Human Biology

Human Biology
Volume 77, Number 1, February 2005



    Warren, Diane M.
    Soria, José Manuel.
    Souto, Juan Carlos.
    Comuzzie, Anthony G.
    Fontcuberta, Jordi.
    Blangero, John.
    MacCluer, Jean W.
    Almasy, Laura.
  • Heritability of Hemostasis Phenotypes and Their Correlation with Type 2 Diabetes Status in Mexican Americans
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    Subject Headings:
    • Hemostasis.
    • Phenotype.
    • Non-insulin-dependent diabetes -- Genetic aspects.
    • Mexican Americans -- Diseases.
      Hypercoagulation often occurs in type 2 diabetes, suggesting pleiotropy of the genes that influence disease liability and hemostasis-related phenotypes. To better understand the relationship between hemostasis and diabetes, we first used maximum-likelihood methods to estimate the relative contribution of additive genetic, measured environmental, and shared household effects to the normal variance of 16 hemostasis-related traits in 813 individuals participating in the San Antonio Family Heart Study. We estimated moderate to high heritabilities (0.20–0.60) for each phenotype. Von Willebrand factor (VWF), thrombin activatable fibrinolysis inhibitor, activated protein C (APC) ratio, factor V, and prothrombin time had heritabilities greater than 0.50. The correlation between type 2 diabetes status and the hemostasis-related traits was then partitioned into genetic and environmental components using bivariate variance-components methods. Significant (p ≤ 0.05) positive genetic correlations (0.37–0.51) occurred with factors II and VIII, VWF, total protein S (tPS), and tissue factor pathway inhibitor. Significant negative genetic correlations were estimated for activated partial thromboplastin time (-0.49) and APC ratio (-0.38). By contrast, significant environmental correlations occurred only with factor II (-0.40) and tPS (-0.31). Our results suggest that genes are important contributors to the normal variation in hemostasis-related traits and that genes influencing hemostasis-related traits pleiotropically influence diabetes risk.
      hemostasis, diabetes, family study, heritability, Mexican Americans, San Antonio family heart study, hemostasis-related traits, protein C, protein S, thrombin activatable fibrinolysis inhibitor (TAFI), prothrombin time, clotting factors, tissue factor pathway inhibitor (TFPI), von willebrand factor (VWF), activated partial thromboplastin time (APTT).
    Almasy, Laura.
    Rainwater, David Luther.
    Cole, Shelley.
    Mahaney, Michael C.
    VandeBerg, John L.
    Hixson, James E.
    Stern, Michael, 1957-
    MacCluer, Jean W.
    Blangero, John.
  • Joint Linkage and Association Analysis of the Hepatic Lipase Promoter Polymorphism and Lipoprotein Size Phenotypes
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    Subject Headings:
    • Lipase.
    • High density lipoproteins.
    • Low density lipoproteins.
      The hepatic lipase gene (LIPC) has been implicated as a potential regulator of HDL-cholesterol concentration and HDL and LDL particle size. Studies have centered on a C to T transition in the promoter region of LIPC, 514 base pairs upstream from the transcription initiation site. We performed a genome-wide linkage screen for several lipoprotein size phenotypes and tested for association of these traits with LIPC -514C-T in 798 individuals from the San Antonio Family Heart Study. Median diameters were measured for HDL particles stained for apoA1 (A1), apoA2 (A2), unesterified cholesterol (UC), and esterified cholesterol (EC) and for LDLs stained for EC. The median diameter of all phenotypes exhibited evidence of linkage to the LIPC region of chromosome 15 (LODs of 1.78 to 3.79). Linkage was also observed for HDL-EC size on chromosome 5p (LOD = 3.50). Association with the LIPC -514C-T polymorphism was detected for HDL-A1, HDL-A2, HDL-UC, and HDL-EC median diameters (p < 0.001) but not for LDL-EC size. Linkage analyses of HDL sizes conditional on the -514C-T polymorphism reduced the LOD scores in the LIPC region only slightly, suggesting that this polymorphism does not explain the observed linkage of lipoprotein sizes to chromosome 15. These results indicate the presence of a lipoprotein size locus in the LIPC region but suggest that -514C-T is not the primary functional variant in this region, implying that additional functional mutations influencing HDL and potentially LDL size variation occur in or near LIPC.
      hepatic lipase gene, LIPC, HDL cholesterol, LDL cholesterol, lipoprotein diameter, genome-wide screen, heritability.
