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PubMed2005

Complete and overlapping congenics proving the existence of a quantitative trait locus for blood pressure on Dahl rat chromosome 17.

Linkage studies suggested that a quantitative trait locus (QTL) for blood pressure (BP) was present in a region on chromosome 17 (Chr 17) of Dahl salt-sensitive (DSS) rats. A subsequent congenic strain targeting this QTL, however, could not confirm it. These conflicting results called into question the validity of localization of a QTL by linkage followed by the use of a congenic strain made with an incomplete chromosome coverage. To resolve this issue, we constructed five new congenic strains, designated C17S.L1 to C17S.L5, that completely spanned the +/-2 LOD confidence interval supposedly containing the QTL. Each congenic strain was made by replacing a segment of the DSS rat by that of the normotensive Lewis (LEW) rat. The only section to be LL homozygous is the region on Chr 17 specified in a congenic strain, as evidenced by a total genome scan. The results showed that BPs of C17S.L1 and C17S.L2 were lower (P < 0.04) than that of DSS rats. In contrast, BPs of C17S.L3, C17S.L4, and C17S.L5 were not different (P > 0.6) from that of DSS rats. Consequently, a BP QTL must be located in an interval of approximately 15 cM shared between C17S.L1 and C17S.L2 and unique to them both, as opposed to C17S.L3, C17S.L4, and C17S.L5. The present study illustrates the importance of thorough chromosome coverage, the necessity for a genome-wide screening, and the use of "negative" controls in physically mapping a QTL by congenic strains.

Animals↗
PubMed2005

Quantitative trait locus mapping in natural populations: progress, caveats and future directions.

Over the last 15 years quantitative trait locus (QTL) mapping has become a popular method for understanding the genetic basis of continuous variation in a variety of systems. For example, the technique is now an integral tool in medical genetics, livestock production, plant breeding and population genetics of model organisms. Ten years ago, it was suggested that the method could be used to understand continuous variation in natural populations. In this review I: (i) clarify what is meant by natural population in the QTL context, (ii) discuss whether evolutionary biologists have successfully mapped QTL in natural populations, (iii) highlight some of the questions that have been addressed by QTL mapping in natural populations, (iv) describe how QTL mapping can be conducted in unmanipulated natural populations, (v) highlight some of the limitations of QTL mapping and (vi) try to predict some future directions for QTL mapping in natural populations.

Biological Evolution↗
PubMedDate not supplied

A rapid method for computing the inverse of the gametic covariance matrix between relatives for a marked quantitative trait locus.

The inverse of the gametic covariance matrix between relatives, G(-1), for a marked quantitative trait locus (QTL) is required in best linear unbiased prediction (BLUP) of breeding values if marker data are available on a QTL. A rapid method for computing the inverse of a gametic relationship matrix for a marked QTL without building G itself is presented. The algorithm is particularly useful due to the approach taken in computing inbreeding coefficients by having to compute only few elements of G. Numerical techniques for determining, storing, and computing the required elements of G and the nonzero elements of the inverse are discussed. We show that the subset of G required for computing the inbreeding coefficients and hence the inverse is a tiny proportion of the whole matrix and can be easily stored in computer memory using sparse matrix storage techniques. We also introduce an algorithm to determine the maximum set of nonzero elements that can be found in G(-1) and a strategy to efficiently store and access them. Finally, we demonstrate that the inverse can be efficiently built using the present techniques for very large and inbred populations.

Algorithms↗
PubMed2000

Hd1, a major photoperiod sensitivity quantitative trait locus in rice, is closely related to the Arabidopsis flowering time gene CONSTANS.

A major quantitative trait locus (QTL) controlling response to photoperiod, Hd1, was identified by means of a map-based cloning strategy. High-resolution mapping using 1505 segregants enabled us to define a genomic region of approximately 12 kb as a candidate for Hd1. Further analysis revealed that the Hd1 QTL corresponds to a gene that is a homolog of CONSTANS in Arabidopsis. Sequencing analysis revealed a 43-bp deletion in the first exon of the photoperiod sensitivity 1 (se1) mutant HS66 and a 433-bp insertion in the intron in mutant HS110. Se1 is allelic to the Hd1 QTL, as determined by analysis of two se1 mutants, HS66 and HS110. Genetic complementation analysis proved the function of the candidate gene. The amount of Hd1 mRNA was not greatly affected by a change in length of the photoperiod. We suggest that Hd1 functions in the promotion of heading under short-day conditions and in inhibition under long-day conditions.

