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At least 595 records · Page 33Linked to original sources
PubMed2002

Joint linkage and linkage disequilibrium mapping of quantitative trait loci in natural populations.

Linkage analysis and allelic association (also referred to as linkage disequilibrium) studies are two major approaches for mapping genes that control simple or complex traits in plants, animals, and humans. But these two approaches have limited utility when used alone, because they use only part of the information that is available for a mapping population. More recently, a new mapping strategy has been designed to integrate the advantages of linkage analysis and linkage disequilibrium analysis for genome mapping in outcrossing populations. The new strategy makes use of a random sample from a panmictic population and the open-pollinated progeny of the sample. In this article, we extend the new strategy to map quantitative trait loci (QTL), using molecular markers within the EM-implemented maximum-likelihood framework. The most significant advantage of this extension is that both linkage and linkage disequilibrium between a marker and QTL can be estimated simultaneously, thus increasing the efficiency and effectiveness of genome mapping for recalcitrant outcrossing species. Simulation studies are performed to test the statistical properties of the MLEs of genetic and genomic parameters including QTL allele frequency, QTL effects, QTL position, and the linkage disequilibrium of the QTL and a marker. The potential utility of our mapping strategy is discussed.

Algorithms↗
PubMed2006

Gene by environment QTL mapping through multiple trait analyses in blood pressure salt-sensitivity: identification of a novel QTL in rat chromosome 5.

BACKGROUND: The genetic mechanisms underlying interindividual blood pressure variation reflect the complex interplay of both genetic and environmental variables. The current standard statistical methods for detecting genes involved in the regulation mechanisms of complex traits are based on univariate analysis. Few studies have focused on the search for and understanding of quantitative trait loci responsible for gene x environmental interactions or multiple trait analysis. Composite interval mapping has been extended to multiple traits and may be an interesting approach to such a problem. METHODS: We used multiple-trait analysis for quantitative trait locus mapping of loci having different effects on systolic blood pressure with NaCl exposure. Animals studied were 188 rats, the progenies of an F2 rat intercross between the hypertensive and normotensive strain, genotyped in 179 polymorphic markers across the rat genome. To accommodate the correlational structure from measurements taken in the same animals, we applied univariate and multivariate strategies for analyzing the data. RESULTS: We detected a new quantitative train locus on a region close to marker R589 in chromosome 5 of the rat genome, not previously identified through serial analysis of individual traits. In addition, we were able to justify analytically the parametric restrictions in terms of regression coefficients responsible for the gain in precision with the adopted analytical approach. CONCLUSION: Future work should focus on fine mapping and the identification of the causative variant responsible for this quantitative trait locus signal. The multivariable strategy might be valuable in the study of genetic determinants of interindividual variation of antihypertensive drug effectiveness.

Animals↗
PubMed2006

The great escape: do parasites break Dollo's law?

A long-held assumption in evolutionary studies is that a character that changes from a complex to a simple state is unlikely to return to the same complex state. The extreme version of this assumption has been codified as Dollo's law. Unfortunately, this paradigm has supported the idea that simple and complex traits are qualitatively different, when it is more sensible to suggest that there is a quantitative difference. Dollo's law has been the predominant paradigm in parasitology, where a move from a free-living state to parasitism has been considered a unidirectional pathway or 'one-way trip' because organisms lose the structures required to return to the free-living state. Several recent studies have suggested that complex structures can be regained from simple traits, and we suggest that this is also possible for parasites.

Adaptation, Biological↗
PubMed2001

Molecular genetics of cutaneous lupus erythematosus.

The cutaneous forms of lupus erythematosus (LE) are true complex traits, susceptibility to which is determined by multiple factors. Good evidence exists for both genetic and environmental components to this complexity. Several different experimental techniques have found the strongest genetic associations with cutaneous LE to include sequence polymorphisms of genes encoding HLA, TNF-alpha and complement molecules, particularly in anti-Ro-positive patients. Abnormal expression of multiple other cytokines, adhesion molecules and cellular proteins (such as Ro and La) points towards a range of candidate genes that are currently being examined in cutaneous LE. Combinations of specific polymorphisms of genes encoding these immunoregulatory molecules may determine individual susceptibility to LE.

Cytokines↗
PubMed1998

The genetics of lupus.

