bluuebunny/crossref_metadata_2025 huggingface dataset:
The reliability of locus orderings
Authors: Edwards J. H.
Published: September 2007

Locus orders are frequently presented in graphical form, supported by likelihood statements relating to less likely orders. Many imply genetic distances which are inconsistentwith the meiotic evidence, usually by a factor of about 2. While such orders may be the best possible on the data available, measures of their reliability are difficult: the common assumption that an order is correct because changes lead to less likely orders only relates to the subset of orders tested.

It is only possible to deduce the order of any set of loci if a recombinant separates every pair. This usually requires a number of recombinants substantially exceeding the number of loci. Orders may be inferred from distance in the absence of consistent separation. However, if reasonable reliability is to be achieved, the number of meioses necessary to define distances with sufficient precision will be many times the number of loci. Someestimates of the minimum number of recombinants necessary for a correct ordering to achieve a probability of a half, the' half‐right ' solution, would be helpful. As a first approximation to this, we use the probability of no 'null gap', i.e. no pair of adjacent lociwith no recombination between them. Where the number of recombinant events is not available from counting, rough guidance can be given by estimating the number of equivalent meioses from lod scores.

Where data are not available from homologies from other mammals or from pulsed‐field

studies, deductive methods of family analysis should be used, followed by pairwise optimizing methods for positioning. This will allow orders to be deduced independently for lociconveyed by the male and female gametes and provides a simple test of the procedure: if the orders are not identical a t least one must be wrong.
Genetic polymorphism of human deoxyribonuclease II (DNase II): low activity levels in urine and leukocytes are due to an autosomal recessive allele
Authors: YASUDA T. , NADANO D. , SAWAZAKI K. , KISHI K.
Published: September 2007

The objectives of this study were to elucidate the genetic basis of human deoxyribonuclease II (DNase II) and to evaluate its usefulness as a genetic and/or diagnostic marker. We have devised a novel, specific and highly sensitive assay method for the urinary and leukocytic enzymes (Yasuda et al. 1991). The distribution of the activities of both enzymes displayed clear‐cut bimodality and the Japanese study population could be classified into two distinct types, namely low‐activity (DNASE2 L) and high‐activity (DNASE2 H), which indicates the existence of a genetic polymorphism in the activity levels of urinary and leukocytic DNase Us. Close correlations between the leukocytic and urinary enzyme activity levels from the same individuals were observed and the types in the leukocyte samples agreed with the types found in the corresponding urine samples. In a population study of 528 unrelated Japanese individuals, the gene frequencies of the low activity (DNASE2*L) and the high activity (DNASE2*H) alleles were calculated to be 0·632 and 0·368, respectively. The sex and age of individuals did not affect the distribution of DNase II activity levels. The family study results were compatible with the model that the low activity type is due to an autosomal recessive gene, which indicates that DNASE2 L represents homozygosity for DNASE2*L and DNASE2 H corresponds to homozygosity for DNASE2*H and heterozygosity for DNASE2*L and DNASE2*H.
Genetic relationship between the 3‘‐VNTR and diallelic apolipoprotein B gene polymorphisms: Haplotype analysis in individuals of European and South Asian origin
Authors: RENGES H‐H. , PEACOCK K. , DUNNING A. M. , TALMUD P. , HUMPHRIES S. E.
Published: September 2007

The genetic relationship amongst apolipoprotein B (apo B) gene polymorphisms (signal peptide insertion/deletion (Leu‐Ala‐Leu‐16/‐14), XbaI (Thr2488), EcoRI (Glu4154→ Lys), Asn4311→ Ser, 3′ ‐VNTR) has been investigated in samples of South Asian (Indian) and Swedish individuals. The frequency distribution of alleles at all these sites was found to be significantly different between the South Asian and the Swedish samples (deletion allele: 0·20 v. 0·31, X + (presence of XbaI cutting site): 0·29 v. 0·55, R‐ (absence of EcoRI cutting site): 0·11 v. 0·19, Ser4311: 0·45 v. 0·19). The distribution of allele frequencies at the VNTR site was bimodal in both populations. However, in South Asians, the most common allele was a 35 repeat unit allele, whilst in the Swedish sample, and in all other reports from Caucasian samples the 37 repeat unit allele was the most frequent (South Asian v. Swedish: 35 allele: 0·36 v. 0·19, 37 allele: 0·25 v. 0·48). Furthermore, four new alleles at the apo B gene 3′ ‐VNTR site (15, 17, 32, 38 repeat unit alleles) were observed in South Asians, of which two (15 and 17 repeat unit alleles) were well outside the bimodal distribution. In both samples, strong linkage disequilibrium and allelic association were detected between alleles at the 3′ ‐VNTR and each of the other sites, and also between the ins/del and XbaI sites and between the XbaI and Asn4311→ Ser sites. The same five common haplotypes as defined by ins/del, XbaI, EcoRI and Asn4311→ Ser were found to be present in both samples comprising 97 and 99 % of the haplotypes observed in the South Asian and Swedish samples respectively. Detailed analysis revealed the predominant occurrence of certain 3′ ‐VNTR alleles on specific haplotypes and demonstrates the usefulness of the VNTR site for haplotyping and representative association studies. A model for the evolutionary relationship of the major haplotypes including the 3′ ‐VNTR site is presented. These findings support a mechanism of replication slippage as a major factor for the generation of new alleles at the apo B 3′ ‐VNTR locus rather than unequal crossing over.
Kinetic properties of the common electrophoretic variants of human S‐adenosylhomocysteine hydrolase (AHCY): the effect of four nucleoside analogue inhibitors
Authors: CORBO R. M. , INGIANNA R. , SCACCHP R. , BOZZI A.
Published: September 2007

