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PubMed2003

The evolution of evolvability in genetic linkage patterns.

A number of factors have been proposed that may affect the capacity for an evolutionary system to generate adaptation. One that has received little recent attention among biologists is linkage patterns, or the ordering of genes on chromosomes. In this study, a simple model of genetic interactions, implemented in an evolutionary simulation, demonstrates that clustering of epistatically interacting genes increases the rate of adaptation. Moreover, long-term evolution with inversion can reorganize linkage patterns from random gene ordering into this more modular organization, thereby facilitating adaptation. These results are consistent with a large body of biological observations and some mathematical theory. Although linkage patterns are neutral with respect to individual fitness in this model, they are subject to lineage level selection for evolvability. At least two candidate mechanisms may contribute to improved evolvability under epistatic clustering: clustering may reduce interference between selection on different traits, and it may allow the simultaneous optimization of different recombination rates for gene pairs with additive and epistatic fitness effects.

Adaptation, Physiological↗
PubMed2004

Comparative mapping and marker-assisted selection in Rosaceae fruit crops.

The development of saturated linkage maps using transferable markers, restriction fragment length polymorphisms, and micro-satellites has provided a foundation for fruit tree genetics and breeding. A Prunus reference map with 562 such markers is available, and a further set of 13 maps constructed with a subset of these markers has allowed genome comparison among seven Prunus diploid (x = 8) species (almond, peach, apricot, cherry, Prunus ferganensis, Prunus davidiana, and Prunus cerasifera); marker colinearity was the rule with all of them. Preliminary results of the comparison between apple and Prunus maps suggest a high level of synteny between these two genera. Conserved genomic regions have also been detected between Prunus and Arabidopsis. By using the data from different linkage maps anchored with the reference Prunus map, it has been possible to establish, in a general map, the position of 28 major genes affecting agronomic characters found in different species. Markers tightly linked to the major genes responsible for the expression of important traits (disease/pest resistances, fruit/nut quality, self-incompatibility, etc.) have been developed in apple and Prunus and are currently in use for marker-assisted selection in breeding programs. Quantitative character dissection using linkage maps and candidate gene approaches has already started. Genomic tools such as the Prunus physical map, large EST collections in both Prunus and Malus, and the establishment of the map position of high numbers of ESTs are required for a better understanding of the Rosaceae genome and to foster additional research and applications on fruit tree genetics.

Arabidopsis↗
PubMed2004

Highly significant linkage to the SLI1 locus in an expanded sample of individuals affected by specific language impairment.

Specific language impairment (SLI) is defined as an unexplained failure to acquire normal language skills despite adequate intelligence and opportunity. We have reported elsewhere a full-genome scan in 98 nuclear families affected by this disorder, with the use of three quantitative traits of language ability (the expressive and receptive tests of the Clinical Evaluation of Language Fundamentals and a test of nonsense word repetition). This screen implicated two quantitative trait loci, one on chromosome 16q (SLI1) and a second on chromosome 19q (SLI2). However, a second independent genome screen performed by another group, with the use of parametric linkage analyses in extended pedigrees, found little evidence for the involvement of either of these regions in SLI. To investigate these loci further, we have collected a second sample, consisting of 86 families (367 individuals, 174 independent sib pairs), all with probands whose language skills are >/=1.5 SD below the mean for their age. Haseman-Elston linkage analysis resulted in a maximum LOD score (MLS) of 2.84 on chromosome 16 and an MLS of 2.31 on chromosome 19, both of which represent significant linkage at the 2% level. Amalgamation of the wave 2 sample with the cohort used for the genome screen generated a total of 184 families (840 individuals, 393 independent sib pairs). Analysis of linkage within this pooled group strengthened the evidence for linkage at SLI1 and yielded a highly significant LOD score (MLS = 7.46, interval empirical P<.0004). Furthermore, linkage at the same locus was also demonstrated to three reading-related measures (basic reading [MLS = 1.49], spelling [MLS = 2.67], and reading comprehension [MLS = 1.99] subtests of the Wechsler Objectives Reading Dimensions).

Adaptor Proteins, Signal Transducing↗
PubMed2005

Targeting of cohesin by transcriptionally silent chromatin.

