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PubMed2002

Twin registers across the globe: what's out there in 2002?

Twin research offers the greatest power for the genetic analysis of complex multifactorial traits and diseases in humans. Modern twin analyses extend beyond the classical twin study for estimating the heritability of a trait. The human genome project can fulfil its promises only after functional characterisation of single genes in the context of genetic background and environment. Twin research can make a major contribution in that regard. Twin research is greatly facilitated by the willingness, motivation, cooperation, and generosity of the participants and their families. A second important aspect is the availability of twin registries that serve as a resource for genetic epidemiology. Currently, there is no systematic overview of the twin collections worldwide. This special issue will help to overcome the limited accessibility of this resource by providing basic information on most of the existing twin registers. Furthermore, an additional goal is to facilitate collaboration between registers. Some basic principles, potentials, and problems will be exemplified by my personal experience in the Berlin Twin Study.

Attitude to Health↗
PubMed2005

Identification and validation of Loci and candidate genes linked to cardiac hypertrophy.

Left ventricular hypertrophy (LVH) is a complex quantitative trait that has a strong prognostic value for cardiovascular mortality and morbidity. Cardiac mass is determined in part by the influence of genetic loci that are known as quantitative trait loci (QTLs), the localization of which can be performed experimentally in genetic animal crosses. The present chapter outlines standard procedures for the selection of appropriate animal strains, for assessment of mode of inheritance, for characterizing the cardiac phenotype, for performing whole-genome scans, and for conducting linkage analyses. Identification of QTLs may lead to the identification of candidate genes whose roles can be further investigated in either transgenic, knockout, or pharmacologically manipulated animal models.

Animals↗
PubMed2005

Kinetic fluorescence-quenching detection assay for allele frequency estimation.

The analysis of human genetic variations, such as single-nucleotide polymorphisms (SNPs), has great applications in genome-wide association studies of complex genetic traits. We have developed an SNP genotyping method based on the primer extension assay with fluorescence quenching detection. The template-directed dye-terminator incorporation with fluorescence quenching detection (FQ-TDI) assay is based on the observation that the intensity of fluorescent dye R110- and R6G-labeled acycloterminators is universally quenched once they are incorporated onto a deoxyribonucleic acid (DNA) oligonucleotide primer. By comparing the rate of fluorescence quenching of the two allelic dyes in real time, we have extended this method for allele frequency estimation of SNPs in pooled DNA samples. The kinetic FQ-TDI assay is highly accurate and reproducible both in genotyping and in allele frequency estimation. Allele frequencies estimated by the kinetic FQ-TDI assay correlated well with known allele frequencies, with an r2 value of 0.993. Applying this strategy to large-scale studies will greatly reduce the time and cost for genotyping hundreds and thousands of SNP markers between affected and control populations.

Alleles↗
PubMedDate not supplied

Post-genomic era and gene discovery for psychiatric diseases: there is a new art of the trade? The example of the HUMTH01 microsatellite in the Tyrosine Hydroxylase gene.

The microsatellite HUMTH01, located in the first intron of the Tyrosine Hydroxylase (TH) gene (encoding the rate-limiting enzyme in the synthesis of catecholamines), is characterized by a TCAT repeated motif and has been used in genetic studies of neuropsychiatric and other complex diseases, in which catecholaminergic neurotransmission is implicated. After reporting a positive association between HUMTH01 and bipolar disorder as well as schizophrenia, the authors established that HUMTH01 alleles display the features of regulatory elements. Thereafter, they cloned two proteins (ZNF191 and HBP1), specifically binding to HUMTH01, and demonstrated that allelic variations of HUMTH01 have a quantitative silencing effect on TH gene expression in vitro, and correlate with quantitative and qualitative changes in the binding by ZNF191. The authors aim to characterize the transduction pathway impinging on the HUMTH01 microsatellite and establish its relevance for TH gene regulation in vivo. Since the TCAT repeated sequence is widespread throughout the genome, their approach may lead to the dissection of the mechanisms underlying the quantitative expression of several genes implicated in complex genetic traits, both normal and pathological. Thus, these investigations on the possible contribution and potential role of the HUMTH01 microsatellite in neuro-pathological conditions may represent an example of the different approaches needed to validate genetic targets in the "post-genomic era."

