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PubMed2006

A single transgene locus triggers both transcriptional and post-transcriptional silencing through double-stranded RNA production.

Silencing of a target locus by an unlinked silencing locus can result from transcription inhibition (transcriptional gene silencing; TGS) or mRNA degradation (post-transcriptional gene silencing; PTGS), owing to the production of double-stranded RNA (dsRNA) corresponding to promoter or transcribed sequences, respectively. The involvement of distinct cellular components in each process suggests that dsRNA-induced TGS and PTGS likely result from the diversification of an ancient common mechanism. However, a strict comparison of TGS and PTGS has been difficult to achieve because it generally relies on the analysis of distinct silencing loci. We describe a single transgene locus that triggers both TGS and PTGS, owing to the production of dsRNA corresponding to promoter and transcribed sequences of different target genes. We describe mutants and epigenetic variants derived from this locus and propose a model for the production of dsRNA. Also, we show that PTGS, but not TGS, is graft-transmissible, which together with the sensitivity of PTGS, but not TGS, to RNA viruses that replicate in the cytoplasm, suggest that the nuclear compartmentalization of TGS is responsible for cell-autonomy. In contrast, we contribute local and systemic trafficking of silencing signals and sensitivity to viruses to the cytoplasmic steps of PTGS and to amplification steps that require high levels of target mRNAs.

Epistasis, Genetic↗

PubMed1997

[DNA genotyposcoy in determining paternity: use of hybridized probes].

Analysis of hybridization probes for DNA genotypescopy (DNA genotyping and genome fingerprinting) was performed to detect 21 cases of paternity testing. A system with the highly informative multilocus DNA probe Red4, isolated by us earlier, and two single-locus probes (YNH24 and CMM101) detecting highly polymorphic (H > 96%) loci D2S44 and D14S13 was tested. In the cases analyzed, the Red probe was shown to detect, on average, 19.28 +/- 3.6 polymorphic BsuRI fragments in the DNA profile of presumable fathers and 19.67 +/- 5.84 BsuRI fragments in the DNA profile of mothers. The average number of DNA fragments inherited by a child from either parent was approximately equal (8.72 +/- 3.77 and 7.11 +/- 2.66, respectively). The low population frequency of DNA fragments detected by the Red4 probe allowed highly effective positive paternity identification to be performed. Paternity was established in 86% (with probability > 99.75 or > 99.99%) and excluded in 14% of expertises. Single-locus probes YNH24 and CMM101 were used as an additional criterion in cases when, in the DNA profile of a child, a single band (probable de novo mutation) or several bands (probable false paternity or maternity) were revealed but absent in both presumable parents. In once case, a de novo mutation for the YNH24 probe, not described earlier, was revealed. Therefore, a combination of multilocus and single-locus hybridization probes appeared to be the most promising method for significant paternity testing in forensic and medical genetic practice.

DNA Fingerprinting↗

PubMedDate not supplied

The contribution of epistatic pleiotropy to the genetic architecture of covariation among polygenic traits in mice.

The contribution that pleiotropic effects of individual loci make to covariation among traits is well understood theoretically and is becoming well documented empirically. However, little is known about the role of epistasis in determining patterns of covariation among traits. To address this problem we combine a quantitative trait locus (QTL) analysis with a two-locus model to assess the contribution of epistasis to the genetic architecture of variation and covariation of organ weights and limb bone lengths in a backcross population of mice created from the M16i and CAST/Ei strains. Significant epistasis was exhibited by 14 pairwise combinations of QTL for organ weights and 10 combinations of QTL for limb bone lengths, which contributed, on average, about 5% of the variation in organ weights and 8% in limb bone lengths beyond that of single-locus QTL effects. Epistatic pleiotropy was much more common in the limb bones (seven of 10 epistatic combinations affecting limb bone lengths were pleiotropic) than the organs (three of the 14 epistatic combinations affecting organ weights were pleiotropic). In both cases, epistatic pleiotropy was less common than single-locus pleiotropy. Epistatic pleiotropy accounted for an average of 6% of covariation among organ weights and 21% of covariation among limb bone lengths, which represented an average of one-fifth (for organ weights) and one-third (for limb bone lengths) of the total genetic covariance between traits. Thus, although epistatic pleiotropy made a smaller contribution than single-locus pleiotropy, it clearly made a significant contribution to the genetic architecture of variation/covariation.

Animals↗

PubMed1989

Mating system in rye: variability in relation to the population and plant density.

