BOLIVARIAN REPUBLIC OF VENEZUELA
UNIVERSIDAD DEL ZULIA
NEUROSCIENCES INSTITUTE
GENETICS OF COMMON HERITABLE DISORDERS IN VENEZUELA RESEARCH
TRAINING PROGRAM
PROFESSOR: GLADYS MAESTRE, M.D
Development of the Neutral Theory:
Some molecular evidences
for the neutralism vs. selectionism debate
Evelyn B. Córdova Villanueva
Maracaibo, December 2005
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Development of the Neutral Theory: Some molecular evidences for the
neutralism vs. selectionism debate
Evelyn B. Córdova Villanueva
The hypothesis that most molecular polymorphism and substitutions are due to neutral mutations and
genetic drift, the neutral theory, was first proposed in the 1960’s [1]. Based on amino acid sequences,
Zuckerkandl and Pauling [2] proposed that there was a constant rate of amino acid substitution over
time. Accordingly, Kimura [3] proposed that many of the substituted alleles must be neutral, and later
([4]) argued that the rate of amino acid substitutions of homologous proteins (the rate of molecular
evolution) is almost constant. He further argued that protein evolution is uncorrelated with phenotypic
evolution. The apparent constancy of the amino acid substitution rate, the molecular clock, was
thought to support the neutral theory [1]. In 1969, King and Jukes [5] published a paper that
independently proposed that most amino acid substitutions are neutral and stated the inverse
relationship between the importance of a protein or site within a protein and its rate of evolution. This
would later be developed into the Principle of Molecular Evolution that provided support for the neutral
theory [6]1.
Since the theory and application of molecular clocks (the neutral theory) was proposed in the 1960s,
much controversy has arisen (cfr. [1], [7], [8]). Through the next four decades, the most debated
topics on molecular clocks - and, hence, on Neutral Theory - concerns variations in the mutation rate
and substitution rate among lineages in a phylogeny; the influence of life history (e.g. generation time,
body size, metabolic rate) on the rate of substitution; lineage–specific rate variation in the
mitochondrial genome of animals [9]; and the role of adaptive selection in protein evolution. In this
short essay, how the generation time, very low mutation rate and adaptive selection related to
changes in the environment can affect the molecular clock will be discussed. To illustrate this
discussion, consider a pair of orthologs in mouse and rat. The discussion will start by explaining how
the evolution of the mouse lineage at a significantly shorter generation time will affect the molecular
clock as kept by orthologs; then, it will be explained the effect on the molecular clock when the rat
lineage evolves at very low mutation rates; and, finally, changes in the environment that cause the
mouse orthologs to be unnecessary and its effect on the molecular clock will be discussed.
One of the curious facts that appeared to be contrary to predictions of the neutral theory is the
generation-time effect [1]. Let consider the case of the evolution of the mouse lineage at a shorter
generation time. The natural unit of time for the neutral theory is a single generation. Therefore,
species with shorter generation times should evolve faster in real (clock) time than those with longer
generation times [1] (cfr. [8]). This implies that the molecular clock for the mouse lineage will tick
faster, since the rate of substitution will be higher than in those species with longer generation times.
Martin and Palumbi [10] stated, as a hypothesis, that generation-time effect might rely on the concept
of nucleotide generation time: the amount of time needed for a given nucleotide position to be copied.
Nucleotide positions that have short generation times are those that are replicated most often. Thus,
species with short organism generation times may also have high substitution rates because of short
nucleotide generations, associated with fast rates of molecular evolution and faster molecular clocks if
compared with other species (cfr. [11]).
During the 1990s, several theories of molecular evolution where natural selection rather than genetic
drift is the main force, causing fixations, have been pursued. One of these is called the mutational
landscape model ([12], [13], [14]), which was proposed to explain the episodic nature of amino acid
“Functionally less important molecules or parts of a molecule evolve (in terms of mutant substitutions) faster than more
important ones” [6: 2848]
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substitutions. The model pictures molecular evolution as generally stagnated at a local optimum due to
the very low mutation rates to sequences that are more than one mutational step away from the locally
optimal sequence. An environmental shift is needed to move the population off of the local peak and
into a burst of substitutions until it stagnates once again at another local maximum. Thus,
environmental changes set the pace of evolution rather than the mutation rate [1]. This model seems
to explain the case of the rat lineage that evolves at very low mutation rates – which would lead to
stagnation due to the slow tick of the molecular clock. However, this mutational landscape model does
not account for where new genes come from or why some others become unnecessary.
