中性突变neutral mutation

http://baike.baidu.com/view/226162.htm?fr=aladdin

http://en.wikipedia.org/wiki/Neutral_mutation

中性突变：生物的进化主要由中性突变决定的，这些中性突变经自然选择保留下来，再经隔离形成新物种。

中文名

中性突变漂变学说

外文名

neutral mutation

别    称

中性说

提出者

木村资生

提出时间

1968

应用学科

生物科学 遗传

适用领域范围

遗传学

目录

1定义

2历史

3随机漂变假说

4意义

1定义编辑

在分子层面发生的突变，如果不考虑对生殖不利的话，基本上都是无所谓有利还是不利的“中性突变”，有利的突变其实非常少，简直可以忽略不计。

2历史编辑

60年代以来，随着分子生物的异军突起，人们对进化的认识也开始深入到分子水平。生物分子的进化是生物进化的重要组成部分，综合进化理论的“选择”仍是指自然选择，因而它发展了达尔文的进化论。但它未能在分子水平上阐述遗传机制，故仍然是不完美的。随着分子生物学的建立与发展，这一不足为另一新说“中性突变论”所克服。1968年，日本学者木村资生根据分子生物学的研究资料，首先提出了分子进化的中性学说，简称“中性学说”或“中性突变的随机漂变理论”。向达尔文的自然选择学说提出了挑战。此后，许多学者又根据大量的研究成果予以肯定。美国学者J.L.金和T.H.朱克斯用大量分子生物学实验和资料肯定了这一学说，并把这一学说称为非达尔文主义。

20世纪50年代，科学家们先后搞清了不同生物体内具有相同功能的一些蛋白质的氨基酸序列和核酸的核苷酸序列。他们发现，生物间的亲缘关系越近，这些生物大分子间的差异越小；亲缘关系越远，差异越大。科学家们还发现，随着生物由低级到高级的演化，同一种分子中的氨基酸或核苷酸以一定的速率置换着，有就是说每一种生物大分子不论在哪种生物体内，都以一定的速度进化着。例如，各种脊椎动物血红蛋白分子α链中的氨基酸，都是以每年大约10个的速度置换着，并且置换的速度与环境的变化和生物时代的长短无关。这种分子水平上的置换是由基因突变造成的，其中多数对生物的性状既没有表现出有利也没有表现有害，属于中性突变或近中性突变。例如，决定苯丙氨酸的密码子可以是UUU，也可以是UUC，如果RNA分子中的一个碱基被置换（U→C），使UUU突变成了UUC，新密码的意义与原密码的相同。由于中性突变对生物的生存和繁殖能力没有影响，自然选择对它们也就不起作用。它们在种群中的保存、扩散和消失完全是随机的，这种现象称为随机漂变。随机漂变经过日积月累，积少成多，会使同种生物的不同种群间出现巨大的差异，就可能形成不同的物种。该理论认为：生物在分子水平上的进化是基于基因不断产生“中性突变”的结果，它也是在群体中产生的，而不像综合进化理论所主张的突变有好有坏那样，而这种“中性突变”既无好处也无坏处。它并不受自然选择的作用，而是通过群体内个体的随机交配以及突变基因随同一些基因型固定下来或消失不见（即被淘汰掉），新种的形成主要不是由微小的长期有利变异积累而成，而是由那些无适应性的、无好坏利害之分的中性突变积累而成。即生物在分子水平的大多数突变是中性的或近似中性的，它们既没有好坏利害之别，又没有适应和不适应之分，因此自然选择对它们不起作用。中性学说的出发点是中性突变，在中性突变过程中，哪一种变异能够保存下来，哪一种变异趋于消失，全靠机遇，而不是达尔文的自然选择，这个过程叫做“遗传漂变”。由于它完全不受自然选择的作用，实际上就否定了自然选择，甚至还认为生物进化与环境无关，故此理论是“非达尔文主义”的。

该学说对认识物种进化的贡献在于：揭示了基因突变在分子水平上进化的特殊性，这为达尔文主义和综合进化理论所不及。但它最大的缺陷是解释不了“基因型”（也就是某种可能性）怎样变成“表型”（也就是现实性）以及物种形成的原因，因此，它在解释生物进化上仍是不足的。在目前的科学条件下，它可以看做是达尔文进化论（包括综合进化理论）的补充和发展。 　 100多年来，进化论经受了各种考验，同时也在不断从科学发展中吸取营养，进化论的研究正从原来的个体进化水平向群体进化水平发展，进化论也在不断地进化中，另一方面它又朝着分子进化水平纵深发展。

