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Optimal replication and the importance of experimental design for gel-based quantitative proteomics.

Quantitative proteomic studies, based on two-dimensional gel electrophoresis, are commonly used to find proteins that are differentially expressed between samples or groups of samples. These proteins are of interest as potential diagnostic or prognostic biomarkers, or as proteins associated with a trait. The complexity of proteomic data poses many challenges, so while experiments may reveal proteins that are differentially expressed, these are often not significant when subjected to rigorous statistical analysis. However, this can be addressed through appropriate experimental design. A good experimental design considers the impact of different sources of variation, both analytical and biological, on the statistical importance of the results. The design should address the number of samples that must be analyzed and the number of replicate gels per sample, in the context of a particular minimum difference that one is seeking to achieve. In this study, we explore the ways to improve the quality of protein expression data from 2-DE gels, and describe an approach for defining the number of samples required and the number of gels per sample. It has been developed for the simplest of situations, two groups of samples with variation at two levels: between samples and between gels. This approach will also be useful as a guide for more complex designs involving more than two groups of samples. We describe some Internet-accessible tools that can assist in the design of proteomic studies.

Algorithms↗

PubMed1999

Analysis of background-dependent genetic interactions without inbred strains.

Experimental analysis of background dependent effects of genetic interactions can be designed using strains generated by introgression of small genetic regions containing identical genotypes at loci in question into different inbred strains. We use a novel multilocus paradigm, denoted conditional intergenic functional association (CIFA), to simulate this procedure, with the trade-off of power for convenience that is affordable when sufficiently strong effects are present. We analyze nine enzyme loci at three chromosomes in groups of D. melanogaster with different developmental rates that showed similar allelic frequencies at individual loci. Results obtained suggest the presence of adaptive interaction between particular alleles at two loci when genetic variation at seven background loci is eliminated. Biochemical considerations show that, in the resulting developmental context, strong interaction between these genes may emerge from shifted control of the pentose phosphate pathway, with cascading effects on the glycolysis, TCA cycle, and biosynthetic pathways: one gene may assume control of the irreversible rate-limiting step in the pentose phosphate pathway, whereas the other gene may assume control of the NADP+ level that regulates the same rate-limiting step as an electron acceptor. The newly developing functional genomics research and the absence of inbreeding make CIFA directly applicable to complex human traits in large samples.

Animals↗

PubMed2000

Proteomics: a link between genomics, genetics and physiology.

Thanks to spectacular advances in the techniques for identifying proteins separated by two-dimensional electrophoresis and in methods for large-scale analysis of proteome variations, proteomics is becoming an essential methodology in various fields of plant biology. In the study of pleiotropic effects of mutants and in the analysis of responses to hormones and to environmental changes, the identification of involved metabolic pathways can be deduced from the function of affected proteins. In molecular quantitative genetics, proteomics can be used to map translated genes and loci controlling their expression, which can be used to identify proteins accounting for the variation of complex phenotypic traits. Linking gene expression to cell metabolism on the one hand and to genetic maps on the other, proteomics is a central tool for functional genomics.

Genomics↗

PubMed2001

Genetic susceptibility to asthma and atopy among Chinese in Singapore--linkage to markers on chromosome 5q31-33.

BACKGROUND: Asthma and atopy are complex genetic traits, influenced by the interaction of multiple genes and environmental factors. Linkage of these traits to chromosome 5q31-33 has been shown in other populations, but has not been well studied in the Chinese. We studied linkage between asthma and atopy with markers on chromosome 5q31-33 in the Singapore Chinese. This region contains many candidate genes, including the cytokine gene cluster. METHODS: We recruited 88 Chinese families with at least two affected offspring, totaling 373 subjects, with 125 and 119 sib-pairs for atopy and asthma, respectively. All individuals were genotyped with 19 polymorphic microsatellite markers spanning a distance of 41 cM along chromosome 5q31-33. Affected sib-pair and multipoint linkage analysis was performed. RESULTS: There was evidence for linkage of the asthma and atopy phenotypes with three markers, D5S2110, D5S2011, and D5S412 (P values of 0.001 to 0.00001). Multipoint analysis further substantiated this (nonparametric linkage scores of 1.8-2.9). These findings suggest that susceptibility genes for asthma and atopy are found in this region in the Chinese. CONCLUSION: This study has shown linkage of atopy and asthma to chromosome 5q31-33 in a heterogeneous Chinese population. These findings further substantiate the notion that chromosome 5q31-33 contains "universally" important susceptibility genes for these traits.