The amount of outcrossing was estimated using seven enzyme loci assayed in seven populations of rye (Secale cereale L.). Single-locus outcrossing values fluctuated widely from locus to locus in each population. The weighted mean single-locus estimates ranged from 0.716 to 0.946, and multilocus estimates ranged from 0.701 to 0.910. The analysis showed that self-pollination occurred in the rye populations, and, as a result of selfing, populations contained homozygotes in excess of random mating expectations at the seedling stage of development. Low plant density, which causes low pollen density during fertilization, seems to weaken the self-incompatibility system; at low plant density, the outcrossing estimate was significantly lower than was obtained at high plant density.

Breeding↗

PubMed2000

The relationship between the sibling recurrence-risk ratio and genotype relative risk.

The recurrence-risk ratio of disease in siblings, lambdaS, is a standard parameter used in genetic analysis to estimate the statistical power for detection of a disease locus. However, the relationship between the underlying risk conferred by a disease-susceptibility allele and lambdaS has not been well described. The former is generally quantified as a genotype relative risk, gamma, and measures the ratio of disease risks between those with and those without the susceptibility genotype(s). We demonstrate that lambdaS varies significantly more with respect to gamma and the disease-allele frequency for two-locus multiplicative models than for other two-locus and for single-locus models. For the single- and two-locus dominant-inheritance models that we studied, when a disease-susceptibility allele had a frequency >/=.2, lambdaS had an upper limit of <10. In general, lambdaS values >10 are possible only under recessive inheritance, dominant inheritance with relatively rare (<5%) disease-susceptibility alleles, or when two or more disease loci have alleles acting either epistatically or multiplicatively. We introduce the idea of a restricted sib recurrence-risk ratio (lambda*S) estimated by restriction of sibships to those ascertained through a proband who already has a putative high-risk allele. A lambda*S larger than the lambdaS value estimated from randomly selected probands can serve as an indirect way of testing whether the posited susceptibility allele increases disease risk. Our results demonstrate that a lambdaS of 2-3 may portend successful mapping for a variety of genetic models but that, for some two-locus models, a lambdaS as high as 10 does not guarantee underlying genes easily mapped by linkage.

Alleles↗

PubMed1995

[Analysis of sex chromosomal DNA markers by a molecular biological method and it's application to forensic medicine].

We attempted sex and individual identifications of several forensic specimens by detecting various sex chromosome-specific sequences by the polymerase chain reaction (PCR) method. The specimens were 30 blood stains that were attached to gauze and stored for 11 months -15 years (15 males, 14 females and 1 of unknown gender) and 10 bleached white bones (8- about 10000 years after death). Of the known 29 blood stains, the sex determination rate was the highest by DYZ-1 (amplified DNA fragment = 149bp, about 3000 copies on Y chromosome) recombinated with DXZ-1 (28 of the 29 samples) although 27 samples could be determined by DYZ-1 (amplified DNA fragment = 1000bp, about 3000 copies on Y chromosome) recombinated with DXZ-1. The sex determination rate was relatively low by DYZ-3 (amplified DNA fragment = 170bp, about 100 copies on Y chromosome) recombinated with DXZ-1 (23 of the 29 samples). The sex determination rate by two single locus markers, PAB or Amelogenin was markedly low (7 and 9 of 29 samples, respectively). The sex determination rate by the 27H39 locus was 27 of the 29 samples; 14 of the 15 male were determined (A = 186bp, 1; B = 190bp, 7; C = 194bp, 5; D = 198bp, 1; E = 202bp, 0). One unknown gender could be identified as male by multiple locus markers, but could not be identified by any single locus markers except for the 27H39 locus.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗

PubMed1996

[Personal identification using DNA polymorphism--the identification of forensic biological materials].