Amino Acid Sequence↗
PubMed2003

Exaggerated response to restraint stress in rats congenic for the chromosome 1 blood pressure quantitative trait locus.

1. To understand the roles of a putative hypertension gene in the chromosome 1 quantitative trait locus (QTL) region, the response to restraint stress was studied in strains congenic for this QTL. 2. To establish congenic strains, the QTL region was introgressed from stroke-prone spontaneously hypertensive rats (SHRSP)/Izm to Wistar-Kyoto/Izm (WKY/Izm) rats by repeated backcrossing. Two congenic strains (WKYpch1.0 and WKYpch1.1) were established to cover the whole QTL region between D1Wox29 and D1Arb21 (approximately 40 cM) and a smaller region between D1Smu11 and D1Arb21 (approximately 10 cM), respectively. After telemetry probes were implanted, rats were exposed to restraint stress to investigate the blood pressure response. 3. Basal blood pressure measured by radiotelemetry differed significantly between WKY rats and WKYpch1.0 (103 +/- 10 and 116 +/- 4 mmHg, respectively; P = 0.002 by anova). When exposed to restraint stress, WKYpch1.0 showed a greater increase in blood pressre than did WKY rats. The exaggerated response in the WKYpch1.0 strain was abolished by chemical sympathectomy using guanethidine. The WKYpch1.1 rats did not differ significantly from WKY rats either in basal blood pressure or in the response to restraint stress. 4. In conclusion, a QTL for high blood pressure was successfully introgressed in the established congenic strain, WKYpch1.0. A gene (or genes) in the chromosome 1 QTL region modulates the cardiovascular responses to restraint stress in these congenic rats, probably through the sympathetic nervous system.

Animals↗
PubMed2005

Quantitative trait locus mapping and DNA array hybridization identify an FLM deletion as a cause for natural flowering-time variation.

Much of the flowering time variation in wild strains of Arabidopsis thaliana is due to allelic variation at two epistatically acting loci, FRIGIDA (FRI) and FLOWERING LOCUS C (FLC). FLC encodes a MADS (MCM1/AGAMOUS/DEFICIENS/SRF1) domain transcription factor that directly represses a series of flowering-promoting genes. FRI and FLC, however, do not explain all of the observed variation, especially when plants are grown in short days. To identify loci that act in addition to FRI and FLC in controlling flowering of natural accessions, we have analyzed a recombinant inbred line population derived from crosses of accession Niederzenz (Nd) to Columbia, both of which contain natural FRI lesions. Quantitative trait locus mapping and genomic DNA analysis by microarray hybridization were used to identify candidate genes affecting variation in flowering behavior. In both long and short days, the quantitative trait locus of largest effect, termed FLOWERING 1 (FLW1), was found to be associated with a Nd-specific deletion of FLOWERING LOCUS M (FLM), which encodes a floral repressor closely related to FLC. Analysis of near isogenic lines and quantitative transgenic complementation experiments confirmed that the FLM deletion is, in large part, responsible for the early flowering of the Nd accession.

Alleles↗
PubMed2004

A Leishmania major response locus identified by interval-specific congenic mapping of a T helper type 2 cell bias-controlling quantitative trait locus.

The propensity of naive CD4 T cells to become T helper (Th) type 2 cells correlates with susceptibility to infection by the protozoal parasite Leishmania major. Using genetic linkage analysis, we earlier identified Dice1 as a Th2 cell bias-controlling quantitative trait locus on chromosome 16. Using interval-specific congenic mapping, we now resolve Dice1 into two independent genetic loci, Dice1.1 and Dice1.2, which control Il4 expression from naive Th cells and thereby indirectly control Th2 cell bias. Interestingly, only one of the two congenic intervals containing Dice1.1 and Dice1.2, respectively, also contained an L. major response locus, indicating that L. major responsiveness can be insensitive to determinants that influence Th2 cell bias by controlling naive T cell Il4 expression. These results lay the groundwork for identifying the Dice1.1 and Dice1.2 genes controlling naive T cell Il4 expression and L. major responses, and for testing whether these control other Th2 cell-dependent processes such as worm expulsion, allergic asthma, and dermatitis.

Animals↗
PubMed2003

Quantitative trait locus analysis of plasma cholesterol and triglyceride levels in KK x RR F2 mice.