Adolescent↗

PubMed2002

Genetic association of the catalase gene (CAT) with vitiligo susceptibility.

Vitiligo susceptibility is a complex genetic trait that may involve genes important for melanin biosynthesis, response to oxidative stress, and/or regulation of autoimmunity, as well as environmental factors. We report here case-control and family-based association studies for the catalase gene (CAT) in vitiligo patients. The CAT gene was selected as a candidate gene because of the reduction of catalase enzyme activity (EC 1.11.1.6) and concomitant accumulation of excess hydrogen peroxide observed in the entire epidermis of vitiligo patients. One of three CAT genetic markers studied was found to be informative for genotypic analysis of Caucasian vitiligo patients and control subjects. Both case/control and family-based genetic association studies of the T/C single nucleotide polymorphism (SNP) in exon 9 of the CAT gene, which is detectable with the restriction endonuclease BstX I, suggest possible association between the CAT gene and vitiligo susceptibility. The observations that T/C heterozygotes are more frequent among vitiligo patients than controls and that the C allele is transmitted more frequently to patients than controls suggest that linked mutations in or near the CAT gene might contribute to a quantitative deficiency of catalase activity in the epidermis and the accumulation of excess hydrogen peroxide (H2O2). The CAT gene may, therefore, be a susceptibility gene in some vitiligo patients, further supporting the epidermal oxidative stress model for vitiligo pathogenesis.

Biomarkers↗

PubMed2003

Development of personality in early and middle adulthood: set like plaster or persistent change?

Different theories make different predictions about how mean levels of personality traits change in adulthood. The biological view of the Five-factor theory proposes the plaster hypothesis: All personality traits stop changing by age 30. In contrast, contextualist perspectives propose that changes should be more varied and should persist throughout adulthood. This study compared these perspectives in a large (N = 132,515) sample of adults aged 21-60 who completed a Big Five personality measure on the Internet. Conscientiousness and Agreeableness increased throughout early and middle adulthood at varying rates; Neuroticism declined among women but did not change among men. The variety in patterns of change suggests that the Big Five traits are complex phenomena subject to a variety of developmental influences.

Adult↗

PubMed1999

A general approach to single-nucleotide polymorphism discovery.

Single-nucleotide polymorphisms (SNPs) are the most abundant form of human genetic variation and a resource for mapping complex genetic traits. The large volume of data produced by high-throughput sequencing projects is a rich and largely untapped source of SNPs (refs 2, 3, 4, 5). We present here a unified approach to the discovery of variations in genetic sequence data of arbitrary DNA sources. We propose to use the rapidly emerging genomic sequence as a template on which to layer often unmapped, fragmentary sequence data and to use base quality values to discern true allelic variations from sequencing errors. By taking advantage of the genomic sequence we are able to use simpler yet more accurate methods for sequence organization: fragment clustering, paralogue identification and multiple alignment. We analyse these sequences with a novel, Bayesian inference engine, POLYBAYES, to calculate the probability that a given site is polymorphic. Rigorous treatment of base quality permits completely automated evaluation of the full length of all sequences, without limitations on alignment depth. We demonstrate this approach by accurate SNP predictions in human ESTs aligned to finished and working-draft quality genomic sequences, a data set representative of the typical challenges of sequence-based SNP discovery.

Algorithms↗

PubMed1996

Doyne revisited.

Inherited retinal dystrophies are important causes of blindness in the Western world. Molecular genetic techniques, and the use of large pedigrees exhibiting such conditions, have been instrumental in finding causative disease genes. The genealogy of families with a rare condition known as Doyne's honeycomb retinal degeneration was first described in 1899. Investigating this phenotype is extremely important because of the similarities it shares with age-related macular degeneration, and it may lead us to a gene that is involved in this complex genetic trait. In this paper we review the original genealogy of the families described by Doyne, and explain the methods used to identify the living descendants of these families.

Choroiditis↗

PubMed1998

Mapping a gene for combined hyperlipidaemia in a mutant mouse strain.