Red blood cell S‐adenosylhomocysteine hydrolase (AHCY) from individuals of 1, 2‐1 and 3‐1 phenotypes was partially purified and Km and Vmax determined in the absence and in the presence of the following inhibitors: 3‐deaza‐adenosine (DZA), 3‐deaza‐aristeromycin (DZAry), 2–chloro adenosine (2‐Cl‐ado) and purine riboside (or nebularine). The three phenotypes 1, 2‐1, 3‐1 showed similar Km (32·58, 39·22 and 34·84 μm respectively), but the ratio Km/Vmax was statistically different. DZA and DZAry appeared to be strong competitive inhibitors. The AHCY 1 phenotype was more resistant to their action, while the 3‐1 variant was more sensitive. 2‐Cl‐ado and purine riboside were weaker inhibitors; the type of inhibition varied among the three phenotypes, but, again, the AHCY 1 phenotype was less sensitive than the other two.
Apparent heterozygote deficiencies observed in DNA typing data and their implications in forensic applications
Authors: CHAKRABORTY R. , ANDRADE M. DE , DAIGER S. P. , BUDOWLE B.
Published: September 2007

Restriction fragment length polymorphisms (RFLP) analysis using the Southern blot technique can be used to recognize copy number variation of variable number of tandem repeats (VNTR) of conserved core sequences at several regions of the human genome. This new class of polymorphisms reveals a high degree of genetic variation, useful for individual identification purposes. Criticisms against forensic applications of such DNA typing data include the limitation of employing Hardy Weinberg expectation of genotype frequencies, since several surveys indicate apparent deficiency of heterozygosity (or excess homozygosity) in comparison with Hardy‐Weinberg expectations. This research postulates an alternative explanation of deficiency of apparent heterozygosity which is caused by the inability to detect extremely small‐sized alleles (called ‘non‐detectable’ alleles) due to the sensitivity of Southern gel electrophoresis. We show that the presence of ‘non‐detectable’ alleles can produce pseudo‐homozygosity and their frequencies can be predicted from the observed proportional heterozygote deficiency. Furthermore, in the covert presence of such ‘non‐detectable’ alleles, we show that the gene‐count method provides over‐estimates of allele frequencies in the sample population, and hence the Hardy Weinberg predictions of genotype frequencies avoid wrongful bias against suspects in forensic applications of DNA typing data. Applications of this theory to population data on six VNTR loci in US Caucasians and US Blacks suggest that the presence of ‘non‐detectable’ alleles could be the major cause of apparent heterozygote deficiency, and the current approaches of predicting the population frequency of specific DNA phenotypes are practically free of the possible wrongful bias in courtroom applications of DNA typing data.
Metrical Venn diagrams
Authors: EDWARDS A. W. F. , EDWARDS J. H.
Published: September 2007

A type of Venn diagram is described which enables the observed frequencies in a 2 × 2 × 2 contingency table to be compared with their expectations on the hypothesis of no associations.
Mitochondrial and nuclear variants in a U.S. Black population: origins of a hybrid population
Authors: HSIEH C.‐L. , SUTTON H. E.
Published: September 2007

The maternal transmission of mitochondria in higher eukaryotes makes it possible to distinguish between reciprocal matings, since offspring possess the mitochondrial DNA variants received from the mother. This possibility can be extended to hybrid populations, the mitochondrial frequencies reflecting the relative maternal contributions from the parental populations. Nuclear variations reflect the relative genetic contributions of the parental populations, irrespective of parental sex. The U.S. Black population is a hybrid of West African and European populations. The African‐European matings that contributed to the present Black population are traditionally considered to have been almost exclusively between African females and European males. We have studied nuclear and mitochondrial variants in a sample of U.S. Blacks, comparing them with published frequencies from African and Caucasian groups. Our results suggest that the mitochondria of present‐day American Blacks are derived from Caucasians to an extent similar to nuclear genes. In contrast to traditional beliefs, the contribution from Caucasian females is of the same magnitude as that from Caucasian males.
Structure and chromosomal localization of the human 2‘,3’‐cyclic nucleotide 3‘‐phosphodiesterase gene
Authors: DOUGLAS A. J. , FOX M. F. , ABBOTT C. M. , HINKS L. J. , SHARPE G. , POVEY S. , THOMPSON R. J.
Published: September 2007

Human brain cDNA clones for the myelin associated enzyme 2′ 3′ ‐cyclic nucleotide 3′ ‐phosphodiesterase (CNPase) have been isolated and sequenced. The only 5′ untranslated region (UTR) sequence found was that of a human CNPII mRNA, with no direct evidence for a CNPI mRNA. Human CNPase cDNAs were used to isolate genomic clones containing the human CNPase gene which is 9 kb long. Four exons were identified, separated by three introns, and the sequence of each exon and intron/exon boundary has been established.

