bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of robust variance components models to analyse triglyceride data in families
Authors: BEATY T. H. , SELF S. G. , LIANG K. Y. , CONNOLLY M. A. , CHASE G. A. , KWITEROVICH P. O.
Published: September 2007

A robust approach for analysis of variance components models is presented which does not rely on the assumption of multivariate normality for its validity. This approach uses the multivariate normal distribution as a ‘working model’ but obtains standard errors for the final estimators which do not depend on this underlying distribution. By using the observed variance in the first derivatives of the multivariate normal ‘working model’ to modify the conventional score test, hypotheses regarding specific components can also be tested without relying directly on the assumption of multivariate normality. A special case is presented where both the modified score test and the likelihood ratio test are equally robust, and simulated data are used to illustrate this situation. Measurements of triglyceride levels in 391 individuals in 60 families randomly selected from the membership of a health maintenance organization are used to illustrate this robust approach to variance components.
Assignment of the gene determining human carbonic anhydrase, CAI, to chromosome 8
Authors: EDWARDS Y. H. , BARLOW J. H. , KONIALIS C.P. , POVEY S. , BUTTERWORTH P.H.W.
Published: September 2007

A cDNA clone complementary to the mRNA encoding the rabbit erythrocyte specific carbonic anhydrase, CAI, has been used as probe for human CAI sequences in the analysis of DNA from panels of rodent/human somatic cell hybrids. The presence of the human CAI gene in all hybrids correlates with the presence of chromosome 8. Together with published mapping data, this assignment indicates that three CA loci are situated on chromosome 8.
A test statistic for the affected‐sib‐set method
Authors: LANGE K.
Published: September 2007

This paper discusses generalizations of the affected‐sib‐pair method. First, the requirement that sib identity‐by‐descent relations be known unambiguously is relaxed by substituting sib identity‐by‐state relations. This permits affected sibs to be used even when their parents are unavailable for typing. In the limit of an infinite number of marker alleles each of infinitesimal population frequency, the identity‐by‐state relations coincide with the usual identity‐by‐descent relations. Second, a weighted pairs test statistic is proposed that covers affected sib sets of size greater than two. These generalizations make the affected‐sib‐pair method a more powerful technique for detecting departures from independent segregation of disease and marker phenotypes. A sample calculation suggests such a departure for tuberculoid leprosy and the HLAD locus.
Very close linkage between D2S1 and ACP1 on chromosome 2p
Authors: LOTHE R. A. , GEDDE‐DAHL T. , OLAISEN B. , BAKKERS E. , PEARSON P.
Published: September 2007

The genomic DNA‐probe L2.30 was used to assign D2S1 to 2p23–pter by in situ hybridization. The RFLP revealed by BglII was then used for linkage studies in the Oslo‐NHIK families segregating for the acid phosphatase ACPl protein polymorphism. Evidence for very close linkage was found by a lod score of +17.17 at recombination fraction θ= 001. By this close linkage 92 informative meioses could be inferred from the families and with only a single crossover. The upper probability limit to the recombination fraction is 006 according to the HGM 8 criterion. No association between ACP1 alleles and D2S1 BglII alleles was found. The Norwegian gene frequencies for 0251 were A1 (9–0 kb) = 065 and A2 (6.3 kb) = 0.35.
EM investigations of surface spread synaptonemal complexes in a human male carrier of a pericentric inversion inv(13)(p12q14): the role of heterosynapsis for spermatocyte survival
Authors: SAADALLAH N. , HULTÉN M.
Published: September 2007

EM investigations of surface spread synaptonemal complexes of pachytene spermatocytes were performed on a human male carrier of a pericentric inv(13), ascertained through his daughter with a duplication‐deficiency of the same chromosome. The inv(13) bivalent could be unambiguously identified by either its asymmetrical kinetochores or its nucleolar association or both. There was scarcity of reversed homosynapsis of the inverted segments with inversion loops, possibly related to the small size of the inversion. The majority of pachytene spermatocytes showed the inverted segment to be either asynapsed or heterosynapsed. Generally initial homosynapsis is highly efficient with high fidelity, while heterosynapsis at the secondary pachytene pairing phase may take place with any available partner remaining unsynapsed and including the differential segments of the XY. It is suggested that survival of spermatocytes to later stages of meiosis may be ensured by heterosynapsis, and the recombinant chromosome in the offspring might be the result of a U‐type exchange.
Maximum likelihood estimation of components of variance and correlations in the analysis of family data
Authors: BENER A. , HUDA S.
Published: September 2007

A simple iterative method is developed for computing the maximum likelihood estimates of the components of variance and thereby the intraclass and interclass correlations, under multivariate normal assumptions involving two classes. The method works efficiently for both balanced and unbalanced data and can be readily extended to situations involving three or more classes. It is particularly suitable for application to studies of quantitative variables in genetics and is illustrated by using some dermatoglyphic data.
Family and population studies of SAHH and ADA polymorphisms. A possible pitfall in the ascertainment of SAHH electrophoretic phenotypes
Authors: SCOZZARI R. , SELLITTO D. , TASSONE F. , CERRONI L. , ALIQUÒ M. C.
Published: September 2007

Typing of both SAHH and ADA red cell electrophoretic patterns was carried out among the members of about 80 families from Latium (Central Italy) and in a random sample of about 350 individuals from two Italian regions, Latium and Sardinia.

