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PubMed1997

Dissection of a synthesized quantitative trait to characterize transgene interactions.

Six transgenic tobacco lines, each homozygous for the beta-glucuronidase (GUS) gene at a different locus, and wild type were selfed and intercrossed to evaluate GUS activity in all possible hemizygous, homozygous and dihybrid combinations of GUS alleles. The transgenic lines are characterized by their GUS activity (two low, three intermediate, one high), T-DNA complexity (four single-copy, two more complex single-locus) and the presence of the chicken lysozyme matrix-associated region (MAR) around the full T-DNA (two lines). Gene action and interaction was analyzed by weighted linear regression with parameters for additivity, dominance and epistasis. The analysis showed that each of the four single-copy lines acted fully additively. In contrast, the two complex single-locus lines showed classical single-locus overdominance and were epistatic dominant over all other GUS alleles. The latter is manifested in severe suppression of GUS activity in dihybrid lines, irrespective of the presence of MAR elements around the GUS gene. Such elements apparently do not protect against epistatic dominance. The quantitative data suggested that the epistatic dominance and overdominance are based on the same molecular mechanism. Our approach of a genetic analysis of quantitative variation in well-characterized transgenic lines provides a powerful tool to gain insight into complex plant traits.

Alleles↗
PubMed2005

A population-based LD map of the human chromosome 6p.

The recent publication of the complete sequence of human chromosome 6 provides a platform from which to investigate genomic sequence variation. We report here a detailed linkage disequilibrium (LD) pattern map across the entire human chromosome 6p by using a set of 1152 single nucleotide polymorphisms (SNPs) in a population of 198 Singaporean Chinese, with 326 SNPs focused in the major histocompatibility complex (MHC) region. Our analysis shows some unexpectedly high segments of strong LD in a 10-Mb region that includes the extremely polymorphic and gene-rich MHC loci and many non-MHC genes. These include the telomeric peri-MHC region that harbors olfactory receptors, histones and zinc finger clusters, and the centromeric peri-MHC region that contains several unknown open reading frames. The data also help refine a human-mouse synteny break in the region between 28.6 and 29.4 Mb. The population-based LD map presented here will provide an essential resource for understanding the genomic sequence variation of chromosome 6p and LD mapping of disease genes of complex genetic traits.

Chromosome Mapping↗
PubMedDate not supplied

Heredity and systemic lupus erythematosus: dissecting a complex genetic disease.

The etiology of SLE appears to be exceedingly complex and possibly heterogeneous, with genetics and environment both making substantial contributions. A schematic representation of potential mechanisms is depicted in Figure 2. We may not fully understand the pathogenesis of this disease until we unravel the relative contributions of each component to the development of SLE. While genetic mechanisms involved in SLE remain obscure, we now have available elegant laboratory techniques for analysis of genetic loci as well as computer technology which permits simulation and analysis of the transmission of complex genetic traits among multiple families and demographic groups. What remains is the painstaking task of collecting families multiplex for SLE and analyzing multiple sets of clinical, serologic, and genetic data within and between these pedigrees. Such studies are currently underway and will hopefully increase understanding of this enigmatic and complex autoimmune disorder.

Female↗
PubMed2003

Congenic strains of mice for verification and genetic decomposition of quantitative trait loci for femoral bone mineral density.

