RESUMEN
Since 2005, genome-wide association (GWA) datasets have been largely biased toward sampling European ancestry individuals, and recent studies have shown that GWA results estimated from self-identified European individuals are not transferable to non-European individuals because of various confounding challenges. Here, we demonstrate that enrichment analyses that aggregate SNP-level association statistics at multiple genomic scales-from genes to genomic regions and pathways-have been underutilized in the GWA era and can generate biologically interpretable hypotheses regarding the genetic basis of complex trait architecture. We illustrate examples of the robust associations generated by enrichment analyses while studying 25 continuous traits assayed in 566,786 individuals from seven diverse self-identified human ancestries in the UK Biobank and the Biobank Japan as well as 44,348 admixed individuals from the PAGE consortium including cohorts of African American, Hispanic and Latin American, Native Hawaiian, and American Indian/Alaska Native individuals. We identify 1,000 gene-level associations that are genome-wide significant in at least two ancestry cohorts across these 25 traits as well as highly conserved pathway associations with triglyceride levels in European, East Asian, and Native Hawaiian cohorts.
Asunto(s)
Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Estudio de Asociación del Genoma Completo/métodos , Humanos , Herencia Multifactorial , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Grupos RacialesRESUMEN
OBJECTIVE: Body mass index (BMI) is commonly used to assess obesity, which is associated with numerous diseases and negative health outcomes. BMI has been shown to be a heritable, polygenic trait, with close to 100 loci previously identified and replicated in multiple populations. We aim to replicate known BMI loci and identify novel associations in a trans-ethnic study population. SUBJECTS: Using eligible participants from the Population Architecture using Genomics and Epidemiology consortium, we conducted a trans-ethnic meta-analysis of 102 514 African Americans, Hispanics, Asian/Native Hawaiian, Native Americans and European Americans. Participants were genotyped on over 200 000 SNPs on the Illumina Metabochip custom array, or imputed into the 1000 Genomes Project (Phase I). Linear regression of the natural log of BMI, adjusting for age, sex, study site (if applicable), and ancestry principal components, was conducted for each race/ethnicity within each study cohort. Race/ethnicity-specific, and combined meta-analyses used fixed-effects models. RESULTS: We replicated 15 of 21 BMI loci included on the Metabochip, and identified two novel BMI loci at 1q41 (rs2820436) and 2q31.1 (rs10930502) at the Metabochip-wide significance threshold (P<2.5 × 10-7). Bioinformatic functional investigation of SNPs at these loci suggests a possible impact on pathways that regulate metabolism and adipose tissue. CONCLUSION: Conducting studies in genetically diverse populations continues to be a valuable strategy for replicating known loci and uncovering novel BMI associations.
Asunto(s)
Índice de Masa Corporal , Grupos Raciales/genética , Grupos Raciales/estadística & datos numéricos , Estudio de Asociación del Genoma Completo , Genómica , Humanos , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
BACKGROUND/OBJECTIVES: Central adiposity measures such as waist circumference (WC) and waist-to-hip ratio (WHR) are associated with cardiometabolic disorders independently of body mass index (BMI) and are gaining clinically utility. Several studies report genetic variants associated with central adiposity, but most utilize only European ancestry populations. Understanding whether the genetic associations discovered among mainly European descendants are shared with African ancestry populations will help elucidate the biological underpinnings of abdominal fat deposition. SUBJECTS/METHODS: To identify the underlying functional genetic determinants of body fat distribution, we conducted an array-wide association meta-analysis among persons of African ancestry across seven studies/consortia participating in the Population Architecture using Genomics and Epidemiology (PAGE) consortium. We used the Metabochip array, designed for fine-mapping cardiovascular-associated loci, to explore novel array-wide associations with WC and WHR among 15 945 African descendants using all and sex-stratified groups. We further interrogated 17 known WHR regions for African ancestry-specific variants. RESULTS: Of the 17 WHR loci, eight single-nucleotide polymorphisms (SNPs) located in four loci were replicated in the sex-combined or sex-stratified meta-analyses. Two of these eight independently associated with WHR after conditioning on the known variant in European descendants (rs12096179 in TBX15-WARS2 and rs2059092 in ADAMTS9). In the fine-mapping assessment, the putative functional region was reduced across all four loci but to varying degrees (average 40% drop in number of putative SNPs and 20% drop in genomic region). Similar to previous studies, the significant SNPs in the female-stratified analysis were stronger than the significant SNPs from the sex-combined analysis. No novel associations were detected in the array-wide analyses. CONCLUSIONS: Of 17 previously identified loci, four loci replicated in the African ancestry populations of this study. Utilizing different linkage disequilibrium patterns observed between European and African ancestries, we narrowed the suggestive region containing causative variants for all four loci.
