摘要:

SummaryThe objectives of this study were to elucidate the structural organization of the gene for human deoxyribonuclease I (DNase I) and to identify the mutation site underlying its classical genetic polymorphism. In order to determine the organization of this gene, we utilized a combination of direct polymerase chain reaction (PCR)‐amplification of human genomic DNA and isolation of the overlapping clones from a cosmid human genomic library. Restriction endonuclease mapping, Southern blotting and DNA sequencing showed that the DNase I gene was approximately 3·2 kilobases long, it comprised 9 (I‐IX) exons separated by eight introns and its complete sequence was determined. The first exon contained only the non‐translated sequences of mRNA. In addition to several putative regulatory elements, TATA‐like and CAAT‐like sequences were observed in the region upstream of the translation initiation codon. These results provide information that will help to understand the expression and regulation of DNase I. The isoelectric focusing patterns of human DNase I showed that it exhibits classical genetic polymorphism (Kishiet al.1989, 1990). A comparison of the entire translated sequences of the DNase I gene from two pairs of individuals with common DNase I phenotypes 1 and 2 revealed only one nucleotide residue difference in exon VIII, A for phenotype 1 and G for phenotype 2, thus producing Gin and Arg amino acid substitutions respectively at position 222 from the NH2‐terminus of the mature enzyme. The predicted charge changes attributable to these amino acid substitutions are entirely consistent with the isoelectric focusing profiles of these two DNase I isozymes. We conclude that this substitution is solely responsible for the classical polymorphism of DNa

ISSN:0003-4800    

DOI:10.1111/j.1469-1809.1995.tb01601.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

SummaryProteolytic imbalance may play a role in the pathogenesis of abdominal aortic aneurysms (AAA). CLG4B, which encodes the 92‐kDa form of type IV collagenase, is a candidate gene for AAA. We genotyped a polymorphic dinucleotide repeat in the 5′ flanking region of CLG4B in 94 unrelated Caucasian controls and in 127 unrelated Caucasian AAA cases. Eight alleles were detected in 188 control chromosomes with an observed heterozygosity of 0·68. There was no significant difference in allele distribution between cases and controls. We genotyped the dinucleotide repeat in 10 CEPH reference pedigrees and performed pairwise linkage analysis with markers on each of the 22 human autosomes. Lod scores between 10·45 and 20·29 were observed with markers spanning chromosome region 20q11.2‐q13.1. Further support for assignment of CLG4B to chromosome 20 was provided by analysis of human‐rodent somatic cell hybrids. This work describes a highly polymorphic marker in the CLG4B gene and assigns this gene to chr

ISSN:0003-4800    

DOI:10.1111/j.1469-1809.1995.tb01602.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

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

ISSN:0003-4800    

DOI:10.1111/j.1469-1809.1995.tb01603.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

SummaryTo determine whether the common 5 base pair deletion (δAAAGA) at codon 1309 of theAPCgene occurs preferentially on a particular haplotype background, three intragenic polymorphisms were typed using the polymerase chain reaction in ten patients with this deletion as the disease‐causing mutation. Each case was due to fresh mutation. The data obtained provide no evidence in support of a preferential haplotype predisposing to this mutati

ISSN:0003-4800    

DOI:10.1111/j.1469-1809.1995.tb01604.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

SummaryA large and ethnically well defined Mandenka sample from Senegal is analysed for 80 nuclear DNA RFLPs, and compared with eight previously studied human populations. A high level of genetic diversity is found in this sample, comparable to that observed in two African Pygmy samples, but lower than that of a European sample. High population variation is observed for most markers. A neutrality test reveals that the markers used in this study can be considered as neutral. A high correlation is found between genetic and geographic distances (r= 0·62), suggesting that geography does also affect long range population genetic relationships and is an important factor behind differentiation among human populations

ISSN:0003-4800    

DOI:10.1111/j.1469-1809.1995.tb01605.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