    Yamada, Yoshiji.
    Ando, Fujiko.
    Niino, Naoakira.
    Shimokata, Hiroshi.
  • Association of a - 1997G → T Polymorphism of the Collagen Iα1 Gene with Bone Mineral Density in Postmenopausal Japanese Women
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    Subject Headings:
    • Osteoporosis in women -- Japan -- Genetic aspects.
    • Genetic polymorphisms -- Japan.
    • Collagen.
      Genetic variants that affect collagen Iα1 metabolism may be important in the development of osteoporosis or osteoporotic fractures. A – 1997G → T polymorphism in the promoter of the collagen Iα1 gene (COL1A1) was shown to be associated with bone mineral density (BMD) for the lumbar spine in postmenopausal Spanish women. The relation of this polymorphism to BMD in Japanese women or men has now been examined in a population-based study. The subjects (1,110 women, 1,126 men) were 40 to 79 years of age and were randomly recruited for a population-based prospective cohort study of aging and age-related diseases. BMD for the lumbar spine, right femoral neck, right trochanter, and right Ward's triangle was measured using dual-energy x-ray absorptiometry. Genotypes for the – 1997G → T polymorphism of COL1A1 were determined with a fluorescence-based allele-specific DNA primer assay system. When all women were analyzed together, BMD for the lumbar spine and trochanter was significantly lower in subjects with the COL1A1*G/*G genotype than in those in the combined group of COL1A1*G/*T and COL1A1*T/*T genotypes. When postmenopausal women were analyzed separately, BMD for the femoral neck and trochanter was also significantly lower in those with the COL1A1*G/*G genotype than in those with the COL1A1*G/*T genotype or those in the combined group of COL1A1*G/*T and COL1A1*T/*T genotypes. BMD was not associated with — 1997G → T genotype in premenopausal women or in men. Multivariate regression analysis revealed that – 1997G → Tgenotype affected BMD at various sites with a variance of 0.46–0.62% for all women and 0.61–1.01% for postmenopausal women. The – 1997G → T genotype was not related to the serum concentration of osteocalcin, the serum activity of bone-specific alkaline phosphatase, or the urinary excretion of deoxypyridinoline or cross-linked N-telopeptides of type I collagen in men or in premenopausal or postmenopausal women. These results suggest that COL1A1 is a susceptibility locus for reduced BMD in postmenopausal Japanese women.
      bone mineral density, collagen Iα1, COLA1A, osteoporosis, Japan.
    Branco, Claudia C.
    Mota-Vieira, Luisa.
  • Surnames in the Azores: Analysis of the Isonymy Structure
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    Subject Headings:
    • Human population genetics -- Azores.
    • Population geography -- Azores.
    • Inbreeding -- Azores.
    • Names, Personal -- Azores.
      Geographic isolation is a significant factor to consider when characterizing human populations. The knowledge of the genetic structure of isolated populations has been of great importance to disease-locus positioning and gene identification. To investigate the genetic structure of the Azorean population, we conducted a survey based on the frequencies of surnames listed in the 2001 telephone book. We calculated the following parameters: isonymy (I), the random component of inbreeding (FST), genetic diversity according to Fisher (α), Karlin-McGregor's migration rate (ν), and Nei's distance. For the 1,271 subscribers and 163 different surnames, Graciosa island presented the lowest value of abundance of surnames (α = 15.75), suggesting great genetic isolation compared to the other eight islands. Migration, calculated on the basis of the diversity of surnames within islands, ranged from 0.2747 (Corvo island) to 0.0026 (São Miguel island), indicating that people migrated preferentially toward the economically more developed islands. The value of the random component of inbreeding obtained for the whole population (FST = 0.0039) indicates little genetic differentiation (Wright's FST<0.05). Moreover, isonymy similarity revealed using the UPGMA method shows three subclusters corresponding to the geographic distribution of the islands.