Some findings on adaptive selection in protein evolution ([15], [16], [17], [18], [19]) have shed some
light on when and how new functions in genes – and new genes – have appeared as a result from
adaptive fixation of selectively advantageous mutations rather than a steady accumulation of neutral
ones. Furthermore, the cited evidences, and many more that has been neglected in this essay due to
the lack of space, have shown that positive selection in protein-coding genes are not as rare as the
neutral theory proposed, contrary to what the previously stated Principle of Molecular Evolution
argued2.
Different genes evolve at different rates because of natural selection on gene function [9]. Molecular
clocks therefore have wide applicability across the tree of life, from recent divergences among
populations (using fast evolving genes) to the deepest splits among prokaryotes and eukaryotes
(using the slowest evolving genes). Nevertheless, if the rate with which a particular gene or protein
evolves is not the same in all lineages, then use of a single rate will result in biased time estimates.
Some rate variation could go undetected, possibly resulting in biased time estimates. On the other
hand, it has been proposed that some lineages might increase in substitution rate concordantly during
an adaptive radiation, resulting in biased time estimates. Moreover, a correlated rate increase in many
lineages would cause a distortion in the timescale, leading to inconsistencies between molecular times
and the earlier or later fossil record [9].
References
[1] Ohta T, Gillespie J (1996). Development of Neutral and Nearly Neutral Theories. Theoretical
Population Biology 49: 128-142.
[2] Zuckerkandl E, Pauling L (1965). Evolutionary divergence and convergence in proteins, in Evolving
Genes and Proteins (V. Bryson and H. J. Vogel, Eds.), pp. 97-166, Academic Press, New York.
[3] Kimura M (1968). Evolutionary rate at the molecular level. Nature 217: 624-626.
[4] Kimura M (1969). The rate of molecular evolution considered from the standpoint of population
genetics. Proc. Natl. Acad. Sci. USA 63: 1181-1188.
[5] King J L, Jukes T H (1969). Non-Darwinian evolution. Science 164: 788-798.
[6] Kimura M, Ohta T (1974). On some principles governing molecular evolution. Proc. Natl. Acad. Sci.
USA 71: 2848-2852.
[7] Beatty J (1984). Chance and Natural Selection. Philosophy of Science, 51: 183-211.
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Special attention must be paid to [15] and [16] for this purpose.
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[8] Kreitman M, Akashi H (1995). Molecular Evidence for Natural Selection. Annual Review of Ecology
and Systematics, 26: 403-422.
[9] Hedges SB, Kumar S (2003). Genomic clocks and evolutionary timescales. TRENDS in Genetics,
19(4): 200-206.
[10] Martin AP, Palumbi SR (1993). Body size, metabolic rate, generation time, and the molecular
clock. Proc. Natl. Acad. Sci. USA 90: 4087-4091.
[11] Ohta T (1993). An examination of the generation–time effect on molecular evolution. Proc. Natl.
Acad. Sci. USA 90: 10676-10680.
[12] Gillespie JH (1984). Molecular evolution over the mutational landscape. Evolution 38: 1116-1129.
[13] Gillespie JH (1986). Natural Selection and the Molecular Clock. Mol. Biol. Evol. 3(2):138-155.
[14] Gillespie JH (1991). The Causes of Molecular Evolution, Oxford Univ. Press, New York.
[15] Stewart CB, Wilson AC (1987). Sequence convergence and functional adaptation of stomach
lysozymes from foregut fermenters. Cold Spring Harbor Symp. Quant. Biol., 52: 891-899.
[16] McDonald JH, Kreitman M (1991). Adaptive protein evolution at the Adh locus in Drosophila.
Nature 351: 652-654.
[17] Messier W, Stewart CB (1997). Episodic adaptive evolution of primate lysozymes. Nature, 385:
151-154.
[18] Nielsen R, Bustamante C, Clark AG, Glanowski S, Sackton TB, et al. (2005) A scan for positively
selected genes in the genomes of humans and chimpanzees. PLoS Biol 3(6): e170.
[19] Piertney SB, Oliver MK (2006). The evolutionary ecology of the major histocompatibility complex.
Heredity, 96: 7-21.