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Quantitative Neurogenetics & QTL Mapping

Genetic Structure of Recombinant Inbred Mice.

A comprehensive analysis of linkage maps of recombinant inbred strains with comparisons to F2, N2, and advanced intercross maps. We genotyped just over 100 RI strains using a set of approximately 1600 microsatellite markers. Published October 2001 in Genome Biology by Rob Williams, Jing Gu, Shuhua Qi, and Lu Lu. The papers is available both in PDF and HTML versions. Our own local HTML version includes updated links to new RI genotype data files. Users of RI strains (AXB-BXA, BXD, BXH, and CXB) will find the mapping data sets useful.

Complexities of Cancer Research: Mouse Genetics Models.

Cancer susceptibility is a complex interaction of an individual's genetic composition and environmental exposures. Huge strides have been made in understanding cancer over the past 100 yr, from recognition of cancer as a genetic disease, to identification of specific carcinogens, isolation of oncogenes, and recognition of tumor suppressors. A tremendous amount of knowledge has accumulated about the etiology of cancer. Cancer genetics has played a significant role in these discoveries. Analysis of high-risk familial cancers has led to the discovery of new tumor suppressor genes and important cancer pathways. These families, however, represent only a small fraction of cancer in the general population. Most cancer is instead probably the result of an intricate interaction of polymorphic susceptibility genes with the sea of environmental exposures that humans experience. Although the central cadre of cancer genes is known, little is understood about the peripheral genes that likely comprise the polymorphic susceptibility loci. The challenge for cancer genetics is therefore to move forward from the Mendelian genetics of the rare familial cancer syndromes into the field of quantitative trait loci, susceptibility factors, and modifier genes. By identifying the genes that modulate an individual's susceptibility to cancer after an environmental exposure, researchers will be able to gain important insights into human biology, cancer prevention, and cancer treatment.

Strength in Numbers: Chasing the Engram Using Microarrays.

A short report of a symposium at the 2001 IBANGS meeting.

QTL analysis and genome-wide mutagenesis in mice: Complementary genetic approaches to the dissection of complex traits.

An upbeat commentary in Behavior Genetics on complex trait analysis and "cloning" QTLs that we hope will counterbalance the gloomy assessment by Joe Nadeau and Wayne Frankel (2000). Our review (John Belknap and colleagues) is in a special issue of Behavior Genetics devoted to QTL mapping and complex trait analysis. Spread the word: QTL analysis is thriving, and yes they can be cloned.

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 use some of our unpublished data in this review.

Genetic Control of Neuron Number

Richelle C. Strom's Ph.D. dissertation (July 1999) on the quantitative genetic analysis of brain weight and retinal ganglion cell number in mice. Seven chapters containing lots of great new data on QTLs that modulate brain weight and neuron number.
An example of a 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, see the JN paper by Lu and colleages below.

Genetic Architecture of the Mouse Hippocampus

Reprint of a paper by Lu Lu and colleagues published in The Journal of Neuroscience (May 2001). We discovered QTLs on chromosomes 1 and 5 that modulate size and neuron number in the mouse hippocampus. In addition to the mapping, this paper contains extensive morphometric data and cell counts on hippocampus and its components as a function of age, sex, and brain weight. We found an interesting gain in hippocampal weight with age that may be related to continuous adult neurogenesis. We see a similar increase in the olfactory bulbs, but not in the cerebellum.

Neurogenetic Analysis of the Olfactory Bulbs in Mice

The olfactory bulbs are a great neural system for quantitative genetic analysis (they are modular, discrete, and easy to dissect). Here we describe a set of four QTLs that control the weight of the olfactory bulbs. This paper also details differences in bulb as a function of age, sex, and brain weight. Published in Behavior Genetics, 2001.
Graphic illustration of the segregation of genotypes and phenotypes modulating cerebellar size. Select the figure to get a higher quality image. The left panel illustrates the distribution of cerebellar weights for BXD strains that have been categorized by genotype at the Cbs1a interval on Chr 1. C57BL/6J alleles (BB) at Cbs1a are marked by blue circles; DBA/2J alleles at Cbs1a are marked by red circles. The middle panel illustrates the even more striking difference between strains categorized as BB or DD in the Cbs8a interval on Chr 8. The right panel illustrates the conjoint and almost perfectly additive action of these two QTLs.

Biometric and QTL Analysis of the Cerebellum

Reprint of a paper in The Journal of Neuroscience by David C. Airey and colleagues. This study covers both the total size of the cerebellum and the fractional volume of different cerebellar compartments. David and I mapped five QTLs with relatively intense effects on cerebellar size in a cross between C57BL/6J and DBA/2J and in BXD recombinant inbred strains. The figure above shows the effects of two of these QTLs—singly and jointly—on cerebellar weight in the BXD RI strains.

Complex Trait Analysis of the Mouse Striatum

A stereological and genetic analysis of the caudate nucleus by Rosen and Williams published in BMC Neuroscience (2001; available online at While there is considerable strain variation in caudate volume, there is less variation in the number of caudate neurons (mostly medium spiny neurons). Using an F2 intercross we were able to map two QTLs that independently control striatal volume (Chr 10) and striatal neuron number (Chr 19).

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, pdf). This paper address 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 The Journal of Neuroscience (1998, pdf). 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 published in The Journal of Neuroscience (1998, pdf).

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 was 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. However, there are some very interesting differences in the severity of cell death among strains that would be worth following up on.


Results and Discussion RI consensus maps of mouse chromosomes

Sample of the strain similarity matrix. The fraction of identical genotypes was computed for all two-way combinations of 109 RI strains. Those pairs of strains for which the percentage of shared genotypes was greater than 75% were flagged and one member of the pair was eliminated from the BXN set. Corresponding matrices: AXB-BXA, BXD, BXH and the complete BXN matrix in text format. more
Growth Cones
Growth Cones

Growth Cones, Dying Axons, and Developmental Fluctuation in the Fiber Population of the Cat's Optic Nerve more
Three-Dimensional Counting
Three-Dimensional Counting

An Accurate and Direct Method to Estimate Numbers of Cells in Sectioned Material . more
Example of a hippocampus
Genetic Control of Neuron Number

An example of a hippocampus used for gene mapping. This dissection is from the left hemisphere. Five cross-sections illustrate internal structure.more
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