Eukaryotic DNA replication produces sister chromatids that are linked together until anaphase by cohesin, a ring-shaped protein complex that is thought to act by embracing both chromatids. Cohesin is enriched at centromeres, as well as discrete sites along chromosome arms where transcription positions the complex between convergent gene pairs. A relationship between cohesin and Sir-mediated transcriptional silencing has also begun to emerge. Here we used fluorescence microscopy and site-specific recombination to characterize interactions between newly replicated copies of the silent HMR mating-type locus. HMR was tagged with lac-GFP and flanked by binding sites for an inducible site-specific recombinase. Excision of the locus in cells with sister chromatids produced two chromatin circles that remained associated with one another. Pairing of the circles required silent chromatin, cohesin, and the RSC chromatin-remodeling complex. Chromatin immunoprecipitation showed that targeting of cohesin to the locus is Sir-dependent, and functional tests showed that silent chromatin acts in a continuous fashion to maintain cohesion. Remarkably, loss of silencing led to loss of cohesin from linear chromosomal templates but not from excised chromatin circles. The results are consistent with a model in which cohesin binds silent chromatin via topological linkage to individual chromatids.

Cell Cycle Proteins↗
PubMed2005

Challenges for identifying functionally important genetic variation: the promise of combining complementary research strategies.

Strategies for the identification of functional genetic variation underlying phenotypic traits of ecological and evolutionary importance have received considerable attention in the literature recently. This paper aims to bring together and compare the relative strengths and limitations of various potentially useful research strategies for dissecting functionally important genetic variation in a wide range of organisms. We briefly explore the relative strengths and limitations of traditional and emerging approaches and evaluate their potential use in free-living populations. While it is likely that much of the progress in functional genetic analyses will rely on progress in traditional model species, it is clear that with prudent choices of methods and appropriate sampling designs, much headway can be also made in a diverse range of species. We suggest that combining research approaches targeting different functional and biological levels can potentially increase understanding the genetic basis of ecological and evolutionary processes both in model and non-model organisms.

Gene Expression Profiling↗
PubMed2005

Stable two-element control of dTph1 transposition in mutator strains of Petunia by an inactive ACT1 introgression from a wild species.

The high copy dTph1 transposon system of Petunia (Solanaceae) is one of the most powerful insertion mutagens in plants, but its activity cannot be controlled in the commonly used mutator strains. We analysed the regulation of dTph1 activity by QTL analysis in recombinant inbred lines of the mutator strain W138 and a wild species (P. integrifolia spp. inflata). Two genetic factors were identified that control dTph1 transposition. One corresponded to the ACT1 locus on chromosome I. A second, previously undescribed locus ACT2 mapped on chromosome V. As a 6-cM introgression in W138, the P. i. inflata act1(S6) allele behaved as a single recessive locus that fully eliminated transposition of all dTph1 elements in all stages of plant development and in a heritable fashion. Weak dTph1 activity was restored in act1S6/ACT2S6 double introgression lines, indicating that the P. i. inflata allele at ACT2 conferred a low level of transposition. Thus, the act1S6 allele is useful for simple and predictable control of transposition of the entire dTph1 family when introgressed into an ultra-high copy W138 mutator strain. We demonstrate the use of the ACT1W138/act1S6 allele pair in a two-element dTph1 transposition system by producing 10,000 unique and fixed dTph1 insertions in a population of 1250 co-isogenic lines. This Petunia system produces the highest per plant insertion number of any known two-element system, providing a powerful and logistically simple tool for transposon mutagenesis of qualitative as well as quantitative traits.

Chromosome Mapping↗
PubMed2006

Flanking HS-62.5 and 3' HS1, and regions upstream of the LCR, are not required for beta-globin transcription.

The locus control region (LCR) was thought to be necessary and sufficient for establishing and maintaining an open beta-globin locus chromatin domain in the repressive environment of the developing erythrocyte. However, deletion of the LCR from the endogenous locus had no significant effect on chromatin structure and did not silence transcription. Thus, the cis-regulatory elements that confer the open domain remain unidentified. The conserved DNaseI hypersensitivity sites (HSs) HS-62.5 and 3'HS1 that flank the locus, and the region upstream of the LCR have been implicated in globin gene regulation. The flanking HSs bind CCCTC binding factor (CTCF) and are thought to interact with the LCR to form a "chromatin hub" involved in beta-globin gene activation. Hispanic thalassemia, a deletion of the LCR and 27 kb upstream, leads to heterochromatinization and silencing of the locus. Thus, the region upstream of the LCR deleted in Hispanic thalassemia (upstream Hispanic region [UHR]) may be required for expression. To determine the importance of the UHR and flanking HSs for beta-globin expression, we generated and analyzed mice with targeted deletions of these elements. We demonstrate deletion of these regions alone, and in combination, do not affect transcription, bringing into question current models for the regulation of the beta-globin locus.

5' Flanking Region↗
PubMed2006

Identification of QTLs controlling gene expression networks defined a priori.