Asunto(s)
Adiposidad/genética , Población Negra/genética , Variación Genética , Población Blanca/genética , Adulto , Distribución de la Grasa Corporal , Femenino , Predisposición Genética a la Enfermedad/etnología , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Obesidad Abdominal/etnología , Obesidad Abdominal/genética , Polimorfismo de Nucleótido Simple/genética , Relación Cintura-CaderaRESUMEN
STUDY QUESTION: Do genetic associations identified in genome-wide association studies (GWAS) of age at menarche (AM) and age at natural menopause (ANM) replicate in women of diverse race/ancestry from the Population Architecture using Genomics and Epidemiology (PAGE) Study? SUMMARY ANSWER: We replicated GWAS reproductive trait single nucleotide polymorphisms (SNPs) in our European descent population and found that many SNPs were also associated with AM and ANM in populations of diverse ancestry. WHAT IS KNOWN ALREADY: Menarche and menopause mark the reproductive lifespan in women and are important risk factors for chronic diseases including obesity, cardiovascular disease and cancer. Both events are believed to be influenced by environmental and genetic factors, and vary in populations differing by genetic ancestry and geography. Most genetic variants associated with these traits have been identified in GWAS of European-descent populations. STUDY DESIGN, SIZE, DURATION: A total of 42 251 women of diverse ancestry from PAGE were included in cross-sectional analyses of AM and ANM. MATERIALS, SETTING, METHODS: SNPs previously associated with ANM (n = 5 SNPs) and AM (n = 3 SNPs) in GWAS were genotyped in American Indians, African Americans, Asians, European Americans, Hispanics and Native Hawaiians. To test SNP associations with ANM or AM, we used linear regression models stratified by race/ethnicity and PAGE sub-study. Results were then combined in race-specific fixed effect meta-analyses for each outcome. For replication and generalization analyses, significance was defined at P < 0.01 for ANM analyses and P < 0.017 for AM analyses. MAIN RESULTS AND THE ROLE OF CHANCE: We replicated findings for AM SNPs in the LIN28B locus and an intergenic region on 9q31 in European Americans. The LIN28B SNPs (rs314277 and rs314280) were also significantly associated with AM in Asians, but not in other race/ethnicity groups. Linkage disequilibrium (LD) patterns at this locus varied widely among the ancestral groups. With the exception of an intergenic SNP at 13q34, all ANM SNPs replicated in European Americans. Three were significantly associated with ANM in other race/ethnicity populations: rs2153157 (6p24.2/SYCP2L), rs365132 (5q35/UIMC1) and rs16991615 (20p12.3/MCM8). While rs1172822 (19q13/BRSK1) was not significant in the populations of non-European descent, effect sizes showed similar trends. LIMITATIONS, REASONS FOR CAUTION: Lack of association for the GWAS SNPs in the non-European American groups may be due to differences in locus LD patterns between these groups and the European-descent populations included in the GWAS discovery studies; and in some cases, lower power may also contribute to non-significant findings. WIDER IMPLICATIONS OF THE FINDINGS: The discovery of genetic variants associated with the reproductive traits provides an important opportunity to elucidate the biological mechanisms involved with normal variation and disorders of menarche and menopause. In this study we replicated most, but not all reported SNPs in European descent populations and examined the epidemiologic architecture of these early reported variants, describing their generalizability and effect size across differing ancestral populations. Such data will be increasingly important for prioritizing GWAS SNPs for follow-up in fine-mapping and resequencing studies, as well as in translational research.
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Menarquia/genética , Menopausia/genética , Polimorfismo de Nucleótido Simple , Factores de Edad , Estudios Transversales , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Menarquia/etnología , Menopausia/etnologíaRESUMEN
High-resolution genetic linkage maps are indispensable for positional cloning of disease genes. Current procedures for map construction, although aided considerably by many existing computer programs, require extensive user-intervention at each of many repetitive steps. This is time consuming, labour intensive and increases the chance of error. We have developed an expert system computer program, MultiMap, which automates this step-by-step procedure. MultiMap is based on a novel map construction algorithm and allows investigator control of marker locus characteristics, such as informativeness, scorability or distance to nearest neighbours. We used MultiMap to construct a human genetic map at an average resolution of 6 cM, using published genotypes at 1266 microsatellite markers, and further extended this map by adding 397 VNTR and polymorphic gene markers.
