neutral theory of molecular evolution

neutral theory of molecular evolution
Name	Neutral theory of molecular evolution
Field	Population genetics, Molecular evolution
Year	1968
Proponents	Motoo Kimura, Tomoko Ohta, James F. Crow
Related	Modern synthesis (20th century), Nearly neutral theory of molecular evolution

neutral theory of molecular evolution. The neutral theory of molecular evolution posits that the majority of evolutionary changes at the molecular level are caused not by natural selection but by the random genetic drift of mutant alleles that are selectively neutral. It was first formally proposed by the Japanese biologist Motoo Kimura in 1968, with significant later contributions from Tomoko Ohta and others. The theory provides a null hypothesis for molecular evolution, challenging the then-prevailing view that most genetic variation was maintained by balancing selection.

Overview and historical context

The theory emerged in the late 1960s following advances in techniques like protein electrophoresis, which revealed unexpectedly high levels of genetic variation within species like Drosophila pseudoobscura. This "paradox of variation" was difficult to reconcile with classical neo-Darwinism, which expected stronger purifying selection. Motoo Kimura, building on the mathematical foundations of population genetics laid by Sewall Wright and J.B.S. Haldane, calculated that the rate of observed molecular substitution was too high to be explained by positive selection alone. His seminal 1968 paper, published in the journal Nature, argued that most nucleotide substitutions are effectively neutral. This sparked immediate controversy with selectionist proponents like Theodosius Dobzhansky and Ernst Mayr, who were central figures in the Modern synthesis (20th century).

Core principles and the neutral mutation model

The core principle is that most mutations at the molecular level are either deleterious or selectively neutral, with the latter far outnumbering those that are advantageous. A neutral mutation's fate within a population is determined solely by genetic drift, a stochastic process described by models like the Wright–Fisher model. A key prediction is the existence of a "molecular clock," where the rate of neutral substitution equals the rate of neutral mutation and is constant over evolutionary time, independent of factors like generation time. The theory distinguishes between polymorphisms within a species and fixed differences between species, both seen as phases of the same neutral process. Tomoko Ohta later extended the model with the nearly neutral theory of molecular evolution, which accounts for very slightly deleterious mutations whose behavior is influenced by effective population size.

Evidence and supporting observations

Strong empirical support came from comparative studies of proteins and DNA sequences. The discovery of the molecular clock in proteins like cytochrome c and hemoglobin by researchers such as Emile Zuckerkandl and Linus Pauling was a key precursor. Observations consistent with the theory include higher evolutionary rates in functionally less constrained sequences (e.g., pseudogenes versus exons), and the correlation between genetic diversity (π) and effective population size across species from Escherichia coli to Homo sapiens. The development of statistical tests like the Tajima's D and the McDonald–Kreitman test provided tools to detect deviations from neutrality, often confirming it as a robust null model in genomes from the National Center for Biotechnology Information.

Relationship to other evolutionary theories

The neutral theory is not an alternative to Darwinism but a complement, focusing on a different level of biological organization. It operates within the framework of the Modern synthesis (20th century) but challenges the assumption that selection governs all variation. It is fundamentally integrated with the concept of genetic drift from the work of Sewall Wright. The theory also interfaces with models of speciation, suggesting that most genetic differences accumulating between isolated populations, like those on the Galápagos Islands, are neutral byproducts of divergence. It provided a theoretical basis for the field of molecular phylogenetics, enabling the reconstruction of evolutionary relationships among taxa from Archaea to Mammalia.

Impact and applications

The theory revolutionized the fields of molecular evolution and comparative genomics. It underpins all methods for estimating evolutionary distances and constructing phylogenetic trees, such as those for the Tree of Life (biology). It is essential for interpreting data from major projects like the Human Genome Project and the 1000 Genomes Project, distinguishing between functional and non-functional genomic regions. In practical applications, it guides the study of pathogen evolution, including the influenza virus and HIV, and informs conservation genetics efforts by organizations like the International Union for Conservation of Nature to assess genetic diversity in endangered species.

Criticisms and ongoing debates

Initial criticism from prominent evolutionary biologists like Stephen Jay Gould and Richard Lewontin centered on the perceived downplaying of natural selection's role. A major ongoing debate concerns the proportion of the genome that is subject to selection, with projects like the ENCODE project challenging the view that most DNA is non-functional. The prevalence of linkage disequilibrium and the effects of background selection complicate the identification of truly neutral sites. Furthermore, phenomena like GC-content variation in genomes and evidence for widespread adaptive evolution in genes involved in host–pathogen interaction, such as in the major histocompatibility complex, demonstrate that neutrality and selection are not mutually exclusive, leading to a more nuanced modern synthesis.

Category:Evolutionary biology Category:Population genetics Category:Molecular biology