      Azore Islands, surnames, isonymy, inbreeding, diversity, isolated population.
    Tagarelli, Antonio.
    Piro, Anna.
    Tagarelli, G.
    Lagonia, P.
    Bulo, A.
    Falchi, A.
    Varesi, L.
    Vona, G.
    Calò, C. M.
  • Genetic Characterization of the Historical Albanian Ethnic Minority of Calabria (Southern Italy)
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    Subject Headings:
    • Albanians -- Italy -- Calabria.
    • Human population genetics -- Italy -- Calabria.
      Three historical ethnic minorities are present in Calabria: Albanians, Greeks, and Occitans. The Albanian ethnic minority is the more populous, having settled in Calabria between the 15th and 17th centuries, and these populations are now located in the provinces of Cosenza and Catanzaro. In the present study the Albanian population structure is analyzed based on the allele frequencies of six classic genetic markers: ACP, GC, PGM1, AK, ADA, and 6PGD. The results show a significant heterogeneity between the Albanian population in Calabria and the population in Molise. Therefore the cultural and reproductive isolation of the Albanian ethnic minority of Calabria is related to a great genetic peculiarity. Moreover, the frequencies of some alleles, particularly those of the PGM*1W31 variant, and the analysis of the R matrix still show the actual peculiar genetic structure of the Albanians of Calabria, although the genetic flow is evident in the decrease of endogamy and in the increase in the degree of mixing.
      Albanians, Calabria, ACP, GC, PGM1, AK, ADA, 6PGD.
    Cherni, Lotfi.
    Loueslati, Besma Yaacoubi.
    Pereira, Luísa.
    Ennafaâ, Hajer.
    Amorim, António.
    Gaaied, Amel Ben Ammar el.
  • Female Gene Pools of Berber and Arab Neighboring Communities in Central Tunisia: Microstructure of mtDNA Variation in North Africa
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    Subject Headings:
    • Mitochondrial DNA -- Africa, North.
    • Human population genetics -- Africa, North.
    • Women -- Tunisia.
    • Phylogeography -- Africa, North.
      North African populations are considered genetically closer to Eurasians than to sub-Saharans. However, they display a considerably high mtDNA heterogeneity among them, namely in the frequencies of the U6, East African, and sub-Saharan haplogroups. In this study, we describe and compare the female gene pools of two neighboring Tunisian populations, Kesra (Berber) and Zriba (non-Berber), which have contrasting historical backgrounds. Both populations presented lower diversity values than those observed for other North African populations, and they were the only populations not showing significant negative Fu's Fs values. Kesra displayed a much higher proportion of typical sub-Saharan haplotypes (49%, including 4.2% of M1 haplogroup) than Zriba (8%). With respect to U6 sequences, frequencies were low (2% in Kesra and 8% in Zriba), and all belonged to the subhaplogroup U6a. An analysis of these data in the context of North Africa reveals that the emerging picture is complex, because Zriba would match the profile of a Berber Moroccan population, whereas Kesra, which shows twice the frequency of sub-Saharan lineages normally observed in northern coastal populations, would match a western Saharan population except for the low U6 frequency. The North African patchy mtDNA landscape has no parallel in other regions of the world and increasing the number of sampled populations has not been accompanied by any substantial increase in our understanding of its phylogeography. Available data up to now rely on sampling small, scattered populations, although they are carefully characterized in terms of their ethnic, linguistic, and historical backgrounds. It is therefore doubtful that this picture truly represents the complex historical demography of the region rather than being just the result of the type of samplings performed so far.
      mtDNA variation, Tunisia, Berbers, Arabs.
    Ruiz-Narváez, Edward A.