We performed personal identification by DNA polymorphism using forensic specimens. DNA was purified by the potassium iodine method instead of the phenol extraction method. When DNA is amplified by PCR, there are inhibitors of PCR such as melanin in hairs or blood and inorganic salts in bone. This problem was solved by the potassium iodine method. The genotype of the ABO blood groups could be determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in all 29 old blood-stain specimens (obtained 11 months-15 years before) and 14 fingerprint specimens on a glass plate. In sexual assaults against women, one key to identifying the suspect is ABO phenotyping or the typing of other polymorphic markers of the seminal fluid in the victim's vagina. However, ABO phenotyping is frequently unsuccessful, since mixtures of fluids cannot be separated to be subjected to conventional methods for the detection of antibody or antigen material. We therefore studied ABO blood group genotyping of sperm DNA isolated from contaminating vaginal fluid by the PCR-RFLP method. Seminal samples of genotypes OO, AO, BO and AB were experimentally mixed with vaginal fluid (OO, AO, BO and AB), and were successfully separated and genotyped by this method. In practice, we also separated and genotyped the seminal DNA of suspects from contaminated postcoital vaginal fluid obtained in 4 sexual assaults. These forensic samples were easily separated and completely genotyped. This reliable ABO genotyping method by PCR-RFLP, using separated sperm DNA, should be of value in forensic identification in sexual assaults. We attempted sex and individual identifications of several forensic specimens by detecting various sex chromosome-specific sequences by the polymerase chain reaction (PCR) method. The specimens were 30 blood stains that were attached to gauze and stored 11 months-15 years (15 males, 14 females and 1 of unknown gender) and 10 bleached white bones (8-about 10000 years after death). Of the known 29 blood stains, the sex determination rate was the highest by DYZ-1 (amplified DNA fragment = 149bp, about 3000 copies on Y chromosome) recombinated with DXZ-1 (28 of the 29 samples) although 27 samples could be determined by DYZ-1 (amplified DNA fragment = 1000bp, about 3000 copies on Y chromosome) recombinated with DXZ-1. The sex determination rate was relatively low by DYZ-3 (amplified DNA fragment = 170bp, about 100 copies on Y chromosome) recombinated with DXZ-1 (23 of the 29 samples). The sex determination rate by two single locus markers, PAB or Amelogenin was markedly low (7 and 9 of 29 samples, respectively). The sex determination rate by the 27H39 locus was 27 of the 29 samples; 14 of the 15 male were determined (A = 186bp, 1; B = 190bp, 7; C = 194bp, 5; D = 198bp, 1; E = 202bp, 0). One unknown gender could be identified as male by multiple locus markers, but could not be identified by any single locus markers except for the 27H39 locus. Of the 10 bleached white bone specimens, 9 could be determined by the combination of DYZ-1 and DXZ-1, but the results of determination were inconsistent with the anthropological characteristics in 3 cases. The 27H39 locus showed polymorphism in 4 of the 6 anthropologically male beached bones. Studies on a new microsatellite on the Y chromosome are needed for evaluation of polymorphism on the Y chromosome because it is not necessary to consider the alleles from the female in the paternity test in male children or female-derived elements in sexual delict, and there is a distance between the alleles using 27H39 alone. In this study, We evaluated the allele distribution of DYS384, DYS388, DYS389, DYS390, DYS391, DYS392, and DYS393, in Japanese subjects and found the usefulness of DYS384 and DYS390. Future studies on personal identification by DNA polymorephism will mainly evaluate short tandem repeat (STR).

ABO Blood-Group System↗

PubMed1967

Hu-1: Major histocompatibility locus in man.

A single locus with 15 or more alleles controls reactivity in mixed leukocyte culture tests. Genes at this locus also control most of the specificities measured by cytotoxic antiserums to leukocytes. Both of these tests can be used to predict survival of skin grafts. It is proposed that this is the major histocompatibility locus in man.

Antigens↗

PubMed1988

Segregation analysis of juvenile myoclonic epilepsy.

We examined the inheritance of juvenile myoclonic epilepsy (JME). We looked at both the trait of "epilepsy" and the trait of "epilepsy-plus-EEG abnormalities," since EEG abnormalities are frequently found in the clinically unaffected sibs of JME patients. We tested several modes of inheritance including the fully penetrant recessive and several two-locus models. We could reject all models tested (fully penetrant single-locus and two-locus models) when abnormal EEGs were classified as "unaffected." We could also reject the fully penetrant single locus models when family members with abnormal EEGs were considered "affected." We also rejected the two-locus model where the inheritance at both loci was dominant. The two-locus model where both loci showed recessive inheritance could not be rejected, nor could the model where one locus was dominant and the other recessive. Our results suggest that the underlying predisposition for JME is genetically determined and is partially reflected in the abnormal EEGs found in clinically unaffected family members.

Adult↗

PubMed1993

A note on the reduction of the dynamics of multilocus diploid genetic systems with multiplicative fitness.

The dynamics of any diploid multilocus genetic system with two alleles and uniform dynamics per locus can be deduced from that of the corresponding single-locus system by trinomial sampling to produce the frequencies of the different mutant classes, provided that fitness is multiplicative, and there is linkage equilibrium (allowing for physical linkage, however). The component processes that can be considered are mutation, gene conversion, gamete production (with recombination) and random mating, and selection. If mutations occur according to Bernoulli trials, outcrossing sexual systems have a genetic load exactly deducible from that of the single-locus system.

