bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic and morphometric variances in three human populations
Authors: SCHMITT L. H. , HARRISON G. A. , HIORNS R. W.
Published: September 2007

Data from three human populations were used to investigate the putative relationship between genetic and morphological variances. There was no evidence to support the hypothesis that individuals heterozygous at a small number of marker loci are more often near the mean for anthropometric characters than are homozygotes. In one population (Otmoor), apparent support for the hypothesis was due to the confounding factors of correlations between anthropometric traits and population subdivision. It is unlikely that such relationships can be detected by intrapopulation comparisons because of the low association between measured and total heterozygosity.
Bkm sequences from the human X chromosome contain large clusters of GATA/GACA repeats
Authors: ERICKSON R. P. , ROSS C. E. , GORSKI J. L. , STALVEY J. R. D. , DRUMM M. M.
Published: September 2007

In order to determine whether the regional localizations of Bkm repeats detected on the human X chromosome consisted of typical GATA/GACA repeats, clones were isolated, mapped, and sequenced. Nine Bkm‐hybridizing clones from Kunkel's fluorescent‐activated, cell‐sorted X‐chromosome library were all unique. Five were mapped in detail with restriction enzymes and the Bkm‐hybridizing segments were localized. Confirmation of X chromosomal homology was obtained for 2 of the clones and Bkm segments from these 2 clones were sequenced. Seventeen contiguous GATA repeats were found in each clone and the overall repeat arrangement showed relatively few differences from previously sequenced Bkm sequences. These are the first sequences of human Bkm repeats. The results, when compared with previously published results, suggest that there may be significant differences between the organization of Bkm repeats on the human X and on the human Y chromosome.
Cloning and chromosomal mapping of human cytochrome b5 reductase (DIA1)
Authors: BULL P. C. , SHEPHARD E. A. , POVEY S. , SANTISTEBAN I. , PHILLIPS I. R.
Published: September 2007

We have isolated a cDNA clone that codes for human cytochrome b5 reductase. The cDNA was used to analyse, by Southern‐blot hybridization, DNA isolated from a panel of 11 independent human‐rodent somatic cell hybrids. The results indicate that cytochrome b5 reductase is encoded by a single gene located on human chromosome 22.
The analysis of close linkage in large families
Authors: EDWARDS J. H.
Published: September 2007

In large families, if two closely linked loci both have rare alleles and several distant members are ascertained through one having rare alleles at both loci, simple estimates of their recombination fraction are possible. This information is free from errors due to both reduced penetrance and erratic paternity. Simple estimates based on counting will often have high efficiency and limited bias. Some problems of linkage analysis between loci with codominant expression in complete three generation families are also considered. The omission of individuals of uncertain genotype at the test locus will be more efficient than their inclusion.
Cytosolic aldehyde dehydrogenase (ALDH1) variants found in alcohol flushers
Authors: Yoshida A. , Davé V. , Ward R. J. , Peters T. J.
Published: September 2007

Although mitochondrial aldehyde dehydrogenase (ALDH2) has been thought to play a major role in acetaldehyde detoxification, and the high incidence of ‘alcohol flushing’ among Orientals is attributed to the inherited deficiency of ALDH2, the role of cytosolic aldehyde dehydrogenase (ALDH1) cannot be ignored. On the premise that alcohol flushing in Caucasians could be related to ALDH1 abnormalities, we examined the enzyme properties and electrophoretic mobilities of ALDH1 partially purified from red blood cells of nine unrelated alcohol flushers. One exhibited very low activity (10–20% of control level), and another exhibited moderately low activity (60%) and altered kinetic properties. The electrophoretic mobilities of these two samples were also distinguishable from the control samples. Immunological quantitation indicated that the amounts of ALDH1 protein in these two samples were not reduced in parallel with their enzyme deficiency. In the first case, the two characteristics, i.e. very low enzyme activity and alcohol flushing, were inherited by her daughter.
Assignment of the coding sequence for carcinoembryonic antigen (CEA) and normal cross‐reacting antigen (NCA) to human chromosome 19 q 13.
Authors: Willcocks T.C. , Craig S.P. , Craig I. W.
Published: September 2007

We have isolated and localized to chromosome 19 a gemomic sequence for carcinoembryonic antigen (CEA). A human cosmide bank was screened with two degenerate oligonucleotide sequences corresponding to N‐terminal segments of the protein. Seqence analysis of a selected cosmid has confirmed the presence of an exon representing the 107 amino acids of the first protein domain (plus part of a putative leader sequence). In situ hybridization of both the exon DNA sequence and a more extensive genomic fragment to replication banded chromosomes has indicated that CEA and strongly cross‐hybridizing members of the CEA family can be assigned to 19q13. This conclusion is supported by studies with a somatic cell hybrid cell‐line.
Localization of the Surfeit gene cluster containing the ribosomal protein gene L7a to chromosome bands 9q33‐34.
Authors: YON J. , PALMER R. W. , SHEER D. , FRIED M.
Published: September 2007

The Surfeit gene cluster which contains at least four very tightly spaced unrealted genes, of which encodes the ribosomal protein L7a, has been localized by an analysis of somatic cell hybrids to the long arm of chromosome 9. By the use of in situ hybridization the Surfeit locus has been further mapped to 9q3‐34.
An investigation of the properties and possible clinical significance of the lysosomal α‐glucosidase GAA* 2 allele
Authors: SWALLOW D. M. , KROOS M. , PLOEG A. T. Van der , GRIFFITHS B. , ISLAM I. , MARENAH C. B. , REUSER A. J. J.
Published: September 2007