Familial combined hyperlipidaemia (FCHL) is a common, multifactorial disorder associated with elevated levels of plasma triglyceride, cholesterol, or both. A characteristic feature is increased secretion of very low density lipoproteins (VLDL) and apolipoprotein B (apoB). Although FCHL is the most common cause of premature coronary artery disease (CAD), accounting for over 10% of cases, its aetiology remains largely unknown. One powerful approach to the dissection of complex genetic traits involves the use of animal models. We have identified a mouse strain, HcB-19/Dem (HcB-19), which exhibits hypertriglyceridaemia, hypercholesterolaemia and elevated levels of plasma apoB. Like FCHL patients, HcB-19 mice also exhibit increased secretion of triglyceride-rich lipoproteins, and their hyperlipidaemia becomes progressively more severe with age. It is likely that the hyperlipidaemia results from a mutation of a novel gene that arose during development of strain HcB-19. We mapped the hyperlipidaemia gene (Hyplip1) to the distal portion of mouse chromosome 3. This region is syntenic to human chromosome 1q21-q23, which has recently been shown to harbour a gene associated with FCHL in families from a Finnish isolate.

Age Factors↗

PubMed1993

Genomic mismatch scanning: a new approach to genetic linkage mapping.

Genomic mismatch scanning (GMS) is a new method of genetic linkage analysis that does not require conventional polymorphic markers or gel electrophoresis. GMS is ideally suited to affected-relative-pair mapping. DNA fragments from all regions of identity-by-descent between two relatives are isolated based on their ability to form extensive mismatch-free hybrid molecules. The genomic origin of this selected pool of DNA fragments is then mapped in a single hybridization step. Here we demonstrate the practicality of GMS in a model organism, Saccharomyces cerevisiae. GMS is likely to be applicable to other organisms, including humans, and may be of particular value in mapping complex genetic traits.

Chromosome Mapping↗

PubMed2003

Association of cadherin 23 with polygenic inheritance and genetic modification of sensorineural hearing loss.

Age-related hearing loss (AHL) in common inbred mouse strains is a genetically complex quantitative trait. We found a synonymous single-nucleotide polymorphism in exon 7 of Cdh23 that shows significant association with AHL and the deafness modifier mdfw (modifer of deafwaddler). The hypomorphic Cdh23(753A) allele causes in-frame skipping of exon 7. Altered adhesion or reduced stability of CDH23 may confer susceptibility to AHL. Homozygosity at Cdh23(753A) or in combination with heterogeneous secondary factors is a primary determinant of AHL in mice.

Aging↗

PubMed2005

Genetic variation in laboratory mice.

Characterizing the patterns of genetic variation in an organism provides fundamental insight into the evolutionary history of the organism and defines the scope and nature of studies that must be designed to correlate genotype to phenotype. Given the pre-eminent role of the inbred mouse in biomedical research, considerable effort has been undertaken in recent years to describe more fully the nature and amount of genetic variation among the numerous strains of mice that are in widest use. Here, we discuss recent studies that have contributed to an emerging understanding of the unique variation patterns found in inbred strains of mice and how they have arisen through a combination of natural evolution and human-directed breeding. These preliminary results have ramifications for genetic research into complex biomedical traits and are the basis for the development of future variation resources.

Animals↗

PubMed2001

Experimentally-derived haplotypes substantially increase the efficiency of linkage disequilibrium studies.

The study of complex genetic traits in humans is limited by the expense and difficulty of ascertaining populations of sufficient sample size to detect subtle genetic contributions to disease. Here we introduce an application of a somatic cell hybrid construction strategy called conversion that maximizes the genotypic information from each sampled individual. The approach permits direct observation of individual haplotypes, thereby eliminating the need for collecting and genotyping DNA from family members for haplotype-based analyses. We describe experimental data that validate the use of conversion as a whole-genome haplotyping tool and evaluate the theoretical efficiency of using conversion-derived haplotypes instead of conventional genotypes in the context of haplotype-frequency estimation. We show that, particularly when phenotyping is expensive, conversion-based haplotyping can be more efficient and cost-effective than standard genotyping.

Animals↗

PubMed2003

A future for transgenic livestock.

The techniques that are used to generate transgenic livestock are inefficient and expensive. This, coupled with the fact that most agriculturally relevant traits are complex and controlled by more than one gene, has restricted the use of transgenic technology. New methods for modifying the genome will underpin a resurgence of research using transgenic livestock. This will not only increase our understanding of basic biology in commercial species, but might also lead to the generation of animals that are more resistant to infectious disease.

Animals↗

PubMed2001

Mannan-binding lectin (MBL) gene polymorphisms in ulcerative colitis and Crohn's disease.