Genetic factors strongly influence the risk for systemic lupus erythematosus (SLE). Studies in both animal models and humans suggest that SLE is a complex trait with contributions from multiple genes. Recent genetic studies have shown that polymorphisms at several loci, including the major histocompatibility complex, complement proteins, immunoglobulin receptors, cytokines, and other as yet unmapped genes, are associated with SLE. Ethnic factors are also important because some of these genetic associations are only found in certain populations. Murine models of SLE have provided rational candidate loci to begin genome-wide studies in humans. Promising results are now emerging from such studies.

Animals↗
PubMed2004

Low-density lipoprotein particle size loci in familial combined hyperlipidemia: evidence for multiple loci from a genome scan.

OBJECTIVE: Low-density lipoprotein (LDL) size is associated with vascular disease and with familial combined hyperlipidemia (FCHL). METHODS AND RESULTS: We used logarithm of odds (lod) score and Bayesian Markov chain Monte Carlo (MCMC) linkage analysis methods to perform a 10-cM genome scan of LDL size, measured as peak particle diameter (PPD) and adjusted for age, sex, body mass index, and triglycerides in 4 large families with FCHL (n=185). We identified significant evidence of linkage to a chromosome 9p locus (multipoint lod(max)=3.70; MCMC intensity ratio [IR]=21) in a single family, and across all 4 families to chromosomes 16q23 (lod(max)=3.00; IR=43) near cholesteryl ester transfer protein (CETP) and to 11q22 (lod(max)=3.71; IR=120). Chromosome 14q24-31, a region with previous suggestive LDL PPD linkage evidence, yielded an IR of 71 but an lod(max)=1.79 in the combined families. CONCLUSIONS: These results of significant evidence of linkage to 3 regions (9p, 16q, and 11q) and confirmatory support of previous reported linkage to 14q in large FCHL pedigrees demonstrate that LDL size is a trait influenced by multiple loci and illustrate the complementary use of lod score and MCMC methods in analysis of a complex trait.

Adult↗
PubMed2003

Mapping of quantitative trait loci associated with ultraviolet-B resistance in rice (Oryza sativa L.).

The detection of quantitative trait loci (QTLs) associated with UV-B resistance in rice should allow their practical application in breeding for such a complex trait, and may lead to the identification of gene characteristics and functions. Considerable variation in UV-B resistance exists within cultivated rice (Oryza sativa L.), but its detailed genetic control mechanism has not been well elucidated. We detected putative QTLs associated with the resistance to enhanced UV-B radiation in rice, using 98 BC(1)F(5) (backcross inbred lines; BILs) derived from a cross between Nipponbare (a resistant japonica rice variety) and Kasalath (a sensitive indica rice variety). We used 245 RFLP markers to construct a framework linkage map. BILs and both parents were grown under visible light with or without supplemental UV-B radiation in a growth chamber. In order to evaluate UV-B resistance, we used the relative fresh weight of aerial parts (RFW) and the relative chlorophyll content of leaf blades (RCC). The BIL population exhibited a wide range of variation in RFW and RCC. Using composite interval mapping with a LOD threshold of 2.9, three putative QTLs associated with both RFW and RCC were detected on chromosomes 1, 3 and 10. Nipponbare alleles at the QTLs on chromosome 1 and 10 increased the RFW and RCC, while the Kasalath allele at the QTL on chromosome 3 increased both traits. Furthermore, the existence of both QTLs on chromosomes 1 and 10 for UV-B resistance was confirmed using chromosome segment substitution lines. Plants with Kasalath alleles at the QTL on chromosome 10 were more sensitive to UV-B radiation than plants with them on chromosome 1. These results also provide the information not only for the improvement of UV-B resistance in rice though marker-associated selection, but also for the identification of UV-B resistance mechanisms by using near-isogenic lines.

Chromosome Mapping↗
PubMed2005

Evolution of body size in Galapagos marine iguanas.