Properties of the acid α‐glucosidase, GAA2, the product of the GAA*2 allele have been compared with those of the common allele product GAA1. GAA2 has an altered affinity for glycogen but resembles GAA1 in its affinity for low molecular weight substrates, and also in its processing, as judged by immunoblot analysis of the denatured polypeptides. Starch gel electrophoretic analysis of fibroblasts from 15 patients with late onset glycogen storage disease type II (GSDII) failed to reveal either homozygotes or heterozygotes for the GAA*2 allele (GAA2‐2 or GAA2‐0) providing evidence that neither of these genotypes lead to late onset GSDII despite the impaired activity of the enzyme towards glycogen.
An investigation of the possible influence of neutral α‐glucosidases on the clinical heterogeneity of glycogenosis type II
Authors: PLOEG A. T. Van der , KROOS M. A. , SWALLOW D. M. , REUSER A. J. J.
Published: September 2007

The lysosomal storage disorder glycogenosis type II, caused by a deficiency of lysosomal α‐glucosidase, is very heterogeneous in its clinical presentation. It has been suggested that this heterogeneity may be due to differential expression of neutral α‐glucosidases. We have therefore analysed the activity of the major neutral α‐glucosidases in cultured fibroblasts or muscle cells from 26 patients with glycogenosis type II. The results indicate that there is no correlation between the expression of neutral α‐glucosidase isoenzymes and the clinical phenotype of this disease.
Isolation of a cDNA clone and localization of the human glutathione S‐transferase 3 genes to chromosome bands 11q13 and 12q13‐14
Authors: BOARD P. G. , WEBB G. C. , COGGAN M.
Published: September 2007

A partial cDNA clone of the glutathione S‐transferase 3 gene (GST3) was obtained by screening a Agtll human lung cDNA library with antiserum to human lung GST3. The sequence of this cDNA showed two base differences from the coding sequence of a GST3 cDNA isolated from a human placental cDNA library.

Hybridization of the cloned GST3 cDNA to human chromosomes resulted in a primary peak of grains over band 11q13, a localization predicted by prior experiments. An unexpected strong secondary peak of grains was obtained over bands 12q13 and 12q14, indicating that there is a GST3‐like gene on the long arm of chromosome 12 in man.
Regional localization of the sperm‐specific lactate dehydrogenase, LDHC, gene on human chromosome 11
Authors: EDWARDS Y. , WEST L. , HEYNINGEN V. VAN , COWELL J. , GOLDBERG E.
Published: September 2007

A cDNA clone complementary to the mRNA encoding the sperm‐specific lactate dehydrogenase, LDHC, has been used to map the LDHC locus to the short arm of human chromosome 11. In situ hybridization data and analysis of mouse/human somatic cell hybrids carrying deletions of human chromosome 11 suggest that the gene is localized at p15.3‐p15.5 close to the LDHA gene.
How much difference does chromosome banding make?: Adjustments in prevalence and mutation rates of human structural cytogenetic abnormalities
Authors: HOOK E. B. , HEALY N. P. , WILLEY A. M.
Published: September 2007

A collaborative analysis was undertaken of 226 karyotypes with structural chromosome abnormalities diagnosed primarily with low level banding resolution, about 300 to 400 bands per karyotype. We estimate that in this series, use of low level banding was required to detect about 78% of pericentric inversions, about 51% of reciprocal translocations, about 47% of all balanced translocations, about 35% of unbalanced rearrangements other than rings, Robertsonian translocations and extra structurally abnormal chromosomes, about 11% of all unbalanced rearrangements, and about 35% of all structural abnormalities. Adjustment factors derived from these figures were applied to prevalence and mutation rates of structural mutation rates derived from published large scale studies of livebirths. Had low level banding been used in these earlier studies we estimate that the rate of all structural abnormalities would have been about 60% higher than those reported (3.8 per 1000 vs. 2.3 per 1000 in the original studies). The increase is much higher for balanced abnormalities, 75% (3.4 per 1000 vs. 1.9 per lOOO), than for unbalanced abnormalities, 5% (0.42 per 1000 vs. 0.405 per 1000). The increase in mutation rates for de novo cytogenetic abnormalities was similarly, considerably higher after such adjustment: the rates per 100000 gametes increased from 18.0 to 35.0 for balanced rearrangements, from 8.2 to 10.1 for unbalanced abnormalities and from 26.2 to 45.1 for all abnormalities. These estimates illustrate the difference even low level banding makes to detection of structural cytogenetic abnormalities and why contemporary studies using such methods cannot be compared with earlier large scale population studies or livebirths without some type of adjustment such as those suggested here. Comparisons should be done at a constant level of diagnostic resolution, e.g. limited to lesions detectable without banding.
MAP, an expert system for multiple pairwise linkage analysis
Authors: MORTON N. E. , ANDREWS V.
Published: September 2007

The logic of a program for multiple pairwise linkage analysis under interference is set forth, including a seriation algorithm to obtain a trial order, a mapping bootstrap to improve the trial order, and three procedures for quality control to detect mistyping. This approach is compared with multipoint analysis under null interference, which substantially overestimates map length and cannot incorporate a variety of data.
Some simple methods for linkage analysis
Authors: SMITH C. A. B.
Published: September 2007