The polymerase chain reaction (PCR) was used to detect the presence of the human CNPase gene in DNA from a panel of rodent/human somatic cell hybrids. By this means the human CNPase gene was mapped to chromosome 17. In situ hybridization of a human CNPase genomic clone to metaphase chromosomes further localized this gene to chromosomal band 17q21.
Nucleotide sequence and chromosomal assignment of a cDNA encoding the large isoform of human glutamate decarboxylase
Authors: KELLY C. D. , EDWARDS Y. , JOHNSTONE A. P. , HARFST E. , NÓGRÁDI A. , NUSSEY S. S. , POVEY S. , CARTER N. D.
Published: September 2007

Glutamic acid decarboxylase (GAD) catalyses the conversion of l‐glutamic acid to the inhibitory neurotransmitter γ‐aminobutyric acid (GABA). Two forms of human GAD, GAD65 and GAD67, are encoded by two separate genes.

A full length human GAD67 cDNA has been isolated from a human frontal cortex cDNA library and the nucleotide sequence determined. The GAD67 gene has been mapped to chromosome 2 using the polymerase chain reaction to amplify specifically the human sequence in rodent/human somatic cell hybrid DNA. This confirms that human GAD67 is not syntenic with the smaller GAD isoform GAD65 which has been assigned to chromosome 10. Production of polyclonal antiserum to a baculovirus‐expressed GAD67 enabled immunocytological detection of GAD in the rat brain.
A study on Lu‐null families in South Wales
Authors: ROWE G. P. , GALE S. A. , DANIELS G. L. , GREEN C. A. , TIPPETT P.
Published: September 2007

Red cells of 75614 blood donors in South Wales were screened with anti‐Lub revealing 54 Lu(b –) donors of which 15 were also Lu(a –) giving a frequency of 0–0002 for the Lu(a ‐b ‐) phenotype in South Wales. The families of 11 Lu‐null propositi were investigated to determine which of the three known genetic backgrounds, dominant, recessive or X‐linked recessive, was responsible for their Lu–null phenotype. In 10 of the 11 families the Lu–null phenotype was caused by the dominant suppressor gene In(Lu). The first reported family demonstrating independence of In(Lu) and LU, through the Au groups, is described together with the third family demonstrating suppression of P1 by In(Lu). The families showed that In(Lu) is not closely linked to HLA. The genetic background for the 11th propositus was not determined; homozygosity of the silent allele LU is a possible but unproved explanation.
Interphase cytogenetics of the ICF syndrome
Authors: MARASCHIO P. , CORTINOVIS M. , DAINOTTI E. , TUPLER R. , TIEPOLO L.
Published: September 2007

Interphase behaviour of centromeric heterochromatin of chromosomes 1 and 16 has been investigated in lymphocytes and fibroblasts of patients with ICF syndrome and of normal subjects with non‐isotopic in situ hybridization, using the satellite II‐related probe pHuR 195.

We found evidence for interphase somatic pairing in ICF lymphocytes with a frequency higher than that found in normal cells. Lymphocytes of ICF patients showed nuclear protrusions and micronuclei and these nuclear abnormalities consistently involved a hybridization signal.

Somatic pairing was also present in fibroblasts, but with frequencies similar in normal and ICF subjects. The fibroblasts do not have the major chromosomal abnormalities found in lymphocytes.

The degree of heterochromatin condensation in fibroblasts was lower than that in lymphocytes and we postulate that the more decondensed state of chromocentres in the fibroblasts could be the reason for the absence of the major chromosomal abnormalities.
Hazard and probabilities of unknown genotypes
Authors: JEANPIERRE M.
Published: September 2007

The likelihood of a genotype of an unsampled individual depends upon genetic data from relatives. When these relatives may be carriers of a mutation as in X‐linked disease, the likelihood of a genotype is altered by the consequences of the possible genotypes on offspring. The probabilities of the possible genotypes are easily derived from the probabilities conditional on the genotype obtained from a computer program aimed at risk calculation. This procedure of genotype reconstruction brings to light a potential hazard in the interpretation of computer data: a compound risk may be better represented as the harmonic mean of a set of conditional probabilities than the simple average of these probabilities.
Genetic polymorphism in the 3‘ ntranslated region of human phosphoglucomutase‐1
Authors: March R. E. , Hollyoake M. , Putt W. , Hopkinson D. A. , Edwards Y. H. , Whitehouse D. B.
Published: September 2007

A 317‐bp segment of DNA from the 3′ region of the human phosphoglucomutase‐1 (PGMl) gene has been examined by a non‐radioactive technique for the occurrence of single‐strand conformation polymorphism (SSCP), Eight phenotypes were detected and attributed to the presence of four alleles. Genetic analysis of 75 unrelated individuals and six CEPH families whose PGMl protein phenotypes were known revealed strong association between the PGMl ‘+’ and ‘−’ isozyme phenotypes and the variation detected in this region, but no association with the PGMl 1 and PGMl 2 isozyme phenotypes. DNA sequence analysis demonstrated the presence of three nucleotide substitutions underlying the alleles, which were located in the untranslated region of the PGMl gene. There was complete correlation between the nucleotide sequence and the phenotype detected by SSCP analysis. This study provides support for the model that the PGMl isozyme polymorphism is determined at two distinct sites in the coding sequence, one coding for the ‘1’ and ‘2’ alleles and the other coding for the ‘+’ and ‘−’ alleles, separated by a region where intragenic recombination occurs.
Complex polymorphisms are revealed by Y chromosome probe 49a with BglII, HindIII, PstI and SstI
Authors: SPURDLE A. B. , JENKINS T.
Published: September 2007