BACKGROUND: Gene expression microarrays allow the quantification of transcript accumulation for many or all genes in a genome. This technology has been utilized for a range of investigations, from assessments of gene regulation in response to genetic or environmental fluctuation to global expression QTL (eQTL) analyses of natural variation. Current analysis techniques facilitate the statistical querying of individual genes to evaluate the significance of a change in response, also known as differential expression. Since genes are also known to respond as groups due to their membership in networks, effective approaches are needed to investigate transcriptome variation as related to gene network responses. RESULTS: We describe a statistical approach that is capable of assessing higher-order a priori defined gene network response, as measured by microarrays. This analysis detected significant network variation between two Arabidopsis thaliana accessions, Bay-0 and Shahdara. By extending this approach, we were able to identify eQTLs controlling network responses for 18 out of 20 a priori-defined gene networks in a recombinant inbred line population derived from accessions Bay-0 and Shahdara. CONCLUSION: This approach has the potential to be expanded to facilitate direct tests of the relationship between phenotypic trait and transcript genetic architecture. The use of a priori definitions for network eQTL identification has enormous potential for providing direction toward future eQTL analyses.

Arabidopsis↗
PubMed2003

Exploring pleiotropy using principal components.

A standard multivariate principal components (PCs) method was utilized to identify clusters of variables that may be controlled by a common gene or genes (pleiotropy). Heritability estimates were obtained and linkage analyses performed on six individual traits (total cholesterol (Chol), high and low density lipoproteins, triglycerides (TG), body mass index (BMI), and systolic blood pressure (SBP)) and on each PC to compare our ability to identify major gene effects. Using the simulated data from Genetic Analysis Workshop 13 (Cohort 1 and 2 data for year 11), the quantitative traits were first adjusted for age, sex, and smoking (cigarettes per day). Adjusted variables were standardized and PCs calculated followed by orthogonal transformation (varimax rotation). Rotated PCs were then subjected to heritability and quantitative multipoint linkage analysis. The first three PCs explained 73% of the total phenotypic variance. Heritability estimates were above 0.60 for all three PCs. We performed linkage analyses on the PCs as well as the individual traits. The majority of pleiotropic and trait-specific genes were not identified. Standard PCs analysis methods did not facilitate the identification of pleiotropic genes affecting the six traits examined in the simulated data set. In addition, genes contributing 20% of the variance in traits with over 0.60 heritability estimates could not be identified in this simulated data set using traditional quantitative trait linkage analyses. Lack of identification of pleiotropic and trait-specific genes in some cases may reflect their low contribution to the traits/PCs examined or more importantly, characteristics of the sample group analyzed, and not simply a failure of the PC approach itself.

Blood Pressure↗
PubMed2005

Quantitative genomics of starvation stress resistance in Drosophila.

BACKGROUND: A major challenge of modern biology is to understand the networks of interacting genes regulating complex traits, and the subset of these genes that affect naturally occurring quantitative genetic variation. Previously, we used P-element mutagenesis and quantitative trait locus (QTL) mapping in Drosophila to identify candidate genes affecting resistance to starvation stress, and variation in resistance to starvation stress between the Oregon-R (Ore) and 2b strains. Here, we tested the efficacy of whole-genome transcriptional profiling for identifying genes affecting starvation stress resistance. RESULTS: We evaluated whole-genome transcript abundance for males and females of Ore, 2b, and four recombinant inbred lines derived from them, under control and starved conditions. There were significant differences in transcript abundance between the sexes for nearly 50% of the genome, while the transcriptional response to starvation stress involved approximately 25% of the genome. Nearly 50% of P-element insertions in 160 genes with altered transcript abundance during starvation stress had mutational effects on starvation tolerance. Approximately 5% of the genome exhibited genetic variation in transcript abundance, which was largely attributable to regulation by unlinked genes. Genes exhibiting variation in transcript abundance among lines did not cluster within starvation resistance QTLs, and none of the candidate genes affecting variation in starvation resistance between Ore and 2b exhibited significant differences in transcript abundance between lines. CONCLUSIONS: Expression profiling is a powerful method for identifying networks of pleiotropic genes regulating complex traits, but the relationship between variation in transcript abundance among lines used to map QTLs and genes affecting variation in quantitative traits is complicated.

Adaptation, Physiological↗
PubMed2004

[Advance on insulin-like growth factor 2].

Insulin-like growth factors play an important role in fetal growth and development, tumour cell proliferation and muscle growth. This review is focused on the insulin-like growth factor 2 gene structures, and their imprintings in mammalian genomes. In addition, we also discussed that IGF2 is the major paternally expressed candidate gene affecting muscle mass.