1. The SAHH1 enzyme product provided another interesting example of a change in the electrophoretic pattern brought about by the haemolysate ageing. In vitro storage of SAHH 1 red cell lysates leads to the production of a pattern similar to that expected from a heterozygote SAHH 2–1. This change has been shown to be abolished by pretreating the sample with mercaptoethanol.

The results indicate that the systematic use of sulphydril reducing agents can provide a more reliable means of analysing the SAHH polymorphism if differently stored samples are to be compared by starch gel electrophoresis.

2. Evidence against complete linkage of the SAHH and ADA loci has been obtained from two informative SAHH/ADA matings encountered in this study.

3. The SAHH allele frequencies observed in the two samples analysed were: SAHH1= 0.969, SAHH2= 0.024, SAHH3= 0.007 (Latium) and SAHH1= 0.973, SAHH2= 0.011, SAHH3= 0.016 (Sardinia).

4. The ADA2 allele frequency estimates were: 0.083 (Latium) and 0.059 (Sardinia). These figures are almost identical to those already reported for the same two regions.
Biological performance in β‐thal heterozygotes and normals: results of a longitudinal comparison in a former malarial environment
Authors: CANELLA R. , BARBUJANI G. , CUCCHI P. , SINISCALCO M. , VULLO C. , BARRAI I.
Published: September 2007

Families of β‐thal heterozygotes and of normals studied in 1956 by Silvestroni and Bianco in the small town of Berra near Ferrara were studied again in 1981–85. It was possible to compare mortality, fertility, and migration, in the two groups of heterozygotes and normals after the lapse of one generation. At the power of resolution of the sample available and of the methods used, no difference was visible. However, it was possible to establish the upper limits of the differences in average age at death and in average fertility at the 5% level of significance.
Restriction fragment length polymorphisms of the complement component C4 loci on chromosome 6: studies with emphasis on the determination of gene number
Authors: TEISBERG P. , JONASSEN R. , MEVÅG B. , GEDDE‐DAHL T. , OLAISEN B.
Published: September 2007

Restriction fragment length polymorphisms of the C4 region of human chromosome 6 have been studied in family material where the haplotypes are defined with regard to other genetic markers in this region. Employing one near full‐length C4 probe and the combination ofBglII andXbaI enzymes, five different C4 genes were characterized. Studies of the segregation of DNA patterns in families made possible the reliable determination of DNA C4 haplotype pattern including gene number. In the total material of 76 haplotypes, 13 different types with regard to number and/or DNA type of C4 gene(s) were encountered. Twelve of the haplotypes had one C4 gene only, 58 had two genes, while 6 had three C4 genes. This fits fairly well with the hypothesis that the one‐ and three‐gene haplotypes have originated through unequal crossing‐over between chromosomes carrying duplicated C4 genes.
Regional localization of CD18, the β‐subunit of the cell surface adhesion molecule LFA‐1, on human chromosome 21 by in situ hybridization
Authors: SOLOMON E. , PALMER R. W. , HING S. , LAW S. K. A.
Published: September 2007

The gene coding for the β‐subunit of the cell surface adhesion glycoprotein LFA‐1 has been localized to the tip of the long arm of chromosome 21 at 21q22.1‐qter.
Mitochondrial DNA polymorphism in four Sardinian villages
Authors: SARTORIS S. , VARETTO O. , MIGONE N. , CAPPELLO N. , PIAZZA A. , FERRARA G. B. , CEPPELLINI R.
Published: September 2007

Polymorphism of mitochondrial DNA has been studied in two highland (Desulo, Tonara) and in two lowland (Galtellì, Orosei) Sardinian isolates, formerly subjected to different selective pressure due to malaria, and in 103 individuals from Northern Italy (Bergamo area), where malaria never appeared to be endemic. Two mitochondrial restriction endonuclease patterns (morphs) never described before have been found, one in the Bergamo and Orosei samples, and the other one only in Orosei. Four new mitochondrial types (mitotypes) due to different combinations of morphs have been identified; two of them have been found only in Sardinia, but with such a low frequency that they cannot be defined as typical Sardinian mitotypes. One mitotype (BamHI ‐ morph 3, MspI ‐ morph 4, AvaII ‐ morph 9 and HaeII ‐ morph 1) showed a significantly higher frequency in the highland rather than in the lowland Sardinian villages or in the Bergamo area. Since this mitotype has been found at a relatively high frequency in Central and Southern Italy, while it has been reported to be rare in Caucasians of Central European origin and absent in other ethnic groups (Africans, Chinese, Japanese and Israeli Jews), we suggest it may represent an ancient Mediterranean type. The analysis of these data suggests that drift or other evolutive forces different from malaria might be the major cause of mitochondrial DNA variation in Sardinia.
Effects of environmental changes on the phenotypic expression of human polygenic traits
Authors: ULIZZI L. , CORREANI R. , TERRENATO L.
Published: September 2007