Y chromosome probe 49a detects complex polymorphisms with BglII, HindIII, PstI and SstI, involving 19, 13, 18 and 11 variant bands respectively. The haplotype, a description of the arrangement of fragments in an individual, exhibits great variation. Most haplotypes are population‐specific and occur infrequently. In a study of approximately 60 individuals of Caucasoid, Negroid and San origin, 21, 23, 28 and 24 haplotypes were revealed by BglII, HindIII, PstI and SstI respectively. Reduced genetic diversity in the Negroid population was ascribed to both the proposed recent common origin of the Bantu‐speaking Negroid population from a proto‐Bantu stock and the common practice of polygamy in African Negroids, as were specific correlations between the different polymorphisms within the Negroid population only. In general, no single haplotype for a given enzyme system strictly correlated with a haplotype from any of the other three systems, suggesting that each polymorphism results from a combination of restriction site mutations and rearrangement events. This tremendous variability has potential in paternity testing for male offspring.
The common, Near‐Eastern origin of Ashkenazi and Sephardi Jews supported by Y‐chromosome similarity
Authors: BENERECETTI A. S. SANTACHIARA , SEMINO O. , PASSARINO G. , TORRONI A. , BRDICKA R. , FELLOUS M. , MODIANO G.
Published: September 2007

About 80 Sephardim, 80 Ashkenazim and 100 Czechoslovaks were examined for the Y‐specific RFLPs revealed by the probes p12f2 and p49a, f on TaqI DNA digests. The aim of the study was to investigate the origin of the Ashkenazi gene pool through the analysis of markers which, having an exclusively holoandric transmission, are useful to estimate paternal gene flow. The comparison of the two groups of Jews with each other and with Czechoslovaks (which have been taken as a representative source of foreign Y‐chromosomes for Ashkenazim) shows a great similarity between Sephardim and Ashkenazim who are very different from Czechoslovaks. On the other hand both groups of Jews appear to be closely related to Lebanese. A preliminary evaluation suggests that the contribution of foreign males to the Ashkenazi gene pool has been very low (1% or less per generation).
Description of a dinucleotide repeat polymorphism in the human elastin gene and its use to confirm assignment of the gene to chromosome 7
Authors: FOSTER K. , FERRELL R. , KING‐UNDERWOOD L. , POVEY S. , ATTWOOD J. , RENNICK R. , HUMPHRIES S. E. , HENNEY A. M.
Published: September 2007

Informative polymorphisms have been very difficult to detect in the elastin gene, and this has hampered the analysis of heritable connective tissue disorders, notably the Marfan syndrome. We have recently detected a dinucleotide repeat polymorphism in intron 17 of the human elastin gene consisting of 8 alleles with sizes between 161 and 175 bp. Analysis of 540 chromosomes from unrelated Caucasian individuals revealed a bimodal frequency distribution typical of (dC‐dA)n (dG‐dT)n repeat polymorphisms, with allele frequencies ranging from 0.004 (161 bp) to 0.574 (163 bp). As the elastin gene was originally assigned to chromosome 2q31‐ter and because more recent data have suggested an assignment to 7q11.1–21.1, we have genotyped a sub‐set of the CEPH pedigrees and carried out pairwise linkage analysis with markers on chromosomes 7 and 2. Lod‐scores of between +3.70 and +13.69 were obtained with markers spanning 7p13‐q22.1, whilst negative lod‐scores were observed with the chromosome 2 markers. Analysis of type II human ovarian teratomas placed the elastin gene within 11 cM of the centromere on chromosome 7. Additionally, we detected the dinucleotide repeat in human‐rodent cell hybrids containing chromosome 7, but not those containing chromosome 2. These data confirm the assignment of elastin to chromosome 7 and provide a new, highly informative marker for the analysis of heritable disorders of connective tissue for which elastin is a candidate gene.
Power comparison of various sibship tests of association
Authors: GREEN J. R. , SHAH S.
Published: September 2007

There are several tests available for use with family studies to test if there is significant evidence of association with a particular disease gene locus, especially of HLA. We have used large simulations to compare the powers of tests using criteria N, R, T, PR, WP and some new tests involving both affecteds and unaffecteds in a sibship. It was found that tests using both affected and unaffected siblings were often more powerful.
A new approach for interpreting the genetic diversity in space: ‘Mobile Site Method’. Application to Gm haplotype distribution of twenty‐seven Amerindian tribes from North and Central America
Authors: HAZOUT S. , GUASP G. , LOIRAT F. , MAURIERES P. , LARROUY G. , DUGOUJON J. M.
Published: September 2007

We present a new approach, called ‘Mobile Site Method’ (MSM), to the construction of ‘genetic similarity maps’ more efficient than that described in a preceding paper (Hazout et al. 1991). After building a triangular mesh between the geographical sites, the method consists of moving these locations at each iteration to reduce the overall differences between the geographic and genetic distances. The genetic similarity map, i.e. the final distorted map, allows the interpretation of the genetic diversity of a population set. We have applied this method to the study of Gm immunoglobulin allotypes of twenty‐seven Amerindian groups from North and Central America. By a local weighted linear regression, we have reconstituted the distorted contour of America. This representation completes the observations of the sites during the map distortion. In this study, we have defined a large geographical factor in the genetic data (84% of the variability explained), related to a linguistic factor.
Lack of RH C/E expression in the Rhesus D– phenotype is the result of a gene deletion
Authors: BLUNT T. , STEERS F. , DANIELS G. , CARRITT B.
Published: September 2007