Peak femoral volumetric bone mineral density (femoral bone mineral density) in C57BL/6J (B6) 4-month-old female mice is 50% lower than in C3H/HeJ (C3H) and 34% lower than in CAST/EiJ (CAST) females. Genome-wide analyses of (B6 x C3H)F2 and (B6 x CAST)F2 4-month-old female progeny demonstrated that peak femoral bone mineral density is a complex quantitative trait associated with genetic loci (QTL) on numerous chromosomes (Chrs) and with trait heritabilities of 83% (C3H) and 57% (CAST). To test the effect of each QTL on femoral bone mineral density, two sets of loci (six each from C3H and CAST) were selected to make congenic strains by repeated backcrossing of donor mice carrying a given QTL-containing chromosomal region to recipient mice of the B6 progenitor strain. At the N6F1 generation, each B6.C3H and B6.CAST congenic strain (statistically 98% B6-like in genomic composition) was intercrossed to obtain N6F2 progeny for testing the effect of each QTL on femoral bone mineral density. In addition, the femoral bone mineral density QTL region on Chr 1 of C3H was selected for congenic subline development to facilitate fine mapping of this strong femoral bone mineral density locus. In 11 of 12 congenic strains, 6 B6.C3H and 5 B6.CAST, femoral bone mineral density in mice carrying c3h or cast alleles in the QTL regions was significantly different from that of littermates carrying b6 alleles. Differences also were observed in body weight, femoral length, and mid-diaphyseal periosteal circumference among these 11 congenic strains when compared with control littermates; however, these latter three phenotypes were not consistently correlated with femoral bone mineral density. Analyses of eight sublines derived from the B6.C3H-1T congenic region revealed two QTLs: one located between 36.9 and 49.7 centiMorgans (cM) and the other located between 73.2 and 100.0 cM distal to the centromere. In conclusion, these congenic strains provide proof of principle that many QTLs identified in the F2 analyses for femoral bone mineral density exert independent effects when transferred and expressed in a common genetic background. Furthermore, significant differences in femoral bone mineral density among the congenic strains were not consistently accompanied by changes in body weight, femur length, or periosteal circumference. Finally, decomposition of QTL regions by congenic sublines can reveal additional loci for phenotypes assigned to a QTL region and can markedly refine genomic locations of quantitative trait loci, providing the opportunity for candidate gene testing.

Alleles↗
PubMed2002

Complex genetic control of susceptibility to malaria in mice.

Malaria is a major infectious disease worldwide, with over 1 million deaths in African children every year. The molecular pathways of pathogenesis of the Plasmodium parasite and the host mechanisms of defense against this infection remain poorly understood. Epidemiological studies, together with linkage analyses in endemic areas have clearly pointed at a genetic component of innate susceptibility and severity of disease. In humans, this genetic trait is complex, and has been studied in a mouse experimental model over the past few years. Inbred strains of mice show different degrees of susceptibility to infection with Plasmodium chabaudi, and the genetic component of these inter-strain differences has been studied in standard informative backcross and F2 populations, as well as in recombinant inbred strains and more recently, in recombinant congenic strains. These studies have shown that genetic susceptibility to malaria is also complex in mice, and have led to the mapping of major susceptibility Char (Chabaudi resistance) loci, located on chromosomes 9 (Char1), 8 (Char2), 17 (Char3) and 3 (Char4).

Animals↗
PubMed2001

The genetic bases of divergence in desiccation and starvation resistance among tropical and temperate populations of Drosophila melanogaster.

Desiccation and starvation resistance are two stress-related traits which vary geographically with climate in Drosophila melanogaster. To investigate the contribution of epistasis to population divergence for these traits, we crossed tropical and temperate populations from two different geographical regions to produce F1, F2 and first backcross generations. Line-cross analysis of generation means revealed that genetic bases of divergence for both traits were complex and remarkably similar in a number of respects. Strong additive and dominance effects were present in most of the models, whereas epistatic and maternal effects were less common. The presence of epistatic effects in approximately half of the models presented in this study is consistent with line-cross studies of diverged traits in other animals, and does not support the view that epistasis is the predominant means by which populations diverge. In addition, evidence of maternal effects in both traits adds to a growing body of recent evidence that suggests maternal contributions to population differentiation are more widespread than previously thought. This finding undermines the accuracy of studies inferring epistasis directly from the magnitude of F2 breakdown. More line-cross analysis studies of naturally diverged populations that take into account maternal effects will shed further light on the true incidence of epistasis and its importance in the evolutionary process.

Adaptation, Physiological↗
PubMed2025

Genotypic and phenotypic consequences of domestication in dogs.

Runs of homozygosity (ROH) are genomic regions that arise when two copies of identical haplotypes are inherited from a shared common ancestor. In this study, we leverage ROH to identify associations between genetic diversity and non-disease phenotypes in Canis lupus familiaris (dogs). We find significant association between the ROH inbreeding coefficient (FROH) and several phenotypic traits. These traits include height, weight, lifespan, muscled, white coloring of the head and chest, furnishings, and fur length. After correcting for population structure, we identified more than 45 genes across the examined quantitative traits that exceed the threshold for suggestive significance. We observe distinct distributions of inbreeding and elevated levels of long ROH in modern breed dogs compared to more ancient breeds, which aligns with breeding practices during Victorian era breed establishment. Our results highlight the impact of non-additive variation and of polygenicity on complex quantitative phenotypes in dogs due to domestication and the breed formation bottleneck.