The very large increase in adult stature during the last century is well documented for many countries and this phenomenon has been associated with the rapid improvement of environmental conditions. In the case of Italy, data relative to its regions and drawn from the military records of the last century showed a rapid normalization (i.e. elimination of both negative skewness and hyperkurtosis) of the distribution (1874–1938), followed by acceleration of the average increase (1938–57), which is now approaching a plateau (1957–64). Two different interactions between genotype and environment are hypothesized: the curve normalization is interpreted as being due to the elimination of extremely unfavourable conditions which inhibit growth, while the rapid stature increase is possibly due to the achievement of an environmental threshold, such as to permit a complete expression of the genetic potential. In fact, under the multifactorial model, a perfectly normal distribution is expected, unless there is differential selection before age 18.
Assignment of the gene encoding the beta‐subunit of the human fibronectin receptor (β‐FNR) to chromosome 10p11.2
Authors: Goodfellow P. J. , Nevanlinna H. A. , Gorman P. , Sheer D. , Lam G. , Goodfellow P. N.
Published: September 2007

A cDNA corresponding to the β‐subunit of the human fibronectin receptor (β‐FNR) was used as a probe in Southern blot analysis of mouse/human somatic cell hybrid DNAs and in in situ hybridization to metaphase chrmosomes. The β‐FNR cDNA detects sequences prosent on parent of the somatic cell hybrids. In situ hybridization refined the localization of human sequences reacting with the β‐FNR cDNA to 10p11.2. The A‐1A5 monoclonal antibody which recognizes the beta‐subunit of the fibronectin receptor on the cell surface was used to confirm that the sequences present on chromosome 10 correspond to those required for expression of β‐FNR.
Efficient computation of lod scores: genotype elimination, genotype redefinition, and hybrid maximum likelihood algorithms
Authors: Lange K. , Weeks D. E.
Published: September 2007

Calculation of multilocus lod scores presents challenging problems in numerical analysis, combinatories, programming, and genetics. It is possible to accelerate these computations by exploiting the simple pedigree structure of a CEPH‐type pedigree consisting of a nuclear family plus all four grandparents. Lathropet al.(1986) have done’ this by introducing likelihood factorization and transformation rules and Lander & Green (1987) by the method of ‘hidden Markov chains’. The present paper explores an alternative approach based on genotype redefinition in the grandparents and systematic phase elimination in all pedigree members. All three approaches accelerate the computation of a single likelihood. Equally relevant to multilocus mapping are search strategies for finding the maximum likelihood estimates of recombination fractions. Hybrid algorithms that start with the EM algorithm and switch midway to quasi‐Newton algorithms show promise. These issues are investigated in the context of a simulated 10 locus example. This same example allows us to illustrate a simple strategy for determining locus order.
Sequence of full length cDNA for human S‐adenosylhomocysteine hydrolase.
Authors: COULTER‐KARIS D.E. , HERSHFIELD M.S.
Published: September 2007

Two cDNA clones for human S‐adenosylhomocysteine hydrolase isolated from a placental cDNA library were sequenced. Each contained a sequence of 1299 nucleotides encoding a 432 amino‐acide protein of MW 47660. Clone 16‐1 contained 47 nucleotides 5′ of the coding region, and a 780 nucleotide 3′ flanking region terminating in apoly A tail. In addition, a 101 nucleotide unprocessed intron interrupted the coding sequence at nucleotide 854 (second base of codon 285). Clone 20‐1 contianed 43 nucleotides 5′ and 742 nucleotides 3′ flanking the uninterrupted coding region. Besides the intron, the clones differed in one position of the coding sequence and at two positions of the 3′ non‐coding region. The cDNAs for human and rat S‐adenosylhomocysteine hydrolase were identical at 91.5% of position in the coding sequence and showed 70% homology in the 3′ non‐coding regions. Human and rat S‐adenosylhomocysteine hydrolases are identical at 97% of amino‐acid residues, and the Dictyostelium and human enzymes at 75%.
Isonymy and migration distance
Authors: BARRAI I. , FORMICA G. , BARALE R. , BERETTA M.
Published: September 2007

The distribution of surnames of the living immigrants in the population of the town of Ferrara was studied by sex of immigrants and by distance of their place of origin from Ferrara. It was found that isonymy decreases with distance from the place of origin and that there is sexual dimorphism in migration distance: females migrate preferentially at short distances and males at long and very long distances. As indicators of the abundance of surnames in a distribution, the common ecological indices derived from entropy were used, and compared between migration ranges. It was found that redundancy, like isonymy, decreases with migration distance, and that it may be useful in detecting very‐long‐distance migration.
Isolation of a human cytochrome P‐450 reductase cDNA clone and localization of the corresponding gene to chromosome 7q11.2
Authors: SHEPHARD E. A. , PHILLIPS I. R. , SANTISTEBAN I. , WEST L. F. , PALMER C. N. A. , ASHWORTH A. , POVEY S.
Published: September 2007

We have isolated and sequenced cDNA clones that code for rat and human NADPH dependent cytochrome P‐450 reductase. The cDNA coding for the human protein was used to analyse, by Southern blot hybridization, DNA isolated from a panel of 8 independent humanrodent somatic cell hybrids. The results indicate that cytochrome P‐450 reductase is encoded by a single gene (POR) located on human chromosome 7(pter‐q22). Analysis of human metaphase chromosomes by hybridization in situ confirmed the results and refined the localization to 7q11.2. Northern blot hybridization revealed that in human liver the expression of the gene varies by less than 3‐fold between different individuals.
Inbreeding in the Utah Mormons: an evaluation of estimates based on pedigrees, isonymy, and migration matrices
Authors: JORDE L. B.
Published: September 2007