We have investigated the arrangement of genes in the rare Rh (Rhesus) partial null condition D–, Southern blot and PCR studies under conditions which distinguish the highly homologous RH D and RH C/E genes show that in an Icelandic family with the D– haplotype at least 85% of the RH C/E gene is deleted. This finding is in contrast to one other published case of this phenotype, where intact RH D and C/E genes were found, and also to the full amorph Rhnull phenotype, where an intact RH C/E gene was found, accompanied by the deletion of the RH D gene typical of Rh D‐negative individuals.
Genetic analysis of atopy and asthma as quantitative traits and ordered polychotomies
Authors: LAWRENCE S. , BEASLEY R. , DOULL I. , BEGISHVILI B. , LAMPE F. , HOLGATE S. T. , MORTON N. E.
Published: September 2007

Traits related to atopy and asthma were defined in a random cohort of 131 families with three or more children. Correlation analysis provides no evidence of imprinting, maternal effect, or a major role of environment shared by sibs. Commingling analysis favours more than one distribution, the upper one being common for asthma and very common for atopy. Segregation analysis of rank‐transformed variables provides only equivocal evidence of major genes against a polygenic background but suggests that such genes (if present) are individually common and not of large effect. Segregation analysis under a two‐locus model gives consistent results with minimal distributional assumptions. To enter combined segregation analysis we favour a restricted model in which the major locus is additive on the liability scale and the pseudopolygenic modifier locus accounts for at least half the genetic variance. Total IgE and bronchial reactivity are proposed for meta‐analysis of atopy and asthma respectively. Genetic analysis of complex inheritance is discussed and it is shown that allelic association with random loci is not a feasible approach.
Physical mapping of 38 highly informative genetic markers to 10 intervals of chromosome 11q: integration of the physical and genetic maps
Authors: HUNT D. , HEYNINGEN V. VAN , JONES C. , McCONVILLE C. , BENHAM F. J.
Published: September 2007

A large number of highly polymorphic microsatellite markers particularly suitable for genetic linkage analysis have recently been developed. In order to facilitate integration of the genetic maps of chromosome 11q generated using these types of markers with the physical maps of 11q currently being assembled, we have regionally assigned the Genethon markers and the 11q designated index plus other commonly used polymorphic markers to ten physical intervals of 11q. These intervals are defined by translocation breakpoints immortalized in somatic cell hybrid lines and can therefore serve as readily accessible and stable landmarks for detailed map integration and facilitate the derivation and placement of new markers and cloned contigs.
Analysis of CAG trinucleotide repeats from mouse cDNA sequences
Authors: ABBOTT C. , CHAMBERS D.
Published: September 2007

A number of human single gene disorders are now known to result from abnormal expansion of trinucleotide repeats. Spinal muscular bulbar atrophy, myotonic dystrophy, Huntington's Disease, spinocerebellar ataxia and dentatorubral‐pallidoluysian atrophy are all caused by expansions of CAG repeats. Abnormal expansion of trinucleotide repeats has only so far been described in humans, and no mouse models exist for these diseases. In order to investigate trinucleotide repeat stability in mice, the Genbank and EMBL nucleotide databases were screened to find genes containing CAG repeats. Of the sequences selected, 32 were from mouse, and in 12 of these the repeat was in transcribed sequence and contained at least seven perfect repeats. These repeats were then analysed by PCR to evaluate the degree of variability of repeat length in the various genes. Two of the genes containing variable length CAG repeats, seven in absentia homologue 1b (Sinh1b), and choline acetyl transferase (Chat), which had not previously been mapped in the mouse genome, were mapped by linkage analysis in an interspecific backcross. Sinh1b maps very distally on the X chromosome, and Chat maps to chromosome 14.
Frequent normal allele loss and maternal origin of the mutation shown by DNA homoduplex analysis in a severely affected patient with adenomatous polyposis coli
Authors: GAYTHER S. A. , REES M. , DELHANTY J. D. A.
Published: September 2007

An atypically high frequency of loss of heterozygosity at chromosome 5q22 in small adenomas from a severely affected new mutation patient with adenomatous polyposis coli was recently reported. DNA homoduplex analysis has now been used to show that the deletion in the adenomas extends to include the APC locus and that the normal allele is lost. These data also prove the maternal origin of the mutation.
Using risk calculation to implement an extended relative pair analysis
Authors: CURTIS D. , SHAM P. C.
Published: September 2007

A new nonparametric method of linkage analysis is described based on identity by descent relationships between all pairs of affected relatives within a pedigree. This approach is an extension of ESPA, which only uses information from pairs of affected siblings. The new method, called ERPA, uses the risk calculation facilities of the LINKAGE programs to obtain the necessary information in a fashion which is simple to implement and which automatically generalizes to allow for marker loci which may be multiple, non‐codominant and sex‐linked. We have investigated the relative performance of ERPA, ESPA and the lod score method on simulated data. ERPA appears to be more sensitive than ESPA for detecting linkage in pedigrees with small sibships, though both nonparametric methods are inferior to the lod score method when the true mode of transmission can be specified.
Evidence of mitochondrial DNA diversity in South American aboriginals
Authors: MONSALVE M. V. , RESTREPO H. GROOT de , ESPINEL A. , CORREAL G. , DEVINE D. V.
Published: September 2007

