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At least 19 recordsLinked to original sources
PubMed2001

Detecting population outliers and null alleles in linkage data: application to GAW12 asthma studies.

Error-checking procedures are essential to ensure accurate and powerful linkage analysis. Genotype information across families can be used to identify non-amplification of alleles (null alleles) and between-family population sub-structuring, which can result in loss of power in linkage studies if undetected. Methods to identify population outlier individuals and null alleles are applied to genotype data from two asthma genome searches (German and CSGA) available from Genetic Analysis Workshop 12. Two clear population outliers are observed in the German data set, with further evidence of population sub-structuring. In the CSGA data, a significant excess of homozygous individuals is found at D8S1106, suggestive of a null allele at this marker with an estimated frequency of 0.17 (African-American) and 0.20 (Caucasian).

Alleles↗
PubMed2004

Eight novel MICB alleles, including a null allele, identified in gastric MALT lymphoma patients.

MICA and MICB, as members of the major histocompatibility complex (MHC) class I-chain-related genes (MIC), encode stress-inducible glycoproteins that act as activating ligands for NKG2D and gammadelta T-cell receptor-bearing cells. We here describe the identification of eight novel MICB variants, including a null allele, which were identified in peripheral blood leukocytes of gastric MALT lymphoma patients. Only two of the novel alleles are characterized by point mutations, whereas the other variants display a recombination of known exonic MICB sequences that may be best explained by intragenic conversions. The novel MICB null allele is characterized by a Cytosin (C) deletion in a stretch of four Cs beginning from nucleotide 135 of exon 2 that leads to a premature stop codon (TGA) at codon 66.

Alleles↗
PubMed2003

Molecular comparison of waxy null alleles in common wheat and identification of a unique null allele.

PCR selection markers for the identification of null waxy alleles were used to screen for waxy mutations in 168 common wheat cultivars. In all cultivars where the Wx-B1 protein was absent, the Wx-B1 allele was identical to the previously identified mutation carried by Kanto 107. Although most cultivars missing the Wx-A1 protein also carried the same Wx-A1 mutation as found in Kanto 107, all of the Turkey Wx-A1 mutants produced a different PCR fragment, implying the presence of a different mutation. Sequencing of this fragment indicated the mutation, which consisted of a 173-bp insertion in an exon, was in a different location than the previously identified Wx-A1 mutation. An 8-bp duplication of the Wx-A1 sequence flanked each end of the insertion, and an element with reverse complementary sequences was present at both ends of the insertion. These structures correspond with the features of class II transposable elements. Hence, the Turkey null Wx-A1 mutation was likely caused by the movement of a transposon, and this spontaneous mutation appears to be present in a limited geographical area.

Alleles↗
PubMed1999

Prenatal diagnosis of osteogenesis imperfecta type I by COL1A1 null-allele testing.

Osteogenesis imperfecta (OI) type I is caused by a reduction of type I collagen resulting from the presence of a non-functional COL1A1 allele (null-allele). Owing to the lack of mutant mRNA, genomic screening of the COL1A1 and COL1A2 genes is required to identify a causal mutation, which is a costly and time consuming endeavour. We have developed an alternative approach for confirmation of a suspected diagnosis of OI type I based on the detection of a COL1A1 null-allele. Here we report the application of this COL1A1 null-allele detection test for prenatal diagnosis in a patient with OI type I in which it was shown that the fetus had inherited the normal COL1A1 allele from his affected mother and would not be affected with OI.

3' Untranslated Regions↗
PubMed2006

Estimating relatedness and relationships using microsatellite loci with null alleles.

Relatedness is often estimated from microsatellite genotypes that include null alleles. When null alleles are present, observed genotypes represent one of several possible true genotypes. If null alleles are detected, but analyses do not adjust for their presence (ie, observed genotypes are treated as true genotypes), then estimates of relatedness and relationship can be incorrect. The number of loci available in many wildlife studies is limited, and loci with null alleles are commonly a large proportion of data that cannot be discarded without substantial loss of power. To resolve this problem, we present a new approach for estimating relatedness and relationships from data sets that include null alleles. Once it is recognized that the probability of the observed genotypes is dependent on the probabilities of a limited number of possible true genotypes, the required adjustments are straightforward. The concept can be applied to any existing estimators of relatedness and relationships. We review established maximum likelihood estimators and apply the correction in that setting. In an application of the corrected method to data from striped hyenas, we demonstrate that correcting for the presence of null alleles affect results substantially. Finally, we use simulated data to confirm that this method works better than two common approaches, namely ignoring the presence of null alleles or discarding affected loci.

Alleles↗
PubMed1999

A single nucleotide deletion resulting in a premature stop codon is associated with marked reduction of transcripts from a goat beta-casein null allele.