Animals↗

PubMed1995

Analysis of mutational changes at the HLA locus in single human sperm.

Using a simple and efficient single sperm PCR and direct sequencing method, we screened for HLA-DPB1 gene mutations that may give rise to new alleles at this highly polymorphic locus. More than 800 single sperm were studied from a heterozygous individual whose two alleles carried 16 nucleotide sequence differences clustered in six polymorphic regions. A potential microgene conversion event was detected. Unrepaired heteroduplex DNA similar to that which gives rise to postmeiotic segregation events in yeast was observed in three cases. Control experiments also revealed unusual sperm from DPB1 homozygous individuals. The data may help explain allelic diversity in the MHC and suggest that a possible source of human mosaicism may be incomplete DNA mismatch repair during gametogenesis.

Alleles↗

PubMed2003

Ancestral processes for non-neutral models of complex diseases.

We consider non-neutral models for unlinked loci, where the fitness of a chromosome or individual is not multiplicative across loci. Such models are suitable for many complex diseases, where there are gene-interactions. We derive a genealogical process for such models, called the complex selection graph (CSG). This coalescent-type process is related to the ancestral selection graph, and is derived from the ancestral influence graph by considering the limit as the recombination rate between loci gets large. We analyse the CSG both theoretically and via simulation. The main results are that the gene-interactions do not produce linkage disequilibrium, but do produce dependencies in allele frequencies between loci. For small selection rates, the distributions of the genealogy and the allele frequencies at a single locus are well-approximated by their distributions under a single locus model, where the fitness of each allele is the average of the true fitnesses of that allele with respect to the distribution of alleles at other loci.

Genetic Predisposition to Disease↗

PubMed1999

Virtual DNA analysis as a platform for interlaboratory data exchange of HLA DNA typing results.

In 1998, the German DNA Exchange offered the possibility to report typing data as virtual DNA. Participating labs have been equipped with software based on the principle of Virtual DNA Analysis (VDA). This approach allows the combination of sequence-specific oligonucleotide (SSO), sequence-specific primer (SSP) and sequence-based typing (SBT) results. The use of all types of test kits has been allowed without any limitations, as long as basic sequence information on SSOs or SSPs was available, at least the sequence and the position of the detected motif on the sample DNA. Typing raw data of the actual SSO-SSP and, if performed, SBT information was collected. Participating labs received 20 DNA samples to type. Fourteen labs returned data on 1,250 single-locus testings. Reported data consisted of 317 SBT data, 452 SSO kits and 1,795 SSP kits with 43,312 single SSO/ SSP reactivities. One hundred and twenty-six different typing kits (unique laboratory-specific kits, commercial kits from 7 companies) have been used. In 30 (2.4%) single-locus testings, at least one single SSO/SSP reactivity has been false-positive or -negative, thus not leading to a valid result on primary evaluation. Eight of these 30 cases were due to the presence of a new DRB1*14 allele in sample no. 2. Thirty-five tests (2.8%) showed wrong allele assignments. This first attempt to collect raw typing data instead of typing interpretation on a larger scale shows the advantages of Virtual DNA Analysis like interlaboratory data exchange without loss of information, transparency of typing interpretation and reinterpretation of typing data with an updated allele database. The VDA format is a useful tool for workshops and bone marrow donor registries.

Alleles↗

PubMed2001

Molecular characterisation of camptothecin-induced mutations at the hprt locus in Chinese hamster cells.

The capacity of the topoisomerase I inhibitor camptothecin (CPT) to induce single locus mutations at the hypoxanthine-guanine phosphoribosyltransferase (hprt) gene and the DNA changes underlying induced mutations were analysed in Chinese hamster ovary cells. Camptothecin treatments increased hprt mutations up to 50-fold over the spontaneous levels at highly cytotoxic doses. Genomic DNA was isolated from 6-thioguanine resistant clones and subjected to multiplex PCR to screen for gross alterations in the gene structure. The molecular analysis revealed that deletion mutants represented 80% of the analysed clones, including total hprt deletion, multiple and single exon deletions. Furthermore, a fraction of the analysed clones showed deletions of more than one exon that were characterised by the absence of non-contiguous exons. These data show that single locus mutations induced by camptothecin are characterised by large deletions or complex rearrangements rather than single base substitutions and suggest that the recombinational repair of camptothecin-induced strand breaks at replication fork may be involved in the generations of these alterations at the chromatin structure level.

Animals↗

PubMed1987

Determination of DR beta 1 alleles of DR4/Dw subtypes by oligonucleotide probing.

The extensive Dw polymorphism of HLA-D has, to date, been defined using cumbersome and lengthy techniques involving T-cell proliferative reactions. These techniques have not necessarily provided information about the genotype at any single locus of HLA-D because the products of more than a single locus of HLA-D (e.g., DR beta 1 and DR beta 2 of the DR2 haplotypes and in some cases DQ) can contribute to T-cell proliferation and thus to assignment of Dw phenotype. We have recently reported that DR beta 1 alleles relating to the Dw polymorphism can vary by only a single, or a very few, nucleotide differences; the products of this locus are recognized in allo- and restricted responses. Given the importance of defining this polymorphism, we have used specific oligonucleotides as hybridization probes to differentiate between these very closely related alleles. This approach provides the basis for a rapid method for HLA-D typing which, as additional sequence information becomes available, will likely be generally applicable. In addition, oligonucleotide probing allows definition of a gene transcript from an individual locus of HLA-D rather than the phenotype results provided by Dw typing.

Alleles↗

PubMed1992

Human gastric cathepsin E gene. Multiple transcripts result from alternative polyadenylation of the primary transcripts of a single gene locus at 1q31-q32.

Genomic clones containing portions of the human cathepsin E (CTSE) gene were isolated from cosmid and lambda recombinant libraries. The regions corresponding to coding, the 5'- and 3'-untranslated, and the exon-intron boundaries of the CTSE gene were identified by sequence and hybridization analysis. The size and placement of the nine exons found in the 17.5-kilobase CTSE gene was highly conserved relative to other aspartic proteinases and provided additional evidence that these proteinases are derived from a common ancestral gene. Segregation and linkage analysis of two informative restriction fragment length polymorphisms (MspI and DraI) indicated that there is a single human CTSE locus located at chromosome 1q31-q32 which is closely linked to the renin gene. Three CTSE transcripts (3.6, 2.6, and 2.1 kilobases) were identified in gastric fundic and antral mucosa poly (A+) RNA, and these appeared identical in size and relative abundance to those contained in poly(A+) RNA from cultured gastric adenocarcinoma cell lines containing CTSE. Sequence analysis of cDNA clones and comparison with the 3'-flanking untranslated region in genomic clones provided evidence that alternative polyadenylation of the primary transcript resulted in the 2.6- and 2.1-kilobase transcripts which constituted greater than 95% of CTSE transcripts found in the stomach.

Amino Acid Sequence↗

PubMed1989

Linkage data on affective disorders in an epidemiologic context.

Recent data on chromosomal linkage markers in affective disorders indicate that single locus inheritance is involved in these disorders. The presence of a single locus has not been detectable using segregation analysis on family study data from large populations, possibly because of both heterogeneity and birth cohort and sex differences in diagnostic frequencies.

Affective Disorders, Psychotic↗

PubMed2003

Development, characterization and variability analysis of microsatellites in lychee (Litchi chinensis Sonn., Sapindaceae).

We report 12 microsatellites enriched in CT repeats obtained from a genomic library of the lychee ( Litchi chinensis Sonn.) cultivar Mauritius. The polymorphisms revealed by these microsatellites were evaluated in a collection of 21 lychee cultivars. A total of 59 fragments were detected with these 12 SSRs, with an average of 4.9 bands/SSR. Three primer pairs seem to amplify more than a single locus. The mean expected and observed heterozygosities over the 9 single-locus SSRs averaged 0.571 (range: 0.137-0.864) and 0.558 (range: 0.169-0.779) respectively. The total value for the probability of identity was 7.53 x 10(-5). In addition, the selected SSRs were used to amplify DNA from four longan cultivars. Eleven of the 12 SSRs produced amplification fragments in longan, and eight of these fragments were polymorphic. All except two of the products amplified from longan were the same size as those amplified from lychee, suggesting a close genetic proximity between the two species. The SSRs studied produced 22 different patterns, allowing the unambiguous identification of 16 lychee and the 4 longan cultivars studied. Discrimination was possible with just four selected microsatellites. Two groups with two and three undistinguishable cultivars were obtained, reflecting probable synonymies. Unweighted pair-group method of artimetic averages (UPGMA) cluster analysis divided the lychee cultivars studied into two main groups, one consisting of ancient cultivars and the other with more diverse recent cultivars. This is the first report of microsatellite development in the Sapindaceae, and the results demonstrate the usefulness of microsatellites for identification, similarity studies and germplasm conservation in lychee and related species.

Litchi↗