The absence in South American aboriginals of an Asian‐specific marker, a 9‐bp deletion between the genes for the second subunit of cytochrome oxidase II and lysine transfer RNA in region V, has been interpreted as a bottlenecking effect at the Isthmus of Panama during the peopling of the Americas. We screened mitochondrial DNA (mtDNA) for this 9‐bp tandem repeat and for polymorphisms in specific regions of the mtDNA in 2 ancient and 31 contemporary samples from South American aboriginals. We found additional (mtDNA) diversity in South American aboriginals in three ways. First, an Asian‐specific marker not previously reported in South American aboriginals was identified by a sequencing analysis in both the contemporary Andean and Amazonian aboriginal peoples. Second, two new haplotypes so far unique to South American aboriginals were found. Additionally, we show that South American aboriginals fall into discrete populations. These results suggest that the prehistoric colonization of South America is the outcome of multiple migrations; the data do not support a bottlenecking effect at the Isthmus of Panama.
Genetic epidemiology of hereditary non‐polyposis colorectal cancer syndromes in Modena, Italy: results of a complex segregation analysis
Authors: SCAPOLI C. , LEON M. PONZ DE , SASSATELLI R. , BENATTI P. , RONCUCCI L. , COLLINS A. , MORTON N. E. , BARRAI I.
Published: September 2007

Complex segregation analysis was conducted in a series of patients with hereditary non‐polyposis colorectal cancer (HNPCC) ascertained through probands registered in the Cancer Registry of the Health Care District of Modena in Northern Italy. Altogether there were 71 nuclear families segregating for HNPCC in 28 pedigrees. The analysis favoured the two‐loci model, in which the segregation at the major locus is compatible with codominant transmission with a frequency of 0·0044 for the high‐risk allele for HNPCC and a lifetime penetrance of 0·728 for heterozygotes.
Cladistic analysis of the apolipoprotein AI‐CIH‐AIV gene cluster using a healthy French Canadian sample. I. Haploid analysis
Authors: HAVILAND M. B. , KESSLING A. M. , DAVIGNON J. , SING C. F.
Published: September 2007

A cladistic analysis was carried out to identify haplotypes hypothesized to differ for functional DNA sequence variations within the apolipoprotein (apo) AI‐CIII‐AIV gene cluster that affect plasma lipid, lipoprotein and apolipoprotein levels. A sample of unrelated healthy French Canadians was studied. First, a cladogram of the observed apo AI‐CIII‐AIV haplotypes was estimated. Then this cladogram was used to define a statistical analysis of the association between haplotype variation and variation in plasma lipid, lipoprotein and apolipoprotein levels. Three haplotypes were identified which were associated with small (5–12% of the total sum of squares) pleiotropic effects on plasma lipid, lipoprotein and apolipoprotein traits and these effects were context, i.e. gender, dependent.
Evolutionary dynamics of the FMR1 locus
Authors: MORRIS A. , MORTON N. E. , COLLINS A. , LAWRENCE S. , MACPHERSON J. N.
Published: September 2007

Rare haplotypes for close flanking markers are associated with increased allele size and frequency of the fragile X mutation. Exceptional founder haplotypes can be identified, but many haplotypes with rare alleles contribute to full mutations.

A transition matrix constructed from the data predicts that a population with reduced variability will manifest a slowly increasing frequency of premutations and full mutations, reach a distribution close to the observed one after a few hundred generations, and then slowly be depleted of these alleles. This prediction is opposite to less well supported inference of increasing frequency of progressive amplification, but the data are inadequate to reach any firm conclusions. Factors that may determine the evolution of these systems, but cannot now be evaluated, are discussed.
Exclusion from proximal 11q of a common gene with megaphenic effect on atopy
Authors: WATSON M. , LAWRENCE S. , COLLINS A. , BEASLEY R. , DOULL I. , BEGISHVILI B. , LAMPE F. , HOLGATE S. T. , MORTON N. E.
Published: September 2007

We have typed three markers on proximal 11q in 131 random families with three or more children studied for atopy. A summary map that includes the FCER1B candidate was constructed. Using a 2‐locus disease model, we performed combined segregation and linkage analysis of three models, none of which suggested linkage. Nine marker loci on other chromosomes were also negative. In the regions swept by these 12 markers we cannot rule out a rare gene, perhaps of large effect, nor a common gene of small effect. However, a common gene of large effect is excluded. These results and alternative strategies are discussed in the perspective of inconsistent evidence for a major atopy gene.
Integrated genetic map of human chromosome 2
Authors: COX S. , BRYANT S. P. , COLLINS A. , WEISSENBACH J. , DONIS‐KELLER H. , KOELEMAN B. P. C. , STEINKASSERER A. , SPURR N. K.
Published: September 2007

A framework genetic map of human chromosome 2 is described, integrating data from the Centre d'Étude du Polymorphisme Humain (CEPH) version 6 database, the CEPH chromosome 2 consortium database, the National Institute of Health (NIH)/CEPH Collaborative Mapping group and other laboratories. A comprehensive map is also presented, showing regional locations of a large number of additional loci. The framework map is used to identify an informative set of meiotic breakpoints within the CEPH families, and the utility of this information for mapping new markers is discussed. The degree of typing error within the data set is estimated, as are the sex‐specific interference parameters. A location database for these genetic and additional cytogenetic data is constructed using algorithms which map genetic distances on to a physical scale, and the potential for this approach to aid the integration of genetic and physical data is examined.
Mapping of human non‐muscle type cofilin (CFL1) to chromosome 11q13 and muscle‐type cofilin (CFL2) to chromosome 14
Authors: GILLETT G. T. , FOX M. F. , ROWE P. S. N. , CASIMIR C. M. , POVEY S.
Published: September 2007

Cofilin is a widely‐distributed, intracellular, actin binding protein which is involved in the translocation of actin‐cofilin complex from cytoplasm to nucleus. We have cloned a non‐muscle‐type cofilin (CFL1) from a human promyelocytic cDNA library and mapped this to human chromosome 11 by PCR amplification of 3' untranslated sequence in a panel of rodent‐human somatic cell hybrids, and to the interval 11q12‐q13.2 in a chromosome 11 somatic cell hybrid mapping panel. Confirmation of regional localisation to 11q13 has been obtained by fluorescent in situ hybridisation of genomic cosmid clones, by demonstration of the presence of both SEA (the human homologue of avian retrovirus pro viral tyrosine kinase, 11q13) and CFL1 in some of these clones and by close linkage of CFL1 to SEA in a panel of high‐dose irradiation hybrids.