Animals↗
PubMed2000

PWD/Ph and PWK/Ph inbred mouse strains of Mus m. musculus subspecies--a valuable resource of phenotypic variations and genomic polymorphisms.

PWD/Ph and PWK/Ph (abbreviated PW*) are highly inbred mouse strains (F66 and F70) derived from wild mice of Mus musculus musculus subspecies. When compared with laboratory inbred strains, they display a plethora of differences in many complex phenotypes such as body weight, fat distribution pattern, blood levels of intermediary metabolites, sensitivity to type-1 diabetes or behaviour patterns. The PWD/Ph genes can rescue the lethal effect of lack of the Igf2 receptor. The male-limited hybrid sterility of (PWD/Ph x laboratory strain)F1 hybrids is a specific phenotype controlled by three or four unlinked loci. These complex phenotypic traits can be genetically dissected by QTL analysis using microsatellite markers of known genetic location. The PW strains are particularly useful for such genome-wide scans since 70-80% of randomly chosen microsatellite markers are polymorphic in (PW x laboratory strain) crosses compared to 35-45% in crosses between two laboratory strains. The list of polymorphic microsatellite loci is included in this report. The high degree of sequence polymorphism allows easier distinction between paternal and maternal mRNA transcripts in PW hybrids, which makes the PW* strains a useful tool also in molecular studies of genomic imprinting. The high frequency of phenotypic differences together with the high degree of sequence polymorphism and the relatively easy breeding of PW strains make them a valuable mammalian model organism for the functional genomics of the traits of biomedical importance.

Alleles↗
PubMed2003

Haplotype analysis in population genetics and association studies.

Several studies of haplotype structures in the human genome in various populations have been published recently. Such knowledge may provide valuable information on human evolutionary history and lead to the development of more efficient strategies to identify genetic variants that increase susceptibility to human diseases. In this review, we summarize the current understanding of haplotype structure, diversity, and distribution in the human genome, with a focus on statistical issues in using haplotypes for studies of population genetics and evolutionary history, as well as to identify genetic variants underlying complex human traits.

Evolution, Molecular↗
PubMed2004

The genetic architecture of the behavioral ontogeny of foraging in honeybee workers.

The initiation of foraging during the life course of honeybee workers is of central interest to understanding the division of labor in social insects, a central theme in sociobiology and behavioral research. It also provides one of the most complex phenotypic traits in biological systems because of the interaction of various external, social, and individual factors. This study reports on a comprehensive investigation of the genetic architecture of the age of foraging initiation in honeybees. It comprises an estimation of genetic variation, the study of candidate loci, and two complementary quantitative trait loci (QTL) maps using two selected, continually bred lines of honeybees. We conclude that considerable genetic variation exists between the selected lines for this central life history component. The study reveals direct pleiotropic and epistatic effects of candidate loci (including previously identified QTL for foraging behavior). Furthermore, two maps of the honeybee genome were constructed from over 400 AFLP markers. Both maps confirm the extraordinary recombinational size of the honeybee genome. On the basis of these maps, we report four new significant QTL and two more suggestive QTL that influence the initiation of foraging.

Aging↗
PubMed2005

No evidence for linkage and association between 4q microsatellite markers and nonsyndromic cleft lip and palate in chilean case-parents trios.

OBJECTIVE: Nonsyndromic cleft lip/palate (NSCLP) has the characteristics of a complex genetic trait. Linkage and association studies have suggested that one or more clefting loci may be located on chromosome 4q. The goal of this study was to evaluate the possible linkage and association due to linkage disequilibrium between five microsatellite markers located on 4q28 to 4q33 and NSCLP, using the case-parent trio design. SUBJECTS AND METHODS: A total of 56 Chilean families (32 simplex and 24 multiplex) were recruited. Microsatellite markers were analyzed using polymerase chain reaction with fluorescent-labeled forward primers, followed by electrophoresis on a laser-fluorescent sequencer. Case-parents trios were ascertained to assess linkage and linkage disequilibrium through a multistage procedure. Transmission disequilibrium tests for multiple alleles were carried out to assess the statistical significance of 4q28 to 4q33 microsatellite markers. RESULTS: Only weak evidence for linkage was obtained for the FGA marker (asymptotic uncorrected p value = .08 and empirical p value = .05). Only the FGA and UCP1 markers were selected for association analysis in trios, with unrelated cases achieving a nearly significant result for the UCP1 marker (asymptotic uncorrected p value = .07 and empirical p value = .19). CONCLUSION: Though the FGA and UCP1 markers showed nearly significant p values for linkage and association, respectively, the results of the present study provided insufficient evidence of the existence of a major susceptibility locus in the 4q region that was analyzed in the present study.

