroencefalografia , Epilepsia Generalizada/diagnóstico , Feminino , Testes Genéticos , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Fenótipo , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVES: To characterize clinical features of a very large pedigree with early-onset Alzheimer disease (AD) in which all affected individuals carry the identical glutamic acid-to-alanine mutation at codon 280 in the presenilin-1 gene. DESIGN: Clinical histories were obtained by patient and family interviews and through medical or civil records. Using standard diagnostic criteria, a case series of 128 individuals was identified, of which 6 have definitive (autopsy-proven) early-onset AD, 93 have probable early-onset AD, and 29 have possible early-onset AD. SETTING: Community based in Antioquia, Colombia. PATIENTS: A population-based sample in which all members of 5 extended families (nearly 3000 individuals) were surveyed. Criteria for inclusion required obtaining sufficient information to categorize the individual as affected. MAIN OUTCOME MEASURES: Age at onset, neuropsychological profile, neurologic history, and examination. RESULTS: The patients had a mean age at onset of 46.8 years (range, 34-62 years). The average interval until death was 8 years. Headache was noted in affected individuals significantly more frequently than in those not affected. The most frequent presentation was memory loss followed by behavior and personality changes and progressive loss of language ability. In the final stages, gait disturbances, seizures, and myoclonus were frequent. CONCLUSIONS: Other than the early onset, this clinical phenotype is indistinguishable from sporadic AD except that affected individuals frequently complained of headache preceding and during the disease. Despite the uniform genetic basis for the disease, there was significant variability in the age at onset, suggesting an important role for environmental factors or genetic modifiers in determining the age at onset.