A method of analysis of suitable many‐locus linkage data used by Fisher in 1922 is reexamined in detail, and it is pointed out that it could be used also in human genetics as a simple method for preliminary examination of data.
Testing for non‐randomness of events in sparse data situations
Authors: TARONE R. E.
Published: September 2007

In experiments involving cytogenetic assays or mutation assays it is often of interest to determine if there are hot spots for certain events, that is, to determine if the events occur more often at certain sites than would be expected under the assumption of randomness. In examining chromosome aberrations using banded chromosome preparations, for example, it may be of interest to determine if a particular type of aberration occurs more often in a particular band than would be expected given the relative length of the band. In a mutation assay it may be of interest to determine if a mutation occurs more often at a particular nucleotide in a given sequence than would be expected given the length of the sequence in question. Such experiments typically result in data following a multinomial distribution with a large number of classes and relatively few observations. For such data, De Braekeleer & Smith (1988) have suggested analysis of the frequencies in individual classes using an exact binomial test. Two cautions are noted for application of the binomial analysis in the usual situation in which the locations of potential hot spots are not specified beforehand.
Expression of the myeloid differentiation antigen CD33 depends on the presence of human chromosome 19 in human‐mouse hybrids
Authors: ADRIAANSEN H. J. , VAN KESSEL A. H. M. GEURTS , BRESSER J. H. F. M. WIJDENES‐DE , VAN DRUNEN‐SCHOENMAKER E. , VAN DONGEN J. J. M.
Published: September 2007

Interlineage human‐mouse hybrids were constructed by fusion of human acute undifferentiated leukaemia cells with the mouse thymoma cell line BW5147. Some of the hybrids expressed the human differentiation antigens CD4, CD7, CD33, and CD71 (transferrin receptor). Chromosome analysis revealed that the expression of the myeloid antigen CD33 is dependent on the presence of human chromosome 19, which is in agreement with the location of CD33‐coding sequences on chromosome 19, as recently reported by Peiper et al. (1987). Furthermore, these hybrids allowed us to confirm the assignment of the CD4 antigen, the CD7 antigen, and the CD71 antigen to human chromosomes 12, 17 and 3, respectively.
Regional localization of polymorphic markers on chromosome 10 by physical and genetic mapping
Authors: MATHEW C. G. P. , WAKELING W. , JONES E. , EASTON D. , FISHER R. , STRONG C. , SMITH B. , CHIN K. , LITTLE P. , NAKAMURA Y. , SHOWS T. B. , JONES C. , GOODFELLOW P. J. , POVEY S. , PONDER B. A. J.
Published: September 2007

The human vimentin gene and a random DNA segment (D10S39) were mapped to the short arm of human chromosome 10 by linkage analysis. A panel of somatic cell hybrids and monosomy cell‐lines, which divide chromosome 10 into seven regions, was used to localize 10 polymorphic markers on this chromosome. The physical map locations obtained correlate well with linkage maps of chromosome 10. Two markers which have been shown to be closely linked to the gene for multiple endocrine neoplasia type 2A map distal to a translocation breakpoint in band 10qll.2
The polymorphic human DNA sequence D8S8 assigned to 8ql3‐21.1, close to the carbonic anhydrase gene cluster, by isotopic and non‐isotopic in situ hybridization and by linkage analysis
Authors: EDWARDS Y. , WILLIAMS S. , WEST L. , LIPOWICZ S. , SHEER D. , ATTWOOD J. , SPURR N. , SARKAR R. , SAHA N. , POVEY S.
Published: September 2007

Restriction fragment length polymorphism at the D8S8 locus is explained by the occurrence of at least two alternative alleles at two separate TaqI sites; Taql‐A allele frequencies 0–73 and 0–27 and Taql‐B allele frequencies 0–94 and 0–06. The D8S8 locus has been assigned to 8q 13–21.1, near to the carbonic anhydrase (CA) gene cluster, by in situ hybridization to metaphase chromosomes using both tritium and immunofluorescently labelled probes. Linkage analysis using the CEPH family DNA panel indicates a close genetic linkage between D8S8 and CA3, with a lod score of + 7–80 at TH – 0.05 in males.
Y chromosome DNA polymorphisms in human populations: differences between Caucasoids and Africans detected by 49a and 49f probes
Authors: TC‐RRONI A. , SEMINO O. , SCOZZARI R. , SIRUGO G. , SPEDINI G. , ABBAS N. , FELLOUS M. , BENERECETTI A. S. SANTACHIARA
Published: September 2007

Several Y‐specific TaqI fragments are recognized by 49a and 49f probes in human male DNA digests. The occurrence of polymorphic variations in six of these fragments (A, B, C, D, F and I) has recently been reported, providing a potentially powerful tool for the study of the population genetics of the Y chromosome. The 49a‐49f/71agl polymorphisms were studied in 121 Africans (Senegal and Cameroon) and 125 Caucasians (Italy). In addition to the variability described already, four new bands were observed. Moreover, three patterns were found in which bands constantly present so far (G, 0 and H‐P‐R) were missing.

At variance with previously reported findings, the coexistence of two different fragments of the same ‘allelic’ series (A or D) was frequently observed in the Italian sample (10‐4%). For some of these ‘double‐banded’ patterns their holoandric transmission could be demonstrated by family studies. In the light of these new findings, the hypothesis of A or D fragments being allelic forms, as advanced by the authors who first described these polymorphisms, has to be reconsidered.

