Human Biology

Human Biology
Volume 77, Number 5, October 2005



    Blangero, John.
    Göring, Harald H. H.
    Kent, Jack W.
    Williams, Jeff T.
    Peterson, Charles P.
    Almasy, Laura.
    Dyer, Thomas D.
  • Quantitative Trait Nucleotide Analysis Using Bayesian Model Selection
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    Subject Headings:
    • Genetics -- Statistical methods.
    • Nucleotide sequence -- Statistical methods.
    • Quantitative genetics.
    • Bayesian statistical decision theory.
      Although much attention has been given to statistical genetic methods for the initial localization and fine mapping of quantitative trait loci (QTLs), little methodological work has been done to date on the problem of statistically identifying the most likely functional polymorphisms using sequence data. In this paper we provide a general statistical genetic framework, called Bayesian quantitative trait nucleotide (BQTN) analysis, for assessing the likely functional status of genetic variants. The approach requires the initial enumeration of all genetic variants in a set of resequenced individuals. These polymorphisms are then typed in a large number of individuals (potentially in families), and marker variation is related to quantitative phenotypic variation using Bayesian model selection and averaging. For each sequence variant a posterior probability of effect is obtained and can be used to prioritize additional molecular functional experiments. An example of this quantitative nucleotide analysis is provided using the GAW12 simulated data. The results show that the BQTN method may be useful for choosing the most likely functional variants within a gene (or set of genes). We also include instructions on how to use our computer program, SOLAR, for association analysis and BQTN analysis.
      Statistical genomics, model averaging, sequence data, single nucleotide polymorphisms, bayesian quantitative trait nucleotide (BQTN) analysis
    Soria, José Manuel.
    Almasy, Laura.
    Souto, Juan Carlos.
    Sabater-Lleal, Maria.
    Fontcuberta, Jordi.
    Blangero, John.
  • The F7 Gene and Clotting Factor VII Levels: Dissection of a Human Quantitative Trait Locus
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    Subject Headings:
    • Blood coagulation factors.
    • Human genetics -- Variation -- Statistical methods.
    • Quantitative genetics.
    • Bayesian statistical decision theory.
      Localization of human quantitative trait loci (QTLs) is now routine. However, identifying their functional DNA variants is still a formidable challenge. We present a complete dissection of a human QTL using novel statistical techniques to infer the most likely functional polymorphisms of a QTL that influence plasma levels of clotting factor VII (FVII), a risk factor for cardiovascular disease. Resequencing of 15 kb in and around the F7 gene identified 49 polymorphisms, which were then genotyped in 398 people. Using a Bayesian quantitative trait nucleotide (BQTN) method, we identified four to seven functional variants that completely account for this QTL. These variants include both rare coding variants and more common, potentially regulatory polymorphisms in intronic and promoter regions.
      Clotting factor VII, F7 Gene, Hemostasis, Thrombosis, Cardiovascular Disease, variance components, Quantitative Trait Loci, Quantitative Trait Nucleotide, Gait Study.
    Xue, Fuzhong.
    Wang, Jiezhen.
    Hu, Ping.
    Ma, Daoxin.
    Liu, Jing.
    Li, Guifu.
    Zhang, Li.
    Wu, Min.
    Sun, Guoqing.
    Hou, Haifeng.
  • Identification of Spatial Genetic Boundaries Using a Multifractal Model in Human Population Genetics
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    Subject Headings:
    • Ecological genetics -- China -- Mathematical models.
    • Human ecology -- China -- Mathematical models.
    • Human population genetics -- China -- Mathematical models.
      There are two purposes in displaying spatial genetic structure. One is that a visual representation of the variation of the genetic variable should be provided in the contour map. The other is that spatial genetic structure should be reflected by the patterns or the gradients with genetic boundaries in the map. Nevertheless, most conventional interpolation methods, such as Cavalli-Sforza's method in genography, inverse distance-weighted methods, and the Kriging technique, focus only on the first primary purpose because of their arbitrary thresholds marked on the maps. In this paper we present an application of the contour area multifractal model (CAMM) to human population genetics. The method enables the analysis of the geographic distribution of a genetic marker and provides an insight into the spatial and geometric properties of obtained patterns. Furthermore, the CAMM may overcome some of the limitations of other interpolation techniques because no arbitrary thresholds are necessary in the computation of genetic boundaries. The CAMM is built by establishing power law relationships between the area A (≥ρ) in the contour map and the value ρ itself after plotting these values on a log-log graph. A series of straight-line segments can be fitted to the points on the log-log graph, each representing a power law relationship between the area A (≥ρ) and the cutoff genetic variable value for ρ in a particular range. These straight-line segments can yield a group of cutoff values, which can be identified as the genetic boundaries that can classify the map of genetic variable into discrete genetic zones. These genetic zones usually correspond to spatial genetic structure on the landscape. To provide a better understanding of the interest in the CAMM approach, we analyze the spatial genetic structures of three loci (ABO, HLA-A, and TPOX) in China using the CAMM. Each synthetic principal component (SPC) contour map of the three loci is created by using both Han and minority groups data together. These contour maps all present an obvious geographic diversity, which gradually increases from north to south, and show that the genetic differences among populations in different districts of the same nationality are greater than those among different nationalities of the same district. It is surprising to find that both the value of ρ and the fractal dimension α have a clear north to south gradient for each locus, and the same clear boundary between southern and northern Asians in each contour map is still seen in the zone of the Yangtze River, although substantial population migrations have occurred because of war or famine in the last 2,000 or 3,000 years. A clear genetic boundary between Europeans and Asians in each contour map is still seen in northwestern China with a small value of α, although the genetic gradient caused by gene flow between Europeans and Asians has tended to show expansion from northwestern China. From the three contour maps another interesting result can be found: The values of α north of the Yangtze River are generally less than those south of the Yangtze River. This indicates that the genetic differences among the populations north of the Yangtze River are generally smaller than those in populations south of the Yangtze River.