GWAS↗
PubMed2006

A third locus for Eosinophilia on chromosome 1 of the MES rats.

Matsumoto Eosinophilia Shinshu (MES) is a rat strain that spontaneously develops eosinophilia and eosinophil-related inflammatory lesions in many organs. In a previous study, we performed chromosomal mapping of the gene for eosinophilia in MES rats using backcross progeny and found that the major locus for eosinophilia was located on chromosome 19. In addition, another quantitative trait locus showing suggestive linkage for blood eosinophil count was found on chromosome 2. In this study, we examined additional marker loci in the backcross progeny and discovered that a third locus for eosinophilia was also located on chromosome 1. These data reinforce the notion that eosinophilia in MES rats is a rather complex genetic trait. However, these results will form the basis for identifying the candidate genes for eosinophilia.

Animals↗
PubMedDate not supplied

Genetics of quantitative and qualitative aspects of lung tumorigenesis in the mouse: multiple interacting Susceptibility to lung cancer (Sluc) genes with large effects.

Inbred strains of mice exhibit large differences in their susceptibility to various complex quantitative genetic traits, among which is the susceptibility to lung cancer. These differences are caused by the combined effects of multiple quantitative trait loci (QTLs). Due to their multiplicity, it is relatively difficult and laborious to study the effects of individual QTLs. To dissect complex genetic traits the authors make use of recombinant congenic strains (RCS), a system of mouse inbred strains in which the genetic complexity is reduced. The susceptibility to lung cancer is studied by using the series of O20-congenic-B10.O20 (OcB) RC strains. They are derived from the parental background strain O20 and the parental donor strain B10.O20, two mouse inbred strains that differ from each other in both quantitative and qualitative aspects of lung tumorigenesis. This study describes the segregation of lung tumor number, size, and histology among the OcB RC strains, and indicates that these traits are influenced by multiple interacting QTLs with considerable individual effects. The results suggest that some of the susceptibility loci to lung cancer affect the susceptibility to other types of cancer as well, possibly by functioning systematically.

Adenoma↗
PubMed1997

Evidence for linkage of chromosome 12q15-q24.1 markers to high total serum IgE concentrations in children of the German Multicenter Allergy Study.

Linkage of asthma and high total serum IgE levels to chromosome 12q15-q24.1 has been recently described. To evaluate this region further in regard to total IgE responsiveness, we genotyped 52 unrelated German children with persistently "high" total serum IgE (selected from a noninterventional prospective multicenter cohort study) and their parents. We carefully defined a most extreme IgE phenotype and analyzed it as a dichotomous trait. We tested for linkage between high total IgE concentrations and nine polymorphic microsatellite markers on chromosome 12q15-q24.1 using the transmission/disequilibrium test. Evidence for linkage and allelic association for high total IgE was observed for four markers in this region. This study demonstrates the value of using extreme phenotypes in genetic analysis of a complex quantitative trait.

Child, Preschool↗
PubMed2006

Integrating genetic and gene expression data: application to cardiovascular and metabolic traits in mice.

The millions of common DNA variations that occur in the human population, or among inbred strains of mice and rats, perturb the expression (transcript levels) of a large fraction of the genes expressed in a particular tissue. The hundreds or thousands of common cis-acting variations that occur in the population may in turn affect the expression of thousands of other genes by affecting transcription factors, signaling molecules, RNA processing, and other processes that act in trans. The levels of transcripts are conveniently quantitated using expression arrays, and the cis- and trans-acting loci can be mapped using quantitative trait locus (QTL) analysis, in the same manner as loci for physiologic or clinical traits. Thousands of such expression QTL (eQTL) have been mapped in various crosses in mice, as well as other experimental organisms, and less detailed maps have been produced in studies of cells from human pedigrees. Such an integrative genetics approach (sometimes referred to as "genetical genomics") is proving useful for identifying genes and pathways that contribute to complex clinical traits. The coincidence of clinical trait QTL and eQTL can help in the prioritization of positional candidate genes. More importantly, mathematical modeling of correlations between levels of transcripts and clinical traits in genetic crosses can allow prediction of causal interactions and the identification of "key driver" genes. An important objective of such studies will be to model biological networks in physiologic processes. When combined with high-density single nucleotide polymorphism (SNP) mapping, it should be feasible to identify genes that contribute to transcript levels using association analysis in outbred populations. In this review we discuss the basic concepts and applications of this integrative genomic approach to cardiovascular and metabolic diseases.