A total of 34 haplotypes were encountered, 22 of which are new. The Africans tested all lack C and D fragments. Moreover, about 80% of them are characterized by a band, A1 not present in the Italian group. The combination of A1C0D0 could therefore be a powerful genetic marker of paternal African ancestry. This combination occurs in five haplo types, one of which, haplotype IV, accounts for 68% of the African sample.

In contrast with the results of the mtDNA analysis on the same population samples, the degree of variability displayed by the Y chromosome sequences appears to be much lower in Africans than in Caucasians.
The Oxford Grid
Authors: EDWARDS J.H.
Published: September 2007

The ‘Oxford Grid’ is a term used to denote a method of displaying homologous loci from two species. It may also be used as a basis for historical inferences relating to co‐ancestry. These uses are discussed with special reference to man and mouse. It is inferred that as few as 30 reciprocal translocations are sufficient to explain the differences defined by the present grid and that the telocentric karyotype, through which the mouse differs from both man and many closely related rodents, including the rat, must have evolved mainly through the formation and suppression of centromeres rather than through pericentric inversions. Mouse and man share the widest distribution of any mammal and their success appears to be related to being omnivorous with behavioural modifications allowing a wide range of habitat.
A generalized non‐iterative approach to the analysis of family data
Authors: ELIASZIW M. , DONNER A.
Published: September 2007

A unified non‐iterative approach to point and interval estimation of interclass and intraclass correlations is presented in the context of family studies where there may be more than one individual in each of two classes. The procedure involves a generalization of the Pearson product‐moment correlation coefficient, where one permits different weights for the pairs of scores. Unlike the maximum likelihood approach, these estimators are not derived under the assumption of a particular parametric form nor do they require an iterative solution. The asymptotic distributions of the generalized product‐moment estimator and of the maximum likelihood estimator are derived under the assumption of normality. Also, several methods for constructing confidence intervals about the interclass correlation parameter are outlined, and the effectiveness of these methods is evaluated by Monte Carlo simulation. Although the focus of this paper is on the analysis of familial data, the methods discussed are applicable to more general situations, including the assessment of correlations between any two variables where each variable is replicated a different number of times for each sample unit.
EcoRI‐RFLP of the Apo B gene: a study in a sample group from South Italy
Authors: BENEDICTIS G. DE , ROSE G. , MAZZEI R. , LEONE O. , CRESCIBENE L. , BRANCATI C. , CAROTENUTO L.
Published: September 2007

EcoRI restriction analysis at codon 4154 of the Apo B gene was performed in a sample of 90 subjects from southern Italy (sample S), using total blood cell DNA amplified by PCR. A group of 46 subjects from northern Italy (sample N) was also investigated for comparison. Southern Italians showed an incidence of the R2 allele (absence of the cutting site) twice as high as that found in northern Italians (48 v. 21 %). By ASPCR the mutation which abolishes the restriction site was confirmed as being G→A at the first base of the 4154 codon of the Apo B gene (Glu→Lys) in both S and N samples. By studying the variability of cholesterolaemia among different EcoRI genotypes in the S sample, it was estimated that the average effect of the R2 allele is to lower serum cholesterol by 8‐5 mg/dl.
The molecular basis and diagnosis of familial hypercholesterolaemia in South African Afrikaners
Authors: KOTZE M. J. , LANGENHOVEN E. , WARNICH L. , PLESSIS L. DU , RETIEF A. E.
Published: September 2007

Three different point mutations were recently identified in South African familial hypercholesterolaemics. These mutations result in the modification of recognition sites of specific restriction endonucleases. This study describes rapid methods for presymptomatic detection of these defects based on restriction enzyme analysis or allele‐specific hybridization of enzymatically amplified genomic DNA. These methods were used to determine the frequencies of the three known low‐density lipoprotein (LDL) receptor gene mutations in 138 chromosomes of Afrikaner FH patients. It has been shown that a common mutation at the 3′ end of exon 4 (base 681) of the LDL receptor gene is present in about 70% of alleles, while the mutations in exons 9 (base 1285) and 4 (base 523) of the gene are present in about 20 and 10% respectively of the genes studied. These mutations were found in approximately 95% of Afrikaner familial hypercholesterolaemic patients studied, indicating at least three founder members for the disease in this population of South Arica.
Assignment of eight human genomic DNA sequences detecting high frequency restriction fragment length polymorphisms
Authors: SPURR N. K. , KELSELL D. , ROOKE L. , CAVALLI‐SFORZA L. L. , BOWCOCK A. , FEDER J.
Published: September 2007

From a lambda Charon 4A library digested with EcoRI, eight human genomic clones have been isolated, each detecting a high frequency RFLP. These phage clones have been assigned to eight different human chromosomes using Southern blot analysis and human‐rodent somatic cell hybrids.
The human chromosome 19 linkage group FUT1 (H), FUT2 (SE), LE, LU, PEPD, C3, APOC2, D19S7 and D19S9
Authors: BALL S. P. , TONGUE N. , GIBAUD A. , PENDU J. LE , MOLLICONE R. , GERARD G. , ORIOL R.
Published: September 2007

Families segregating for deficiency of the H α‐2‐L‐fucosyltransferase, FUT1, have been investigated for linkage between FUT1 and other markers on chromosome 19. The results provide evidence for close linkage between FUT1 and FUT2 and for looser linkage between FUT1 and APOG2 and between FUT1 and D19S7. Pairwise linkage data are also reported between other markers investigated.
Population genetics of vitamin D‐dependent rickets in northeastern Quebec
Authors: Braekeleer M. De , Larochelle J.
Published: September 2007