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Algoritmos , Mapeo Cromosómico/métodos , Sistemas Especialistas , Ligamiento Genético , Genoma Humano , Cromosomas Humanos , ADN Satélite/genética , Procesamiento Automatizado de Datos/métodos , Femenino , Marcadores Genéticos , Humanos , Funciones de Verosimilitud , Masculino , Polimorfismo Genético , Recombinación GenéticaRESUMEN
Hirschsprung disease (HSCR) is characterized by a congenital absence of enteric ganglia along a variable length of the intestine. Although long considered to be a multifactorial disease, we have identified linkage in a subset of five HSCR families to the pericentromeric region of chromosome 10, thereby providing monogenic inheritance in some families. A maximum two-point lod score of 3.37 (theta = 0.045) was observed between HSCR and D10S176, under an incompletely penetrant dominant model. Multipoint, affecteds-only and non-parametric analyses supported this finding and localize this gene to a region of approximately 7 centiMorgans, in close proximity to the locus for multiple endocrine neoplasia type 2 (MEN2). The co-occurrence of these two entities in some families might be attributable to shared pathogenetic origins.
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Centrómero , Cromosomas Humanos Par 10 , Enfermedad de Hirschsprung/genética , Alelos , Mapeo Cromosómico , Familia , Femenino , Ligamiento Genético , Marcadores Genéticos , Genotipo , Humanos , Masculino , LinajeRESUMEN
The field of phenomics has been investigating network structure among large arrays of phenotypes, and genome-wide association studies (GWAS) have been used to investigate the relationship between genetic variation and single diseases/outcomes. A novel approach has emerged combining both the exploration of phenotypic structure and genotypic variation, known as the phenome-wide association study (PheWAS). The Population Architecture using Genomics and Epidemiology (PAGE) network is a National Human Genome Research Institute (NHGRI)-supported collaboration of four groups accessing eight extensively characterized epidemiologic studies. The primary focus of PAGE is deep characterization of well-replicated GWAS variants and their relationships to various phenotypes and traits in diverse epidemiologic studies that include European Americans, African Americans, Mexican Americans/Hispanics, Asians/Pacific Islanders, and Native Americans. The rich phenotypic resources of PAGE studies provide a unique opportunity for PheWAS as each genotyped variant can be tested for an association with the wide array of phenotypic measurements available within the studies of PAGE, including prevalent and incident status for multiple common clinical conditions and risk factors, as well as clinical parameters and intermediate biomarkers. The results of PheWAS can be used to discover novel relationships between SNPs, phenotypes, and networks of interrelated phenotypes; identify pleiotropy; provide novel mechanistic insights; and foster hypothesis generation. The PAGE network has developed infrastructure to support and perform PheWAS in a high-throughput manner. As implementing the PheWAS approach has presented several challenges, the infrastructure and methodology, as well as insights gained in this project, are presented herein to benefit the larger scientific community.
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Estudios de Asociación Genética/estadística & datos numéricos , Bases de Datos Genéticas , Etnicidad/genética , Variación Genética , Estudio de Asociación del Genoma Completo/estadística & datos numéricos , Humanos , Modelos Genéticos , Modelos Estadísticos , Fenotipo , Polimorfismo de Nucleótido Simple , Grupos Raciales/genéticaRESUMEN
The human genome is thought to harbor 50,000 to 100,000 genes, of which about half have been sampled to date in the form of expressed sequence tags. An international consortium was organized to develop and map gene-based sequence tagged site markers on a set of two radiation hybrid panels and a yeast artificial chromosome library. More than 16,000 human genes have been mapped relative to a framework map that contains about 1000 polymorphic genetic markers. The gene map unifies the existing genetic and physical maps with the nucleotide and protein sequence databases in a fashion that should speed the discovery of genes underlying inherited human disease. The integrated resource is available through a site on the World Wide Web at http://www.ncbi.nlm.nih.gov/SCIENCE96/.