A null beta-casein allele (CSN2O) was investigated in Creole and Pyrenean goats producing milk devoid of beta-casein (CSN2). Northern blot analyses of total mammary RNA showed much lower amounts of CSN2 transcripts that were similar in size to the wild-type counterpart. The amount of CSN2O mRNA was roughly 5% of the amount of mRNA obtained at the same age and stage of lactation from CSN2A/A goats. Comparative sequence analyses of full-length CSN2O and CSN2A cDNAs showed that both alleles were of similar size, but allele CSN2O had a one-nucleotide deletion in the 5' end of exon 7, which introduces a premature stop codon. The open reading frame of allele CSN2O encodes a shortened polypeptide of 72 amino acids, compared to 223 amino acids for caprine pre beta-casein A. Comparative analyses of RT-PCR products suggested that alleles CSN2O and CSN2A might also differ in the amount and relative ratio of minor deleted CSN2 transcripts. The lower amount of CSN2O mRNA was associated with the occurrence of the premature stop codon which may mediate a rapid decay of CSN2O mRNA and promote skipping of nucleotide stretches containing premature nonsense triplets.

Alleles↗
PubMed2006

Microsatellite null alleles and estimation of population differentiation.

Microsatellite null alleles are commonly encountered in population genetics studies, yet little is known about their impact on the estimation of population differentiation. Computer simulations based on the coalescent were used to investigate the evolutionary dynamics of null alleles, their impact on F(ST) and genetic distances, and the efficiency of estimators of null allele frequency. Further, we explored how the existing method for correcting genotype data for null alleles performed in estimating F(ST) and genetic distances, and we compared this method with a new method proposed here (for F(ST) only). Null alleles were likely to be encountered in populations with a large effective size, with an unusually high mutation rate in the flanking regions, and that have diverged from the population from which the cloned allele state was drawn and the primers designed. When populations were significantly differentiated, F(ST) and genetic distances were overestimated in the presence of null alleles. Frequency of null alleles was estimated precisely with the algorithm presented in Dempster et al. (1977). The conventional method for correcting genotype data for null alleles did not provide an accurate estimate of F(ST) and genetic distances. However, the use of the genetic distance of Cavalli-Sforza and Edwards (1967) corrected by the conventional method gave better estimates than those obtained without correction. F(ST) estimation from corrected genotype frequencies performed well when restricted to visible allele sizes. Both the proposed method and the traditional correction method have been implemented in a program that is available free of charge at http://www.montpellier.inra.fr/URLB/. We used 2 published microsatellite data sets based on original and redesigned pairs of primers to empirically confirm our simulation results.

Alleles↗
PubMed1989

Genetic dissection of Drosophila myofibril formation: effects of actin and myosin heavy chain null alleles.

We used null mutations of Drosophila actin and myosin genes to investigate two aspects of myofibril assembly. First, we eliminated all actin or myosin in flight muscles to evaluate contributions of thick and thin filaments to sarcomere formation. Results demonstrate that thick and thin filament arrays can assemble independently but that both are essential for sarcomeric order and periodicity. Second, we examined how filament stoichiometry affects myofibril assembly. We find that heterozygotes for actin (Act88F) or myosin heavy chain (Mhc36B) null alleles have complex myofibrillar defects, whereas Mhc36B-/+; Act88F-/+ double heterozygotes have nearly normal myofibrils. These results imply that most defects observed in single heterozygotes are due to filament imbalances, not deficits, and suggest that thick and thin filament interactions regulate myofibrillar growth and alignment.

Actins↗
PubMed2005

HLA class I null alleles and new alleles affect unrelated bone marrow donor searches.

Unrecognized HLA null alleles or new alleles may affect the outcome of bone marrow transplants using unrelated donors. Some reports suggest that null alleles occur in the range of 0.003-0.07% (1, 2), which has led some transplant programs to stop performing serologic typing. We describe nine cases involving expression variants or new alleles. Three cases involved expression variants, including two null alleles and A*24020102L. One of the null alleles was a new variant of A*02. Seven cases involved new alleles. In five cases, there where discrepancies between HLA typing by serology and PCR-SSP. These included the three expression variants, one new B40 allele that typed serologically as B41 and one new B*07 allele that typed serologically as B42. Eight of these cases were found in the course of typing bone marrow transplant patients or potential unrelated donors since May of 2001 (total tested, 710 patients, 1914 donors). Thus, the incidence of null alleles was two in 2,624 (0.08%). Sequence-based typing (SBT) was performed on 676 of these samples. The decision to perform SBT was influenced by finding a serologic typing discrepancy in two cases. In one of those cases, SBT would probably have been performed at a later time, prior to final selection of a donor. Thus, the incidence of new alleles was between 4 and 6 of 676 (0.59-0.89%). We conclude that new HLA alleles and null alleles are uncommon but not extremely rare, and they continue to affect a significant number of unrelated donor searches.

