Genetic and environmental control of variation in retinal ganglion cell number in mice

How much of the remarkable variation in neuron number within a species is generated by genetic differences, and how much is generated by environmental factors? We address this problem for a single population of neurons in the mouse CNS. Retinal ganglion cells of inbred and outbred strains, wild species and subspecies, and F1 hybrids were studied using an unbiased electron microscopic method with known technical reliability. Ganglion cell numbers among diverse types of mice are highly variable, ranging from 32,000 to 87,000. The distribution of all cases (n = 252) is close to normal, with a mean of 58,500 and an SD of 7800. Genetic factors are most important in controlling this variation; 76% of the variance is heritable and up to 90% is attributable to genetic factors in a broad sense. Strain averages have an unanticipated bimodal distribution, with distinct peaks at 55,500 and 63,500 cells. Three pairs of closely related strains have ganglion cell populations that differ by > 20% (10,000 cells). These findings indicate that different alleles at one or two genes have major effects on normal variation in ganglion cell number. Nongenetic factors are still appreciable and account for a coefficient of variation that averages approximately 3.6% within inbred strains and isogenic F1 hybrids. Age- and sex-related differences in neuron number are negligible. Variation within isogenic strains appears to be generated mainly by developmental noise.