    Santos, Fabricio R.
    Carvalho-Silva, Denise de.
    Azofeifa, Jorge.
    Barrantes, Ramiro.
    Pena, S. D. J. (Sergio D. J.)
  • Genetic Variation of the Y Chromosome in Chibcha-Speaking Amerindians of Costa Rica and Panama
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    Subject Headings:
    • Chibcha Indians -- Costa Rica.
    • Chibcha Indians -- Panama.
    • Y chromosome.
    • Y chromosome.
      Genetic variation of the Y chromosome in five Chibchan tribes (Bribri, Cabecar, Guaymi, Huetar, and Teribe) of Costa Rica and Panama was analyzed using six microsatellite loci (DYS19, DYS389A, DYS389B, DYS390, DYS391, and DYS393), the Y-chromosome-specific alphoid system (αh), the Y-chromosome Alu polymorphism (YAP), and a specific pre-Columbian transition (C → T) (M3 marker) in the DYS199 locus that defines the Q-M3 haplogroup. Thirty-nine haplotypes were found, resulting in a haplotype diversity of 0.937. The Huetar were the most diverse tribe, probably because of their high levels of interethnic admixture. A candidate founder Y-chromosome haplotype was identified (15.1% of Chibchan chromosomes), with the following constitution: YAP-, DYS199*T, αh-II, DYS19*13, DYS389A*17, DYS389B*10, DYS390*24, DYS391*10, and DYS393*13. This haplotype is the same as the one described previously as one of the most frequent founder paternal lineages in native American populations. Analysis of molecular variance indicated that the between-population variation was smaller than the within-population variation, and the comparison with mtDNA restriction data showed no evidence of differential structuring between maternally and paternally inherited genes in the Chibchan populations. The mismatch-distribution approach indicated estimated coalescence times of the Y chromosomes of the Q-M3 haplogroup of 3,113 and 13,243 years before present; for the mtDNA-restriction haplotypes the estimated coalescence time was between 7,452 and 9,834 years before present. These results are compatible with the suggested time for the origin of the Chibchan group based on archeological, linguistic, and genetic evidence.
      Chibchan tribes, Bribri, Cabecar, Guaymi, Huetar, Teribe, Y chromosome, microsatellite loci, gene diversity, MTDNA, DYS19, DYS389A, DYS389B, DYS390, DYS391, DYS393, DYS199, alphoid system, Alu polymorphism, Costa Rica, Panama.
    Karafet, Tatiana M.
    Lansing, J. S.
    Redd, Alan J.
    Watkins, Joseph C.
    Surata, S. P. K.
    Arthawiguna, W. A.
    Mayer, Laura.
    Bamshad, Michael.
    Jorde, Lynn B.
    Hammer, Michael F.
  • Balinese Y-Chromosome Perspective on the Peopling of Indonesia: Genetic Contributions from Pre-Neolithic Hunter-Gatherers, Austronesian Farmers, and Indian Traders
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    Subject Headings:
    • Y chromosome.
    • Balinese (Indonesian people) -- Population.
    • Human population genetics -- Indonesia.
