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PubMedDate not supplied

Testing mode of inheritance of a candidate mutation at a quantitative trait locus.

Here is presented an approach to testing whether the effect of a candidate gene on a quantitative trait is dominant and for testing whether the effect is recessive. The approach uses parental genotype information in nuclear families to adjust for bias due to population admixture. The approach is applicable regardless of the nature of the sampling. The results of an application of the methods to a candidate mutation for diabetic nephropathy are used for illustration.

Diabetes Mellitus, Type 1↗

PubMed2001

High-resolution quantitative trait locus mapping for body weight in mice by recombinant progeny testing.

A major obstacle to the positional cloning of quantitative trait loci (QTLs) lies in resolving genetic factors whose allelic effects are blurred by environmental and background genetic variation. We investigate a fine-mapping approach that combines the use of an interval-specific congenic strain with progeny testing of recombinants for markers flanking a QTL. We apply the approach to map a murine QTL with an approximately 20% effect on growth rate by progeny testing 39 recombinants in a 12 cM region of the X chromosome. We use a likelihood analysis in an attempt to maximize the information on QTL map location and effect. The major X-linked effect is mapped to an approximately 2 cM region flanked by markers about 5 cM apart, outside which LOD support for the QTL drops extremely steeply by about 80. Nearly unambiguous assignment of the QTL genotypic state is obtained for each recombinant. The resolution of individual recombinants in the region is therefore sufficiently high to facilitate the positional cloning of the locus, although progress has been hampered because the genomic region containing the QTL shows an exceptionally low level of polymorphism in comparison with recent studies.

Alleles↗

PubMed2006

Complex genetic interactions in a quantitative trait locus.

Whether in natural populations or between two unrelated members of a species, most phenotypic variation is quantitative. To analyze such quantitative traits, one must first map the underlying quantitative trait loci. Next, and far more difficult, one must identify the quantitative trait genes (QTGs), characterize QTG interactions, and identify the phenotypically relevant polymorphisms to determine how QTGs contribute to phenotype. In this work, we analyzed three Saccharomyces cerevisiae high-temperature growth (Htg) QTGs (MKT1, END3, and RHO2). We observed a high level of genetic interactions among QTGs and strain background. Interestingly, while the MKT1 and END3 coding polymorphisms contribute to phenotype, it is the RHO2 3'UTR polymorphisms that are phenotypically relevant. Reciprocal hemizygosity analysis of the Htg QTGs in hybrids between S288c and ten unrelated S. cerevisiae strains reveals that the contributions of the Htg QTGs are not conserved in nine other hybrids, which has implications for QTG identification by marker-trait association. Our findings demonstrate the variety and complexity of QTG contributions to phenotype, the impact of genetic background, and the value of quantitative genetic studies in S. cerevisiae.

3' Untranslated Regions↗

PubMed2001

Multiple quantitative trait locus analysis of bovine chromosome 6 in the Israeli Holstein population by a daughter design.

Nine Israeli Holstein sire families with 2978 daughters were analyzed for quantitative trait loci effects on chromosome 6 for five milk production traits by a daughter design. All animals were genotyped for 2 markers. The three families with significant effects were genotyped for up to 10 additional markers spanning positions 0-122 cM of BTA6. Two sires were segregating for a locus affecting protein and fat percentage near position 55 cM with an estimated substitution effect of 0.18% protein, which is equivalent to one phenotypic standard deviation. This locus was localized to a confidence interval of 4 cM. One of these sires was also heterozygous for a locus affecting milk, fat, and protein production near the centromere. The hypothesis of two segregating loci was verified by multiple regression analysis. A third sire was heterozygous for a locus affecting milk and protein percentage near the telomeric end of the chromosome. Possible candidates for the major quantitative gene near position 55 cM were determined by comparative mapping. IBSP and SSP1 were used as anchors for the orthologous region on human chromosome 4. Twelve genes were detected within a 2-Mbp sequence. None of these genes have been previously associated with lactogenesis.

Animals↗

PubMed1999

A quantitative trait locus for live weight maps to bovine chromosome 23.