We have identified human muscle‐type cofilin sequences by comparison of human expressed sequence tags with M‐type cofilins of other species and we have mapped the human M‐type cofilin, CFL2, to chromosome 14.
Reproductive Reproductive behaviour and natural selection for the sickle gene in the Baiga Tribe of Central India: The role of social parenting
Authors: REDDY P. H. , MODELL B.
Published: September 2007

We have investigated the transmission of the sickle cell gene in relation to tribal structure, and genetic fitness in a primitive Indian tribal population, the Baiga. Factors operating on gene frequency include protection of AS individuals against falciparum malaria, a high frequency of genetic factors capable of moderating the severity of sickle cell anaemia (α‐thalassaemia and Xmn I polymorphism in G gamma gene), a high frequency of consanguineous marriage, and reproductive compensation by couples at risk for sickle cell anaemia. The study incidentally made it possible to measure the extent of ‘social parenting’ in such a tribal society for the first time: deviation from expectation in the distribution of the Hb A and S genes within families suggests that up to 30 % of children may not be offspring of their ostensible parents.
The early history of the statistical estimation of linkage
Authors: EDWARDS A. W. F.
Published: September 2007

The history of the statistical estimation of linkage is traced from its beginnings in 1912 to its coming‐of‐age in 1928, with special reference to the forgotten contribution of G. U. Yule and F. L. Engledow in 1914 introducing the method of minimum χ2 as the first efficient procedure.
Population stratifications can cause false positive linkage results if founders are untyped
Authors: CURTIS D. , SHAM P. C.
Published: September 2007

We wish to draw attention to the fact that population stratifications can produce a bias towards yielding false positive linkage results when founder genotypes are missing. It is now fairly well known that misspecification of allele frequencies can produce such a bias ‐ if a common allele is misspecified as rare then the fact that it is frequently observed among affected individuals will be incorrectly taken as evidence of increased sharing of alleles identical‐by‐descent (Ott, 1992). What may be less widely recognized is that similar effects can occur even if the correct population allele frequencies are used. Independently of us, Miller et al. (1995) and Gu et al. (1995) have recently shown that population stratifications can produce false positive linkage results for Lange's (1985) identity‐by‐state affected sib‐set analysis and for the affected‐pedigree‐member method (APM, Weeks & Lange, 1988). In fact, the problem applies to any method of linkage analysis when applied to datasets with untyped founders.
Chromosomal localisation of genes coding for human and mouse liver cytosolic cysteine dioxygenase
Authors: JEREMIAH S. , McCANN K. P. , WILLIAMS A. C. , RAMSDEN D. B. , PILZ A. J. , FOX M. F. , POVEY S.
Published: September 2007

A panel of 22 hybrids was tested for the presence of the gene coding for human cysteine dioxygenase (CDO) by using human specific oligonucleotide primers in the polymerase chain reaction. Detection of human CDO completely correlated with the presence of human chromosome 5. A human total genome cosmid library was screened with a PCR product from the coding region of human CDO cDNA and the two positive clones identified were used in fluorescent in situ hybridisation (FISH) analysis on metaphase chromosome spreads. Fluorescent signals were seen on chromosome 5q22–23. Interspecific backcross mapping in the mouse indicated that Cdo, the mouse homologue of CDO, is situated in the central region of mouse chromosome 18 which shares a region of homology with human chromosome 5.
From Asia to Europe: mitochondrial DNA sequence variability in Bulgarians and Turks
Authors: CALAFELL F. , UNDERHILL P. , TOLUN A. , ANGELICHEVA D. , KALAYDJIEVA L.
Published: September 2007

Two hypervariable sequence segments in the control region of mitochondrial DNA were determined in samples of Bulgarians and Turks. The Turkish sample presented a higher degree of internal diversity, in terms of total number of variable nucleotides, as well as in the average pairwise nucleotide difference. Pairwise difference distributions were built for both samples, yielding smooth bell shapes in agreement with the Rogers and Harpending model. The Bulgarian and Turkish data were compared with several European and W. Asian Caucasoid populations (Basques, Tuscans, Sardinians, British, Middle Easterners and Indians). Mean pairwise differences suggest that a demographic expansion occurred sequentially in the Middle East, through Turkey, to the rest of Europe (Bulgaria included). Current mutation rate estimates date this expansion in times ranging between 50000 and 100000 years ago and, thus, would correspond to the arrival of anatomically modern humans in Europe. Sequence trees for segment I show that European and Middle Eastern sequences derived from the reference sequence. Coalescence times for segment I sequences agree with those predicted by pairwise distributions. Genetic trees were constructed between populations and revealed an extreme homogeneity between European samples.
Racial heterogeneity of DNA polymorphisms linked to the A and the O alleles of the ABO blood group gene
Authors: ZAGO M. A. , TAVELLA M. H. , SIMõES B. P. , FRANCO R. F. , GUERREIRO J. F. , SANTOS S. B.
Published: September 2007