Alleles↗
PubMed2005

HLA-G*0105N null allele encodes functional HLA-G isoforms.

Expression of the nonclassical HLA class I antigen, HLA-G, is associated with immune tolerance in view of its role in maintaining the fetus in utero, allowing tumor escape, and favoring graft acceptance. Expressed on invasive trophoblast cells, HLA-G molecules bind inhibitory receptors on maternal T lymphocytes and NK cells, thereby blocking their cytolytic activities and protecting the fetus from maternal immune system attack. The HLA-G gene consists of 15 alleles, including a null allele, HLA-G*0105N. HLA-G*0105N presents a single base deletion, preventing translation of both membrane-bound (HLA-G1) and full-length soluble isoforms (HLA-G5) as well as of the spliced HLA-G4 isoform. The identification of healthy subjects homozygous for this HLA-G null allele suggests that the HLA-G*0105N allele may generate other HLA-G isoforms, such as membrane-bound HLA-G2 and -G3 and the soluble HLA-G6 and -G7 proteins, which may substitute for HLA-G1 and -G5, thus assuming the immune tolerogeneic function of HLA-G. To investigate this point, we cloned genomic HLA-G*0105N DNA and transfected it into an HLA-class I-positive human cell line. The results obtained indicated that HLA-G proteins were indeed present in HLA-G*0105N-transfected cells and were able to protect against NK cell lysis. These findings emphasize the role of the other HLA-G isoforms as immune tolerogeneic molecules that may also contribute to maternal tolerance of the semiallogenic fetus as well as tumor escape and other types of allogeneic tissue acceptance.

Alleles↗
PubMed1997

Null alleles of creA, the regulator of carbon catabolite repression in Aspergillus nidulans.

CreA is the major regulatory protein involved in carbon catabolite repression in Aspergillus nidulans. Previously we have reported the molecular characterization of a number of in vivo selected mutant alleles and showed that they were unlikely to represent total loss of function alleles (Shroff et al., 1996) and that a deletion of the creA gene and surrounding DNA has an extremely severe effect on morphology under both carbon catabolite repressing and carbon catabolite nonrepressing conditions (Dowzer and Kelly, 1991). Here we present an analysis of in vivo selected creA mutations with an extreme morphological phenotype and show that some of these alleles would be predicted to result in no functional CreA. The most extreme of these alleles resulted in a truncation of the protein within the first zinc finger. Precise gene disruptions, leaving the flanking sequences intact, show essentially the same phenotype as this truncated allele. Thus, a strain containing a null allele is viable, and the leaky-lethal phenotype of previous deletion alleles (Dowzer and Kelly, 1991) must be due to the deletion of additional 3' genomic sequence. A strain containing an allele that results in a deletion of the final 80 amino acids shows reduced sensitivity to carbon catabolite repression for a number of systems, thus localizing a region of the protein involved in repression. Surprisingly, the phenotypically most extreme allele studied is not a null allele, but results in an amino acid substitution that would disrupt the zinc finger region and abolish binding to DNA. This is the only allele that produces a full-length protein, predicted to be nuclear localized, but which completely abolishes DNA binding. The phenotype may be more extreme than the null alleles due to the nuclear located CreA protein titrating interacting proteins.

Alleles↗
PubMed1988

Alpha-1-antitrypsin and transferrin null alleles in the Portuguese population.

In a Portuguese family, a null allele was found in the Pi system. An apparent 'exclusion' of the mother was found to be due to the presence of null alleles in mother and child. A transferrin (Tf) null allele was found in a case of disputed paternity. The mother and putative father were heterozygous for Tf null alleles and the child was homozygous (TfQ0) and presented hypotransferrinemia.

Alleles↗
PubMedDate not supplied

Microsatellite marker development and analysis in the eastern oyster (Crassostrea virginica): confirmation of null alleles and non-Mendelian segregation ratios.

Eighteen microsatellite markers were developed for the Crassostrea virginica nuclear genome, including di-, tri-, and tetranucleotide microsatellite repeat regions that included perfect, imperfect, and compound repeat sequences. A reference panel with DNA from the parents and four progeny of 10 full-sib families was used for a preliminary confirmation of polymorphism at these loci and indications of null alleles. Null alleles were discovered at three loci; in two instances, primer redesign enabled their amplification. Two to five representative alleles from each locus were sequenced to ensure that the targeted loci were amplifying. The sequence analysis revealed not only variation in the number of simple sequence repeat units, but also polymorphisms in the microsatellite flanking regions. A total of 3626 bp of combined microsatellite flanking region from the 18 loci was examined, revealing indels as well as nucleotide site substitutions. Overall, 16 indels and 146 substitutions were found with an average of 4.5% polymorphism across all loci. Eight markers were tested on the parents and 39-61 progeny from each of four families for examination of allelic inheritance patterns and genotypic ratios. Twenty-six tests of segregation ratios revealed eight significant departures from expected Mendelian ratios, three of which remained significant after correction for multiple tests. Deviations were observed in both the directions of heterozygote excess and deficiency.