Vitamin D‐dependent rickets (VDD1) is an autosomal recessive disorder that was recognized in Saguenay‐Lac‐St‐Jean (SLSJ) in 1970. The great majority of the VDDl cases reportedin the French Canadian population of Quebec originated from SLSJ, Charlevoix, and the Haute CGte Nord, all regions located in northeastern Quebec. The prevalence a t birth in SLSJ was estimated a t 112916 live borns, and the carrier rate was estimated a t 1/27 inhabitants in the SLSJ region. The mean coefficient of inbreeding was not elevated in the VDDlgroup of SLSJ compared with three matched control groups. The mean coefficient of kinshipwas 2.5 times higher in the VDDl group than in the control groups. In the SLSJ region, the places of origin of the VDDl children and their children did not show a clustered non‐uniform distribution. Endogamy was not found to be higher in the VDDl group than in controlgroups. The genealogical reconstruction showed all the obligate carriers of the VDDl gene, but one, to be related to a small set of founders who settled in New France in the 17thcentury. All these results, as well as a strong linkage disequilibrium between RFLPs located on the long arm of chromosome 12 and the VDDl locus, support the hypothesis of a founder effect for VDDl. They also suggest that a unique mutation accounts for most, if not all, of the cases known in northeastern Quebec.
Using a dummy quantitative variable to deal with multiple affection categories in genetic linkage analysis
Authors: Curtis D. , Gurling H. M. D.
Published: September 2007

Some diseases which have a genetic contribution to aetiology do not demonstrate a clear correspondence between genotype and phenotype. A variety of different clinical syndromes may be thought to reflect the action of a gene, but the probability of affection conditional on genotype may vary between these different diagnostic categories. The normal approach of repeating linkage analyses several times using different diagnoses to define individuals as affected loses power in two ways: multiple testing must be allowed for, and the distinction between more and less extreme forms of affection is lost. It is shown that for fully dominant or recessive autosomal diseases it is straightforward to assign a quantitative value to each diagnostic category to obtain the desired ratio of the likelihoodsof affection conditional on the three possible genotypes. The increased power provided byusing this quantitative value in linkage analysis is demonstrated by application to simulated pedigrees containing cases of bipolar and unipolar affective disorder.
The number of loci needed for ELOD calculations
Authors: LEWIS C. M. , CANNINGS C.
Published: September 2007

This theoretical approach to multiple markers considers the problem of a trait locus flanked by an arbitrary number of linked, ordered markers. Using the criterion of the Expected LOD score (ELOD) for mating, an algorithm is developed to specify the subset of markers required to provide the full linkage information available from a given parental genotype.
Strategies based on marker information for the study of human diseases
Authors: CLERGET‐DARPOUX F. , BONAÏTI‐PELLIÉ C.
Published: September 2007

The goals and the ways of using genetic marker information when studying human disease are very different according to whether the disease or sub‐entity of the disease is mendelian or if a ‘disease gene’ in the sense of a rare mutated allele does not exist but rather common genetic risk factors, each one normal if considered alone. In the former case, genetic markers are used in the aim of localizing the defective gene and a systematic screening of the genome seems to be an efficient strategy provided there is not too much ambiguity in the correspondence between phenotypes and genotypes. In the latter case, the goal is to find risk factors allowing us to predict better the risk for an individual and to define different risk groups resulting in greater power to show the potential role of other factors (genetic or environmental). In this situation, the use of the lod score method with random markers presents several disadvantages: first, the multiple testing problem is particularly crucial; second, false rejection of linkage may be induced by misspecification of the model describing the genetic basis of the disease; and last, the power of detecting linkage may be low. A strategy focusing on ‘candidate gene’ markers may be then more efficient.
The AD1 locus in familial Alzheimer disease
Authors: LAWRENCE S. , KEATS B. J. , MORTON N. E.
Published: September 2007

The AD1 locus on chromosome 21 (MIM 104300) maps to the β‐amyloid precursor locus (APP) at approximately 27·7 Mb from pter (10·9 cM in males and 33·9 cM in females), flanked proximally by D21S8 and distally by D21S111, with D21S124 and D21S210 close but of uncertain order. AD1 accounts for 63±11 % of multiplex Alzheimer pedigrees for which lod scores have been reported. Since a much smaller proportion of pedigrees have mutations in the cDNA for β‐amyloid (APP exons 16 and 17), it is likely that the AD1 locus spans controlling elements near those exons. There is no evidence for a second locus on chromosome 21. The remaining pedigrees may include sporadic cases as well as mutations at an AD2 locus on another chromosome.
A Y‐associated allele may be characteristic of certain ethnic groups in Asia
Authors: NAKAGOME Y. , YOUNG S. R. , AKANE A. , NUMABE H. , JIN D. K. , YAMORI Y. , SEKI S. , TAMURA T. , NAGAFUCHI S. , SHIONO H. , NAKAHORI Y.
Published: September 2007

The probe 47z detects DNA polymorphisms on both the X and Y chromosomes. Blood samples were collected from Korean, Chinese, Jewish, Caucasian and Negro populations and polymorphisms of both loci were compared with findings previously reported in Japanese. Both Y1 and Y2 alleles were detected in Japanese and Koreans. However, only the Y1 allele was detected in each of the other populations. Although, both X1 and X2 alleles were detected in all examined populations, the frequency of the X2 allele was very low among Negroes.
Human regeneration protein/lothostathine genes map to chromosome 2p 12
Authors: Gharib B. , Fox M.F. , Bartoli C. , Giorgi D. , Sansonetti A. , Swallow D. M. , Dargorn J. C. , Berge‐Lefrance J. L.
Published: September 2007