A multiple-marker mapping approach was used to search for quantitative trait loci (QTLs) affecting production, health, and fertility traits in Finnish Ayrshire dairy cattle. As part of a whole-genome scan, altogether 469 bulls were genotyped for six microsatellite loci in 12 families on Chromosome (Chr) 23. Both multiple-marker interval mapping with regression and maximum-likelihood methods were applied with a granddaughter design. Eighteen traits, belonging to 11 trait groups, were included in the analysis. One QTL exceeded experiment level and one QTL genome level significance thresholds. Across-families analysis provided strong evidence (P(experiment) = 0.0314) for a QTL affecting live weight. The QTL for live weight maps between markers BM1258 and BoLA DRBP1. A QTL significant at genome level (P(genome) = 0.0087) was mapped for veterinary treatment, and the putative QTL probably affects susceptibility to milk fever or ketosis. In addition, three traits exceeded the chromosome 5% significance threshold: protein percentage of milk, calf mortality (sire), and milking speed. In within-family analyses, protein percentage was associated with markers in one family (LOD score = 4.5).

Alleles↗

PubMed2005

Genetic basis for the psychostimulant effects of nicotine: a quantitative trait locus analysis in AcB/BcA recombinant congenic mice.

Genetic differences in sensitivity to nicotine have been reported in both animals and humans. The present study utilized a novel methodology to map genes involved in regulating both the psychostimulant and depressant effects of nicotine in the AcB/BcA recombinant congenic strains (RCS) of mice. Locomotor activity was measured in a computerized open-field apparatus following subcutaneous administration of saline (days 1 and 2) or nicotine on day 3. The phenotypic measures obtained from this experimental design included total basal locomotor activity, as well as total nicotine activity, nicotine difference scores, nicotine percent change and nicotine regression residual scores. The results indicated that the C57BL/6J (B6) were insensitive to nicotine over the entire dose-response curve (0.1, 0.2, 0.4 and 0.8 mg/kg). However, the 0.8-mg/kg dose of nicotine produced a significant decrease in the locomotor activity in the A/J strain and a wide and continuous range of both locomotor excitation and depression among the AcB/BcA RCS. Single-locus association analysis in the AcB RCS identified quantitative trait loci (QTL) for the psychostimulant effects of nicotine on chromosomes 11, 12, 13, 14 and 17 and one QTL for nicotine-induced depression on chromosome 11. In the BcA RCS, nicotine-induced locomotor activation was associated with seven putative regions on chromosomes 2, 7, 8, 13, 14, 16 and 17. There were no overlapping QTL and no genetic correlations between saline- and nicotine-related phenotypes in the AcB/BcA RCS. A number of putative candidate genes were in proximity to regions identified with nicotine sensitivity, including the alpha2 subunit of the nicotinic acetylcholine receptor and the dopamine D3 receptor.

Analysis of Variance↗

PubMed2003

Recent advances in human quantitative-trait-locus mapping: comparison of methods for discordant sibling pairs.

Extreme discordant sibling pairs (EDSPs) are theoretically powerful for the mapping of quantitative-trait loci (QTLs) in humans. EDSPs have not been used much in practice, however, because of the need to screen very large populations to find enough pairs that are extreme and discordant. Given appropriate statistical methods, another alternative is to use moderately discordant sibling pairs (MDSPs)--pairs that are discordant but not at the far extremes of the distribution. Such pairs can be powerful yet far easier to collect than extreme discordant pairs. Recent work on statistical methods for QTL mapping in humans has included a number of methods that, though not developed specifically for discordant pairs, may well be powerful for MDSPs and possibly even EDSPs. In the present article, we survey the new statistics and discuss their applicability to discordant pairs. We then use simulation to study the type I error and the power of various statistics for EDSPs and for MDSPs. We conclude that the best statistic(s) for discordant pairs (moderate or extreme) is (are) to be found among the new statistics. We suggest that the new statistics are appropriate for many other designs as well-and that, in fact, they open the way for the exploration of entirely novel designs.

Genetics, Population↗

PubMed2002

hairy: A quantitative trait locus for drosophila sensory bristle number.

