Lorraine Flaherty

Bio: Lorraine Flaherty is an academic researcher from Wadsworth Center. The author has contributed to research in topics: Antigen & Major histocompatibility complex. The author has an hindex of 35, co-authored 112 publications receiving 4897 citations. Previous affiliations of Lorraine Flaherty include Oklahoma State Department of Health & University of Alabama at Birmingham.

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

Abstract: 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?

Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice.

Abstract: Huntington disease (HD), an autosomal dominant, progressive neurodegenerative disorder, is caused by an expanded CAG repeat sequence leading to an increase in the number of glutamine residues in the encoded protein. The normal CAG repeat range is 5-36, whereas 38 or more repeats are found in the diseased state; the severity of disease is roughly proportional to the number of CAG repeats. HD shows anticipation, in which subsequent generations display earlier disease onsets due to intergenerational repeat expansion. For longer repeat lengths, somatic instability of the repeat size has been observed both in human cases at autopsy and in transgenic mouse models containing either a genomic fragment of human HD exon 1 (ref. 9) or an expanded repeat inserted into the endogenous mouse gene Hdh (ref. 10). With increasing repeat number, the protein changes conformation and becomes increasingly prone to aggregation, suggesting important functional correlations between repeat length and pathology. Because dinucleotide repeat instability is known to increase when the mismatch repair enzyme MSH2 is missing, we examined instability of the HD CAG repeat by crossing transgenic mice carrying exon 1 of human HD (ref. 16) with Msh2-/- mice. Our results show that Msh2 is required for somatic instability of the CAG repeat.

H-2 haplotypes, genes, regions, and antigens: First listing

Abstract: H-2, the major his tocompatibi l i ty complex of the mouse, is a cluster of loci posit ioned in the middle por t ion of ch romosome 17 (Fig. 1). Present da t a indicate that the cluster is composed of ten loci grouped into regions and subregions (Fig. 2). Tradit ionally, the borders of the H-2 complex are thought to lie in the K region at the centromeric end of the cluster and the D region at the telomeric end. At the lat ter portion of chromosome 17 lies another cluster of seven loci compris ing the T region, originally identified by the Tla locus. The loci in the T region show certain similarities to some of the tl-2 loci, and it is possible that , genetically, the region is, in fact, par t of the H-2 complex. Fur ther down at the telomeric por t ion o f ch romosome 17 is a group of i sozyme loci, which are becoming useful markers in his tocompatibility studies. The H-2 loci occur in many v a r i a n t s a l l e l e s a n d the combinat ions of certain [1-2 alleles in a single ch romosome form many different haplotypes . F o r example,

Habituation of activity in an open field: A survey of inbred strains and F1 hybrids.

Abstract: To determine if there is genetic variability in habituation of activity in an open field, we examined a number of inbred strains and F1 hybrids. Using 5-min exposures to a dark open field, we measured changes in exploratory behavior over 3 consecutive days in 129S3/SvImJ, A/J, BALB/ cByJ, C3H/HeJ, C57BL/6J, CBA/J, DBA/2J, FVB/NJ, (B6 × 129)F1/J, and (B6 × C3H) F1/J male and female mice. Strain differences in open-field activity and in habituation were evident. Some of the strain differences were further modified by sex. The strains and F1's could be separated into groups that increased, decreased, or did not modify their activities across testing sessions. In a second study, the effects of altering the floor surface on habituation were examined in male 129S3/SvImJ, C57BL/6J, DBA/2J, and (B6 × 129)F1/J mice. When the floor was altered after 3 consecutive days of habituation, increased activity levels were evident. There were strain differences in the responsiveness to the changes in the floor. These results confirm a genetic role in intersession habituation to an open field.

Biology of natural killer cells.

Abstract: Publisher Summary Studies of cytotoxicity by human lymphocytes revealed not only that both allogeneic and syngeneic tumor cells were lysed in a non-MHC-restricted fashion, but also that lymphocytes from normal donors were often cytotoxic. Lymphocytes from any healthy donor, as well as peripheral blood and spleen lymphocytes from several experimental animals, in the absence of known or deliberate sensitization, were found to be spontaneously cytotoxic in vitro for some normal fresh cells, most cultured cell lines, immature hematopoietic cells, and tumor cells. This type of nonadaptive, non-MHC-restricted cellmediated cytotoxicity was defined as “natural” cytotoxicity, and the effector cells mediating natural cytotoxicity were functionally defined as natural killer (NK) cells. The existence of NK cells has prompted a reinterpretation of both the studies of specific cytotoxicity against spontaneous human tumors and the theory of immune surveillance, at least in its most restrictive interpretation. Unlike cytotoxic T cells, NK cells cannot be demonstrated to have clonally distributed specificity, restriction for MHC products at the target cell surface, or immunological memory. NK cells cannot yet be formally assigned to a single lineage based on the definitive identification of a stem cell, a distinct anatomical location of maturation, or unique genotypic rearrangements.

MHC-restricted cytotoxic T cells: studies on the biological role of polymorphic major transplantation antigens determining T-cell restriction-specificity, function, and responsiveness.

Abstract: Publisher Summary This chapter focuses on the important discovery that virus-specific cytotoxic T cells are dually specific for virus and for a self cell surface antigen encoded by the major histocompatibility complex (MHC). The initial work was carried out on the lymphocytic choriomeningitis virus system but it soon became evident that the same phenomenon applied to many other viruses. In addition, the same principle has been found to hold for other antigenic systems, such as trinitrophenyl coupled to cells, minor histocompatibility antigens, and the H-Y model. Graft rejection and the need for genetically homogeneous inbred mouse strains for cancer research led to the development of transplantation immunology and immunogenetics. The result is that the gene complex coding for major transplantation antigens is one of the better understood mammalian genetic regions. Cytotoxic T-cell specificity is comparable to serological specificity. Because quantification of specificity or cross-reactivity is difficult, and because of the technical limitations of these cytotoxic T-cell assays, results are interpreted with great reservation. MHC restriction reflects the fact that the effector function of T cells is determined by the kind of Self-H recognized together with the foreign antigen on cell surfaces: K and D are receptors for lytic signals, I determinants are receptors for cell differentiation signals that are delivered antigen-specifically by T cells.

Mixed linear model approach adapted for genome-wide association studies.

Abstract: Mixed linear model (MLM) methods have proven useful in controlling for population structure and relatedness within genome-wide association studies. However, MLM-based methods can be computationally challenging for large datasets. We report a compression approach, called ‘compressed MLM’, that decreases the effective sample size of such datasets by clustering individuals into groups. We also present a complementary approach, ‘population parameters previously determined’ (P3D), that eliminates the need to re-compute variance components. We applied these two methods both independently and combined in selected genetic association datasets from human, dog and maize. The joint implementation of these two methods markedly reduced computing time and either maintained or improved statistical power. We used simulations to demonstrate the usefulness in controlling for substructure in genetic association datasets for a range of species and genetic architectures. We have made these methods available within an implementation of the software program TASSEL.