      The island of Bali lies near the center of the southern chain of islands in the Indonesian archipelago, which served as a stepping-stone for early migrations of hunter-gatherers to Melanesia and Australia and for more recent migrations of Austronesian farmers from mainland Southeast Asia to the Pacific. Bali is the only Indonesian island with a population that currently practices the Hindu religion and preserves various other Indian cultural, linguistic, and artistic traditions (Lansing 1983). Here, we examine genetic variation on the Y chromosomes of 551 Balinese men to investigate the relative contributions of Austronesian farmers and pre-Neolithic hunter-gatherers to the contemporary Balinese paternal gene pool and to test the hypothesis of recent paternal gene flow from the Indian subcontinent. Seventy-one Y-chromosome binary polymorphisms (single nucleotide polymorphisms, SNPs) and 10 Y-chromosome-linked short tandem repeats (STRs) were genotyped on a sample of 1,989 Y chromosomes from 20 populations representing Indonesia (including Bali), southern China, Southeast Asia, South Asia, the Near East, and Oceania. SNP genotyping revealed 22 Balinese lineages, 3 of which (O-M95, O-M119, and O-M122) account for nearly 83.7% of Balinese Y chromosomes. Phylogeographic analyses suggest that all three major Y-chromosome haplogroups migrated to Bali with the arrival of Austronesian speakers; however, STR diversity patterns associated with these haplogroups are complex and may be explained by multiple waves of Austronesian expansion to Indonesia by different routes. Approximately 2.2% of contemporary Balinese Y chromosomes (i.e., K-M9*, K-M230, and M lineages) may represent the pre-Neolithic component of the Indonesian paternal gene pool. In contrast, eight other haplogroups (e.g., within H, J, L, and R), making up approximately 12% of the Balinese paternal gene pool, appear to have migrated to Bali from India. These results indicate that the Austronesian expansion had a profound effect on the composition of the Balinese paternal gene pool and that cultural transmission from India to Bali was accompanied by substantial levels of gene flow.
      Bali, Indonesia, Y chromosome, Austronesian expansion, Indian traders, pre-neolithic hunter-gatherers, Vietnamese, Malaysians, Philippinos, Taiwanese aboriginals, southern Chinese, Indians, Sri Lankans, Syrians, Saudi Arabians, Melanesia, Micronesia, Polynesia, Papua New Guinea, Oceania.
    Rickards, Olga.
    Martínez-Labarga, Cristina.
    Trucchi, Emiliano.
    Renzi, Fabio.
    Casalotti, Rosa.
    Babalini, Carla.
    Biondi, Gianfranco.
    Pepe, Guglielmina.
    De Stefano, Gianfranco.
  • Restriction Fragment Length Polymorphisms of Type I Collagen Locus 2 (COL1A2) in Two Communities of African Ancestry and Other Mixed Populations of Northwestern Ecuador
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    Subject Headings:
    • Genetic polymorphisms -- Ecuador.
    • Collagen.
    • Racially mixed people -- Ecuador.
    • Human population genetics -- Ecuador.
      Restriction fragment length polymorphisms are good anthropological markers for discriminating geographically distinct populations at both the allele and the haplotype level. Two communities of African ancestry and ladinos, mestizos, and mulattoes living in the Esmeraldas province in northwestern Ecuador were analyzed for three RFLPs (EcoRI, RsaI, and MspI) of the COL1A2 gene. Also, the same markers were studied in a population sample from Spain to compare the allele and haplotype frequencies of the Esmeraldas populations with those of their representative European parental population. Data for the native American and sub-Saharan African founder components were available from the literature. No significant levels of differentiation between the two African Ecuadoran communities emerged from either the frequency analysis of each single marker and all three RFLP markers together or from the AMOVA. The ladinos and mestizos also showed a rather similar distribution of allele and haplotype frequencies, confirming that the two ethnic terms do not correspond to genetically different populations. The comparison with the supposed founding European, sub-Saharan African, and native American populations indicated a large presence of African genes in the gene pool of both communities, with a higher proportion of the Amerindian component in Viche than in Rio Cayapas. The present findings confirm the previous genetic admixture estimates based on nuclear and mitochondrial DNA markers and the demographic data.
      COL1A2, EcoRI, RsaI, MspI, Ecuadoran mixed populations, Spanish population, Ecuador.
    Cabello, Giselda M. K.
    Cabello, Pedro H.
    Otsuki, Koko.
    Gombarovits, Maria Emília.
    Llerena, Juan C.
    Fernandes, Octavio.
  • Molecular Analysis of 23 Exons of the CFTR Gene in Brazilian Patients Leads to the Finding of Rare Cystic Fibrosis Mutations
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    Subject Headings:
    • Exons (Genetics)
    • Cystic fibrosis gene -- Brazil -- Rio de Janeiro.