Advances in medicine, agriculture, and an understanding of evolution depend on resolving the genetic architecture of quantitative traits, which is challenging since variation for complex traits is caused by multiple interacting quantitative trait loci (QTL) with small and conditional effects. Here, we show that the key developmental gene, hairy (h), is a QTL for Drosophila sternopleural bristle number, a model quantitative trait. Near-isoallelic lines (NIL) for the h gene region exhibited significant variation in bristle number and failed to complement a hairy mutation. Sequencing 10 h alleles from a single population revealed 330 polymorphic sites in approximately 10 kb. Genotypes for 25 of these and 14 additional sites in the flanking regions were determined for the 57 NIL and associated with variation in bristle number in four genetic backgrounds. A highly significant association was found for a complicated insertion/deletion polymorphism upstream of the transcription start site. This polymorphism, present in 17.5% of the h alleles, was associated with an increase of 0.5 bristle and accounted for 31% of the genetic variance in bristle number in the NIL.

Animals↗

PubMed2006

A quantitative trait locus for oleic fatty acid content on Sus scrofa chromosome 7.

A partial genome scan using microsatellite markers was conducted to detect quantitative trait loci (QTLs) for 10 fatty acid contents of backfat on 15 chromosomes in a porcine resource population. Two QTLs were discovered on Sus scrofa chromosome 4 (SSC4) and SSC7. The QTL on SSC4 was located between marker loci sw1336 and sw512, and this QTL was detected (P < 0.05) only for linoleic acid. Its position was in proximity of those mapped for linoleic acid content in previous studies. The QTL on SSC7 was mapped between markers swr1343 and sw2155, and it was significant (P < 0.05) only for oleic acid. A novelty of the QTL for oleic acid was suggested because the QTL was located far from any other QTLs previously mapped for fatness traits. The QTL on SSC7 explained 19% of phenotypic variation for oleic acid content. Further studies on fine mapping and positional comparative candidate gene analysis would be the next step toward better understanding of the genetic architecture of fatty acid contents.

Animals↗

PubMed2000

Quantitative trait locus mapping using human pedigrees.

In the past decade phenomenal progress has been made in molecular and statistical genetic methods for localizing quantitative trait loci. Because of these advances, we can anticipate a long period of active genetic research in which the genes influencing human quantitative variability will be mapped and their effects accurately evaluated. Here, we review the current state of the science in statistical genetic methods for quantitative trait linkage analysis. In particular, we detail a variance component-based framework for localizing quantitative trait loci and for accurately estimating their relative effect sizes. Attention is paid to the optimal design of human family studies for localizing genes of small to moderate effect. In addition, methods and strategies are described for dealing with the most important complications of quantitative variation, including the assessment of genotype x environment interaction and epistasis.

Bias↗

PubMed2005

A genome scan for fasting insulin and fasting glucose identifies a quantitative trait locus on chromosome 17p: the insulin resistance atherosclerosis study (IRAS) family study.

Plasma insulin and glucose concentrations are important quantitative phenotypes related to diabetes and the metabolic syndrome. Reports purporting to identify quantitative trait loci (QTLs) that contribute to the variation in fasting insulin and glucose concentrations are discrepant. As part of the Insulin Resistance Atherosclerosis Study (IRAS) Family Study, a genome scan was performed in African-American (n = 42) and Hispanic (n = 90) extended families to identify regions that may contain positional candidate genes for fasting insulin and fasting glucose (n = 1,604 subjects). There was significant evidence for linkage of fasting insulin to the short arm of chromosome 17 (logarithm of odds [LOD] = 3.30; 54 cM between D17S1294 and D17S1299, P = 1.0 x 10(-4)). The strongest evidence for linkage over all pedigrees for fasting glucose was also observed in this region (LOD = 1.44; 58 cM, P = 9.9 x 10(-3)). The results of this study provide impetus for future positional cloning of QTLs regulating insulin and glucose levels. Identifying genes in these regions should provide insight into the nature of genetic factors regulating plasma glucose and insulin concentrations.

Black or African American↗

PubMed1998

Linkage of a major quantitative trait locus to Yaa gene-induced lupus-like nephritis in (NZW x C57BL/6)F1 mice.