Carrier Proteins↗
PubMed1997

Alexithymic characteristics in responses to the Synthetic House-Tree-Person (HTP) Drawing Test.

This study examined the association of certain complex personality traits assessed by the Synthetic House-Tree-Person Drawing Test and alexithymic characteristics assessed by the 20-item Toronto Alexithymia Scale for a sample of 589 Japanese college students. Alexithymic students who scored over 61 points on the Toronto Alexithymia Scale-20 exhibited two characteristics relative to the test: poor relationships between figures and additional written explanations. These two characteristics projected on the Synthetic House-Tree-Person Drawing Test may be related to alexithymic characteristics and related factors.

Adult↗
PubMed2025

Efficient CRISPR/Cas9-mediated genome editing of phytoene desaturase in Musa-AAA: a critical step for genetic improvement of east African highland bananas.

East African highland bananas (EAHBs), locally referred to as "matooke", are an important staple crop in Uganda. The EAHBs have a triploid genome (AAA) with a large phenotypic diversity in the Great Lakes region of Africa and are challenged by both abiotic and biotic factors. The EAHBs have been improved through conventional breeding and genetic engineering though facing challenges such as genetic drag of unfavorable traits and complex regulatory processes, respectively. Therefore, a more precise approach for crop improvement such as genome editing is highly recommended. In the current study, we assessed the feasibility and applicability of the CRISPR/Cas9 mediated-genome editing in EAHBs. Two sgRNAs were designed from the Nakitembe phytoene desaturase (PDS) gene and used to edit the PDS gene in Nakitembe (NKT) and NAROBan5 (M30) cultivars. A total of 47 NKT and 130 M30 events were regenerated via agrobacterium-mediated transformation of banana embryogenic cell suspensions. Up to 100% and 94.6% albinism rates were observed in Nakitembe and M30 cultivars respectively with additional albino-variegated and variegated phenotypes observed in M30 only. Carotenoid analysis revealed a significant reduction of total carotenoid content in edited events with all complete albinos showing no detectable carotenoids implying that the carotenoid biosynthetic pathway was effectively disrupted. Sequence analysis revealed that all of the edited events had frameshift mutations leading to PDS disruption. Overall, this study presents the first report of CRISPR/Cas9 genome editing in EAHBs and more interestingly on a hybrid, M30 showing high precision and efficiency. This validated genome editing system provides a robust platform for targeted EAHB improvement.

CRISPR/Cas9↗
PubMed2026

Genome Editing in Solanaceae: Harnessing CRISPR-Cas Technology for Precision Crop Improvement.

Malnutrition and climate-induced stress remain major constraints to global food and nutritional security despite the yield gains of the Green Revolution. Solanaceae crops such as tomato, potato, brinjal, and pepper are key sources of vitamins, minerals, and bioactive compounds. Yet, their genetic improvement has been limited by narrow diversity and complex polygenic traits. The advent of CRISPR/Cas-mediated genome editing provides a transformative platform for precision crop improvement by enabling targeted modification of genes controlling stress tolerance, yield, and nutritional quality. In Solanaceae, CRISPR/Cas applications have successfully enhanced resistance against major pathogens (SlMlo1, SlPelo, SlDCL2), improved abiotic stress tolerance through editing of SlMAPK3, SlCBF1, and SlBZR1, and optimized fruit quality traits via modulation of Psy1, CrtR-b2, and fiAD2/3. Emerging innovations, such as base and prime editing, and RNP-mediated transgene-free delivery, are expanding the precision and scope of editing. However, challenges persist, including genotype-dependent transformation, low HDR efficiency, and incomplete understanding of off-target and epigenetic effects. Integrating CRISPR with omics-guided gene discovery, efficient transformation systems, and regulatory harmonization can accelerate the development of nutritionally enriched, stress-resilient, and sustainable Solanaceae varieties. This review synthesizes recent advances, identifies critical limitations, and outlines future opportunities for deploying CRISPR/Cas technology to achieve next-generation breeding and food system resilience.