Animals↗
PubMed2001

The search for complex disease genes: fault by linkage or fault by association?

With the human DNA sequence nearing completion, the search for complex disease genes is gaining momentum, as is the debate over gene-finding strategies. This overview contrasts two pivotal methods: linkage analysis and association mapping. Linkage analysis has been used successfully to identify the genes underlying rare mendelian disorders. It has also played a role in attempts to map genes for common non-mendelian (also known as 'complex' or 'multifactorial') diseases such as psychiatric disorders. However, despite extensive efforts progress has been slow, marred by inconsistent or ambiguous results. Uncertainties about the utility of the linkage approach for complex genetic traits has spurred interest in association studies with candidate genes, as an alternate strategy. Recently, with the advent of new molecular tools, in particular high-density, single-nucleotide polymorphisms (SNPs) maps, it has been argued that, while linkage analysis may retain some role, genome-wide association studies with SNPs offer a superior strategy for unraveling genetic complexity. In this paper I review these issues, stressing the pros and cons of the various strategies. I propose that: (1) the uncertainties in association studies may have been underestimated; (2) neither method is sufficient or optimal; and (3) a joint linkage and association approach, together with genomic, statistical and computational advances, may have greater promise for understanding the genetic underpinnings of complex disorders in the new millennium.

Genetic Diseases, Inborn↗
PubMed2006

Age and sex effects on human mutation rates: an old problem with new complexities.

Base substitution mutations are far more common in human males than in females, and the frequency increases with paternal age. Both can be accounted for by the greater number of pre-meiotic cell divisions in males, especially old ones. In contrast, small deletions do not show any important age effect and occur with approximately equal frequency in the two sexes. Mutations in most genes include both types, and the sex and paternal age effect depends on the proportion of the two types. A few traits, of which Apert Syndrome is best understood, are mutation hot spots with all the mutations occurring in one or two codons, usually at one nucleotide. They occur with very high frequency almost exclusively in males and the frequency increases rapidly with paternal age. It has been suggested that the mutant cells have a selective advantage in the male germ-line prior to meiosis. Evidence for this surprising, but important, hypothesis is discussed. A possible mechanism is the conversion of asymmetrical stem-cell divisions into symmetric ones. Some traits with complex etiology show a slight paternal age effect. There is also a short discussion of the high deleterious mutation rate and the role of sexual reproduction in reducing the consequent mutation load.

Adolescent↗
PubMed2002

Molecular haplotyping at high throughput.

Reconstruction of haplotypes, or the allelic phase, of single nucleotide polymorphisms (SNPs) is a key component of studies aimed at the identification and dissection of genetic factors involved in complex genetic traits. In humans, this often involves investigation of SNPs in case/control or other cohorts in which the haplotypes can only be partially inferred from genotypes by statistical approaches with resulting loss of power. Moreover, alternative statistical methodologies can lead to different evaluations of the most probable haplotypes present, and different haplotype frequency estimates when data are ambiguous. Given the cost and complexity of SNP studies, a robust and easy-to-use molecular technique that allows haplotypes to be determined directly from individual DNA samples would have wide applicability. Here, we present a reliable, automated and high-throughput method for molecular haplotyping in 2 kb, and potentially longer, sequence segments that is based on the physical determination of the phase of SNP alleles on either of the individual paternal haploids. We demonstrate that molecular haplotyping with this technique is not more complicated than SNP genotyping when implemented by matrix-assisted laser desorption/ionisation mass spectrometry, and we also show that the method can be applied using other DNA variation detection platforms. Molecular haplotyping is illustrated on the well-described beta(2)-adrenergic receptor gene.