The pancreatic stone protein (lithostathine) secreted by the exocrine pancreas is an inhibitor of CaCO3 crystal growth. This protein, which is also present in endocrine pancreas, has also been called the regeneration protein (reg). Here we report the mapping of the REG gene to chromosome 2 using the polymerase chain reaction for the specific amplification of human reg sequences in rodentlhuman somatic cell hybrid DNA. A regional assignment has been made by in situ hybridization to metaphase chromosomes using two different fluorescently labelled genomic probes corresponding to the REG gene and a related gene REGL. Both probes hybridized to chromosome 2p12 suggesting the tandem organization of these genes.
Optical density profile analysis of trypsin‐Giemsa bands in human X‐chromosomes
Authors: PÁSARO E. , FERNÁNDEZ R. , MÉNDEZ J.
Published: September 2007

Mean Optical Density (M.O.D.) determination of six G‐bands on X‐chromosomes was performed on 45 patients with Turner's syndrome and cjompared with X‐chromosomes from women controls with a normal karyotype by a Chromosome Image Analysis System. Density profiles were constructed to obtain standard values for the staining intensity and frequency of occurrence of chromosome bands. Statistical analysis showed that the M.O.D. were significantly different for Xq12, Xq21, Xq25 and Xq27 G‐bands between the Turner and Control groups. Most within‐group differences were small and appeared not to be statistically significant.
Estimation of the intraclass correlation coefficient
Authors: SRIVASTAVA M. S.
Published: September 2007

When families have different numbers of offspring, the maximum likelihood procedure for estimating the intraclass correlation is iterative, requiring considerable computation. Occasionally, the iterations do not even converge. To overcome this difficulty, several noniterative estimators have been proposed by Smith (1956). However, to choose from among these estimators, some prior knowledge of the intraclass correlation is needed. In this paper, a combination estimator is proposed. The asymptotic variance of this estimator is given and compared with those of the two most commonly used estimators. The comparison shows that the combination estimator always performs better than the uniform weight estimator and the loss in efficiency is not more than 7% when it is used in place of Fisher's estimator.
Identification and regional localization of a highly polymorphic dinucleotide repeat D11S614 to the interval in 11q23.3 flanked by recurrent translocation breakpoints
Authors: BENHAM F. , SUGIYAMA R. , HUNT D. , GILLETT G. , SMITH M.
Published: September 2007

A higly informative dinucleotide repeat polymorphism has been identified at the D11S614 locus on chromosome 11q23. Ten differen alleles have been observed at this locus, and the heterozygosity frequency is approximately 85%. Physical localization of this marker in a panel of somatic cell hybrids containing chromosome 11 translocation showed that is maps to 11q23.3, within the interval between the recurrent t(4;11) leukaemia breakpoint and the t(11;22) Ewing's sarcoma breakpoint. This physical mapping data is consistent withs the genetic mapping which indicates tight linkage to other markers in the q23.3 region including PBGD, CD3D and D11S29. Regional localization of highly informative markers such as D11S614 will facilitate integration of the genetic and physical maps.
Localization of the Tamm‐Horsfall glycoprotein (unomodulin) gene to chromosome 16p12.3‐16p13.11
Authors: POOK M. A. , JEREMIAH S. , SCHEINMAN S. J. , POVEY S. , THAKKER R. V.
Published: September 2007

Mapping studies using a panel of 22 rodent‐human somatic cell hybrids have helped to localize the Tamm‐Horsfall glycoprotein (uromodulin) gene (UMOD): which has previously been reported to map to 16p13.11, to the region 16p12.3‐qter. The combined results indicate that UMOD is located distal to D16S295 and proximal to D16S287 and in the region 16p12.3‐16p13.11. Uromodulin is known to affect the formation of calcium‐containing kidney stones, and this localization of UMOD will help in studies of families with autosomal forms of nephrolithiasis.
Regional localization of the lactase‐phlorizin hydrolase gene, LCT, to chromosome 2q21
Authors: HARVEY C. B. , FOX M. F. , JEGGO P. A. , MANTEI N. , POVEY S. , SWALLOW D. M.
Published: September 2007

The gene LCT which codes for the intestinal disaccharidase lactase‐phlorizin hydrolase has previously been mapped, using somatic cell hybrids and linkage analysis, using the CEPH families, to chromosome 2. We describe here the regional localization of LCT to chromosome 2q21 by polymerase chain reaction (PCR) analysis of somatic cell hybrids and in situ hybridization. LCT is closely linked to D2844, with a lod score of 30.6 at θ= 0.10.
Testing for haplotype concordance with incomplete parental data ‐ modified Q and correction for modified N
Authors: SHAH S. , GREEN J. R.
Published: September 2007

Some errors have been found in the distribution of modified N in a paper by Green & Grennan (1991). These have now been corrected, also a modified form of a new test ‐ criterion Q is presented. Both are applied to data.
‘SZ like’α1‐antitrypsin phenotypes in PI ZZ children with liver disease
Authors: WHITEHOUSE D. B. , LOVEGROVE J. U. , MIELI‐VERGANI G. , MOWAT A. P. , HOPKINSON D. A.
Published: September 2007