Animals↗
PubMed2004

Microarray gene expression analysis of the Fob3b obesity QTL identifies positional candidate gene Sqle and perturbed cholesterol and glycolysis pathways.

Obesity-related diseases are poised to become the primary cause of death in developed nations. While a number of monogenic causes of obesity have recently been identified, these are responsible for only a small proportion of human cases of obesity. Quantitative trait locus (QTL) studies using animal models have revealed hundreds of potential loci that affect obesity; however, few have been further analyzed beyond the original QTL scan. We previously mapped four QTL in an F(2) between divergently selected Fat (F) and Lean (L) lines. A QTL of large effect on chromosome 15 (Fob3) was subsequently mapped to a higher resolution into two smaller-effect QTL (Fob3a and Fob3b) using crosses between the F-line and a congenic line containing L-line alleles at the Fob3 QTL region. Here we report the gene expression characterization of Fob3b. Microarray expression analysis using the NIA-NIH 15K cDNA array set containing 14,938 mouse ESTs was employed to identify candidate genes and pathways that are differentially expressed between the F-line and a congenic line containing only the Fob3b QTL (Fob3b-line). Our study suggests squalene epoxidase (Sqle), a cholesterol biosynthesis enzyme, as a strong positional candidate gene for Fob3b. Several other cholesterol biosynthesis pathway genes unlinked to Fob3b were found to be differentially expressed, suggesting that a perturbation of this pathway could be in part responsible for the phenotypic difference between the F-line and Fob3b-line mice.

Animals↗
PubMed2001

Gene expression profiling of the nervous system in murine experimental autoimmune encephalomyelitis.

Multiple sclerosis is thought to be a polygenic disease driven by dysregulation of the immune system leading to an autoimmune response against one or several antigens of cerebral white matter tissue. Experimental autoimmune encephalomyelitis (EAE) is a mouse model that is used to study the aetiology and pathogenesis of multiple sclerosis and new therapeutic approaches. We used oligonucleotide microarrays to determine gene expression profiles of the inflamed spinal cords of EAE mice at the onset and at the peak of the disease. Of the approximately 11 000 genes studied, 213 were regulated differentially and 100 showed consistent differential regulation throughout the disease. Inflammation resulted in a profile of increased gene expression of immune-related molecules, extracellular matrix and cell adhesion molecules and molecules involved in cell division and transcription, and differential regulation of molecules involved in signal transduction, protein synthesis and metabolism. Of the 104 genes with defined chromosomal locations, 51 mapped to known EAE-linked quantitative trait loci and as such are putative candidate genes for susceptibility to EAE.

Animals↗
PubMed2005

[Analysis of heading time genotype for a rice photoperiod and thermo--sensitive male sterile line PeiAi64S].

PeiAi64S, a photoperiod and thermo-sensitive genic male sterile, has been wildly applied to hybrid rice seed production in China, but its photoperiod-sensitivity gene for heading date in this sterile line was still unknown. This definitely limited the further use of this sterile line in breeding practice and re-production of hybrid seeds. To solve this problem, using heading time nearly isogenic lines EGO - EG7, ER - LR, T65 - T65m and six heading date QTL-isogenic lines, NIL (Hd1) - NIL (Hd6) with the genes of Nipponbare but Hd1 - Hd6 genes from Kasalath respectively, we performed a genetic analysis of PeiAi64S with special reference to photoperiod-sensitivity loci, in natural long days at Nanjing (32 degrees N) where the average day-length is about 14 h and in natural short days at Linshui county, Hainan province(18 degrees 29'N), where the average day-length is about 11.6 h during the course of rice growing respectively. The F1 and F2 generations from the crosses 'PeiAi64S x heading time nearly isogenic lines' were subjected to genetic analyses. Experimental results showed that PeiAi64S carries photoperiod-sensitivity allele gene E1 and E3 and dominant earliness gene Ef-1 in E1 and E3 and Ef-1 loci, respectively, and a photoperiod insensitivity allele Se-1 degrees in Se-1 locus. Meanwhile, the photoperiod-sensitivity gene E1 and photoperiod-insensitivity gene Se-1e in PeiAi64S were also identified by crossing with the NIL(Hd1) and NIL(Hd4). In addition, a recessive inhibitor for photoperiod-sensitive gene E1 or Se-1(n) and other modified photoperiod-sensitive genes: i-Se-1, E3, Hd3 (En-Se-1), Hd5 and Hd6, were identified in PeiAi64S by crossing with QTL nearly isogenic lines: NIL(Hd2), NIL (Hd3), NIL (Hd5) and NIL( Hd6), The results indicated that the genotype of PeiAi64S's heading date was: E1E1e2e2E3E3Se-1(e)Se-1(e)Ef-1 Ef-1 i-Se-1 i-Se-1.