A previous quantitative trait locus (QTL) study on hyperlipidemia in C57BL/6J x KK-Ay/a F2 mice identified three significant cholesterol QTLs (Cq1 and Cq2 on chromosome 1, and Cq3 on chromosome 3), and a suggestive triglyceride QTL on chromosome 9. An alternative analysis of this study identified a novel cholesterol QTL on chromosome 9 (Cq4), and a significant triglyceride QTL on chromosome 9 (Tgq1). In the present study, QTL analysis was performed on KK x RR F2 mice. A significant cholesterol QTL (Cq5, lod score 5.6) was identified on chromosome 9, and a significant triglyceride QTL (Tgq2, lod score 4.7) was identified on chromosome 8. The Cq5 locus was mapped to a region similar to the Cq4 locus. On the other hand, the Tgq2 locus overlapped with the QTL region responsible for glucose intolerance (Giq1) that was identified in a previous study. The results suggest that a different combination of QTLs is involved in the trait when a different counterpart strain is used. Identification of distinct, but related traits in an identical chromosomal region will facilitate revealing the responsible gene.

Alleles↗
PubMed2001

Optimal sibship selection for genotyping in quantitative trait locus linkage analysis.

In this paper we present a novel method for selecting optimally informative sibships of any size for quantitative trait locus (QTL) linkage analysis. The method allocates a quantitative index of potential informativeness to each sibship on the basis of observed trait scores and an assumed true QTL model. Any sample of phenotypically screened sibships can therefore be easily rank-ordered for selective genotyping. The quantitative index is the sibship's expected contribution to the non-centrality parameter. This expectation represents the weighted sum of chi(2) test statistics that would be obtained given the observed trait values over all possible sibship genotypic configurations; each configuration is weighted by the likelihood of it occurring given the assumed true genetic model. The properties of this procedure are explored in relation to the accuracy of the assumed true genetic model and sibship size. In comparison to previous methods of selecting phenotypically extreme sibships for genotyping, the proposed method is considerably more efficient and is robust with regard to the specification of the genetic model.

Chromosome Mapping↗
PubMed2005

Severe hypertension caused by alleles from normotensive Lewis for a quantitative trait locus on chromosome 2.

Pursuing fully a suggestion from linkage analysis that there might be a quantitative trait locus (QTL) for blood pressure (BP) in a chromosome (Chr) 2 region of the Dahl salt-sensitive rat (DSS), four congenic strains were made by replacing various fragments of DSS Chr 2 with those of Lewis (LEW). Consequently, a BP QTL was localized to a segment of around 3 cM or near 3 Mb on Chr 2 by comparative congenics. The BP-augmenting alleles of this QTL originated from the LEW rat, a normotensive strain compared with DSS. The dissection of a QTL with such a paradoxical effect illustrated the power of congenics in unearthing a gene hidden in the context of the whole animal system, presumably by interactions with other genes. The locus for the angiotensin II receptor AT-1B (Agtr1b) is not supported as a candidate gene for the QTL because a congenic strain harboring it did not have an effect on BP. There are approximately 19 known and unknown genes present in the QTL interval. Among them, no standout candidate genes are reputed to affect BP. Thus the QTL will likely represent a novel gene for BP regulation.

Alleles↗
PubMed2006

Cloning of DOG1, a quantitative trait locus controlling seed dormancy in Arabidopsis.

Genetic variation for seed dormancy in nature is a typical quantitative trait controlled by multiple loci on which environmental factors have a strong effect. Finding the genes underlying dormancy quantitative trait loci is a major scientific challenge, which also has relevance for agriculture and ecology. In this study we describe the identification of the DELAY OF GERMINATION 1 (DOG1) gene previously identified as a quantitative trait locus involved in the control of seed dormancy. This gene was isolated by a combination of positional cloning and mutant analysis and is absolutely required for the induction of seed dormancy. DOG1 is a member of a small gene family of unknown molecular function, with five members in Arabidopsis. The functional natural allelic variation present in Arabidopsis is caused by polymorphisms in the cis-regulatory region of the DOG1 gene and results in considerable expression differences between the DOG1 alleles of the accessions analyzed.

Alleles↗
PubMed2002

Fine linkage mapping of the blood pressure quantitative trait locus region on rat chromosome 1.