Using a computerized genealogical database, inbreeding coefficients were calculated for a sample of 435777 Utah Mormons. The population was divided into ten ten‐year birth cohorts (1846–1945) and 22 geographic subdivisions in order to assess temporal and spatial variation in inbreeding. The average inbreeding coefficient for this population is 0.000 106. The average within‐groups random kinship coefficient is 0.000 312, reflecting consanguinity avoidance. Random kinship matrices were formed by estimating the average kinship within each spatial subdivision and between all pairs of subdivisions. These matrices were compared statistically with kinship matrices previously estimated using migration matrices and isonymy data. The isonymy approach consistently overestimates random and total inbreeding as well as Wright's Fst. This can be attributed primarily to the assumption of monophyletic origin of surnames. The migration matrix method underestimates random inbreeding and Fst. This is due mainly to the assumption that outside immigrants are derived from a genetically homogeneous population. While the absolute values of the kinship coefficients estimated by each method differ substantially, the patterns of between‐groups kinship coefficients given by each method are highly congruent. Logistic and linear regression analyses of 85 235 marriages demonstrate that consanguinity is significantly dependent upon year of marriage, geographic distance between husband's and wife's birthplaces, and the population size of husband's and wife's birthplaces.
Assignment of the human nicotinic acetylcholine receptor genes: the alpha and delta subunit genes to chromosome 2 and the beta subunit gene to chromosome 17
Authors: BEESON D. , JEREMIAH S. , WEST L. F. , POVEY S. , NEWSOM‐DAVIS J.
Published: September 2007

The chromosomal assignments of the genes coding for the alpha, beta and delta subunits of the human nicotinic acetylcholine receptor have been determined from a panel of somatic cell hybrids and by direct in situ hybridization. The results localize CHRNA to 2q24‐2q32. CHRNB to 17p11 17p12, and CHRND to chromosome 2q33‐2qter.
Probabilities of orders in linkage calculations
Authors: SMITH C. A. B.
Published: September 2007

The present state of linkage estimation procedures is surveyed. When information on linkage between several loci on one chromosome is given in the form of lod scores or likelihoods, a method is developed for finding the probabilities of the different possible orders of the loci, and the distribution of the map distances between them. This depends largely on a Monte Carlo method of integrating the probabilities.
A test based on the exact probability distribution of the χ2 statistic ‐ incorporation into the MASC method
Authors: MULLER B. , CLERGET‐DARPOUX F.
Published: September 2007

The MASC method (Clerget‐Darpoux et al. 1988) to test genetic models in HLA associated disease makes use of a test of goodness‐of‐fit on categorized data. This test is composed of a sum of independent χ2s, which are applicable only when expectations in each category are not too small. The commonly used approach to solve this problem is to combine classes in order to raise expectations. This, however, means losing some of the information contained in the data and may decrease greatly the power of discrimination between models. A test based on the exact probability distribution of a test statistic, namely the χ2, has been implemented to avoid this dilemma.
Testing for haplotype sharing by siblings with incomplete information of parental haplotypes
Authors: GREEN J. R. , GRENNAN D. M.
Published: September 2007

Testing for the inheritance of a disease susceptibility gene by analysis of haplotype sharing among affected siblings has been well established for the case where all four parental haplotypes have been ascertained. This paper presents a modification of a published method to cover the situation where there is incomplete information concerning parental haplotypes and this new test is applied in a worked example.
Kinship structures and migration in the Po Delta
Authors: BARRAI I. , CANELLA R. , BERETTA M. , MAMOLINI E. , BARALE R. , SCAPOLI C. , RAVANI A.
Published: September 2007

The kinship analysis of seven genetic systems in the province of Ferrara permits some considerations on the possible chronology of emergence of their polymorphisms in the area. It is proposed that, assuming neutrality of these systems, and under several restrictions, the emergence by migration of the polymorphisms in the seven systems ACP, ESD, GLO, GPT, PGD, PGM1; PGP might have had the following sequence: PGP and GLO and possibly PGD; PGMj and GPT; ACP and ESD. All polymorphisms must be older than the β‐thalassemia polymorphism in the area.
Bayesian methods and optimal experimental design for gene mapping by radiation hybrids
Authors: LANGE K. , BOEHNKE M.
Published: September 2007

Radiation hybrid mapping is a somatic cell technique for ordering human loci along a chromosome and estimating the physical distance between adjacent loci. The present paper considers a realistic model of fragment generation and retention. This model assumes that fragments are generated in the ancestral cell of a clone according to a Poisson breakage process along the chromosome. Once generated, fragments are independently retained in the clone with a common retention probability. Based on this and less restrictive models, statistical criteria such as minimum obligate breaks, maximum likelihood, and Bayesian posterior probabilities can be used to decide order. Distances can be estimated by either maximum likelihood or Bayesian posterior means. The model also permits rational design of radiation dose for optimal statistical precision. A brief examination of some real data illustrates our criteria and computational algorithms.
In the multifactorial model of disease transmission, why is the rank correlation sensitive to choice of bivariate distribution?
Authors: HUTCHINSON T. P.
Published: September 2007

The multifactorial model uses a dichotomization (ill vs. well) that occurs in the extreme tail of a bivariate distribution. The crudeness of this is responsible for rank correlation ‐ which is a summary statistic calculated from the whole bivariate distribution ‐ being sensitive to the choice of the bivariate distributional form.
Linkage and association studies with C8A and C8B RFLPs on chromosome 1
Authors: ROGDE S. , GEDDE‐DAHL T. , TEISBERG P. , JONASSEN R. , HØYHEIM B. , OLAISEN B.
Published: September 2007