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Mapeo Cromosómico , Genoma Humano , Proyecto Genoma Humano , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Línea Celular , Cromosomas Artificiales de Levadura , Redes de Comunicación de Computadores , ADN Complementario/genética , Bases de Datos Factuales , Expresión Génica , Marcadores Genéticos , Humanos , Familia de Multigenes , ARN Mensajero/genética , Homología de Secuencia de Ácido Nucleico , Lugares Marcados de SecuenciaRESUMEN
A map of 30,181 human gene-based markers was assembled and integrated with the current genetic map by radiation hybrid mapping. The new gene map contains nearly twice as many genes as the previous release, includes most genes that encode proteins of known function, and is twofold to threefold more accurate than the previous version. A redesigned, more informative and functional World Wide Web site (www.ncbi.nlm.nih.gov/genemap) provides the mapping information and associated data and annotations. This resource constitutes an important infrastructure and tool for the study of complex genetic traits, the positional cloning of disease genes, the cross-referencing of mammalian genomes, and validated human transcribed sequences for large-scale studies of gene expression.
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Cromosomas Humanos/genética , Genoma Humano , Mapeo Físico de Cromosoma , Animales , Etiquetas de Secuencia Expresada , Expresión Génica , Marcadores Genéticos , Proyecto Genoma Humano , Humanos , Internet , Ratas , Lugares Marcados de SecuenciaRESUMEN
Schizophrenia has a complex pattern of inheritance, indicative of interactions among multiple genes and environmental factors. The detection and replication of specific susceptibility loci for such complex disorders are facilitated by the availability of large samples of affected sib pairs and their nuclear families, along with standardized assessment and systematic ascertainment procedures. The NIMH Genetics Initiative on Schizophrenia, a multisite collaborative study, was established as a national resource with a centralized clinical data base and cell repository. The Millennium Schizophrenia Consortium has completed a genome-wide scan to detect susceptibility loci for schizophrenia in 244 individuals from the nuclear families of 92 independent pairs of schizophrenic sibs ascertained by the NIMH Genetics Initiative. The 459 marker loci used in the scan were spaced at 10-cM intervals on average. Individuals of African descent were higher than those of European descent in their average heterozygosity (79% vs. 76%, P < .0001) and number of alleles per marker (9.2 vs. 8.4, P < .0001). Also, the allele frequencies of 73% of the marker loci differed significantly (P < .01) between individuals of European and African ancestry. However, regardless of ethnic background, this sample was largely comprised of schizophrenics with more than a decade of psychosis associated with pervasive social and occupational impairment.
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Esquizofrenia/genética , Adolescente , Adulto , Mapeo Cromosómico , Confidencialidad , Femenino , Predisposición Genética a la Enfermedad , Genoma Humano , Genotipo , Humanos , Masculino , National Institutes of Health (U.S.) , Grupos Raciales/genética , Esquizofrenia/diagnóstico , Esquizofrenia/etnología , Estados UnidosRESUMEN
The NIMH Genetics Initiative is a multi-site collaborative study designed to create a national resource for genetic studies of complex neuropsychiatric disorders. Schizophrenia pedigrees have been collected at three sites: Washington University, Columbia University, and Harvard University. This article-one in a series that describes the results of a genome-wide scan with 459 short-tandem repeat (STR) markers for susceptibility loci in the NIMH Genetics Initiative schizophrenia sample-presents results for African-American pedigrees. The African-American sample comprises 30 nuclear families and 98 subjects. Seventy-nine of the family members were considered affected by virtue of having received a DSMIII-R diagnosis of schizophrenia (n = 71) or schizoaffective disorder, depressed (n = 8). The families contained a total of 42 independent sib pairs. While no region demonstrated evidence of significant linkage using the criteria suggested by Lander and Kruglyak, several regions, including chromosomes 6q16-6q24, 8pter-8q12, 9q32-9q34, and 15p13-15q12, showed evidence consistent with linkage (P = 0.01-0.05), providing independent support of findings reported in other studies. Moreover, the fact that different genetic loci were identified in this and in the European-American samples, lends credence to the notion that these genetic differences together with differences in environmental exposures may contribute to the reported differences in disease prevalence, severity, comorbidity, and course that has been observed in different racial groups in the United States and elsewhere.