To narrow the area known to contain the blood pressure quantitative trait locus (QTL) on rat chromosome 1, we constructed a fine linkage map covering the blood pressure OTL region on the chromosome using 22 genetic markers informative for stroke-prone spontaneously hypertensive rats of the Izumo colony (SHRSP/Izm) and Wistar-Kyoto rats of the Izumo colony (WKY/Izm). Linkage mapping was done by genotyping 626 backcrossed rats from matings between SHRSP/Izm and WKY/Izm. Nineteen genetic markers informative for the two strains were selected from public databases. Two markers were newly isolated by screening a rat genomic library. One marker was mapped using a restriction endonuclease polymorphism. The region between DlWox29 and D1Smu11 was covered with 22 informative markers placed every 0.6 cM on average. In addition, 6 physiological candidates for a hypertension gene were mapped in this region either by linkage or by radiation hybrid (RH) mapping. This information should be essential for the construction and analysis of congenic strains for this QTL region.

Animals↗
PubMed1999

Bone marrow pre-B-1 (Bomb1): a quantitative trait locus inducing bone marrow pre-B-cell expansion in lymphoma-prone SL/Kh mice.

Abnormalities of regulatory genes in early B-cell development often lead to lymphomagenesis. Our previous study showed that there is an abnormal transient expansion of bone marrow (BM) pre-B cells in lymphoma-prone SL/Kh strain mice. Such expansion is a genetic property of SL/Kh stem cells rather than BM microenvironments. Using the percentage of BP1+ B220+ pre-B cells in total BM lymphoid cells as a quantitative parameter, we studied the genetic control of BM pre-B cells in 159 F2 offspring of crosses between SL/Kh and NFS/N mice and 334 back-crosses to SL/Kh mice. A highly significant quantitative trait locus was identified on the distal segment of chromosome 3, showing logarithm of odds scores of 22.7 in the F2 cohort and 10.7 in back-cross mice. This quantitative trait locus, named bone marrow pre-B-1, colocalized with lymphoid enhancer factor-1, which encodes a high mobility group DNA-binding protein that is expressed in T and pre-B cells.

Animals↗
PubMed1999

A quantitative trait locus of Agaricus bisporus resistance to Pseudomonas tolaasii is closely linked to natural cap color.

A quantitative trait locus (QTL) of resistance to Pseudomonas tolaasii was detected in Agaricus bisporus using a cross between a wild strain from the Sonoran desert and a cultivated strain. The resistance QTL was strongly linked with the brown color allele of PPC1. This QTL explained about 30% of the variation observed for living bacteria-induced symptoms. The use of bacterial toxin did not reproduce living bacteria symptoms but revealed the same QTL. The latter QTL was not affected by environmental variation. No relation was found between the resistance QTL and the tyrosinase gene, which is involved in the browning process.

Agaricus↗
PubMed1996

High-resolution mapping and isolation of a yeast artificial chromosome contig containing fw2.2: a major fruit weight quantitative trait locus in tomato.

A high-resolution physical and genetic map of a major fruit weight quantitative trait locus (QTL), fw2.2, has been constructed for a region of tomato chromosome 2. Using an F(2) nearly isogenic line mapping population (3472 individuals) derived from Lycopersicon esculentum (domesticated tomato) x Lycopersicon pennellii (wild tomato), fw2.2 has been placed near TG91 and TG167, which have an interval distance of 0.13 +/- 0.03 centimorgan. The physical distance between TG91 and TG167 was estimated to be </= 150 kb by pulsed-field gel electrophoresis of tomato DNA. A physical contig composed of six yeast artificial chromosomes (YACs) and encompassing fw2.2 was isolated. No rearrangements or chimerisms were detected within the YAC contig based on restriction fragment length polymorphism analysis using YAC-end sequences and anchored molecular markers from the high-resolution map. Based on genetic recombination events, fw2.2 could be narrowed down to a region less than 150 kb between molecular markers TG91 and HSF24 and included within two YACs: YAC264 (210 kb) and YAC355 (300 kb). This marks the first time, to our knowledge, that a QTL has been mapped with such precision and delimited to a segment of cloned DNA. The fact that the phenotypic effect of the fw2.2 QTL can be mapped to a small interval suggests that the action of this QTL is likely due to a single gene. The development of the high-resolution genetic map, in combination with the physical YAC contig, suggests that the gene responsible for this QTL and other QTLs in plants can be isolated using a positional cloning strategy. The cloning of fw2.2 will likely lead to a better understanding of the molecular biology of fruit development and to the genetic engineering of fruit size characteristics.