Linkage relations for the C8A and C8B BamHI RFLPs have been investigated. A peak lod score of 4·52 at recombination fraction zero was obtained between the two C8 genes. Combined with our previously obtained linkage data (Rogde et al. 1986) the maximum lod score is 7·53 at recombination fraction zero. The compiled C8‐PGM1 linkage data from this and the previous study gave a maximum lod score of 22·02 at recombination fraction 0·11 (0·07–0·16) with no sex difference. A chromosome 1p reference marker, D1S57, has been applied in this linkage study. A maximum lod score of 5·06 between the C8 cluster and D1S57 at θ= 0·18 (0·11–0·28) was recorded. The linkage analyses and triply informative families gave evidence that the C8 loci are situated about halfway between PGM1 and D1S57 on the short arm of chromosome 1. There was no evidence of allelic association between the C8A and C8B BamHI RFLPs in 62 unrelated haplotypes.
The power of the N‐test of haplotype concordance
Authors: GREEN J. R. , SHAH S.
Published: September 2007

The N‐test of haplotype concordance among siblings affected by some disease under investigation is used to decide whether there is a disease susceptibility gene linked to a marker locus or chromosomal region. The use of this test and appropriate modifications of it is briefly reviewed. The power of the ordinary N‐test is then derived as a function of several parameters. The sample size needed to attain a given power is then derived. Some of the parameters are specified and the required sample sizes are given in tables for different values of the main unknown parameters.
Calculation of genetic identity coefficients
Authors: LANGE K. , SINSHEIMER J. S.
Published: September 2007

Genetic identity coefficients define the kind and amount of gene sharing between two relatives at a single locus. Non‐recursive computation of these probabilities depends on cumbersome graph‐tracing algorithms. Closely related to the identity coefficients are certain generalized kinship coefficients which can be computed recursively. The present paper clarifies some ideas of Karigl about how to relate identity coefficients to generalized kinship coefficients.
Linkage analysis of 7 polymorphic markers at chromosome 11p11. 2‐11q13 in 27 multiple endocrine neoplasia type 1 families
Authors: THAKKER R. V. , WOODING C. , PANG J. T. , FARREN B. , HARDING B. , ANDERSON D. C. , BESSER G. M. , BOULOUX P. , BRENTON D. P. , BUCHANAN K. D. , EDWARDS C. R. , HEATH D. A. , JACKSON C. E. , JANSEN S. , LIPS K. , NORUM R. A. , SAMPSON J. , SHALET S. M. , TARGGART R. T. , TAILOR D. , WHEELER M.H. , WOOLLARD P. M. , YATERS J.
Published: September 2007

The multiple endocrine neoplasia type 1 (MEN1) locus has been previously localized to llq13 by combined tumour deletion mapping and linkage studies. Family linkage analysis has defined the locus order as 11cen‐PGA‐(PYGM, MENl)‐(D11S197, D11S146)‐INT2‐11qter, and tumour deletion mapping studies have suggested that the MEN1 locus is proximal to D11S146 but distal to PYGM. In order to establish further the location of MEN1, we have utilized the seven polymorphic DNA probes: D118S88, D11S149, PGA, PYGM, D11S97, D11S146 and INT2, in linkage studies of 339 members (116 affected) from 27 MEN 1 families. Linkage between MEN 1 and 6 of the 7 loci was established, and the highest peak lod scores [Z(θ)] were observed with PYGM and D11S97 at Z(θ) = 13–71, θ= 0.047 and Z(θ) = 13.76, θ= 0.076 respectively. Multilocus analysis suggested the most likely locus order as:11pter‐(D11S288, D11S149)‐11cen‐PGA‐PYGM‐MEN1‐D11S97‐D11S146‐INT2‐11qter. In addition, an examination of individual recombinants indicated a centromeric location of D11S149 in relation to D115288. Thus, the results of our study, which favoured a location of MEN1 proximal to D11S97 and distal to PYGM, have established a panel of recombinants that will facilitate further meiotic mapping studies of the MEN 1 locus.
Correlation between relatives for colorecrtal cancer mortality in familial adenomatous polyposis
Authors: PRESCIUTTINI S. , BERTARIO L. , SALA P. , ROSSETTI C. , LEWONTIN R. C.
Published: September 2007

It has long been realized that age‐specific cancer mortality in Familial Adenomatous Polyposis (FAP) was bimodal, and a theory was proposed in which the involved locus was polymorphic in the general population. After the molecular cloning of the region 5q21, it has been suggested that the phenotypic variability in FAP may be due to the interaction of two loci, one of which is polymorphic. We show that these two hypotheses lead to different predictions of the correlation between relatives for a phenotypic trait, and use colorectal cancer mortality data from the Italian Polyposes Registry to verify them. We conclude that the first of the two is more likely and suggest that the same variation that we observe among the affected subjects is present in the general population. thus causing a significant difference between individuals for colon cancer susceptibility.
Inference of the strength of genotype‐disease association from studies comparing offspring with and without parental history of disease
Authors: TIRET L. , NICAUD V. , EHNHOLM C. , HAVEKES L. , MENZEL H. J. , DUCIMETIERE P. , CAMBIEN F.
Published: September 2007