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Población Negra/genética , Ligamiento Genético , Esquizofrenia/genética , Adolescente , Adulto , Negro o Afroamericano/psicología , Mapeo Cromosómico , Cromosomas Humanos Par 15 , Cromosomas Humanos Par 19 , Cromosomas Humanos Par 4 , Cromosomas Humanos Par 6 , Cromosomas Humanos Par 8 , Cromosomas Humanos Par 9 , Femenino , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , National Institutes of Health (U.S.) , Linaje , Secuencias Repetitivas de Ácidos Nucleicos , Estados UnidosRESUMEN
OBJECTIVES: To identify the chromosomal location of a disease-causing gene and to describe the clinical characteristics of a large family with age-related macular degeneration (ARMD). METHODS: An ARMD pedigree was identified, and the disease state of family members was documented by stereoscopic fundus photography and was classified using a modified version of the Wisconsin Age-Related Maculopathy Grading System. A genome-wide screen at approximately 6-centimorgan spacing using a DNA-pooling strategy combined with shared-segment analysis was used to identify likely chromosomal regions. The entire family was then screened at each likely locus, and 1 positive locus was refined by screening with markers at an average density of 0.5 centimorgan and subjected to parametric linkage analysis. RESULTS: In the 10 affected family members, ARMD was manifest by the presence of large, soft, confluent drusen accompanied by varying degrees of retinal pigment epithelial degeneration and/or geographic atrophy. Age-related macular degeneration segregated as an autosomal-dominant trait, with the disease locus mapping to chromosome 1q25-q31 between markers D1S466 and D1S413, with a multipoint lod score of 3.00. CONCLUSION: Age-related macular degeneration localized to chromosome 1q25-q31 (gene symbol, ARMD1) as a dominant trait in a large family with a predominantly dry phenotype. CLINICAL RELEVANCE: Identification of ARMD genes will facilitate early diagnosis and aid in understanding the molecular pathophysiological mechanisms of ARMD. This knowledge will contribute to the development of preventive and improved treatment strategies.
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Cromosomas Humanos Par 1/genética , Ligamiento Genético/genética , Degeneración Macular/genética , Degeneración Macular/patología , Anciano , Anciano de 80 o más Años , Alelos , ADN/análisis , Femenino , Fondo de Ojo , Marcadores Genéticos , Genotipo , Humanos , Escala de Lod , Masculino , Persona de Mediana Edad , Linaje , Retina/patologíaAsunto(s)
Mapeo Cromosómico , Bases de Datos Factuales , Animales , Clonación Molecular , Biología Computacional , Citogenética , ADN/genética , Ligamiento Genético , Marcadores Genéticos , Genoma Humano , Humanos , Células Híbridas , Ratones , National Library of Medicine (U.S.) , Polimorfismo Genético , Análisis de Secuencia de ADN , Estados UnidosRESUMEN
UNLABELLED: MAP-O-MAT is a web-based server for automated linkage mapping of human polymorphic DNA markers. MAP-O-MAT facilitates the verification of order and map distances for custom mapping sets using genotype data from the CEPH database, and from the Marshfield, SNP Consortium and Rutgers linkage maps (exclusive to the deCODE genotyping data). The CRI-MAP program is used for likelihood calculations and some mapping algorithms, and physical map positions are provided from the human genome assembly. AVAILABILITY: MAP-O-MAT is located at http://compgen.rutgers.edu/mapomat/ CONTACT: matise@biology.rutgers.edu.
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Mapeo Cromosómico/métodos , Marcadores Genéticos/genética , Internet , Alineación de Secuencia/métodos , Análisis de Secuencia de ADN/métodos , Programas Informáticos , Interfaz Usuario-ComputadorRESUMEN
Two tests for allelic association were applied to a simulated complex disease for the Genetic Analysis Workshop 9. The transmission/disequilibrium test [Spielman et al., 1993] and the haplotype-based haplotype relative risk approach [Terwilliger and Ott, 1992] were used to detect disease-associated alleles in a set of 360 computer-simulated markers located on six chromosomes and genotyped in 200 nuclear families. This analysis emulates a genome-based search for linked markers. Computer simulations were also performed to clarify statistical properties of the TDT.
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Mapeo Cromosómico , Enfermedades Genéticas Congénitas/genética , Genoma Humano , Desequilibrio de Ligamiento , Alelos , Distribución de Chi-Cuadrado , Simulación por Computador , Marcadores Genéticos , Haplotipos , Humanos , Valor Predictivo de las Pruebas , Medición de RiesgoRESUMEN
We have developed a novel test of heterogeneity based on the APM method. We present tests of this method on both empiric and simulated data.