Journal Article↗
PubMed2005

qUVR-10, a major quantitative trait locus for ultraviolet-B resistance in rice, encodes cyclobutane pyrimidine dimer photolyase.

Rice qUVR-10, a quantitative trait locus (QTL) for ultraviolet-B (UVB) resistance on chromosome 10, was cloned by map-based strategy. It was detected in backcross inbred lines (BILs) derived from a cross between the japonica variety Nipponbare (UV resistant) and the indica variety Kasalath (UV sensitive). Plants homozygous for the Nipponbare allele at the qUVR-10 locus were more resistant to UVB compared with the Kasalath allele. High-resolution mapping using 1850 F(2) plants enabled us to delimit qUVR-10 to a <27-kb genomic region. We identified a gene encoding the cyclobutane pyrimidine dimer (CPD) photolyase in this region. Activity of CPD photorepair in Nipponbare was higher than that of Kasalath and nearly isogenic with qUVR-10 [NIL(qUVR-10)], suggesting that the CPD photolyase of Kasalath was defective. We introduced a genomic fragment containing the CPD photolyase gene of Nipponbare to NIL(qUVR-10). Transgenic plants showed the same level of resistance as Nipponbare did, indicating that the qUVR-10 encoded the CPD photolyase. Comparison of the qUVR-10 sequence in the Nipponbare and Kasalath alleles revealed one probable candidate for the functional nucleotide polymorphism. It was indicated that single-base substitution in the CPD photolyase gene caused the alteration of activity of CPD photorepair and UVB resistance. Furthermore, we were able to develop a UV-hyperresistant plant by overexpression of the photolyase gene.

Base Sequence↗
PubMed2001

Quantitative trait locus analysis in crosses between outbred lines with dominance and inbreeding.

We provide a theoretical framework for quantitative trait locus (QTL) analysis of a crossed population where parental lines may be outbred and dominance as well as inbreeding are allowed for. It can be applied to any pedigree. A biallelic QTL is assumed, and the QTL allele frequencies can be different in each breed. The genetic covariance between any two individuals is expressed as a nonlinear function of the probability of up to 15 possible identity modes and of the additive and dominance effects, together with the allelic frequencies in each of the two parental breeds. The probabilities of each identity mode are obtained at the desired genome positions using a Monte Carlo Markov chain method. Unbiased estimates of the actual genetic parameters are recovered in a simulated F(2) cross and in a six-generation complex pedigree under a variety of genetic models (allele fixed or segregating in the parental populations and additive or dominance action). Results from analyzing an F(2) cross between Meishan and Large White pigs are also presented.

Alleles↗
PubMed2005

Further evidence of a quantitative trait locus on chromosome 18 influencing postural change in systolic blood pressure: the Hypertension Genetic Epidemiology Network (HyperGEN) Study.

BACKGROUND: Postural change in systolic blood pressure (SBP) is prospectively associated with several disease outcomes including hypertension, stroke, and coronary heart disease. The objective of this study was to characterize further a possible quantitative trait locus on chromosome 18q21 influencing SBP response to a postural challenge. METHODS: A prior genome scan of postural SBP response in 636 subjects of white ethnicity from 285 hypertensive sibships in the Hypertension Genetic Epidemiology Network (HyperGEN) indicated suggestive evidence for linkage on chromosome 18q21. This study included a de novo set of 452 African American pedigrees from the HyperGEN study and an expanded set of 372 white pedigrees. Variance components linkage analysis of postural SBP change was conducted using microsatellite markers on chromosome 18, and association studies were performed with a common single nucleotide polymorphism (variant 13) in the gene encoding NEDD4L, a key regulator of fine sodium reabsorption in the distal nephron. RESULTS: Combined analysis of all white and African American pedigrees yielded a LOD score of 4.25 at 80 cM on chromosome 18q21, with at least nominal evidence of linkage at this position in both white (LOD: 3.43) and African American (LOD: 1.14) subjects. Postural SBP response was associated with variant 13 of the NEDD4L in a subset of white subjects taking medications effective in treating sodium volume-dependent hypertension (alpha1-blockers, calcium channel blockers, and/or diuretics). CONCLUSION: These data provide further evidence for a quantitative trait locus on chromosome 18q21 influencing postural change in SBP.

Adult↗