The association between genetic polymorphisms and a multifactorial disease is generally investigated by case‐control studies. However, inference about the genotype‐disease association can also be drawn from studies comparing offspring having a parental history of disease with offspring having no parental history. In such studies, differences in genotype frequencies between the two groups of offspring will reflect a different transmission of alleles from affected and unaffected parents. We showed that in offspring studies, the odds ratios (ORs) associated with heterozygous and homozygous genotypes are related by the formula: ORhet= (ORhom+1)/2. These ORs depend only on the allele frequencies in affected and unaffected parents, and not on the pattern of genotype‐disease association. Under simple patterns of association, it is possible to infer from the ORs observed among offspring, the expected ORs for the disease. The decrease of power of offspring studies by comparison with classical case‐control studies is evaluated, and an application is given on the association between the apoE polymorphism and coronary heart disease.
Germline rearrangement of MCC and APC detected by pulsed field gel electrophoresis and fluorescent in situ hybridization
Authors: GAYTHER S. , WELLS D. , GULATI K. , CHAPMAN P. , BURN J. , DELHANTY J. D. A.
Published: September 2007

Pulsed field gel electrophoresis was carried out on lymphocyte DNA obtained from ten patients with the inherited premalignant condition adenomatous polyposis coli and a similar number of control samples to search for large scale molecular rearrangements in the vicinity of the APC locus. DNA from one patient showed a rearranged pattern which was interpreted as evidence for an inversion of approximately 150 kb, changing the transcriptional orientation of the neighbouring MCC gene and bringing it closer to APC. Such an interpretation was supported by fluorescent in situ hybridization data.
An Asp8Asn substitution results in the adenosine deaminase (ADA) genetic polymorphism (ADA 2 allozyme): occurrence on different chromosomal backgrounds and apparent intragenic crossover
Authors: HIRSCHHORN R. , YANG D. R. , ISRANI A.
Published: September 2007

We have now determined the molecular genetic basis for the common biochemical polymorphism at the adenosine deaminase (ADA) locus. The ADA*2 allele contains a G to A transition at nt22 (relative to the ATG) that results in substitution of asparagine for aspartic acid at codon 8 (Asp8Asn). Introduction of the nucleotide substitution into an ADA 1 cDNA and transfection into monkey kidney (Cos) cells confirmed that the mutation resulted in expression of an enzyme that comigrated with the naturally occurring ADA 2 allozyme. The substitution of neutral asparagine for anionic aspartic acid is consistent with the more cathodal electrophoretic migration of ADA 2 as compared with ADA 1. The nucleotide substitution was found on at least two different genetic backgrounds, suggesting independent recurrence of the mutation. Consistent with independent recurrence, the G to A transition is at a CpG dinucleotide and represents a type of mutation that occurs with high frequency. We have also unexpectedly identified a probable intragenic crossover in the very large first intron that is rich in repetitive DNA sequences.
The SON gene encodes a conserved DNA binding protein mapping to human chromosome 21
Authors: KHAN I. M. , FISHER R. A. , JOHNSON K. J. , BAILEY M. E. S. , SICILIANO M. J. , KESSLING A. M. , FARRER M. , CARRITT B. , KAMALATI T. , BULUWELA L.
Published: September 2007

We report the identification and characterization of a clone for the DNA binding protein SON, which we have isolated from a human keratinocyte cDNA library. Using this clone we have found that the SON gene is expressed in different cell types and that homologous sequences can be detected in vertebrate and insect genomic DNA. Using the polymerase chain reaction (PCR) to amplify SON sequences from a panel of somatic cell hybrids we have assigned the gene encoding human SON to chromosome 21. By use of hybrids containing regions of chromosome 21 the localization has been refined to 21q 22. 1‐q22.2.
Development of a panel of monochromosomal somatic cell hybrids for rapid gene mapping
Authors: KELSELL D. P. , ROOKE L. , WARNE D. , BOUZYK M. , CULLIN L. , COX S. , WEST L. , POVEY S. , SPURR N. K.
Published: September 2007

We have assembled a panel of monochromosomal somatic cell hybrids for use in gene mapping. DNA from each individual hybrid was used as a probe on normal human metaphases to identify the human chromosome and any fragments by reverse painting. To test the efficiency of the panel PCR amplification of DNA from the monochromosomal somatic cell hybrid panel was used in combination with human specific oligonucleotide primers to assign α‐catenin (CTNNA1) and p21/WAFl to chromosomes 5 and 6 respectively. These genes were localized further using hybrids containing specific translocations to 5qll‐qter and 6p21 respectively. We also developed primers to enable us to assign 17 ESTs sequenced by the HGMP Resource Centre. The hybrid panel was developed with support of the UK HGMP and the DNA is available to all registered users.
Genetic variation in the COL6A1 region is associated with congenital heart defects in trisomy 21 (Down's syndrome)
Authors: DAVIES G. E. , HOWARD C. M. , FARRER M. J. , COLEMAN M. M. , BENNETT L. B. , CULLEN L. M. , WYSE R. K. H. , BURN J. , WILLIAMSON R. , KESSLING A. M.
Published: September 2007