Body size is one of the most important traits of organisms and allows predictions of an individual's morphology, physiology, behaviour and life history. However, explaining the evolution of complex traits such as body size is difficult because a plethora of other traits influence body size. Here I review what we know about the evolution of body size in a group of island reptiles and try to generalize about the mechanisms that shape body size. Galapagos marine iguanas occupy all 13 larger islands in this Pacific archipelago and have maximum island body weights between 900 and 12 000g. The distribution of body sizes does not match mitochondrial clades, indicating that body size evolves independently of genetic relatedness. Marine iguanas lack intra- and inter-specific food competition and predators are not size-specific, discounting these factors as selective agents influencing body size. Instead I hypothesize that body size reflects the trade-offs between sexual and natural selection. We found that sexual selection continuously favours larger body sizes. Large males establish display territories and some gain over-proportional reproductive success in the iguanas' mating aggregations. Females select males based on size and activity and are thus responsible for the observed mating skew. However, large individuals are strongly selected against during El Niño-related famines when dietary algae disappear from the intertidal foraging areas. We showed that differences in algae sward ('pasture') heights and thermal constraints on large size are causally responsible for differences in maximum body size among populations. I hypothesize that body size in many animal species reflects a trade-off between foraging constraints and sexual selection and suggest that future research could focus on physiological and genetic mechanisms determining body size in wild animals. Furthermore, evolutionary stable body size distributions within populations should be analysed to better understand selection pressures on individual body size.

Animals↗
PubMed2005

Genetic modifiers interact with Cpe(fat) to affect body weight, adiposity, and hyperglycemia.

Obesity and Type II diabetes are complex diseases in the human population. The existence of a large number of contributing loci and gene-gene as well as gene-environment interactions make it difficult to identify the disease genes underlying these complex traits. In mouse models of obesity and Type II diabetes such as the murine fat mutation, genetic crosses can be used to dissect the genetic complexity influencing the observed phenotypes. The underlying defect in the fat mutant is a Ser202Pro change in carboxypeptidase E (CPE), an enzyme responsible for the final proteolytic processing step of prohormone intermediates. On the HRS/J (HRS) inbred strain background, mice homozygous for the fat mutation exhibit early onset hyperinsulinemia followed by postpubertal moderate obesity without hyperglycemia. In contrast, on the C57BLKS/J (BKS) genetic background, fat/fat mice become severely obese, hyperinsulinemic, and hyperglycemic. Therefore, in the Cpe(fat) genetic model, the fat mutation is necessary but not sufficient for the development of obesity, Type II diabetes, and related metabolic disorders. To dissect the susceptibility loci responsible for modifying obesity- and diabetes-associated traits, we characterized, both genetically and phenotypically, fat/fat male progeny from a large intercross between BKS. HRS-fat/fat and HRS-+/+ mice. Four major loci were mapped, including a locus for body weight (body weight 1) on chromosome 14; a locus for hyperglycemia (fat-induced diabetes 1) on chromosome 19; a locus for hyperglycemia, hyperinsulinemia, and hypercholesterolemia (fat-induced diabetes 2) on chromosome 5; and a locus for adiposity and body weight (fat-induced adiposity 1) on chromosome 11. The identification of these interacting genetic determinants for obesity and Type II diabetes may allow better definition of the obesity/diabetes-related hormone signaling pathways and ultimately may provide new insights into the pathogenesis of these complex diseases.

Adiposity↗
PubMed2003

Linkage analysis of extremely discordant and concordant sibling pairs identifies quantitative-trait loci that influence variation in the human personality trait neuroticism.

Several theoretical studies have suggested that large samples of randomly ascertained siblings can be used to ascertain phenotypically extreme individuals and thereby increase power to detect genetic linkage in complex traits. Here, we report a genetic linkage scan using extremely discordant and concordant sibling pairs, selected from 34,580 sibling pairs in the southwest of England who completed a personality questionnaire. We performed a genomewide scan for quantitative-trait loci (QTLs) that influence variation in the personality trait of neuroticism, or emotional stability, and we established genomewide empirical significance thresholds by simulation. The maximum pointwise P values, expressed as the negative logarithm (base 10), were found on 1q (3.95), 4q (3.84), 7p (3.90), 12q (4.74), and 13q (3.81). These five loci met or exceeded the 5% genomewide significance threshold of 3.8 (negative logarithm of the P value). QTLs on chromosomes 1, 12, and 13 are likely to be female specific. One locus, on chromosome 1, is syntenic with that reported from QTL mapping of rodent emotionality, an animal model of neuroticism, suggesting that some animal and human QTLs influencing emotional stability may be homologous.

Adult↗
PubMed2005

Comparison of single-nucleotide polymorphisms and microsatellites in detecting quantitative trait loci for alcoholism: the Collaborative Study on the Genetics of Alcoholism.