CRISPR/Cas↗
PubMed2002

A novel susceptibility locus on chromosome 2 in the (New Zealand Black x New Zealand White)F1 hybrid mouse model of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is inherited as a complex polygenic trait. (New Zealand Black (NZB) x New Zealand White (NZW)) F(1) hybrid mice develop symptoms that remarkably resemble human SLE, but (NZB x PL/J)F(1) hybrids do not develop lupus. Our study was conducted using (NZW x PL/J)F(1) x NZB (BWP) mice to determine the effects of the PL/J and the NZW genome on disease. Forty-five percent of BWP female mice had significant proteinuria and 25% died before 12 mo of age compared with (NZB x NZW)F(1) mice in which >90% developed severe renal disease and died before 12 mo. The analysis of BWP mice revealed a novel locus (chi(2) = 25.0; p < 1 x 10(-6); log of likelihood = 6.6 for mortality) designated Wbw1 on chromosome 2, which apparently plays an important role in the development of the disease. We also observed that both H-2 class II (the u haplotype) and TNF-alpha (TNF(z) allele) appear to contribute to the disease. A suggestive linkage to proteinuria and death was found for an NZW allele (designated Wbw2) telomeric to the H-2 locus. The NZW allele that overlaps with the previously described locus Sle1c at the telomeric part of chromosome 1 was associated with antinuclear autoantibody production in the present study. Furthermore, the previously identified Sle and Lbw susceptibility loci were associated with an increased incidence of disease. Thus, multiple NZW alleles including the Wbw1 allele discovered in this study contribute to disease induction, in conjunction with the NZB genome, and the PL/J genome appears to be protective.

Alleles↗
PubMed1997

Identification of multiple sclerosis-associated genes.

Multiple sclerosis (MS) is a complex genetic trait. Analyses to identify genetic variants that increase susceptibility to MS have primarily focused on candidate genes, either in family linkage investigations or in association (linkage disequilibrium) studies in sporadic cases and control subjects. Most of the candidate genes considered to date either influence immune function or encode structural myelin proteins. Recently, three preliminary whole genomic surveys were completed, and they reveal multiple loci of possible genetic linkage that are worthy of further study. No convincing evidence for a single strong locus has emerged from analysis of the three studies. Linkage promises to focus the future choice of candidate genes for further investigation.

Complement System Proteins↗
PubMed2005

[Possible association due to linkage disequilibrium of TGFA, RARA and BCL3 with nonsyndromic cleft lip with or without cleft palate in the Chilean population].

BACKGROUND: Nonsyndromic cleft lip/palate (NSCLP) is a congenital malformation with the characteristics of a complex genetic trait. Based on experimental evidences as well as on association and linkage studies candidate genes TGFA, RARA and BCL3 have been postulated as being involved in the genetic etiology of this pathology. AIM: To test the possible association due to linkage disequilibrium between microsatellite markers located at less than 1cM from the three candidate genes and nonsyndromic cleft lip/palate using the case-parents trio design. PATIENTS AND METHODS: The sample consisted of 58 case-parents trios. Two microsatellite markers, flanking each one of the candidate genes were analyzed by means of the polymerase chain reaction (PCR) with fluorescent labeled microsatellite markers. Electrophoresis of the PCR products was performed on a laser-fluorescent automatic DNA sequencer. Nonparametric ETDT was used to analyze the genotype data. RESULTS: Significant linkage disequilibrium was detected between D2S443 (TGFA) and NSCLP. Significance was almost reached between D17S800 (RARA) and NSCLP. Alleles 239bp (D2S443) and 172bp (D17S800) showed significant preferential transmission from heterozygous parents to affected offspring. In the case of BCL3 both markers showed no significant results. CONCLUSIONS: The results of the present study do not show clear evidence that TGFA or RARA could be involved in the genetic etiology of NSCLP. Even though the importance of retinoic acid in the development of the embryo is well documented the results obtained for RARA are difficult to analyze. In relation to the possible role of BCL3 in NSCLP, recent information postulates that other genes located in the same chromosome region could be involved in NSCLP.

Alleles↗
PubMed2002

[Effects of the speech rate on speakers' personality-trait impressions].