Genetic variation in the COL6A1‐COL6A2 gene cluster on chromosome 21 was studied in 113 controls and 58 European families (including control and family subgroups of British/Irish origin) having a child with trisomy 21. There were statistically significant differences among subgroups of trisomic children with and without congenital heart defects (CHD) in distributions of definitive, 3‐RFLP haplotype classes received from their nondisjoining and disjoining parents. Haplotypes received by trisomic children with CHD from their disjoining parents were not a random sample of controls' haplotypes. Analysis of parental single‐RFLP genotypes and linkage disequilibrium patterns confirmed this parent subgroup differed from a random sample of controls. There were no significant differences in parent subgroup genotype distribution at any of nine control loci distributed along chromosome 21q. This sample showed an association between genetic variation in the COL6A1 gene region and congenital heart defects in trisomy 21.
Integration of gene maps: updating chromosome 1
Authors: FORABOSCO P. , COLLINS A. , MORTON N. E.
Published: September 2007

The first integrated map of chromosome 1 was published in 1992. We present an updated summary map of 371 loci constructed from a location database that includes physical and genetic data. The summary map subsumes a composite physical location, sex‐specific genetic location, cytogenetic assignment, mouse homology, rank and references to physical maps. The genetic length is 208 cM for the male map, in close agreement with the chiasma map, and 371 cM for the female map. There is evidence for a high level of interference on chromosome 1. The location database comprising both data and analytical software is discussed in relation to alternative approaches and possible enhancements.
Identification of VAV2 on 9q34 and its exclusion as the tuberous sclerosis gene TSC1
Authors: HENSKE E. P. , SHORT M. P. , JOZWIAK S. , BOVEY C. M. , RAMLAKHAN S. , HAINES J. L. , KWIATKOWSKI D. J.
Published: September 2007

A novel widely expressed homologue of the VAV oncogene, VAV2 (53% identical residues), has been identified within the critical region for the tuberous sclerosis gene, TSC1, on human chromosome 9q34. By Southern blot analysis, analysis of allele‐specific transcription, and direct sequencing of the VAV2 mRNA/cDNA from patient lymphoblastoid cell lines, we demonstrate that both alleles of this gene are expressed in TSC patients and there are no significant mutations. VAV consists of a novel array of signalling domains and is thought to play an important role in signal transduction in haematopoietic tissues where it is exclusively expressed. VAV2 is likely to serve a similar role more generally in mammalian cells, but is not the TSC1 gene.
Monte Carlo tests for associations between disease and alleles at highly polymorphic loci
Authors: SHAM P. C. , CURTIS D.
Published: September 2007

In an association analysis comparing cases and controls with respect to allele frequencies at a highly polymorphic locus, a potential problem is that the conventional chi‐squared test may not be valid for a large, sparse contingency table. However, reliance on statistics with known asymptotic distribution is now unnecessary, as Monte Carlo simulations can be performed to estimate the significance level of any test statistic. We have implemented a Monte Carlo method for four ‘chi‐squared’ test statistics, three of which involved combination of alleles, and evaluated their performance on a real data set. Combining rare alleles to avoid small expected cell counts, and considering each allele in turn against the rest, reduced the power to detect a genuine association when the number of alleles was very large. We should either not combine alleles at all, or combine them in such a way that preserves the evidence for an association.
A high frequency polymorphism in the candidate region for Tuberous Sclerosis 1 (TSC1) at 9q34
Authors: MOR O. , DUHIG T. , FRIED M.
Published: September 2007

The Surfeit locus contains at least six tightly clustered housekeeping genes (Surf‐1 to ‐6) with novel features (Huxley & Fried, 1990). In contrast to the tens to hundreds of kilobases found between most adjacent mammalian genes only a small region separates any two adjacent Surfeit genes. The organization of the Surfeit locus and the juxtaposition of the Surfeit genes is conserved between mouse, human and chicken (600 million years of divergent evolution) (Williams et al. 1988; Yon et al. 1993; Colombo et al. 1992) indicating that the Surfeit locus gene organization may have biological significance. The Surfeit locus has been mapped to human chromosome band 9q34, within the candidate region for Tuberous Sclerosis 1 (TSC1) (Yon et al. 1993). In the process of screening for mutations correlated with TSC1 by single strand conformation polymorphism (SSCP) (Orita et al. 1989) in this genomic region we detected a polymorphism which occurs at a high frequency.
Genetic analysis of schizophrenia as an example of a putative multifactorial trait
Authors: PRITCHARD D. J.
Published: September 2007

A new method for analysis of multifactorial traits is described which involves mathematical definition of MZ and DZ twin concordances in terms of penetrance and the number of contributory genes. This allows the number of major genes and their joint penetrance to be estimated. Application to familial schizophrenia indicates causation by a single dominant allele, a deduction supported by several treatments of observed risks in other family members. Lifetime empiric risks are analysed in the context of four conditions: genetic predisposition, prenatal trauma, psychological or other trauma in early adult life and possible exacerbation of symptoms associated with close contact with affected family members. Comparative empiric risks for twins and sibs are explained by consideration of coincident gestations, season of birth and the sharing of a chorionic sac and foetal blood supply. The data are consistent with penetrance being complete in homozygotes and generally around 0·33 in heterozygotes, but it increases in additive fashion depending on risk factors associated with the type of relationship with one or more affected family members and factors associated with twinning. The influence of an affected parent is nearly 3 times as great as that of an affected sibling. The population frequency of heterozygotes is deduced to be around 2·6%.
Effects of Prenatal Ethanol Exposure on the Postnatal Development of the Brainstem Auditory Evoked Potential in the Rat
Authors: Church M. W. , Holloway J. A.
Published: September 2007