      Spatial Genetic Boundaries, Boundary Identification, Contour Area Multifractal Model, ABO, HLA-A, Tpox, China.
    Bauduer, Frédéric.
    Feingold, J. (Josué)
    Lacombe, Didier.
  • The Basques: Review of Population Genetics and Mendelian Disorders
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    Subject Headings:
    • Basques -- Diseases.
    • Genetic disorders -- Pyrenees.
    • Human population genetics -- Pyrenees.
      The Basques live at the western end of the Pyrenees along the Atlantic Ocean and are thought to represent the descendants of a pre-Neolithic people. They demonstrate marked specificities regarding language and genetics among the European populations. We review the published data on the population genetics and Mendelian disorders of the Basques. An atypical distribution in some blood group polymorphisms (ABO, Rhesus, and Duffy) was first found in this population. Subsequently, additional characteristics have been described with regard to proteins (enzymes and immunoglobulins) and the HLA system. The advent of molecular biology methods in the 1990s allowed further insights into Basque population genetics based mainly on Y-chromosome and mitochondrial DNA. In addition, the Basques demonstrate peculiarities regarding the distribution of various inherited diseases (i.e., unusual frequencies or founding effects). Taken together, these data support the idea of an ancient and still relatively unmixed population subjected to genetic drift.
      Basques, Mitochondrial Dna Haplogroups, Y-Chromosome Haplotypes, Factor XI Deficiency, Blood Groups, Factor V Leiden, Inherited Diseases, ABO Blood Groups, Rh, Kell, Duffy, HLA, DF50M (ΔF508), Cystic Fibrosis, Thrombosis, Hereditary Hemochromatosis.
    Bogácsi-Szabó, Erika.
    Kalmár, Tibor.
    Csányi, Bernadett.
    Tömöry, Gyöngyvér.
    Czibula, Ágnes.
    Priskin, Katalin.
    Horváth, Ferenc.
    Downes, Christopher Stephen.
    Raskó, István.
  • Mitochondrial DNA of Ancient Cumanians: Culturally Asian Steppe Nomadic Immigrants with Substantially More Western Eurasian Mitochondrial DNA Lineages
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    Subject Headings:
    • DNA, Fossil -- Hungary.
    • Mitochondrial DNA -- Hungary.
    • Nomads -- Hungary.
    • Human population genetics -- Hungary.
      The Cumanians were originally Asian pastoral nomads who in the 13th century migrated to Hungary. We have examined mitochondrial DNA from members of the earliest Cumanian population in Hungary from two archeologically well-documented excavations and from 74 modern Hungarians from different rural locations in Hungary. Haplogroups were defined based on HVS I sequences and examinations of haplogroup-associated polymorphic sites of the protein coding region and of HVS II. To exclude contamination, some ancient DNA samples were cloned. A database was created from previously published mtDNA HVS I sequences (representing 2,615 individuals from different Asian and European populations) and 74 modern Hungarian sequences from the present study. This database was used to determine the relationships between the ancient Cumanians, modern Hungarians, and Eurasian populations and to estimate the genetic distances between these populations. We attempted to deduce the genetic trace of the migration of Cumanians. This study is the first ancient DNA characterization of an eastern pastoral nomad population that migrated into Europe. The results indicate that, while still possessing a Central Asian steppe culture, the Cumanians received a large admixture of maternal genes from more westerly populations before arriving in Hungary. A similar dilution of genetic, but not cultural, factors may have accompanied the settlement of other Asian nomads in Europe.
      Ancient mtDNA, mtDNA, HVS I, HVS II, Cumanians, Hungarians.
    Meriño-Ibarra, Erardo.
    Castillo, Sergio.
    Mozas, Pilar.
    Cenarro, Ana.
    Martorell, Esperanza.
    Díaz, José Luis.