Breeding↗
PubMed2000

Synergistic gene interactions control the induction of the mitochondrial uncoupling protein (Ucp1) gene in white fat tissue.

Among a selected group of mouse strains susceptible to dietary obesity, those with an enhanced capacity for Ucp1 and brown adipocyte induction in white fat preferentially lost body weight following adrenergic stimulation. Based on the generality of this mechanism for reducing obesity, a genetic analysis was initiated to identify genes that control brown adipocyte induction in white fat depots in mice. Quantitative trait locus (QTL) analysis was performed using the variations of retroperitoneal fat Ucp1 mRNA expression in progeny of genetic crosses between the A/J and C57BL/6J parental strains and selected AXB recombinant inbred strains. Three A/J-derived loci on chromosomes 2, 3, and 8 and one C57BL/6J locus on chromosome 19 were linked to Ucp1 induction in retroperitoneal fat. Although A/J-derived alleles seemed to contribute to elevated Ucp1 expression, the C57BL/6J allele on chromosome 19 increased Ucp1 mRNA to levels higher than parental values. Thus, novel patterns of C57BL/6J and A/J recombinant genotypes among the four mapped loci resulted in a transgressive variation of Ucp1 phenotypes. Although the extent of the interchromosomal interactions have not been fully explored, strong synergistic interactions occur between a C57BL/6J allele on chromosome 19 and an A/J allele on chromosome 8. In addition to selective synergistic interactions between loci, variations in recessive and dominant effects also contribute to the final levels of Ucp1 expression.

Adipose Tissue↗
PubMed2006

Carotenoid biosynthesis structural genes in carrot (Daucus carota): isolation, sequence-characterization, single nucleotide polymorphism (SNP) markers and genome mapping.

Carotenoid pigments are important components of the human diet and carrots are the main dietary sources of the vitamin A precursors alpha- and beta-carotene. Carotenoids play essential biological roles in plants and the genes coding for the carotenoid pathway enzymes are evolutionarily conserved, but little information exists about these genes for carrot. In this study, we utilized published carrot sequences as well as heterologous PCR approaches with primers derived from sequence information of other plant species to isolate 24 putative genes coding for carotenoid biosynthesis enzymes in carrot. Twenty-two of these genes were placed on the carrot genetic linkage map developed from a cross between orange-rooted and white-rooted carrot. The carotenoid genes were distributed in eight of the nine linkage groups in the carrot genome recommending their use for merging maps. Two genes co-localized with a genomic region spanning one of the most significant quantitative trait loci (QTL) for carotenoid accumulation. Carotenoid biosynthesis cDNAs linked to root color mutations and to QTL for carotenoid accumulation may suggest a functional role for them as candidate genes. RACE PCR and reverse transcriptase PCR were used to amplify the full-length transcript for twenty expressed carotenoid biosynthesis genes and sequences were submitted to GenBank. The cloning and sequence information of these genes is useful for PCR-based expression studies and may point toward transgenic approaches to manipulate carotenoid content in carrot.

Base Sequence↗
PubMed2004

Chromosomes 6 and 13 harbor genes that regulate pubertal timing in mouse chromosome substitution strains.

Variation in the onset of puberty among inbred strains of mice suggests that quantitative trait loci (QTLs) affect neurological and hormonal aspects of sexual maturation. Taking a novel approach toward identifying factors that regulate the hypothalamic-pituitary-gonadal (HPG) axis, we evaluated pubertal timing [as assessed by vaginal opening (VO)] in two inbred strains of mice, A/J and C57BL/6J (B6), and in a panel of chromosome substitution strains (CSSs) generated from A/J and B6 mice. In each CSS, a single chromosome from A/J has been substituted in a homozygous fashion for the corresponding chromosome in B6, partitioning the A/J genome into 22 strains with a common host (B6) background. VO occurred significantly earlier in A/J compared with B6 mice. Although the majority of the CSSs assessed had a timing of VO that was similar to the progenitor B6 strain, CSSs for chromosomes 6 and 13 each displayed significantly earlier time of VO than B6 mice. F1 (B6 x CSS) mice for chromosomes 6 and 13 displayed phenotypes that were intermediate between the CSS and B6 strains, suggesting that the trait was inherited in a codominant manner. These findings demonstrate that chromosomes 6 and 13 harbor QTLs that control the timing of VO. Identification of the responsible genes may reveal factors that regulate the maturation of the HPG axis and determine the timing of puberty.

Animals↗