Using high resolution isoelectric focusing, α1‐antitrypsin phenotypes were studied in 106 individuals of the PI ZZ genotype including 71 with liver disease, 22 with chest disease and 13 healthy subjects. The resulting Z patterns were found to be highly variable. In the majority of cases (89/106) the maximum staining intensity was either in the most basic isoform or shared equally between two basic isoforms of the Z phenotype. However, in 17 cases there was a marked intensification of the more acidic isoforms resulting in a pattern which closely resembled the SZ phenotype. This ‘SZ like’ pattern occurred more frequently in the liver group (16/71) than the chest group (0/22) or healthy (1/13) controls. One possible consequence of the ‘SZ like’ pattern is confusion with the genuine SZ phenotype leading to misclassification. If this were so, there could be an erroneous exaggeration of the actual incidence of childhood liver disease associated with PI SZ.
Evaluation of a transgenic mouse model for alpha‐1‐antitrypsin (AAT) related liver disease
Authors: ALI R. , PERFUMO S. , ROCCA C. della , AMICONE L. , POZZI L. , McCULLAGH P. , MILLWARD‐SADLER H. , EDWARDS Y. , POVEY S. , TRIPODI M.
Published: September 2007

We have attempted to produce a transgenic mouse model of the neonatal liver disease associated with the human PIZ allele. Analysis of a number of transgenic mouse lines carrying either a normal human PIM gene construct or the mutant Z is reported. Using isoelectric focusing analysis of plasma from transgenic mice, we have shown that the human AAT proteins produced in mice are processed in a similar way to their counterparts in humans. By comparing the level of M and Z mRNA in liver with the levels of M and Z proteins in plasma we have inferred that, as in humans, the mutant protein tends to accumulate within the hepatocyte. Accumulation of Z protein has also been demonstrated by immunocytochemistry. Two of the M transgenic lines produce such high levels of the human protein that it, like the Z protein, accumulates as globules. Histological features of livers from 116 mice of different ages and genotypes were examined: 37 non‐transgenic, 62 Z transgenic (23 low expressing and 39 high expressing) and 17 M transgenic mice, all high expressing. Cirrhosis or fibrosis was not seen in any animal and we were unable to find any evidence for neonatal liver disease. Some necrosis was seen in all genotypes and this increased significantly with age with one Z line showing significantly more frequent necrosis than any other group. This line, the highest expressing Z line, was back crossed onto 7 different genetic backgrounds but no major differences between the back crosses with respect to liver disease were observed. The mouse model we have developed is compared with other transgenic Z mouse models; none of these is representative of human neonatal liver disease. Our view is that the transgenic animals generated in these experiments may be most useful for investigating the liver manifestations that almost invariably occur in ZZ adults. Alteration of additional factors other than accumulation of Z protein, for example inactivation of the endogenous mouse genes or some environmental challenge, might produce a mouse model with more relevance to neonatal liver disease.
Age of onset in familial adenomatous polyposis: heterogeneity within families and among APC mutations
Authors: PRESCIUTTINI S. , VARESCO L. , SALA P. , GISMONDI V. , ROSSETTI C. , BAFICO A. , FERRARA G. B. , BERTARIO L.
Published: September 2007

Heterogeneity among and within FAP pedigrees for the age of symptom onset and the age at death from colorectal cancer was studied in a sample of 583 patients of the Italian Polyposis Registry. The among pedigree variation was largely explained by clustering of families in two groups, ‘early FAP’ (most colorectal cancer deaths below 45 years of age) and ‘late FAP’ families (most deaths above age 45). The within‐family variation was explained by a marked phenomenon of anticipation (15 years per generation, on the average), possibly not due to ascertainment bias. We then considered the pedigrees with identified mutation in the APC gene. Six families shared a common deletion at codon 1309 and showed the early FAP phenotype. Two families shared a mutation at codon 1061 and revealed the late FAP phenotype. Another two families (codons 453 and 302) clustered with the late FAP group, whereas a family with mutation at codon 835 clustered with the early FAP group. We suggest that there are at least two classes of mutations in the APC gene with different consequences at the phenotypic level. It seems that there are several critical points within the APC protein sequence at which truncation causes a more aggressive disease than truncation at other points.
An algorithm for Monte Carlo estimation of genotype probabilities on complex pedigrees
Authors: LIN S. , THOMPSON E. , WIJSMAN E.
Published: September 2007

Exact probability and likelihood computation on complex pedigrees is often infeasible, since exact methods are too computationally intensive even with today's computing technology. A statistical tool, Markov chain Monte Carlo (MCMC), is increasingly being explored as a technique for estimating probabilities of genotypic configurations on pedigrees conditional on phenotypic data. However, this conditional probability distribution on a complex pedigree is, in general, multimodal, and multimodality is one of the major difficulties in MCMC exploration of a probability surface. In this paper, a new member of the MCMC Metropolis‐Hastings class of algorithms is proposed; the heated‐Metropolis algorithm. The algorithm achieves passage through low probability states to other local modes of the probability distribution, and so provides much improved estimates of probabilities of interest. The example considered is the estimation of the probabilities of carrier genotype for the founders of a complex pedigree in which a very rare lethal recessive trait is segregating.
Genetic and environmental effects on coronary heart disease risk factors in Northern Norway. The cardiovascular disease study in Finnmark
Authors: BRENN T.
Published: September 2007