BACKGROUND: The feasibility of effectively analyzing high-density single nucleotide polymorphism (SNP) maps in whole genome scans of complex traits is not known. The purpose of this study was to compare variance components linkage results using different density marker maps in data from the Collaborative Study on the Genetics of Alcoholism (COGA). Marker maps having an average spacing of 10 cM (microsatellite), 0.78 cM (SNP1), and 0.31 cM (SNP2) were used to identify quantitative trait loci (QTLs) affecting maximum number of alcoholic drinks consumed in a 24-hour period (Inmaxalc). RESULTS: Heritability of Inmaxalc was estimated to be 15%. Multipoint variance components linkage analysis revealed similar linkage patterns among the three marker panels, with the SNP maps consistently yielding higher LOD scores. Robust LOD scores > 1.0 were observed on chromosomes 1 and 13 for all three marker maps. Additional LODs > 1.0 were observed on chromosome 4 with both SNP maps and on chromosomes 18 and 21 with the SNP2 map. Peak LOD scores for Inmaxalc were observed on chromosome 1, although none reached genome-wide statistical significance. Quantile-quantile plots revealed that the multipoint distribution of SNP results appeared to fit the asymptotic null distribution better than the twopoint results. CONCLUSION: In conclusion, variance-components linkage analysis using high-density SNP maps provided higher LOD scores compared with the standard microsatellite map, similar to studies using nonparametric linkage methods. Widespread application of SNP maps will depend on further improvements in the computational methods implemented in current software packages.

Alcoholism↗
PubMed2006

Repeated morphological evolution through cis-regulatory changes in a pleiotropic gene.

The independent evolution of morphological similarities is widespread. For simple traits, such as overall body colour, repeated transitions by means of mutations in the same gene may be common. However, for more complex traits, the possible genetic paths may be more numerous; the molecular mechanisms underlying their independent origins and the extent to which they are constrained to follow certain genetic paths are largely unknown. Here we show that a male wing pigmentation pattern involved in courtship display has been gained and lost multiple times in a Drosophila clade. Each of the cases we have analysed (two gains and two losses) involved regulatory changes at the pleiotropic pigmentation gene yellow. Losses involved the parallel inactivation of the same cis-regulatory element (CRE), with changes at a few nucleotides sufficient to account for the functional divergence of one element between two sibling species. Surprisingly, two independent gains of wing spots resulted from the co-option of distinct ancestral CREs. These results demonstrate how the functional diversification of the modular CREs of pleiotropic genes contributes to evolutionary novelty and the independent evolution of morphological similarities.

Animals↗
PubMed2002

Genetics of type 2 diabetes and insulin resistance: knowledge from human studies.

Both type 2 diabetes mellitus (T2DM) and insulin resistance are complex traits in which multiple gene effects and metabolic and environmental factors combine to contribute to the overall pathogenesis of these conditions. This complexity has complicated the search for susceptibility genes and has led to different but complementary approaches being used for the detection of gene effects. These include the study of monogenic cases of insulin resistance and T2DM, association studies of candidate genes and genome-wide scans. The peroxisome proliferator-activated receptor gamma (PPARgamma) and calpain-10 (CAPN10) genes have recently been identified as T2DM susceptibility genes, and the lessons learnt from these studies are helping to shape future strategies to search for additional susceptibility genes in T2DM and insulin resistance.

Calpain↗
PubMed2005

Physical mapping of genes in the porcine ovarian transcriptome.

Reproductive efficiency and associated traits are of major economic importance to the swine industry and have been more difficult to improve genetically than other production traits. Integration of phenotypical data with gene mapping and expression studies provides a powerful approach for dissection of the genetic basis regulating complex traits. We developed a total of 101 polymerase chain reaction-based markers, representing 91 unique genes, for expressed sequence tags previously reported to be putatively differentially expressed in the porcine ovarian transcriptome of a swine line selected on an index of high ovulation rate and embryonic survival. These were subsequently used in physical mapping experiments with a porcine radiation hybrid and somatic cell hybrid panels. Our results increased the information content of the porcine physical map useful for comparative mapping by c. 10%. Moreover, the mapped genes are likely to be biologically relevant to the molecular mechanisms that control ovulation rate in the pig. A total of 12 differentially expressed genes were mapped to regions previously reported to contain quantitative trait loci affecting swine ovulation rate.

Animals↗
PubMed2001

Genetic basis of schizophrenia: trinucleotide repeats. An update.

