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Research Opportunities My colleagues and I are currently looking for collaborators and postdoctoral fellows with shared interests and complementary expertise. If you are interested in gaining experience in an exciting new experimental area of genetics called complex trait analysis, please contact us. Send a copy of your CV and names and phone numbers of three references. Please send email, pdf files, or Word documents to rwilliams@uthsc.edu. Our group's goal is to characterize genes and molecular pathways that control eye and brain development. We are particularly interested in discovering new molecular networks that modulate cell proliferation and cell death. We can offer you a great research environment at the University of Tennessee Medical School in Memphis, plenty of new space and equipment, and bright job prospects in both basic and applied functional genomics. Our work is currently funded by two R01 grants, two program projects, and a large Center for Excellence in Genomics and Bioinformatics. We can introduce you to: cutting-edge genetic analysis using complex trait methods mutation analysis and targeted mutagenesis in mice gene expression and gene array analysis of eye and brain high-throughput genotyping and phenotyping neuronal development and cell differentiation retina and eye development advanced stereological methods advanced statistical and biometric methods light and electron microscopy and image analysis laboratory bioinformatics and relational database design web development and its application in collaborative research We are looking for colleagues to collaborate in several broad areas: Gene identification. We are characterizing novel genes that modulate cell proliferation in brain and eye. We would like to work with a colleague with expertise in mouse molecular genetics. Background in rat or mouse brain or eye development would be advantageous. We have a number of well mapped quantitative trait loci (QTLs) that we are now converting into strong candidate genes by fine-mapping and sequence analysis. We need a colleague to help boost this project. Numerous collaborations with several leading research groups.   Genetic dissection of eye development and the genetic basis of myopia. We would like to work with an immunohistochemist with some background in stereology or image analysis. The goal of this work is to find genes that control eye and retinal development using complex trait analysis. You would collaborate with two other research groups on a set of related projects and become skilled in complex trait analysis and molecular genetics.   Neuroinformatics and advanced methods in image analysis. We would like to work with a biologist with bioengineering, robotics, and programming interests and familarity with database and web interface design. This individual will help to lead and develop a large Neuroinformatics program project (see www.mbl.org). We have just started a robotic microscope program project, so if you like working at the interface between biology, machines, and microscopes, you may be the ideal candidate. All applicants should have a publication history that includes at least two full length papers in print (or in press) in international English language journals. Pay scale will be at or above NIH scale: between $28,000 and $40,000 depending on background and potential. If you are an advanced postdoctoral fellow looking for an independent position and think that your interests would be complementary to what we are doing, please send us a cv. We are expanding rapidly and will have several openings in the next year.   Recent Publications   Genetic Architecture of the Mouse Hippocampus A preprint of a paper by L. Lu, D. C. Airey, and R. W. Williams describing new QTLs that modulate size and neuron number in the mouse hippocampus. This paper contains extensive data on hippocampal weight, volume, and cell number as a function of age, sex, and brain weight. We discovered an interesting gain in weight with age that may be related to neurogenesis in the adult mouse hippocampus. An example of a dissected hippocampus used for gene mapping. This dissection is from the left hemisphere. Five cross-sections illustrate internal structure. For more details on this work and information on QTLs that control hippocampal size and structure, please see the paper by Lu and colleages below. Short Course Tutorial in Quantitative Neurogenetics An introduction to mapping quantitative trait loci (QTLs) written for neuroscientists taking the 1998 Short Course in Quantitative Neuroanatomy. Updated August 2000 with new figures and text on RIX mapping.   Mapping Genes that Modulate Mouse Brain Development: A Quantitative Genetic Approach A review chapter from Mouse Brain Development that explains the power of QTL mapping in exploring CNS development. This review included original data on brain weight and neuron number in different strains of mice (C57BL/6J mice have about 100 million cells in their brains). My thanks to Richelle Strom, Guomin Zhou, and Dan Goldowitz for allowing me to use some of our unpublished data in this review.   Neurogenetic Analysis of the Olfactory Bulbs in Mice A companion to the hippocampus paper above. We describe a set of four QTLs that modulate the weight of the olfactory bulbs. This paper also has lots of data on bulb weight as a function of age, sex, and brain weight. So far, there is no overlap in QTLs that modulate bulb and hippocampus. In press at Behavior Genetics, Aug 2000.   A Biometric and QTL Analysis of the Cerebellum A preprint by David C. Airey and colleagues. This work considers both the overall size of the cerebellum and the fractional volume of different cerebellar compartments. A number of QTLs with relatively intense effects on cerebellar size have been mapped successfully in a cross between C57BL/6J and DBA/2J and in the BXD recombinant inbred strains. The figure below shows the effects of two of these QTLs, singly and jointly, on cerebellar weight in the BXD RI strains.   Genetic Structure of Recombinant Inbred Mice. Release 1 of the BXN RI mapping panel (Jan 15, 2001). This preprint describes a revived resource for mapping complex traits, particularly those that affect CNS structure and behavior. This preprint includes links to new RI genotype data files.   