    • Mutation (Biology)
      To define mutations present in 23 exons and flanking intronic sequences of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 95 patients from Rio de Janeiro, Brazil, we carried out single-strand conformation polymorphism analysis and automated direct sequencing. Mutation detection was achieved in 45% of the alleles presented, and complete genotyping (two mutated alleles) was accomplished in 34.7% of the patients. Twenty patients (21.1%) were found to carry only one mutation, whereas mutated alleles could not be observed in 42 patients (44.2%). Eleven mutations were found, of which four were characterized as rare mutations: P205S (1.05%), Y1092X (0.53%), S549R (0.53%), and S4X (0.53%). The DF508 mutation in this population sample showed a frequency of 28.42%. The low number of individuals (10 of 95; 10.5%) with compound heterozygous (DF508/non-DF508) genotypes could indicate the presence of another severe mutation leading to the premature death of these individuals. In 4 of the aforementioned 10 individuals with compound heterozygous genotypes, the D-7-2-1-2 (XV2c-KM19-IVS6a-TUB9-M470-T854) haplotype was defined.
      cystic fibrosis, CFTR gene, single-strand conformation polymorphism (SSCP) analysis, Brazilian population.
    Curlis, Yvette.
    Zhang, Cuiling.
    Holden, Jeanette J. A.
    Kirkby, K. (Ken)
    Loesch, Danuta Z.
    Mitchell, R. John.
  • Haplotype Study of Intermediate-Length Alleles at the Fragile X (FMR1) Gene: ATL1, FMRB, and Microsatellite Haplotypes Differ from Those Found in Common-Size FMR1 Alleles
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    Subject Headings:
    • Allelomorphism.
    • Fragile X syndrome -- Europe -- Genetic aspects.
    • Comparative genomic hybridization -- Europe.
      The CGG repeat within the X-chromosome-linked FMR1 gene, which in hyperexpansion (> 200 copies) results in fragile X syndrome, is highly polymorphic. The mechanism of expansion is not well understood, but CGG repeats called intermediate-length or gray zone alleles (≅35–60 repeats) are thought to make up the FMR1 alleles showing initial steps in this expansion process. It has been hypothesized that the background haplotype of these alleles plays a role in their susceptibility to expansion. In this study we investigate whether or not the frequencies of alleles and haplotypes at four marker loci in the FMR1 gene region (microsatellites DXS548 and FRAXAC1 and SNPs ATL1 and FMRb) in 84 intermediate-length male chromosomes differ from those in 94 common-size male alleles. The ATL1*G and FMRB*A alleles were more frequent among intermediate-length alleles than among common alleles. In addition, the DXS548-FRAXAC1 T50-T42 and T40-T42 haplotypes were strongly associated with intermediate-length alleles between 41 and 60 CGG repeats (p < 0.001). Two extended haplotypes, DXS548-FRAXAC1-ATL1-FMRb T50-T42-G-A and T40-T42-G-A, are strongly associated (p < 0.001) with intermediate-length alleles between 41 and 60 CGG repeats, and these haplotypes have also been reported as fragile X associated haplotypes in European populations. These data suggest that these haplotypes are among the most susceptible to further expansion among the intermediate-length alleles. T50-T42-G-A was also much more prevalent in males with 35–40 CGG repeats than in males with common-size alleles. ATL1 did not increase discrimination among intermediate-length alleles beyond that detected by DXS548-FRAXAC1 haplotypes, but the FMRb locus did, particularly for the DXS548-FRAXAC1-ATL1 T50-T42-G and T40-T42-G haplotypes. Comparison with fragile X associated haplotypes, from the literature, suggests that repeat hyperexpansion occurs most frequently on chromosomes carrying FMRB*A. Within the intermediate-length allele category, however, there were some significant differences in haplotype frequencies between smaller and larger alleles, and this finding has implications for future studies.
      fragile X dynamic mutation, CGG repeat, FMR1 gene, intermediate-length alleles, DXS548, FRAXAC1, ATL1, FMRb, haplotype associations.

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