    Suárez-Tembra, Manuel.
    Alonso, Rodrigo.
    Civeira, Fernando.
    Mata, Pedro.
    Pocoví, Miguel.
  • Screening of APOB Gene Mutations in Subjects with Clinical Diagnosis of Familial Hypercholesterolemia
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    Subject Headings:
    • Hypercholesteremia -- Spain -- Genetic aspects.
    • Apolipoprotein B -- Spain.
      Monogenic hypercholesterolemia is a group of lipid disorders, most of which have autosomal dominant transmission. Familial defective apoB (FDB) resulting from mutations in the APOB gene is a well-recognized cause of autosomal dominant monogenic hypercholesterolemia (ADMH). However, the frequency of FDB among patients with ADMH is not well established. The aim of our research was to screen for mutations responsible for FDB in subjects with a clinical diagnosis of familial hypercholesterolemia. We studied 408 patients from the Spanish Register of Familial Hypercholesterolemia, proportionally distributed among all Spanish regions. Abnormal SSCP patterns of the APOB gene were checked by DNA sequencing and restriction analysis. Three out of the 408 patients were carriers of the R3500Q mutation, and 2 subjects were carriers of the silent T3552T mutation; in both of these patients functional mutations in the LDL receptor gene were found. We conclude that FDB is not a common cause of ADMH in Spain; the R3500Q mutation is the only mutation in APOB causing FDB, and the LDL receptor binding domain of APOB is highly conserved in the studied sample.
      Familial Defective APOB, Autosomal Dominant Monogenic Hypercholesterolemia (ADMH), Hypercholesterolemia, APOB, LDLR, R3500Q Mutation, T3552T Mutation, SSCP (Single-Strand Conformation Polymorphism) Analysis, Spain.
    Terreros, Maria C.
    Martinez, Laisel.
    Herrera, Rene J.
  • Polymorphic Alu Insertions and Genetic Diversity Among African Populations
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    Subject Headings:
    • Human population genetics -- Africa.
      Thorough assessment of modern genetic diversity and interpopulation affinities within the African continent is essential for understanding the processes that have been at work during the course of worldwide human evolution. Regardless of whether autosomal, Y-chromosome, or mtDNA markers are used, allele- or haplotype-frequency data from African populations are necessary in setting the framework for the construction of global population phylogenies. In the present study we analyze genetic differentiation and population structure in a data set of nine African populations using 12 polymorphic Alu insertions (PAIs). Furthermore, to place our findings within a global context, we also examined an equal number of non-African groups. Frequency data from 456 individuals presented for the first time in this work plus additional data obtained from the literature indicate an overall pattern of higher intrapopulation diversity in sub-Saharan populations than in northern Africa, a prominent differentiation between these two locations, an appreciably high degree of transcontinental admixture in Egypt, and significant discontinuity between Morocco and the Iberian peninsula. Moreover, the topologies of our phylogenetic analyses suggest that out of the studied sub-Saharan groups, the southern Bantu population of Sotho/Tswana presents the highest level of antiquity, perhaps as a result of ancestral or acquired Khoisan genetic signals. Close affinities of eastern sub-Saharan populations with Egypt in the phylogenetic trees may indicate the existence of gene flow along the Nile River.
      Polymorphic ALU Insertions, genetic diversity, human populations, Morocco, Egypt, Sudan, Kenya, Rwanda, Benin, Cameroon, Madras, Brahmins, Formosa, Galicia, Iberian Peninsula, South Africa, Zaire, Bantu, China, Japan, France, Poland, India, APO, B65, COL3A1, HS2, HS4, PV92, SB19, TPA25.
    Bienvenu, T.
    Viel, M.
    Leroy, C.
    Cartault, F.
    Lesure, J. F.
    Renouil, M.
  • Spectrum of CFTR Mutations on Réunion Island: Effect of Neonatal Screening
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    Subject Headings:
    • Cystic fibrosis gene -- Réunion.
    • Infants (Newborn) -- Diseases -- Diagnosis -- Réunion.
      The large heterogeneity in the cystic fibrosis (CF) gene is the main difficulty for genotype characterization. Numerous studies have reported considerable variations in frequencies of CF transmembrane conductance regulator (CFTR) mutations in different populations, such as African, Asian, or European populations. To completely characterize the spectrum of mutations in the CFTR gene in the Réunion Island population, we screened 228 CF chromosomes using denaturing high-pressure liquid chromatography and denaturing gradient gel electrophoresis following by direct sequencing. We identified 27 mutations, accounting for 93% of CF chromosomes. They included three novel mutations (M1T, 3121-3C→G, and L1324P), which are described in this paper. The detection of such a high proportion of Réunion Island CFTR mutations is important for improving neonatal screening of CF on Réunion Island.
      Réunion Island, CFTR Gene, Cystic Fibrosis, Neonatal Screening, CFTR Novel Mutations.

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