Wednesday, April 4, 2007

Sex and evolution: on becoming a trichromat

From the difference in the amino-acid sequences for the various photoreceptor genes it is clear that the human visual system did not evolve according to a single design. Most mammals have two classes of photopigments, one encoded on an autosome and mostly sensitive to short wavelength stimuli, and one sex-linked and mostly sensitive to medium wavelengths. To evolve into a trichromat, is it sufficient to shuffle the sex-linked genes to create an additional sensitivity, or does one first have to evolve the opponent mechanisms supported by the midget bipolar and retinal ganglion cells?

This question is addressed in research at UC Santa Barbara and at John Hopkins in Baltimore published in the latest print-issue of Science magazine. The full reference is Gerald H. Jacobs, Gary A. Williams, Hugh Cahill, Jeremy Nathans, Emergence of Novel Color Vision in Mice Engineered to Express a Human Cone Photopigment, Science 23 March 2007: Vol. 315. no. 5819, pp. 1723 – 1725. If you are an AAAS member, the online version is at this link.

For an overview, the following table Lucia Ronchi and I compiled at the 1993 AIC meeting in Budapest based on 1983 work by Ebehart Zrenner may be useful.

Finding Rod and S Mechanisms L and M Mechanisms
Anatomy Distribution perifoveal foveal
Bipolar circuitry one class (only on) two classes (on and off)
Psychophysics Spatial resolution low high
Temporal resolution low high
Weber fraction high low
Wavelength sensitivity short medium
Electrophysiology Response function saturates does not saturate
Latencies long short
ERG-off-effect negative positive
Ganglion cell response afterpotential no afterpotential
Receptive field large small
Vulnerability high low
autosomal sex-linked

To answer the question whether to evolve into a trichromat, it is sufficient to shuffle the sex-linked genes to create an additional sensitivity, or one does first have to evolve the opponent mechanisms supported by the midget bipolar and retinal ganglion cells, Jacobs et al. designed a human L cone pigment knock-in mouse. Most of the coding sequences for the native mouse M cone pigment were replaced with sequences encoding a human L pigment. Subsequently these mice were backcrossed for five generations. Of interest are the heterozygous females who have a mixture of the two pigments.

Color vision requires both multiple photopigments and appropriate neural wiring, and it has been argued that the organization of the primate retina, and in particular the low-convergence midget bipolar and ganglion cell system, is such that the addition of a new class of cone photoreceptors may be all that is required for comparing M versus L cone signals. This first step in the evolution of primate trichromacy is what the authors modeled with their knock-in mouse.

The authors asked whether the sudden acquisition of an additional and spectrally distinct pigment and its production in a subset of cones suffice to permit a new dimension of chromatic discrimination that would imply that

  1. the mammalian brain is sufficiently plastic that it can extract and compare a new dimension of sensory input and
  2. the heterozygous female primate that first inherited an additional X-chromosome allele would have immediately enjoyed a selective advantage with respect to chromatic discrimination.

How do you do psychophysics with mice? To examine whether vision is altered by the added photopigment, Jacobs et al. tested their mice in a behavioral three-alternative forced-choice discrimination task. In this task, the mouse was required to identify which one of the three test panels was illuminated differently from the other two, with the location of the correct choice varying randomly between trials.

A first experiment demonstrates that their knock-in mice can extract visual information from L cones. The next experiment is to perform experiments for brightness matches, because color vision implies the ability to discriminate variations in spectral composition irrespective of variations in intensity.

In the last experiment, after extensive training (~17,000 trials), an M/L heterozygote female with balanced M:L ratio (44:56) successfully discriminated 500-nm from 600-nm lights. These results imply that color vision in this M/L heterozygous mouse is based on a comparison of quantal catches between the M and L pigments.

The mouse lacks a midget system, and thus the color vision documented in M/L heterozygotes must be subserved by other means. Most mouse retinal ganglion cells have a receptive field center with an antagonistic surround, albeit a weak one, and chromatic information could be extracted based on differences in M versus L input to these two regions. In a variation on this idea, chromatic information could also be extracted simply based on variation among retinal ganglion cells in the total M versus L weightings.

These results have general implications for the evolution of sensory systems. The behavioral or electrophysiological responses show the predicted expansion or modification of sensitivity. The author’s observation that the mouse brain can use this information to make spectral discriminations implies that alterations in receptor genes might be of immediate selective value not only because they expand the range or types of stimuli that can be detected but also because they permit a plastic nervous system to discriminate between new and existing stimuli. Additional genetic changes that refine the downstream neural circuitry to more efficiently extract sensory information could then follow over many generations.

Will this research yield a cure for color blindness? Could we replace the appropriate gene sequence of a color blind father’s spermatozoa the corresponding sequence from the mother’s egg? The answer is a clear no, because the gene sequences do not directly encode the pigment peak sensitivity.

The X chromosome has a number of base repetitions for the gene sequence for peak sensitivity encoding, there is no single and clearly defined L or M gene. The sequence is very labile, i.e., the genes get easily transposed or shuffled, thereby cousing color vision defects in males, who have only a single chromosome. As with all gene sequences, only a portion is active, i.e., transcribed by the messenger RNA (mRNA). Therefore, the X chromosome in the spermatozoa is not conclusive. Examination of the mRNA can only occur post partum and is destructive for the retina, so out of question.

Currently we know far too little of proteonomics to even start thinking about a cure for color vision deficiency.

PS: as usual, since our software does not support links in comments, I am adding the links here