In the present study, we mapped the major quantitative trait loci (QTL) differing between the NZW and C57BL/6 inbred strains of mice by making use of (NZW x C57BL/6.Yaa)F1 mice, a model in which the lupus-like autoimmune syndrome observed in male mice is associated with the presence of an as yet unidentified Y chromosome-linked autoimmune acceleration gene, Yaa. Linkage analysis of 126 C57BL/6 x (NZW x C57BL/6.Yaa)F1 backcross males provided evidence for a major QTL on chromosome 7 controlling both the severity of glomerulonephritis and the production of IgG anti-DNA autoantibody and retroviral gp70-anti-gp70 immune complexes. Two additional QTL of C57BL/6 origin on chromosome 17 had no apparent individual effects, but showed strong epistatic interaction with chromosome 7 QTL for disease severity and anti-DNA autoantibody production. Our data also identified on chromosome 13 a QTL of NZW origin with a major effect on the level of gp70, and showing an additive effect with the chromosome 7 QTL on the level of gp70 immune complexes. Our study thus provides a model to dissect the complex genetic interactions that result in manifestations of murine lupus-like disease.

Animals↗

PubMed1996

Computation of the full likelihood function for estimating variance at a quantitative trait locus.

The proportion of alleles identical by descent (IBD) determines the genetic covariance between relatives, and thus is crucial in estimating genetic variances of quantitative trait loci (QTL). However, IBD proportions at QTL are unobservable and must be inferred from marker information. The conventional method of QTL variance analysis maximizes the likelihood function by replacing the missing IBDs by their conditional expectations (the expectation method), while in fact the full likelihood function should take into account the conditional distribution of IBDs (the distribution method). The distribution method for families of more than two sibs has not been obvious because there are n(n - 1)/2 IBD variables in a family of size n, forming an n x n symmetrical matrix. In this paper, I use four binary variables, where each indicates the event that an allele from one of the four grandparents has passed to the individual. The IBD proportion between any two sibs is then expressed as a function of the indicators. Subsequently, the joint distribution of the IBD matrix is derived from the distribution of the indicator variables. Given the joint distribution of the unknown IBDs, a method to compute the full likelihood function is developed for families of arbitrary sizes.

Alleles↗

PubMed2005

Quantitative trait locus (QTL) isogenic recombinant analysis: a method for high-resolution mapping of QTL within a single population.

In the quest for fine mapping quantitative trait loci (QTL) at a subcentimorgan scale, several methods that involve the construction of inbred lines and the generation of large progenies of such inbred lines have been developed (Complex Trait Consortium 2003). Here we present an alternative method that significantly speeds up QTL fine mapping by using one segregating population. As a first step, a rough mapping analysis is performed on a small part of the population. Once the QTL have been mapped to a chromosomal interval by standard procedures, a large population of 1000 plants or more is analyzed with markers flanking the defined QTL to select QTL isogenic recombinants (QIRs). QIRs bear a recombination event in the QTL interval of interest, while other QTL have the same homozygous genotype. Only these QIRs are subsequently phenotyped to fine map the QTL. By focusing at an early stage on the informative individuals in the population only, the efforts in population genotyping and phenotyping are significantly reduced as compared to prior methods. The principles of this approach are demonstrated by fine mapping an erucic acid QTL of rapeseed at a subcentimorgan scale.

Brassica rapa↗

PubMed2001

Evidence for a language quantitative trait locus on chromosome 7q in multiplex autism families.

Autism is a syndrome characterized by deficits in language and social skills and by repetitive behaviors. We hypothesized that potential quantitative trait loci (QTLs) related to component autism endophenotypes might underlie putative or significant regions of autism linkage. We performed nonparametric multipoint linkage analyses, in 152 families from the Autism Genetic Resource Exchange, focusing on three traits derived from the Autism Diagnostic Interview: "age at first word," "age at first phrase," and a composite measure of "repetitive and stereotyped behavior." Families were genotyped for 335 markers, and multipoint sib pair linkage analyses were conducted. Using nonparametric multipoint linkage analysis, we found the strongest QTL evidence for age at first word on chromosome 7q (nonparametric test statistic [Z] 2.98; P=.001), and subsequent linkage analyses of additional markers and association analyses in the same region supported the initial result (Z=2.85, P=.002; chi(2)=18.84, df 8, P=.016). Moreover, the peak fine-mapping result for repetitive behavior (Z=2.48; P=.007) localized to a region overlapping this language QTL. The putative autism-susceptibility locus on chromosome 7 may be the result of separate QTLs for the language and repetitive or stereotyped behavior deficits that are associated with the disorder.