Alleles↗
PubMed1993

Incidence and origin of "null" alleles in the (AC)n microsatellite markers.

Twenty-three (AC)n repeat markers from chromosome 16 were typed in the parents of the 40 CEPH (Centre d'Etude du Polymorphisme Humain) families. Where parents were informative, the entire families were then typed. There were seven markers in which null alleles were demonstrated, as recognized by the apparent noninheritance, by a sib, of a parental allele. Four of these markers showed a null allele in a single sibship, while in the other three at least 30% of the CEPH sibships were shown to have a null allele segregating. One null allele was sequenced and shown to be the result of an 8-bp deletion occurring within the priming sequence for PCR amplification of the (AC)n repeats. In gene mapping or in application to diagnosis, the presence of a segregating null allele will not corrupt the linkage data but could result in loss of information. In isolated instances a segregating null allele may be interpreted as nonpaternity. The presence of a null allele may generate misleading data when individuals are haplotyped to determine the presence of linkage disequilibrium with a disease gene.

Alleles↗
PubMed1998

Molecular basis of an apolipoprotein[a] null allele: a splice site mutation is associated with deletion of a single exon.

Apolipoprotein[a] (apo[a]), a unique component of atherogenic lipoprotein[a], is highly polymorphic in human and nonhuman primates. Null alleles, producing no detectable circulating Lp[a] or apo[a] isoforms, are found at high frequencies. The molecular basis of null alleles is not yet known. In baboons, approximately two-thirds of null alleles do not produce detectable hepatic transcripts (transcript negative nulls), and one-third of null alleles produce normal amounts of apo[a] transcripts (transcript positive nulls). We have cloned apo[a] cDNA from a baboon carrying a transcript positive null allele defective in secretion from primary hepatocytes. Compared with wild-type cDNA, the null allele contained an in-frame 47 amino acid deletion in the protease domain corresponding to one exon of the apo[a] gene. The null allele contains an A-->T substitution in the third nucleotide position of the intron downstream of the deleted exon which alters the donor splice site consensus sequence. Thus, this null is likely due to a mutation that prevents normal mRNA splicing, yielding a shortened protein that may be defective in intramolecular interactions required for normal processing and secretion of apo[a]. This is the first report of a molecular basis for apo[a] null alleles.

Alleles↗
PubMed1990

Molecular characterisation of C4 null alleles found in Felty's syndrome.

A higher prevalence of C4B null alleles is found in Felty's syndrome. The molecular basis of C4 null alleles was investigated by studying restriction fragment length polymorphisms (RFLPs) obtained with C4 and 21-hydroxylase (21-OH) DNA probes and by pulsed field gel electrophoresis in 30 subjects with Felty's syndrome. C4A null alleles were found in 10 subjects, and in five of these were associated with a deletion that included C4A and adjacent 21-OHA gene sequences. A 6.4 kilobase C4B-5'-specific Taq I fragment usually provided a reliable guide to the presence of a C4A deletion but unusually in one instance this fragment was found to be a marker of a functioning C4A gene. A C4B null allele was found in 17 subjects and was associated with a deletion involving C4B and 21-OHA gene sequences on only two occasions. There were no instances in which deletion of the 21-OHB gene occurred.

Alleles↗
PubMed1991

Influence of C4 null alleles on C4 activation in systemic lupus erythematosus.

Deficiencies of early components of the classical complement pathway are known to be associated with systemic lupus erythematosus (SLE). C4 null alleles, C4A Q0 and C4B Q0, are prime candidates for the major histocompatibility complex associated factor which determines susceptibility to SLE. There is poor correlation, however, between the presence of low concentrations of C4 and possession of C4 null alleles, and thus the basis of the association between C4A Q0, C4B Q0 and SLE remains obscure. The possibility that activation of C4 may be related to the possession of C4 null alleles was examined. C4 phenotypes were investigated, and C4 concentration and activation were estimated in patients with SLE. C4 activation was determined by measuring the concentration of C4d--a split product of C4. Twenty five of 35 patients had C4 phenotypes which include null alleles. No association between low C4 concentrations and C4 null alleles was found, but a significant association between low C4d concentrations and C4 phenotypes including null alleles, particularly those with C4A Q0, was noted. No correlation between concentrations of C4 and C4d was found. These results show an influence of C4 null alleles on the activation of the C4 molecule, which is independent of the concentration of C4. The possession of silent genes coding for C4 null alleles might predispose to SLE by conditioning poor C4 activation, a critical event for the clearance of immune complexes mediated by the classical complement pathway.

Alleles↗