Brainstem auditory evoked potentials (BAEPs) were used to study the postnatal development of the peripheral and brainstem auditory pathways in rat pups prenatally exposed to ethanol. Pups were offspring of dams receiving either a liquid diet containing ethanol (ethanol pups) or a control diet (control pups). Two to four pups from control and ethanol litters were systematically selected for BAEP analysis and examined periodically from the ages of 2 to 10 weeks. BAEPs to 0.1 msec clicks (60 dB HL, B/sec) were recorded with subcutaneous scalp electrodes in nonsedated animals. Latencies of the various BAEP waves decreased with age in both groups, reflecting maturation of the subcortical auditory pathway. Ethanol pups, however, showed retarded BAEP maturation as indicated by significantly longer BAEP wave latencies and smaller wave amplitudes than those of the control pups. While group differences were greatest early in development, the ethanol group still had significantly longer BAEP wave latencies at maturity. These results indicate that prenatal ethanol exposure retards development of the peripheral and brainstem auditory pathways and that prolonged auditory transmission times, despite a “catch‐up” trend, persist in maturity. BAEP data, birth weights, and postnatal weight gains of ethanol pups were not consistent with the effects of pre‐ and postnatal malnutrition as reported by others.
Effect of Sex Bias on Women's Studies on Alcoholism
Authors: Vannicelli Marsha , Nash Laurie
Published: September 2007

Women alcoholics have historically been underrepresented in research studies far out of proportion to the difference in male female prevalence rates. This study examined disparities in the ways in which male and female alcoholics have been studied in the treatment outcome literature and examined the role of sex bias (author sex) as a contributing factor. Two hundred fifty‐nine studies published between 1972 and 1980 were reviewed that reported drinking‐related outcome of subjects treated with psychological intervention or medication. Only 7.8% of subjects sampled in these studies were women. Of greater interest, female authors sampled nearly 3 times as many women in proportion to the number of people they studied as did male authors; women subjects were more than one and one‐half times as likely to be followed up by female than by male authors; and 3 times as many female as male authors presented data examining sex differences. The same kind of differences between male and female authors occurred with respect to specifying precise numbers of male and female subjects studied and followed up, and with respect to examining prognostic variables related to women' outcome. The data suggest that subtle sex bias contributes to inadequate studying of women alcoholics.
Similarity of polygenic profiles limits the potential for elite human physical performance
Authors: Williams Alun G. , Folland Jonathan P.
Published: September 2007

Human physical capability is influenced by many environmental and genetic factors, and it is generally accepted that physical capability phenotypes are highly polygenic. However, the ways in which relevant polymorphisms combine to influence the physical capability of individuals and populations are unknown. Initially, the literature was searched to identify associations between 23 genetic polymorphisms and human endurance phenotypes. Next, typical genotype frequencies of those polymorphisms in the general population were obtained from suitable literature. Using probability calculations, we found only a 0.0005% chance of a single individual in the world having the ‘preferable’ form of all 23 polymorphisms. As the number of DNA variants shown to be associated with human endurance phenotypes continues to increase, the probability of any single individual possessing the ‘preferable’ form of each polymorphism will become even lower. However, with population turnover, the chance of such genetically gifted individuals existing increases. To examine the polygenic endurance potential of a human population, a ‘total genotype score’ (for the 23 polymorphisms) was calculated for each individual within a hypothetical population of 1000 000. There was considerable homogeneity in terms of genetic predisposition to high endurance potential, with 99% of people differing by no more than seven genotypes from the typical profile. Consequently, with population turnover world and Olympic records should improve even without further enhancement of environmental factors, as more ‘advantageous’ polygenic profiles occasionally, though rarely, emerge. More broadly, human potential appears limited by the similarity of polygenic profiles at both the ‘elite sport’ and ‘chronic disorder’ ends of the performance continuum.
Endurance exercise performance: the physiology of champions
Authors: Joyner Michael J. , Coyle Edward F.
Published: September 2007

Efforts to understand human physiology through the study of champion athletes and record performances have been ongoing for about a century. For endurance sports three main factors – maximal oxygen consumption , the so‐called ‘lactate threshold’ and efficiency (i.e. the oxygen cost to generate a give running speed or cycling power output) – appear to play key roles in endurance performance. and lactate threshold interact to determine the ‘performance ‘ which is the oxygen consumption that can be sustained for a given period of time. Efficiency interacts with the performance to establish the speed or power that can be generated at this oxygen consumption. This review focuses on what is currently known about how these factors interact, their utility as predictors of elite performance, and areas where there is relatively less information to guide current thinking. In this context, definitive ideas about the physiological determinants of running and cycling efficiency is relatively lacking in comparison with and the lactate threshold, and there is surprisingly limited and clear information about the genetic factors that might pre‐dispose for elite performance. It should also be cautioned that complex motivational and sociological factors also play important roles in who does or does not become a champion and these factors go far beyond simple physiological explanations. Therefore, the performance of elite athletes is likely to defy the types of easy explanations sought by scientific reductionism and remain an important puzzle for those interested in physiological integration well into the future.