This study found non-linear functional relations between speech-rate and impressions of speakers' personality-traits. University students (N = 376) evaluated speakers' personality impressions for speech sounds that were converted at different speech-rates from the original utterance spoken by four Japanese and four native English speakers. A short version of the Big Five Scale based on the five-factor model of personality was used. Factor analysis showed that listeners recognized each personality-trait independently through speech sounds, and that speech-rate affected personality impressions of speakers differently depending on the traits. Multiple regression analysis revealed that quadratic regression equations could provide good approximations of personality-trait values, and all the non-linear relationships were described fairly well. The locations of the peaks and the spread of the quadratic functions vary from trait to trait. The complex metamorphosis of personality impressions via speech-rate converted sounds can be inferred by combining those five curves. Finally, participants showed more sensitive responses to Japanese speakers than to English speakers.

Adolescent↗
PubMed1999

Efficient approach to unique single-nucleotide polymorphism discovery.

Single-nucleotide polymorphisms (SNPs) are the most frequently found DNA sequence variations in the human genome. It has been argued that a dense set of SNP markers can be used to identify genetic factors associated with complex disease traits. Because all high-throughput genotyping methods require precise sequence knowledge of the SNPs, any SNP discovery approach must involve both the determination of DNA sequence and allele frequencies. Furthermore, high-throughput genotyping also requires a genomic DNA amplification step, making it necessary to develop sequence-tagged sites (STSs) that amplify only the DNA fragment containing the SNP and nothing else from the rest of the genome. In this report, we demonstrate the utility of a SNP-screening approach that yields the DNA sequence and allele frequency information while screening out duplications with minimal cost and effort. Our approach is based on the use of a homozygous complete hydatidiform mole (CHM) as the reference. With this homozygous reference, one can identify and estimate the allele frequencies of common SNPs with a pooled DNA-sequencing approach (rather than having to sequence numerous individuals as is commonly done). More importantly, the CHM reference is preferable to a single individual reference because it reveals readily any duplicated regions of the genome amplified by the PCR assay before the duplicated sequences are found in GenBank. This approach reduces the cost of SNP discovery by 60% and eliminates the costly development of SNP markers that cannot be amplified uniquely from the genome.

Alleles↗
PubMed1999

The FLS mouse: a new inbred strain with spontaneous fatty liver.

BACKGROUND AND PURPOSE: A new strain of mouse, named FLS (fatty liver Shionogi), which develops spontaneous fatty liver without obesity, was established by inbreeding. Morphologic, physiologic, and genetic characterization of the strain was done. METHODS: Characteristics of male FLS mice were compared with those of the sister strain, dd Shionogi (DS), which does not develop spontaneous fatty liver. A genetic cross experiment was performed by mating FLS with C3H/He/Shi mice. RESULTS: The hepatocytes of neonatal FLS mice contained fine lipid droplets throughout the lobules, and large lipid droplets appeared as mice aged. Liver triglyceride concentrations of FLS mice were fivefold higher than those of DS mice, but serum lipid concentrations and the lipoprotein profile did not indicate abnormalities. Higher plasma aspartate transaminase and alanine transaminase activities in FLS, compared with DS mice, suggested hepatocellular lesions. The genetic cross experiment suggested that the fatty liver formation is a complex polygenic trait. CONCLUSION: The FLS mice develop a progressive hepatic steatosis without obesity and diabetes. The FLS mouse might be a good model for investigating hepatic disorders accompanied by fatty liver unrelated to alcoholism or obesity.

Adipose Tissue↗
PubMed1999

Nephrolithiasis.

Genetic factors are important determinants for kidney stone formation. Cystinuria, primary hyperoxaluria, and X-linked nephrolithiasis (Dent's disease) are monogenic kidney stone diseases for which responsible genes have been identified. Familial stone disease with hyperuricosuria or renal tubular acidosis has been described in several clinical settings. Idiopathic hypercalciuria is the most common stone risk factor, and evidence in humans and in a rat model indicates that hypercalciuria is a complex, polygenic trait. Some candidate genes for idiopathic hypercalciuria are suggested by the known physiology, including those encoding the vitamin D receptor, the 1 alpha-hydroxylase of vitamin D, the calcium-sensing receptor, the renal sodium-dependent phosphate transporter, and chloride channels, but others remain to be identified. The multifaceted physiology of hypercalciuria may reflect the combined effects of polymorphisms in several genes.

Animals↗