Autistic Disorder↗

PubMed2002

The effects of selected sampling on the transmission disequilibrium test of a quantitative trait locus.

We investigate how sampling of parents or children based on their extreme phenotypic values selected from clinical databases would affect the power of identification of quantitative trait loci (QTL) by a transmission disequilibrium test (TDT). We consider three selective sampling schemes based on the selection of phenotypic values of parents or children in nuclear families: (1) two children, one of extreme value, the other random; (2) two children extremely discordant; (3) one parent of extreme value. Other family members not specified will be recruited randomly with regard to phenotypic values. Our study shows that the second sampling scheme can always enhance the power for QTL identification, sometimes dramatically so. The increase in the statistical power of the TDT is particularly dramatic when h2 at the QTL under test is small or intermediate (e.g. 0.05 or 0.10). For the other two sampling schemes, under dominant effects at the QTL, the power is always increased relative to random sampling; however, under recessive or additive genetic effects, the power gain is generally minor or even decreased a little sometimes. Allele frequencies at the QTL and the selection stringency are important for determining the effect of selective sampling on the power of QTL identification. Our study is useful as a practical guideline on how to perform the TDT efficiently in practice by taking advantage of the extensive databases accumulated that are enriched with people of extreme phenotypic values.

Disease Transmission, Infectious↗

PubMed2002

Estimation of quantitative trait locus allele frequency via a modified granddaughter design.

A method is described on the basis of a modification of the granddaughter design to obtain estimates of quantitative trait loci (QTL) allele frequencies in dairy cattle populations and to determine QTL genotypes for both homozygous and heterozygous grandsires. The method is based on determining the QTL allele passed from grandsires to their maternal granddaughters using haplotypes consisting of several closely linked genetic markers. This method was applied to simulated data of 10 grandsire families, each with 500 granddaughters, and a QTL with a substitution effect of 0.4 phenotypic standard deviations and to actual data for a previously analyzed QTL in the center of chromosome 6, with substitution effect of 1 phenotypic standard deviation on protein percentage. In the simulated data the standard error for the estimated QTL substitution effect with four closely linked multiallelic markers was only 7% greater than the expected standard error with completely correct identification of QTL allele origin. The method estimated the population QTL allelic frequency as 0.64 +/- 0.07, compared to the simulated value of 0.7. In the actual data, the frequency of the allele that increases protein percentage was estimated as 0.63 +/- 0.06. In both data sets the hypothesis of equal allelic frequencies was rejected at P < 0.05.

Analysis of Variance↗

PubMed2004

Quantitative trait locus mapping for age-related cataract severity and synechia prevalence using four-way cross mice.

PURPOSE: The goal of this study was to map mouse quantitative trait loci (QTL) that influence the development of murine age-related cataract and synechia, by using a genetically heterogeneous mouse population bred by a four-way cross. METHODS: The test population consisted initially of 510 mice bred as the progeny of (BALB/cJ x C57BL/6J)F1 females and (C3H/HeJ x DBA/2J)F1 males. Each mouse was examined by slit lamp at 18 and 24 months of age and scored for degree of lens opacity on a 0 to 4+ scale, and the presence or absence of additional anterior chamber disease was noted. The presence of synechia was confirmed by histology. Each mouse was genotyped at 96 maternal and 92 paternal loci, and the significance of association between genotype and eye lesions was tested by permutation analysis. RESULTS: Significant QTL with effects on lens opacity at 24 months were detected on mouse chromosomes 4, 11, and 12. The effects were additive, and severe cataracts were seen in 80% of the mice with all three high-risk alleles, but in only 28% of the mice with all three low-risk alleles. The risk of synechia was associated with paternal chromosome 1 and on both the maternal and paternally inherited chromosome 4. Mice with all three high-risk alleles had a 68% risk of synechia, compared with a 0% incidence in mice with all three counteralleles. CONCLUSIONS: A four-way cross population of mice can be used to map polymorphic loci that influence cataract severity and synechia prevalence in late life. The results provide a first step toward identification of the individual genes involved and may help to guide the search for homologous human genes.

Aging↗