The inflammatory bowel diseases (IBD), Crohn's disease (CD), and ulcerative colitis (UC), are complex multifactorial traits involving both environmental and genetic factors. Mannan-binding lectin (MBL) plays an important role in non-specific immunity and complement activation. Point mutations in codons 52, 54 and 57 of exon 1 of the MBL gene are associated with decreased MBL plasma concentrations and increased susceptibility to various infectious diseases. If these MBL mutations could lead to susceptibility to putative IBD-etiological microbial agents, or could temper the complement-mediated mucosal damage in IBD, MBL could function as the link between certain microbial, immunological and genetic factors in IBD. In this study, we investigated the presence of the codon 52, 54 and 57 mutations of the MBL gene in 431 unrelated IBD patients, 112 affected and 141 unaffected first-degree relatives, and 308 healthy control individuals. In the group of sporadic IBD patients (n = 340), the frequency of the investigated MBL variants was significantly lower in UC patients when compared with CD patients (P = 0.01) and with controls (P = 0.02). These results suggest that MBL mutations which decrease the formation of functional MBL could protect against the clinical development of sporadic UC, but not of CD. This could be explained by the differential T-helper response in both diseases.

Adolescent↗

PubMed2005

A new approach to the study of genetic variability of complex characters.

A new approach to multivariate genetic analysis of complex organismal traits is developed. It is based on examination of the distribution of parental strains and the F1 and F2 hybrids in a multidimensional space, and the determination of the directions corresponding to heterozygosity, epistatic and additive gene effects. The effect of heterozygosity includes variability produced by interaction between and within heterozygous loci. The additive gene effects and the remaining epistatic interactions between the homozygous loci can be visualized separately from the effects of heterozygosity by an appropriate projection of the points in multidimensional space. In all, 20 morphological, physiological and behavioural characters and 21 craniometric measures were studied in crosses between two laboratory rat strains. Linear combinations of craniometric and of morphophysiological characters with a high narrow-sense heritability could be identified. These combinations characterized the organismal stress response, which had been selected for in one of the strains. The prospects for the practical application of the new approach and also for the evaluation of the contribution of the genetic diversity to phenotypic variability in animals in natural populations are discussed.

Animals↗

PubMed2000

Identification of a genetic locus modulating splenomegaly induced by granulocyte colony-stimulating factor in mice.

Clinically detectable splenomegaly and splenic rupture are uncommon but potentially life-threatening consequences of G-CSF administration. Increased spleen size in mice injected with G-CSF is a complex genetic trait amenable to investigation in experimental inter-strain crosses by quantitative trait analysis. A quantitative trait locus (QTL) with highly significant linkage (LOD 7.9) for splenomegaly was identified within a 22 centimorgan (cM) region on chromosome 1. Inheritance of a C57BL/6 haplotype in this region was associated with a greater spleen weight. The relevance of this locus was confirmed by analysing the responses of mice congenic for the distal 12 cM of this region (C57BL/6 and C57BL/6.SJL-Ptprc(a) Pep3(b)). Consistent with the QTL effect, mice lacking C57BL/6 alleles in this region had reduced splenomegaly induced by G-CSF. Intriguingly, peripheral blood neutrophilia and progenitor cell mobilisation responses to G-CSF were also significantly influenced.

Animals↗

PubMed2002

Association between a serotonin transporter promoter region polymorphism and mood response during tryptophan depletion.

This study investigated the relationship between depressive symptom response during tryptophan (TRP) depletion and a functional polymorphism of the promoter region of the serotonin (5-HT) transporter gene (SLC6A4).(1) Forty-three subjects in remission from a major depressive episode who underwent TRP depletion were genotyped. DNA was extracted from blood lymphocytes or from cheek cells.(2) The two common alleles are designated long (l) and short (s). Depressive symptoms were measured with the 25-item Hamilton Depression Rating Scale (HDRS).(3) There was a significant association between the l homozygous genotype and the depressive response to TRP depletion, with a significant main effect of time (F = 8.763, df = 3, 38, P = <0.001), and time x l homozygous allele interaction (F = 3.676, df = 3, 38, P = 0.02). Individuals whose genotype predicted increased 5-HT transporter activity may be more susceptible to depressive changes in response to transient 5-HT perturbations. The use of endophenotypic markers for affective disorders such as the mood response to TRP depletion may facilitate studies of complex genetic traits such as depression by decreasing its heterogeneity.

Adult↗