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Biomedical subjects

Jonathan Flint

Publications and source records attributed to Jonathan Flint.

46 records · Page 3Linked to original sources
PubMed2003

QTL fine-mapping with recombinant-inbred heterogeneous stocks and in vitro heterogeneous stocks.

We compared strategies to fine-map Quantitative Trait Loci (QTL) in mice with heterogeneous stocks (HS). We showed that a panel of about 100 Recombinant Inbred Lines (RIL) derived from an HS, and which we called an RIHS, was ideally suited to fine-map QTL to very high resolution, without the cost of additional genotyping. We also investigated a strategy based on in vitro fertilization of large numbers of F(1) offspring of HS males crossed with an inbred line (IVHS). This method required some additional genotyping but avoided the breeding delays and costs associated with the construction of an RI panel. We showed that QTL detection was higher by using RIHS than with IVHS and that it was independent of the number of RI lines, provided the total number of animals phenotyped was constant. However, fine-mapping accuracy was slightly better with IVHS. We also investigated the effects of varying the number of HS generations and using multiallelic microsatellites instead of SNPs. We found that quite modest generation times of 10-20 generations were optimal. Microsatellites were superior to SNPs only when the generation time was 30 or more and when the markers were widely spaced.

Analysis of Variance↗
PubMed2003

Fearfulness and sex in F2 Roman rats: males display more fear though both sexes share the same fearfulness traits.

The pattern of sex differences in a large sample (about 400 for each sex) of F2-generation rats, derived from inbred Roman high- and low-avoidance strains differing in fearfulness and brain functioning, was investigated. We obtained measures from responses to a battery of novel/threatening tests [open field (OF), plus maze (PM), hole board (HB), activity (A), and acoustic startle reflex (ASR)] as well as learned fear paradigms [classical fear conditioning (CFC) and shuttlebox avoidance conditioning (SAC)]. The results showed that almost all behaviors assessed fit with a pattern of unidirectional sex effects characterized by male rats as being more fearful than females: males defecated more than females in the OF, PM, HB, ASR, and CFC; ambulated less in the OF, PM, A, and SAC; showed more self-grooming in PM and HB; explored the open arms of the PM and the holes of the HB less; displayed enhanced ASR; and showed poorer performance in the SAC task. We applied two factor analyses to each sex showing that, in general, they shared a common three-factor structure: a Learned Fear Factor comprising SAC and CFC responding, a Fear of Heights/Open Spaces Factor with the highest loadings for open arm behavior in the PM, and an Emotional Reactivity Factor, mainly grouping defecations, ambulation, and self-grooming. These results indicate that the essential components of fearful behavior are similar for both sexes in an inbred but genetically heterogeneous population.

Animals↗
PubMed2003

The use of telomere probes to investigate submicroscopic rearrangements associated with mental retardation.

Idiopathic mental retardation is a common condition the origins of which are poorly understood. Following initial reports that small chromosomal rearrangements affecting telomeres could be an important aetiological contributor, several new methods for screening patients have been developed. Over the past few years, 22 studies have reported results from 2585 patients. The prevalence of abnormalities in the entire group is 5.1%; but the figure is higher (6.8%) in individuals with moderate to severe mental retardation. About half the cases are caused by a de novo deletion, and about half by a balanced translocation segregating in a patient's family. Despite the large sample size available, it is still not clear whether a combination of thorough clinical examination and assiduous cytogenetic investigation might not be as effective at detecting subtelomeric anomalies as molecular assays.

Chromosome Aberrations↗
PubMed2003

Animal models of anxiety and their molecular dissection.

Genetic approaches to psychiatric illness need appropriate animal models both for investigating how genetic variants give rise to behavioural disorder and for identifying genes that may be important in human conditions. Yet the relevance of many animal models to psychiatric illness is often not clear. Here I discuss how genetic approaches can be used to validate animal models of anxiety, an approach which is applicable to other animal models. One drawback of genetic validation is the difficulty inherent in identifying the molecular variants that influence the phenotype. I review genetic approaches that have the potential to overcome this problem.

Animals↗
PubMed2003

The nature and identification of quantitative trait loci: a community's view.

This white paper by eighty members of the Complex Trait Consortium presents a community's view on the approaches and statistical analyses that are needed for the identification of genetic loci that determine quantitative traits. Quantitative trait loci (QTLs) can be identified in several ways, but is there a definitive test of whether a candidate locus actually corresponds to a specific QTL?