Combining Mutagensis and QTL Analysis: The Consomic Mutagenesis Screen This paper describes a new technique to exploit consomic mice (also known as chromosome substitution strains) to increase the sensitivity of a recessive mutagenesis screen by restricting analysis to entire litters of nearly isogenic mice. The method is sensitive enough to detect QTLs and weak alleles. The consomic mutatgenesis screen is being used by the Tenneessee Mouse Genomics Consortium to generate and map CNS and behavioral mutations on chromosome 19. This paper was published in Mammalian Genome (1999).   Genetic Dissection of Retinal Development A paper on the genetic basis of variation in the eye and retina published in Seminars in Cell & Developmental Biology (1998) 9:249–255. We explain how QTL analysis can be used to detect and characterize genes that modulate the architecture of the eye and retina. We include original data on the genetic control of (1) eye weight, (2) numbers of horizontal cells, and (3) numbers of retinal ganglion cells. This paper was coauthored with Richelle Strom, Guomin Zhou, and Yan Zhen.   Sketch of the retina, optic stalk, chiasm, and the lateral geniculate nucleus of a mammal at an early stage of development. The retina (lower left) has two walls—the outer pigment epithelium and the inner neural retina. The choroid fissure splits the lower half of the retina and continues as a groove on the base of the optic stalk. Growth cones of ganglion cells (not shown) extend across the inner surface of the retina and grow toward the root of the fissure (the future optic nerve head) and into the ventral part of the optic stalk (see oblique sketch at bottom right). Illustration adapted by RWW from the Undiscovered Codex.   An Analysis of Variation in Retinal Ganglion Cell Number in Mice An updated and extended version of a paper published in The Journal of Neuroscience (1996). This paper addresses the role of genes and envrionmental factors in controlling the size of cell populations in the central nervous system. Quantitative electron microscopy was used to count neurons in retinas of over 450 animals. We measured effects of sex and age, heritability of differences in neuron populations, and the number of genes responsible for the substantial differences among strains of mice. Updated May 30, 1998.   A Major QTL on Chr 11 Controls Variation in Ganglion Cell Number This paper follows up on the previous article and was published in early 1998 in The Journal of Neuroscience. Our aim in this work was to map genes that produce large differences in numbers of neurons in the retina. We succeeded in mapping a gene locus called Neuron Number Control 1 or Nnc1, on chromosome 11 between Hoxb and Krt1. There are several great candidate genes in this region, particularly the thyroid hormone alpha receptor. Nnc1 is the first gene locus known to control normal variation in neuron number in a vertebrate.   Cell Production and Cell Death in the Generation of Variation in Neuron Number Our third paper in this series on the genetic control of the retinal ganglion cell population in mice. By estimating total cell production in neonates from 10 different inbred strains of mice, Richelle Strom and I were able to determine that the distinct bimodality of strain averages is caused by differences in cell production. This paper demonstrates that Nnc1 modulates cell production and must be expressed before birth. Cell death is comparatively uniform among strains. Published in The Journal of Neuroscience.     Genetics of Eye Size and Myopia   Eye1 and Eye2: Quantitative trait loci that modulate eye size, lens weight, and retinal area This is a preprint of a paper that explores the genetic basis of variation in the growth of the mouse eye. The print edition was published in Investigative Ophthalmology and Visual Science, April, 1999.   The Eye1 locus. Linkage between variation in eye weight and proximal Chr 5. The x-axis represents the entire genetic length of Chr 5—from the proximal end (left) near marker D5Mit346 to the distal end of the chromosome at approximately 60 cM (far right). The y-axis represents the strength of linkage assessed using the likelihood ratio statistic (LRS) computed at 1 cM intervals using an interval mapping procedure without any adjustment for secondary QTLs using data for the 26 BXD strains. The peak LRS of 24.9 is ~1 cM distal to D5Mit346. The horizontal white bar extending from D5Mit346 to just beyond D5Mit1 indicates the 2-LOD confidence interval of the position of the Eye1 QTL. The inset histogram in the upper right shows the distribution of peak LRS scores for a set of 20,000 permutations of eye weight mapped across the entire genome. Only 116 of the permutations (0.58%) attained an LRS as high or higher than that of Eye1. In contrast the LRS for Eye2 is approximately 10, and the genome-wide probability of achieving this level by chance is shown to be about 0.4. Eye2 was subsequently confirmed by analysis of F2 progeny and the cumulative data for this locus have a genome-wide p of < 0.05. Three criterion levels (p = 0.5, 0.05, and 0.005) are shown both on the histogram and on the LRS plot. Mouse Models for the Analysis of Myopia: Variation in Eye and Lens Size of Adult Mice Our aim is to develop mice as a model species for research on myopia. Myopia is casued by a comparatively modest overgrowth of the back part of the eye. We would like to know what genes and molecular mechanisms contribute to eye growth in general, and to the overgrowth of myopia in particular. This paper provide a lot of essential data on the size and growth of the normal mouse eye, lens, and retina. We've included a great deal of information on correlations among several important size parameters. For example, one might expect lens size and eye size to be tightly related in mice, but they are not. The print edition of this paper was published in a special myopia issue of Optometry and Vision Science (1999) 76:408–418..         Background illustration running along the left margin is a drawing of the apical dendrite of a layer V pyramidal cell in the auditory cortex of an adult Mongolian gerbil by RWW (Feb 1979). This work is from a quantitative Golgi analysis of the effects of auditory deprivation on dendritic spine density (Williams et al., 1979, abstract only). Updated 04 February 2001

Short Course Tutorial Neuroscience Meets Quantitative Genetics: Using Morphometric Data to Map Genes that Modulate CNS Architecture Updated August 2000 with new figures and text on RIX mapping.   Learn More More Publications Related Sites Complextrait.org