Alleles↗
PubMed2006

Association of HLA-DRB1*13 with susceptibility to uveitis in juvenile idiopathic arthritis in two independent data sets.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is the commonest rheumatic disease of childhood. Uveitis is the commonest eye complication of JIA, potentially leading to eye surgery and/or visual loss. JIA is a complex genetic trait with well-established HLA-DRB1 associations. The aim of this study was to investigate the involvement of HLA-DRB1 in JIA-associated uveitis. METHODS: A set of 130 UK Caucasian simplex families consisting of healthy parent(s) and a child affected with juvenile oligoarticular idiopathic arthritis (of which 31 had developed uveitis) had previously been screened for multiple markers in the major histocompatibility complex region. Associations with uveitis were investigated through haplotype pattern mining (HPM) and the extended transmission disequilibrium test (ETDT). A further set of 228 UK Caucasian patients with long-standing JIA were fully genotyped for HLA-DRB1 using PCR with sequence-specific primers. Associations of HLA-DRB1 alleles in patients with uveitis (n = 50) were examined individually using the chi 2 test. RESULTS: In the first cohort, HPM identified significant associations of HLA-DRB1*13 with uveitis in juvenile oligoarthritis (P = 0.002). The ETDT confirmed overtransmission of this allele in the families (empirical global P = 0.018). In the second cohort, the significant association of uveitis with HLA-DRB1*13 was replicated (P = 0.0002, odds ratio 3.4, 95% confidence interval 1.7-6.5). CONCLUSIONS: This study has established the HLA-DRB1*13 association with uveitis in JIA. Further work is necessary in order to explore the prognostic potential of this marker.

Alleles↗
PubMed2003

Genetic epidemiology of melanoma.

Melanoma incidence has risen in many Caucasians populations over the last 20 years and research on the potential environmental and genetic risk factors has led to some interesting new findings but also to many more questions. The relationship between melanoma and ultraviolet radiation is complex and this area of research is controversial especially regarding the use of sunbeds and sunscreens. In terms of genetic factors, the discovery of two genes CDKN2A and CDK4 has been a great advance with more understanding of melanocyte biology in relation to defects in senescence. For phenotypic risk factors such as fair skin and high numbers of naevi, the role of genetic factors is clearly evident but these traits are complex and the discovery of genes involved in skin pigmentation and naevi formation is not an easy task. Research on the MC1R gene has not only shown the importance of this gene in hair and skin pigmentation but also in senescence and immunity. Functional studies involving CDKN2A and MC1R are leading to important new findings. There is also some hope regarding the use of micro-arrays in helping to dissect many genetic events in melanoma. The collection of large datasets including family, twin and case-control studies as well as tumour banks with collaborations between countries will hopefully lead to more discoveries. For the primary and secondary prevention of this tumour, efforts need to be sustained in public health campaigns on sun exposure and the recognition of individuals at high risk.

Disease Progression↗
PubMed2005

Genetics of susceptibility and severity in systemic lupus erythematosus.

PURPOSE OF REVIEW: The genetic basis of systemic lupus erythematosus, a complex genetic trait, may provide important insights into autoimmune disease. Innovation in both practical and theoretical approaches will assist in accelerating the pace of discovery and our understanding of pathogenesis. RECENT FINDINGS: Significant progress has been made in the last year with respect to the refinement of genetic intervals to promising candidate genes involved in systemic lupus erythematosus pathogenesis and specific phenotype susceptibility. This review highlights these discoveries and suggests platforms that may affect the future of analysis of this complex disease. SUMMARY: Understanding the genetic basis for systemic lupus erythematosus disease and sub-phenotype susceptibility will have a substantial effect on the therapeutic interventions used to care for patients.

Genetic Predisposition to Disease↗
PubMed1998

Enrichment for loci identical-by-descent between pairs of mouse or human genomes by genomic mismatch scanning.

Mapping genes that underlie complex genetic traits, including genes that determine susceptibility to common diseases, requires an efficient method for high-resolution genotyping. Single-nucleotide differences between pairs of allelic sequences from unrelated individuals occur approximately once in every kilobase. Genomic mismatch scanning (GMS), by analyzing numerous single-nucleotide polymorphisms in a single genome-wide step, offers a potentially powerful and efficient approach to linkage analysis. GMS, originally developed in a yeast system, is shown here to be applicable to the more complex mouse and human genomes.

Adenosine Triphosphatases↗