Animals↗
PubMed2002

Genetic effects on an animal model of anxiety.

Genetic effects on behavioural measures thought to model anxiety have been reported on 15 mouse chromosomes. In general the individual effect from each locus is small, contributing to 10% or less of the total variation, but through use of crosses between inbred rodents the power to detect such effects is high: 39 loci have been reported at stringent levels of significance. Novel multivariate analyses of these data go some way to characterizing the genetic architecture of anxiety and also to validating the tests that are used for its measurement. However, we are still some way from finding the molecular variants that explain the heritability of the trait.

Animals↗
PubMed2002

Learned fear, emotional reactivity and fear of heights: a factor analytic map from a large F(2) intercross of Roman rat strains.

Anxiety-related behaviours were evaluated across various tests in a 800 F(2)-intercross of the Roman high- and low-avoidance inbred rats. These tests either evoke unlearned (open field [OF]; plus-maze [PM]; hole-board [HB]; spontaneous activity [A]; and acoustic startle reflex [ASR]) or learned (classical fear conditioning [CFC]; and shuttlebox avoidance conditioning [SAC]), anxious/fearful responses. Using factor analysis (oblique rotation), we obtained a six-fold solution with 14 variables derived from all tests. These six factors represented SAC, CFC, PM anxiety, PM and OF activity, ASR anxiety, plus a mixed whole of anxious and activity variables (from OF and A), respectively. In searching for a smaller number of meaningful factors, we applied a three-factor solution that coherently corresponded with differentiated facets of fearfulness, rather than with the tests. Results showed that (1) measures of SAC and CFC strongly loaded onto Factor 1, labelled as "Learned Fear"; (2) a blend of almost all variables loaded onto Factor 2, called "Emotional Reactivity"; and (3) open arm behaviour in the PM loaded onto Factor 3, called "Fear of Heights." After discussing limitations of this apparently consistent behavioural map of anxiety, we advance some connections between those factors with quantitative trait loci candidates (genetic markers) as detected in the same sample.

Animals↗
PubMed2002

Simultaneous detection and fine mapping of quantitative trait loci in mice using heterogeneous stocks.

We describe a method to simultaneously detect and fine map quantitative trait loci (QTL) that is especially suited to the mapping of modifier loci in mouse mutant models. The method exploits the high level of historical recombination present in a heterogeneous stock (HS), an outbred population of mice derived from known founder strains. The experimental design is an F(2) cross between the HS and a genetically distinct line, such as one carrying a knockout or transgene. QTL detection is performed by a standard genome scan with approximately 100 markers and fine mapping by typing the same animals using densely spaced markers over those candidate regions detected by the scan. The analysis uses an extension of the dynamic-programming technique employed previously to fine map QTL in HS mice. We show by simulation that a QTL accounting for 5% of the total variance can be detected and fine mapped with >50% probability to within 3 cM by genotyping approximately 1500 animals.

Animals↗
PubMed2002

A quantitative trait locus influencing anxiety in the laboratory rat.

A critical test for a gene that influences susceptibility to fear in animals is that it should have a consistent pattern of effects across a broad range of conditioned and unconditioned models of anxiety. Despite many years of research, definitive evidence that genetic effects operate in this way is lacking. The limited behavioral test regimes so far used in genetic mapping experiments and the lack of suitable multivariate methodologies have made it impossible to determine whether the quantitative trait loci (QTL) detected to date specifically influence fear-related traits. Here we report the first multivariate analysis to explore the genetic architecture of rodent behavior in a battery of animal models of anxiety. We have mapped QTLs in an F2 intercross of two rat strains, the Roman high and low avoidance rats, that have been selectively bred for differential response to fear. Multivariate analyses show that one locus, on rat chromosome 5, influences behavior in different models of anxiety. The QTL influences two-way active avoidance, conditioned fear, elevated plus maze, and open field activity but not acoustic startle response or defecation in a novel environment. The direction of effects of the QTL alleles and a coincidence between the behavioral profiles of anxiolytic drug and genetic action are consistent with the QTL containing at least one gene with a pleiotropic action on fear responses. As the neural basis of fear is conserved across species, we suggest that the QTL may have relevance to trait anxiety in humans.

Alleles↗