1. Recent developments in technologies permit systematic screening of the entire human genome as a strategy for identification of susceptibility genes of small effect that influence risk to complex traits, like schizophrenia (Schz), inflammatory bowel disease, bipolar affective disorder (BPAD) etc. 2. Schizophrenia is known to have a high heritability and a complex inheritance pattern. Several studies provide evidence that both genes and environment play a role in the etiology of schizophrenia. Linkage studies have observed racial and sex bias in the genetic constitution of schizophrenia. Schizophrenia also manifests clinical anticipation and genomic imprinting. 3. "Dynamic mutations" or "tandem repeat expansions" in DNA, explain a number of observations associated with clinical anticipation and genomic imprinting. In patient populations, the repeat expands well beyond the normal range, altering the biological function of the gene. These sequence are unstable and increase in size between family members in successive generations, giving rise to greater severity of disease. 4. Several workers have reported an association of trinucleotide repeat length with adult- and child-onset schizophrenia. One such expanded allele has been found at the CTG18.1 locus on the 18th chromosome. Other genes known to have similar mutation are SEF2-1, which codes for a helix-loop-helix protein, hSKCa3 gene, which codes for a calcium-activated potassium channel and the transthyretin gene. In schizophrenic patients, significant difference in allele frequency distribution of these genes has been reported. 5. Population based genetic research would not only help identify different subgroups of this of schizophrenia.

Animals↗
PubMed2006

Mendelian disorders deserve more attention.

The study of inherited monogenic diseases has contributed greatly to our mechanistic understanding of pathogenic mutations and gene regulation, and to the development of effective diagnostic tools. But interest has gradually shifted away from monogenic diseases, which collectively affect only a small fraction of the world's population, towards multifactorial, common diseases. The quest for the genetic variability associated with common traits should not be done at the expense of Mendelian disorders, because the latter could still contribute greatly to understanding the aetiology of complex traits.

Animals↗
PubMed2002

High-resolution patterns of meiotic recombination across the human major histocompatibility complex.

Definitive characteristics of meiotic recombination events over large (i.e., >1 Mb) segments of the human genome remain obscure, yet they are essential for establishing the haplotypic structure of the genome and for efficient mapping of complex traits. We present a high-resolution map of recombination at the kilobase level across a 3.3-Mb interval encompassing the major histocompatibility complex (MHC). Genotyping of 20,031 single sperm from 12 individuals resulted in the identification and fine mapping of 325 recombinant chromosomes within genomic intervals as small as 7 kb. Several principal characteristics of recombination in this region were observed: (1) rates of recombination can differ significantly between individuals; (2) intense hot spots of recombination occur at least every 0.8 Mb but are not necessarily evenly spaced; (3) distribution in the location of recombination events can differ significantly among individuals; (4) between hot spots, low levels of recombination occur fairly evenly across 100-kb segments, suggesting the presence of warm spots of recombination; and (5) specific sequence motifs associate significantly with recombination distribution. These data provide a plausible model for recombination patterns of the human genome overall.

Adolescent↗
PubMed2026

Integrative haplotype and SNP-based GWAS supports the identification of stable genomic loci controlling yield-related traits in soybean.

Soybean yield is vulnerable to environmental variation, therefore, it is important to detect and implement stable genomic regions associated with yield-related traits in soybean breeding programs. In this study, SNP and haplotype-based GWAS were conducted to reveal important candidate genomic regions and putative candidate genes associated with soybean yield-related traits. This study demonstrates that the integration of haplotype and SNP-based GWAS could improve the detection of genomic regions associated with complex traits, enhance statistical power, and facilitate the identification of biologically relevant candidate genes. Ten stable haplotype blocks and six stable SNPs were detected based on the integration of haplotype and SNP-based GWAS, respectively. Furthermore, multiple candidate genes associated with the yield-related traits were identified. For instance, six genes were identified as transporters, including Glyma.15G092800, encoding serine-type endopeptidase activity, Glyma.15G203300 encoding a major facilitator superfamily (MFS) sugar transporter, Glyma.04G163000, transmembrane transporter, and Glyma.04G164100, leucine-rich repeat receptor-like protein kinase (LRR-RLK), as the most promising candidate genes. Additionally, three genes involved in signaling and pathways of various phytohormones can be promising candidates for increasing seed yield through improving plant architecture in soybean plants. The identified superior haplotypes with favourable alleles will be useful for marker-assisted selection in future breeding programs in soybean.

DArT markers↗