This study comprised 1377 first degree relatives in 575 families ascertained through a comprehensive screening of the general population from 20 to 52 years of age. Path analysis using parsimonious models gave evidence of significant biologic and environmental transmission for total cholesterol (genetic and cultural heritabilities were 0·46 and 0·05, respectively), high density lipoprotein cholesterol (0·42, 0·10), triglycerides (0·21, 0·07), and systolic (0·48, 0·04) and diastolic (0·35, 0·05) blood pressure. Compared with other studies employing the same path analytic model, heritability estimates in general were among the highest reported, except for the somewhat lower genetic component in total cholesterol and triglycerides. For the first time in a single sample from the general population, lipid and blood pressure variables were investigated applying the same methodology, and good agreement was illustrated by the result that identical parsimonious models were reached for all phenotypes, with the exception of a single additional parameter for total cholesterol. About one fourth to one half of the total phenotypic variance could be ascribed to genetic sources, whereas the contribution from shared familial environment was much smaller.
A note on testing the Hardy‐Weinberg law across strata
Authors: TROENDLE J. F. , YU K. F.
Published: September 2007

The problem of testing the Hardy‐Weinberg law when the data are stratified in K strata is considered. Previous methods lose power when the departure from the law is irregular from stratum to stratum. Two methods based on the squared distance are proposed to overcome this problem. Simulations show that the new methods can have a dramatic improvement over the previous methods. The methods are applied to red cell glyoxalase genotype data from populations in India.
The genetic affinity of Polynesians: evidence from Y chromosome polymorphisms
Authors: SPURDLE A. B. , WOODFIELD D. G. , HAMMER M. F. , JENKINS T.
Published: September 2007

Y‐linked polymorphisms were studied in a sample of 60 Polynesians, and results were compared with findings from studies on other major population groups. Three previously unreported 49a/TaqI haplotypes were observed, two of which possess a new polymorphic fragment named 12. Frequency data for the 49a/TaqI, XY275, pDP31 and Y Alu polymorphisms indicate that Polynesians have greater affinity to Caucasoids than to African populations. Similar population frequency trends were not observed for the p21A1/TaqI polymorphism, supporting the hypothesis that this polymorphism has arisen more than once.
Molecular variation of the human elastin (ELN) gene in a normal human population
Authors: RAYBOULD M. C. , BIRLEY A. J. , HULTÉN M.
Published: September 2007

DNA sequence diversity in the human elastin genomic region has been estimated by RFLP analysis in a normal human population. The proportion of polymorphic nucleotides and the degree of nucleotide diversity were 0·0034 and 0·0018 respectively. It is argued that the estimate of nucleotide diversity does not indicate strong purifying selection in the region. A total of 144 restriction sites were sampled in each of 80 independent chromosomes representing the screening of 58080 bp overall. Six main haplotypes were constructed; they represent at least 84% of the 80 chromosomes sampled. Analysis for linkage disequilibrium revealed two statistically significant comparisons out of 54 tests, approximately the proportion that would be statistically significant at the 5% level by chance. A higher order quadrigenic disequilibrium was detected. The relationship between the physical distance separating polymorphic restriction sites and linkage disequilibrium is discussed. The development of elastin haplotypes and knowledge of the pattern of linkage disequilibrium should aid the study of elastin related disease and human evolution.
Genetic epidemiology of breast cancer: interest of survival analysis methods
Authors: ESSIOUX L. , ABEL L. , BONAIÏTI‐PELLIÉ C.
Published: September 2007

In an attempt to explain the controversy resulting from the analysis of the breast cancer data collected by Jacobsen, a segregation analysis was performed using successively the unified mixed model (UM) and the logistic hazard function model (LHM) (Abel & Bonney, 1990). Under the UM, age of onset of the disease cannot be taken into account, each individual being assigned to a liability class according to his age at examination, whereas, in the LHM, variable age of onset is modelled using survival analysis methods.

Under the UM, we confirmed the results of Demenais et al. (1986b), i.e. the transmission probabilities are significantly different from Mendelian expectations. The same results were obtained when taking into account the specific mortality for the computation of the morbid risk observed in a given liability class. Lender the LHM, the analysis provides evidence for a monogenic autosomal model with a rare dominant allele responsible for the disease, and transmission probabilities compatible with Mendelian expectations.
An extended transmission/disequilibrium test (TDT) for multi‐allele marker loci
Authors: SHAM P. C. , CURTIS D.
Published: September 2007

The transmission/disequilibrium test (TDT) was recently introduced by Spielman et al. (1993) as a test for linkage and linkage disequilibrium. The test is based on the unequal probability of transmission of two different marker alleles from parents to affected offspring, when the marker locus and the hypothetical disease locus are linked and are in linkage disequilibrium. The probabilities of marker allele transmission to affected offspring conditional on parental genotype have been derived by Ott (1989) for a biallelic marker and a recessive disorder with no phenocopies. Here, we derive the transmission probabilities for a multi‐allele marker locus and a generalized single locus disease model in a random sample of affected individuals from a randomly mating population. The form of these transmission probabilities suggests an extension of the TDT to multi‐allele marker loci, in which the alternative hypothesis is restricted to take account of the likely pattern of unequal transmission when the recombination fraction is near 0. We show how our extended TDT can be implemented by standard software for logistic regression, although we have also written our own program which is available on request. We have evaluated the approximate power of the test under a range of realistic assumptions, and it appears that the test will often have good power when linkage disequilibrium is strong and if the disease is recessive.