Except for subgroup A2 and minor A, O and B alleles (Ax, O2 and B(A)), which occur at low frequencies in the population, the major ABO alleles are considered to be homogeneous entities. The present study is the first demonstration of an extensive variability linked to the more common alleles of the blood A and O genes by digestion of the genomic DNA with different restriction enzymes and hybridization with a probe generated by PCR amplification of a segment of the last exon of the glycosyltransferase gene. For group A in Whites, two or three‐allele fragment length polymorphisms (RFLP) were demonstrated by Hinc II, Taq I and Hint I; for group O two to five‐allele RFLP were detected in Blacks, Whites and Amerindians with restriction enzymes Hinc II, Bgl I, Kpn I, Taq I and Hint I. These polymorphisms probably originated by single‐base changes, although a length variation due to variable number of tandem repeats cannot be ruled out for some. Allelic association between the different restriction sites permitted the identification of seven O allele haplotypes in Blacks, and two in Whites and Indians. Three different haplotypes were identified for group A in Whites. The greater heterogeneity of the O allele among the Blacks as compared with Whites and Indians is similar to that observed for other gene systems. The polymorphisms of the histoblood group ABH antigen genes seem a useful tool for population genetics, phylogenetics and evolution studies.
Estimating linkage heterogeneity
Authors: SMITH C. A. B. , STEPHENS D. A.
Published: September 2007

The admixture model for linkage heterogeneity is modified to take account of the difference in recombination fractions in the two sexes. The data used may concern a single (marker) locus on one chromosome, which is suspected of being sometimes near a (disease) locus for a particular condition of interest, or there may be data on more than one locus on this chromosome. There may be data on a locus or loci on a second chromosome, which is also suspected of sometimes carrying an allele for the condition in question. The general principle for the analysis is the same in all such cases, though details may differ. The object is to estimate the relevant recombination fractions, and the proportions of cases in which the allele for the condition falls on each chromosome.
Similarities in anthropometrical traits of children and their parents in a Bulgarian population
Authors: NIKOLOVA M.
Published: September 2007

A study has been made of 36 body and 11 craniofacial measurements in a selected sample of 251 Bulgarian families, comprising parents and their children over 15 years. The mid parent‐offspring and correlation coefficients indicate that the extent of genetic determination varies considerably from one measurement to another. There is an evidence of directional dominance for three body traits and for two craniofacial traits. None of the different parent‐offspring correlations is compatible with X‐linked inheritance. A greater maternal than paternal influence is evident for biacromial diameter but a greater paternal influence is seen for head height, nose height and for ear height and breadth.
Investigating a single facet of a multilocus model
Authors: GREEN J. R. , SHAH S.
Published: September 2007

We consider looking at a single locus of a multilocus model, such as that for IDDM, in particular the use of the sib‐pair method concentrating attention on the influence of HLA.
Alcohol, Hypertension, and Stroke
Authors: Taylor John R. , Combs‐Orme Terri , Anderson Dale , Taylor David A. , Koppenol Carolyn
Published: September 2007

The authors compared the drinking habits of stroke patients and controls who were matched for the variables of age, sex, race, and day of the week admitted to the hospital. Rates of alcoholism were similar in the two groups. However, stroke patients were more likely to be current drinkers than controls, and were more likely to have been drinking within 24 hr of admission to the hospital, most of them rather heavily. Among the stroke patients, alcoholism was associated with hypertension, with being a current drinker, and with drinking at index, i.e., within 24 hr of the first symptoms of stroke. Of those stroke patients who were drinking at index, there were significant associations with being Mack, alcoholic, and hypertensive. The implications of these findings are discussed.
Erectile Impotence in Chronic Alcoholics
Authors: Tan Edward T. H. , Johnson Ralph H. , Lambie David G. , Vijayasenan Mithra E. , Whiteside Edwin A.
Published: September 2007

Erectile impotence is a common complaint in alcoholics, but its mechanism is unknown. We have studied nocturnal penile erection in 13 alcoholics who complained of impotence. Seven had normal erections and their impotence was therefore psychogenic. Six were found to have diminished or absent nocturnal erections. Plasma concentrations of follicle‐stimulating hormone (FSH) and luteinizing hormone (LH) were elevated in this latter group, with the exception of one patient who had only raised FSH. They also had more evidence of neurological damage than the other seven alcoholics, and two had evidence of damage to the parasympathetic nervous system. Investigation of erection during steep in alcoholic patients with impotence may be useful in differentiating clinically between patients with psychogenic causes and patients with organic causes of impotence.
Inhibition of Human Aldehyde Dehydrogenase Isozymes by Propiolaldehyde
Authors: Ferencz‐Biro Katalin , Pietnjszko Regina
Published: September 2007

Propiolaldehyde–a metabolite of pargytine (Shirota et al., 1979) can function as an inhibitor or as a substrate of human aldehyde dehydrogenase (EC 1.2.1.3), dependent on conditions. In the presence of high concentration of NAD, propiolaldehyde is a substrate for both the cytoplasmic E, isozyme and the mitochondrial E2 isozyme. The K. values are comparable to those with other short chain aldehydes; the maximal velocity is also similar for E2 but lower by about threefold for E. Preincubation with propiolaldehyde in the absence of NAD produces inactivation with K values of 1.6 μM for E, and 1.8 μ for E2. NAD, but not propanal, protects both isozymes against inactivation with propiolaldehyde.