SummaryThe hypervariable segment I of the control region of the mtDNA (positions 16024–16383) was PCR‐amplified from mouth scrape and hairs and sequenced in 45 unrelated individuals of pure matrilineal Basque descent. Twenty‐seven different sequences were found, of which 21 are unique to the Basques. The allelic partition observed, together with resampling experiments, suggested that much more variation remained to be discovered.The mean pairwise difference in number of nucleotides between individuals was 3·15, a very low value. Moreover, the number of steps for the most parsimonious tree is very low compared to the number of different sequences. Both findings suggest that the Basque population was founded by a few lineages that diverged in a short time span. The number of nucleotide differences between individuals was shown not to be influenced by the distance between their birthplaces, thus validating the sampling strategy useda posteriori.The pairwise difference distribution agreed well with the three‐parameter model proposed by Rogers&Harpending (1992). The parameter estimates found for the Basques implied that a demographic expansion (or perhaps two, given the bimodal shape of the distribution) took place sometime between 14500 and 42000 BP which is in agreement with archaeological data.Our sample was compared to other populations for which D‐loop sequences were available through the Nei&Miller (1990) distance. In a neighbour‐joining tree, all the Caucasoid samples, including the Basques, appeared tightly clustered, whereas African samples were the most distant to the Caucasoids and also the most heterogeneous. Although classical markers, such as blood groups and protein polymorphisms, clearly separate the Basques (and the Sardinians) from other European populations, this distinctiveness was not found using D‐

ISSN:0003-4800    

DOI:10.1111/j.1469-1809.1995.tb01606.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

SummaryLinkage analysis has contributed to the localization of many human disease genes. The presence of locus heterogeneity reduces statistical power and can prejudice the detection of linkage if the analysis assumes homogeneity. Nevertheless, mixed genetic models are not routinely used in gene searches. The null distribution of the test statistic is not uniquely defined. In this paper, a transformation is used to determine an approximate asymptotic distribution of the test statistic under a mixture model. The equivalent critical values of the test are computed and the performance of the test under various levels of heterogeneity and family size is investigated. For gene searches, we recommend the routine use of an admixture model with a critical lod score of 3·44

ISSN:0003-4800    

DOI:10.1111/j.1469-1809.1995.tb01607.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

SummaryIn an association analysis comparing cases and controls with respect to allele frequencies at a highly polymorphic locus, a potential problem is that the conventional chi‐squared test may not be valid for a large, sparse contingency table. However, reliance on statistics with known asymptotic distribution is now unnecessary, as Monte Carlo simulations can be performed to estimate the significance level of any test statistic. We have implemented a Monte Carlo method for four ‘chi‐squared’ test statistics, three of which involved combination of alleles, and evaluated their performance on a real data set. Combining rare alleles to avoid small expected cell counts, and considering each allele in turn against the rest, reduced the power to detect a genuine association when the number of alleles was very large. We should either not combine alleles at all, or combine them in such a way that preserves the evidence for an asso

ISSN:0003-4800    

DOI:10.1111/j.1469-1809.1995.tb01608.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

SummaryIn traditional quantitative genetics, the relationship between the observed value of a quantitative trait in a set of families and its genetic and environmental contributions can be described as a linear additive relationship. Generally, it is assumed that the genetic and environmental effects are independent and normally distributed. Consequently, the quantitative trait also has a normal distribution. However, there are some situations where the phenotype does not follow the normal distribution. To deal with this problem the author suggests the families of distributions that belong to the Johnson Translation System (JTS). As an example, two dependent quantitative traits, weight and height, are investigated assuming that they have a lognormal and normal distribution, respectively. Computational methods for estimating the genotypic variances and covariances are presented.

ISSN:0003-4800    

DOI:10.1111/j.1469-1809.1995.tb01609.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

SummaryTo detect linkage between a trait and a marker, Morton (1955) proposed to calculate the lod score z(θ1) at a given value θ1of the recombination fraction. If z(θ1) reaches +3 then linkage is concluded. However, in practice, lod scores are calculated for different values of the recombination fraction between 0 and 0·5 and the test is based on the maximum value of the lod score Zmax. The impact of this deviation of the test on the probability that in fact linkage does not exist, when linkage was concluded, is documented here. This posterior probability of no linkage can be derived by using Bayes' theorem. It is less than 5% when the lod score at a predetermined θ1is used for the test. But, for a Zmax of +3, we showed that it can reach 16·4%. Thus, considering a composite alternative hypothesis instead of a single one decreases the reliability of the test. The reliability decreases rapidly when Zmax is less than + 3. Given a Zmax of +2·5, there is a 33% chance that linkage does not exist. Moreover, the posterior probability depends not only on the value of Zmax but also jointly on the family structures and on the genetic model. For a given Zmax, the chance that linkage exists may the

ISSN:0003-4800    

DOI:10.1111/j.1469-1809.1995.tb01610.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY