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PubMed1975

A continuous selective model for an X-linked locus.

Neglecting age-structure, but taking into account matings with differential fertility in Mendelian reproduction, a continuous selective model is formulated for a single X-linked locus with an arbitrary number of alleles. Without restricting the mating system, differential equations are derived for the genotypic and allelic frequencies. Assuming random mating, no selection, and constant fertilities and mortalities, these differential equations are solved explicitly. For this case, in contrast to the corresponding phenomenon in the usual model with discrete, non-overlapping generation, the difference between the frequencies of any allele in males and females approaches zero without oscillation.

Age Factors↗
PubMed2000

The probability distribution of the number of loci indicating exclusion in a core set of STR markers.

The distribution of the number of loci out of the 13 in the CODIS STR set that would show an exclusion (i.e., a genotype set incompatible either with the prosecution hypothesis or with Mendelian transmission) was estimated in different scenarios. The knowledge of this distribution would provide a framework against which casework evidence can be compared. I used allele frequencies in Iberian and in Italian populations to generate individual genotypes at random and to test in 1 million simulation replicates, how many of the 13 loci would give an exclusion in an individual identification case, a paternity case, and a double parenthood case. All three scenarios were tested under an expected overall exclusion, both for unrelated individuals and for cases in which the suspect or the alleged father was the brother of the real culprit or real father. Paternity and double parenthood cases were also tested in the true scenario, with exclusionary loci due to mutation. In individual identification cases, the average number of exclusionary loci was 11.95 with a minimum of 7. This STR set also showed sufficient power to resolve identification cases in which the evidence sample came from a suspect's sib. False paternity cases yielded an average of 7.65 exclusionary loci and exclusions with only one (0.0108%) or two (0.14%) exclusionary loci were obtained only rarely. The cases of exclusion with one locus could lead to likelihood ratios in favour of paternity, while both true and false paternity cases with two exclusionary loci would often lead to non-conclusive likelihood ratios. The average number of exclusionary loci in a paternity case where the alleged father was the real father's brother was 3.82, with a significant number of cases where no exclusions were obtained.

Child↗
PubMedDate not supplied

Evidence for hybridization by multilocus enzyme electrophoresis and random amplified polymorphic DNA between Leishmania braziliensis and Leishmania panamensis/guyanensis in Ecuador.

The taxonomic attribution of four Leishmania stocks isolated from humans in Ecuador has been explored by both multilocus enzyme electrophoresis and random amplified polymorphic DNA. For three loci, MLEE results showed patterns suggesting a heterozygous state for a diploid organism, while the corresponding homozygous states are characteristic of the Leishmania panamensis/guyanensis complex and Leishmania braziliensis, respectively. Other enzyme loci showed characters attributable to either the L. panamensis/ guyanensis complex or L. braziliensis. RAPD profiles exhibited for several primers a combination of the Leishmania panamensis/ guyanensis complex and L. braziliensis characters. These data hence suggest that the four stocks are the result of hybridization between L. panamensis/guyanensis and L. braziliensis. MLEE data show that the results cannot be attributed to either mixture of stocks, or an F1 in the framework of a simple Mendelian inheritance.

Animals↗
PubMed2006

Estimation of bias in nongenetic observational studies using "mendelian triangulation".

PURPOSE: Phenotype-disease odds ratios calculated from the effect of a genotype on its phenotype and on disease risk ("Mendelian triangulation") can be used as a standard to assess bias on the corresponding odds ratio from nongenetic studies. Statistical tests are commonly used to compare these odds ratios. We propose a method to estimate the magnitude of the bias and judge the validity of the phenotype-disease association. METHODS: For four published examples, we obtained 10,000 random values from distributions of the odds ratios from both genetic and nongenetic studies. A range of values compatible with an unbiased odds ratio was then calculated from the empirical distribution of the differences between both odds ratios. RESULTS: We show that estimating a range of likely values for an unbiased odds ratio is useful to judge the effect of the phenotype and identify cases for which information from genetic studies adds little to the evaluation of the phenotype-disease association. Conversely, statistical tests could be misleading. CONCLUSIONS: Estimating a range of values for an unbiased odds ratio is more informative and appropriate than statistical tests when using the Mendelian triangulation approach for assessment of bias in phenotype-disease association studies.

Bias↗
PubMed1984

Distorted segregation and linkage of alcohol dehydrogenase genes in Camellia japonica L. (Theaceae).

Alcohol dehydrogenase isozymes in Camellia japonica are encoded by two genes, Adh-1 and Adh-2. Both loci are expressed in seeds, and their products randomly associate into intragenic and intergenic dimers. Electrophoresis of leaf extracts reveals only the products of Adh-2. Formal genetic analysis indicated that the two Adh loci are tightly linked (combined estimate of r = 0.004). Most segregations fit expected Mendelian ratios, but in some families distorted segregation was observed at Adh-1, Adh-2, or both loci. The deficient progeny class varied across families, and in two apparent back-crosses three rather than two phenotypic classes were recovered. The mechanism underlying these distortions is not known, but evidence is presented that suggests that the phenomenon is genic or segmental in nature. Plausible hypotheses include linkage of the Adh structural genes with a gametophytic self-incompatibility locus, translocation heterozygosity involving the segment bearing Adh-1 and Adh-2, or a combination of these two mechanisms.

Alcohol Dehydrogenase↗
PubMed2000

Utility of three restriction fragment length polymorphism probes for genotyping of the chicken major histocompatibility complex class IV region.

Three chicken B-G cDNA probes (gene 8.5, bg28, and bg32.1) were used to detect restriction fragment length polymorphisms (RFLP) in the chicken MHC class IV (B-G). By using inbred and selected chicken lines with different B haplotypes identified by hemagglutination, we identified B haplotypes (B2, B9, B11, B12, B15, B19, B21, B31, and B32) by RFLP using the three probes following digestion of genomic DNA with four restriction endonucleases (BglII, EcoRI, HaeIII, and PvuII). The GSP inbred line, previously shown to contain B-F21 by the use of a monoclonal antibody, did not contain B-G21, based on RFLP tests, whereas line N had B-F21 and B-G21. Consequently, the RFLP typing with the clone of B-G cDNA was able to determine the B haplotype in more detail than typing by hemagglutination. In inbred and selected lines, three B-G cDNA are useful DNA probes for RFLP to identify B genotypes. Two families of chickens with segregating B haplotypes were analyzed by RFLP using these probes; however, identification of the B genotype by this method was difficult in the randomly bred population. Genotypic comparisons of RFLP with gene 8.5 and BglII and bg 28 as probes and digestion by the endonucleases EcoRI, HaeIII, and PvuII between the parents and their offspring were generally compatible within the expectations of Mendelian inheritance.

Animal Husbandry↗
PubMed1985

The genetic control of phenformin 4-hydroxylation.

Previously published results of phenformin 4-hydroxylation in 195 unrelated white British volunteers and 87 family members of 27 randomly selected probands have been subjected to genetic analysis. The results clearly show that about 9% of this population has a genetically determined defect in carrying out this oxidation reaction. The character for the defect is inherited in a Mendelian autosomal recessive fashion. The polymorphism shows a substantial degree of dominance.

Age Factors↗
PubMed1992

Genetic segregation of random amplified polymorphic DNA in diploid cultivated alfalfa.

Polymerase chain reaction was used, with single 10-mer primers of arbitrary sequence, to amplify random regions of genomic DNA from a diploid cultivated alfalfa backcross population. Segregation of the random amplified polymorphic DNA (RAPD) fragments was analysed to determine if RAPD markers are suitable for use as genetic markers. Of the 19 primers tested, 13 amplified a total of 37 polymorphic fragments, of which 28 (76%) segregated as dominant Mendelian traits. RAPD markers appear useful for the rapid development of genetic information in species like alfalfa where little information currently exists or is difficult to obtain.

Base Sequence↗
PubMed2002

Detection rates for genotyping errors in SNPs using the trio design.

One well-known approach for the analysis of transmission-disequilibrium is the investigation of single nucleotide polymorphisms (SNPs) in trios consisting of an affected child and its parents. Results may be biased by erroneously given genotypes. Various reasons, among them sample swap or wrong pedigree structure, represent a possible source for biased results. As these can be partly ruled out by good study conditions together with checks for correct pedigree structure by a series of independent markers, the remaining main cause for errors is genotyping errors. Some of the errors can be detected by Mendelian checks whilst others are compatible with the pedigree structure. The extent of genotyping errors can be estimated by investigating the rate of detected genotyping errors by Mendelian checks. In many studies only one SNP of a specific genomic region is investigated by TDT which leaves Mendelian checks as the only tool to control genotyping errors. From the rate of detected errors the true error rate can be estimated. Gordon et al. [Hum Hered 1999;49:65-70] considered the case of genotyping errors that occur randomly and independently with some fixed probability for the wrong ascertainment of an allele. In practice, instead of single alleles, SNP genotypes are determined. Therefore, we study the proportion of detected errors (detection rate) based on genotypes. In contrast to Gordon et al., who reported detection rates between 25 and 30%, we obtain higher detection rates ranging from 39 up to 61% considering likely error structures in the data. We conclude that detection rates are probably substantially higher than those reported by Gordon et al.

Genotype↗
PubMed1975

Non-mendelian segregation in hybrids between chinese hamster cells.

Mechanisms of segregation have been examined in hybrids between Chinese hamster cells, where chromosome loss in comparison to other systems is minimal. Hybrid cells were grown in HAT medium and subjected to back selection with bromodeoxyuridine (BUDR) or azaguanine (AZG). In AZG or BUDR at 30 mug/ml, segregation began with a random high frequency event that gave rise to cells capable of growth in both HAT and back selection medium, unlike the precursor hybrid or original parental cell types. BUDR-resistant segregants were propagated serially in the presence of BUDR, and were examined by clonal analysis for changes in plating properties during long term culture. Over a period of 300 days the HAT/BUDR plating ratio for sergregant cells declined continuously. A parallel decrease was observed in the rate of H3-thymidine incorporation, along with a drop in thymidine kinase activity. These shifts took place only in the presence of BUDR, and could be reversed by altered selection in HAT medium. Clonal studies showed that the evolution of segregant properties occurred in most if not all cells of the population, and did not arise from variation and selection of minority cell types. These properties of the segregating system are not consistent with models based on gene mutation, chromosome rearrangements, or chromosome loss. The evolution of segregants resembles more closely a sorting-out progress, taking place by intracellular selection over many generations. The segregating units may conceivably be cytoplasmic determinants linked functionally to nuclear genes, and which serve to modulate the events of phenotypic expression. Several lines of evidence which bear on this concept are discussed.

Azaguanine↗
PubMed1997

Efficient detection of DNA polymorphisms by fluorescent RAPD analysis.

A method is presented for the analysis of fluorescently labeled random amplified polymorphic DNA (FRAPD) fragments. A DNA sequencer and collection and analysis software were used to estimate the sizes of DNA fragments based on their mobilities relative to in-lane size markers. This allowed confident identification and comparison of FRAPD markers both within and between polyacrylamide gels. In comparison with analysis of RAPD products using ethidium bromide-stained agarose gels, fluorescent analysis improved the sensitivity, resolution and precision of sizing of RAPD products of about 50-2100 bp. FRAPD fragments produced from amplification of zebrafish DNA are informative as genetic markers that segregate with Mendelian inheritance. FRAPD analysis was found to be very efficient for identifying new DNA polymorphisms.

Animals↗
PubMed1993

Variance components for statistical genetics: applications in medical research to characteristics related to human diseases and health.

RA Fisher introduced variance components in 1918. He synthesized Mendelian inheritance with Darwin's theory of evolution by showing that the genetic variance of a continuous trait could be decomposed into additive and non-additive components. The model can be extended to include environmental factors, interactions, covariation, and non-random mating. Identifiability depends critically on design. Methods of analysis include modelling the mean squares from a fixed effects analysis of variance, and covariance structure modelling, which can be extended to multivariate traits and has been used to study ordinal traits by reference to postulated, unmeasured, latent 'liabilities'. These methods operate on dependent observations within independent groups of the same size and structure, and therefore require balanced designs ('regular' pedigrees). A multivariate normal model handles data in its generic form, utilizes data efficiently from all members of pedigrees of unequal size or varying structure, accommodates individuals missing at random, and allows flexible modelling with tests of distributional assumptions and fit. Most analytical methods use least squares or maximum likelihood under normal theory. Robust methods, scale transformation, ascertainment, path diagrams and correlational path models (popular in behavioural genetics through addressing nonrandom mating and social interactions), 'heritability', and the contribution and limitations of statistical modelling to the 'nature-nurture' debate, are discussed.

Genetic Diseases, Inborn↗
PubMed1993

[The analysis of human DNA fingerprints by the synthetic oligonucleotide probe].

In order to test the practical applicability of oligonucleotide fingerprinting we have investigated 50 unrelated individuals, 11 members in two families and one pair of twin using the probe (CAC)5/(GTG)5. Except the monozygotic twins highly variable patterns were demonstrated, even in a family. The probability of chance association between random individuals was calculated as 3.8 x 10(-10). It seems reasonable to conclude that (CAC)5/(GTG)5 fingerprints are completely individual-specific. The results of the pedigree study showed that the inheritance of alleles was in keeping with the Mendelian Law. This method is not so costly and labor-intensive as the conventional Southern blotting. It increases the speed and lessen the complexity of RFLPs study.

DNA Fingerprinting↗
PubMed1993

Segregation analysis of random amplified polymorphic DNA (RAPD) markers in Picea abies Karst.

The reliability of arbitrarily primed amplification products was tested. The segregation analysis of 266 amplification products obtained using 17 different 10-mer oligonucleotides in 34 megagametophytes from a single tree of Picea abies was carried out. Fifty-four out of the 165 variable bands fit the 1:1 segregation ratio expected for Mendelian traits. The segregation ratio of a subset of six RAPD markers in five other individuals from the same population confirmed their genetic nature. Our results strengthen the evidence previously reported that RAPDs markers can be considered Mendelian traits useful in the detection of genetic variability among both different individuals and populations.

Base Sequence↗
PubMed1999

Segregation analysis of the specific response to allergens: a recessive major gene controls the specific IgE response to Timothy grass pollen.

Segregation analysis of the specific response to allergens (SRA) was performed in a sample of 234 randomly selected Australian families using the regressive models. Various SRA phenotypes were considered using broad and narrow definitions of these phenotypes, according to the type of test used, skin test or RAST test, and the specificity of the response to allergen. Strong evidence for familial dependencies among blood relatives was shown for most SRA phenotypes, especially when using a broad definition. There was no evidence for a Mendelian factor accounting for the familial transmission of these broadest phenotypes, which may involve multiple factors preventing the clear detection of a major effect with Mendelian transmission. However, segregation of a Mendelian recessive major gene was detected for one SRA sub-phenotype, the IgE response to a single allergen, Timothy grass pollen, measured by the RAST test. Identification of a specific SRA phenotype controlled by a major gene may have important implications for further linkage studies.

Adolescent↗
PubMed2001

Enhanced expression and stable transmission of transgenes flanked by inverted terminal repeats from adeno-associated virus in zebrafish.

Mosaic expression of transgenes in the F0 generation severely hinders the study of transient expression in transgenic fish. To avoid mosaicism, enhanced green fluorescent protein (EGFP) gene cassettes were constructed and introduced into one-celled zebrafish embryos. These EGFP gene cassettes were flanked by inverted terminal repeats (ITRs) from adeno-associated virus (AAV) and driven by zebrafish alpha-actin (palpha-actin-EGFP-ITR) or medaka beta-actin promoters (pbeta-actin-EGFP-ITR). EGFP was expressed specifically and uniformly in the skeletal muscle of 56% +/- 8% of the palpha-actin-EGFP-ITR-injected survivors and in the entire body of 1.3% +/- 0.8% of the pbeta-actin-EGFP-ITR-injected survivors. Uniform transient expression never occurred in zebrafish embryos injected with EGFP genes that were not flanked by AAV-ITRs. In the F0 generation, uniformly distributed EGFP could mimic the stable expression in transgenic lines early in development. We established five transgenic lines derived from palpha-actin-EGFP-ITR-injected embryos crossed with wild-type fish and 11 transgenic lines derived from pbeta-actin-EGFP-ITR-injected embryos crossed with wild-type fish. None of these transgenic lines failed to express the transgene, a result confirmed by polymerase chain reaction analysis. Stable mendelian transmission of the transgenes was achieved in both alpha-actin and beta-actin transgenic lines without changing the patterns of expression and integration. Progeny inheritance test and Southern blot analysis results strongly suggest that transgenes flanked by AAV-ITRs were integrated randomly into the genome at a single locus with a concatamerized multiplier. Thus, incorporating AAV-ITRs into transgenes results in uniform gene expression in the F0 generation and stable transmission of transgenes in zebrafish.

Actins↗
PubMed1983

Family studies of the HLA system in acute post-streptococcal glomerulonephritis.

Eighteen families (67 siblings) of index cases with acute post-streptococcal glomerulonephritis (APSGN) were typed for HLA-A,B,C,DR antigens. Twenty cases of clinical nephritis and 10 cases of asymptomatic disease with detected among the sibships. In eight families with more than one affected individual comprising 18 sib pairs random segregation of paternal and maternal HLA haplotypes was found (0.5 less than p less than 0.06), but some antigens (CW1, DR3) showed deviation from the expected 1:1 ratio in affected and nonaffected siblings in backcross families. We had previously noticed the existence of Mendelian recessive ratios in APSGN but in the absence of clear evidence for a dominant or recessive mode of inheritance for a putative APSGN susceptibility gene(s), pedigree data were analyzed twice for linkage with HLA using the two genetic models. The data obtained, although not sufficient to reject the hypothesis of linkage, provide no support for it. Comparison of the frequency of 61 HLA antigens among 42 unrelated APSGN patients and 109 controls, showed that HLA-DRW4 is more frequent among the former (pc = 0.0500).

Acute Disease↗
PubMed2001

Genetic studies of the Roma (Gypsies): a review.

BACKGROUND: Data provided by the social sciences as well as genetic research suggest that the 8-10 million Roma (Gypsies) who live in Europe today are best described as a conglomerate of genetically isolated founder populations. The relationship between the traditional social structure observed by the Roma, where the Group is the primary unit, and the boundaries, demographic history and biological relatedness of the diverse founder populations appears complex and has not been addressed by population genetic studies. RESULTS: Recent medical genetic research has identified a number of novel, or previously known but rare conditions, caused by private founder mutations. A summary of the findings, provided in this review, should assist diagnosis and counselling in affected families, and promote future collaborative research. The available incomplete epidemiological data suggest a non-random distribution of disease-causing mutations among Romani groups. CONCLUSION: Although far from systematic, the published information indicates that medical genetics has an important role to play in improving the health of this underprivileged and forgotten people of Europe. Reported carrier rates for some Mendelian disorders are in the range of 5-15%, sufficient to justify newborn screening and early treatment, or community-based education and carrier testing programs for disorders where no therapy is currently available. To be most productive, future studies of the epidemiology of single gene disorders should take social organisation and cultural anthropology into consideration, thus allowing the targeting of public health programs and contributing to the understanding of population structure and demographic history of the Roma.

Journal Article↗