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Enfermedad de Alzheimer/genética , Ligamiento Genético , Anciano , Enfermedad de Alzheimer/epidemiología , Boston/epidemiología , Mapeo Cromosómico , Cromosomas Humanos Par 19 , Cromosomas Humanos Par 21 , Marcadores Genéticos , Variación Genética , Humanos , Persona de Mediana Edad , North Carolina/epidemiología , Linaje , Estadística como Asunto/métodosRESUMEN
With the advent of the Human Genome Project, the ability to rapidly construct comprehensive and accurate linkage maps based on genetic marker data from family studies is an absolute necessity. In addition to their usefulness in localizing genes for both simple and complex disorders, linkage maps are invaluable tools for genetic counseling using linked marker genes. Several computer program packages are publicly available which aid in the construction of linkage maps by computing multipoint likelihoods for specified locus orders. However, these programs work in a step-by-step fashion, requiring intensive user-intervention and analysis at each step. Such a repetitive process is amenable to computerized automation. We have developed and tested an expert system computer program, MultiMap, for automated genetic linkage mapping. This program greatly reduces the amount of user-computer interaction, increasing the accuracy and speed with which a map can be constructed. In addition, because the total mapping time is greatly reduced through automation, it is now feasible to explore and compare various mapping heuristics and mapping criteria in order to develop the most appropriate approach, or set of approaches, for genetic linkage mapping. MultiMap need not be restricted to the construction of genetic maps, but could be adapted to aid in the automated construction of physical maps as well.
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Mapeo Cromosómico/métodos , Sistemas Especialistas , Ligamiento Genético , Programas Informáticos , Automatización , Cromosomas Humanos Par 21 , Simulación por Computador , Marcadores Genéticos , Humanos , Modelos Genéticos , Reproducibilidad de los Resultados , Factores de TiempoRESUMEN
We have developed a version of the CRI-MAP computer program for genetic likelihood computations that runs the FLIPS and ALL functions of CRI-MAP in parallel on a distributed network of workstations. The performance of CRI-MAP-PVM was assessed in several linkage analyses using the FLIPS option of CRI-MAP on a map of 85 microsatellite markers for human chromosome 1. These analyses showed excellent speedup and efficiency and low distribution overhead. In addition, we have adapted the MultiMap program for automated construction of linkage maps to use CRI-MAP-PVM. These improvements significantly reduce the time required to compare likelihoods of different marker orders. Thus, the construction of linkage maps can proceed in a more timely fashion, in keeping with recent advances in genotyping technology.
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Ligamiento Genético , Programas Informáticos , Algoritmos , Redes de Comunicación de ComputadoresRESUMEN
We have constructed de novo a high-resolution genetic map that includes the largest set, to our knowledge, of polymorphic markers (N=14,759) for which genotype data are publicly available; that combines genotype data from both the Centre d'Etude du Polymorphisme Humain (CEPH) and deCODE pedigrees; that incorporates single-nucleotide polymorphisms; and that also incorporates sequence-based positional information. The position of all markers on our map is corroborated by both genomic sequence and recombination-based data. This specific combination of features maximizes marker inclusion, coverage, and resolution, making this map uniquely suitable as a comprehensive resource for determining genetic map information (order and distances) for any large set of polymorphic markers.
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Mapeo Cromosómico , Bases de Datos Genéticas , Genoma Humano , Mapeo Físico de Cromosoma , Polimorfismo Genético , Marcadores Genéticos/genética , HumanosRESUMEN
Advances in dinucleotide-based genetic maps open possibilities for large scale genotyping at high resolution. The current rate-limiting steps in use of these dense maps is data interpretation (allele definition), data entry, and statistical calculations. We have recently reported automated allele identification methods. Here we show that a 10-cM framework map of the human X chromosome can be analyzed on two lanes of an automated sequencer per individual (10-12 loci per lane). We use this map and analysis strategy to generate allele data for an X-linked recessive spastic paraplegia family with a known PLP mutation. We analyzed 198 genotypes in a single gel and used the data to test three methods of data analysis: manual meiotic breakpoint mapping, automated concordance analysis, and whole chromosome multipoint linkage analysis. All methods pinpointed the correct location of the gene. We propose that multipoint exclusion mapping may permit valid inflation of LOD scores using the equation max LOD-(next best LOD).