3随机漂变假说编辑

中性突变——随机漂变假说

木村的分子进化理论的“中性突变——随机漂变假说”即中性学说的主要内容有：在分子水平上，大多数进化演化和物种内的大多数变异，不是由自然选择引起的，而是通过那些对选择呈中性或近中性的突变等位基因的遗传漂变引起的。从中性学说出发，可以得出进化速率保持每年每个位置恒定的结论。同源蛋白质如同工酶所具有的丰富的多态性表明，这些生物大分子具有同样的高级结构，都能很好地完成其生物功能，它们之中哪一个也不比别的分子更优越。也就是说，在分子水平上，不考虑有利突变。假基因是一些失去功能的基因，完全不受自然选择淘汰，事实证明，假基因的碱基替换确实不受限制，其进化速率等于分子的突变率。

分子进化有五大特征：（1）对每种生物大分子而言，只要分子的三级结构与功能基本不变，那么各进化路线，以突变替代表示的进化速率大致保持每年在每个位置上恒定。（2）机能较次要的分子或分子片段的进化速率，高于机能较重要的分子或分子片段的进化速率。（3）在分子进化进程中，使分子现存结构和功能破坏较小的突变比破坏较大的突变有更高的替换率。（4）基因重复通常发生在一个具有新功能的基因出现之前。（5）明显有害的选择清除和选择上呈中性的或稍有害的突变随机固定，比明显有利突变的正达尔文选择更为频繁。以上五个特征中（1）和（5）是最基本的特征。1983年，木村对中性学说进行了一次全面总结，写成一本专著《分子进化的中性学说》。

4意义编辑

中性学说以其敢于和达尔文的自然选择学说相抗衡而引起学术界的一片骚动，其影响远远超出了群体遗传学，甚至进化生物学范围。随着分子遗传学的发展，中性学说越来越显示它的正确、有效。它打破了综合进化论在群体遗传学领域里一统天下的局面，也使木村登上了一个新高度，从一个偏重数学的群体遗传学家上升为一个有理论建树的进化生物学家。

Neutral mutations are changes in DNA sequence that are neither beneficial nor detrimental to the ability of an organism to survive and reproduce. In population genetics, mutationsin which natural selection does not affect the spread of the mutation in a species are termed neutral mutations. Neutral mutations that are inheritable and not linked to any genes under selection will either be lost or will replace all other alleles of the gene. This loss or fixation of the gene proceeds based on random sampling known as genetic drift. A neutral mutation that is in linkage disequilibrium with other alleles that are under selection may proceed to loss or fixation via genetic hitchhiking and/or background selection.

While many mutations in a genome may decrease an organism’s ability to survive and reproduce, also known as fitness, these mutations are selected against and not passed on to future generations. The most commonly observed mutations detectable as variation in the genetic makeup of organisms and populations appear to have no visible effect on the fitness of individuals and are therefore neutral. The identification and study of neutral mutations has led to the development of the neutral theory of molecular evolution. The neutral theory of molecular evolution is an important and often controversial theory proposing that most molecular variation within and among species is essentially neutral and not acted on by selection. Neutral mutations are also the basis for using molecular clocks to identify such evolutionary events as speciation and adaptive or evolutionary radiations.

Contents

[hide]

• 1 History
• 2 Impact on evolutionary theory
• 3 Types of neutral mutation
  • 3.1 Synonymous mutation of bases
  • 3.2 Neutral amino acid substitution
• 4 Identification and measurement of neutrality
• 5 Molecular clocks
• 6 External links
• 7 References

History[edit]

Charles Darwin in 1868

Charles Darwin commented on the idea of neutral mutation in his work, hypothesizing that mutations that do not give an advantage or disadvantage may fluctuate or become fixed apart from natural selection. "Variations neither useful nor injurious would not be affected by natural selection, and would be left either a fluctuating element, as perhaps we see in certain polymorphic species, or would ultimately become fixed, owing to the nature of the organism and the nature of the conditions." While Darwin is widely credited with introducing the idea of natural selection which was the focus of his studies, he also saw the possibility for changes that did not benefit or hurt an organism.^[1]

Darwin‘s view of change being mostly driven by traits that provide advantage was widely accepted until the 1960s.^[2] While researching mutations that produce nucleotide substitutions in 1968, Motoo Kimura found that the rate of substitution was so high that if each mutation improved fitness, the gap between the most fit and typical genotype would be implausibly large. However, Kimura explained this rapid rate of mutation by suggesting that the majority of mutations were neutral, i.e. had little or no effect on the fitness of the organism. Kimura developed mathematical models of the behavior of neutral mutations subject to random genetic drift in biological populations. This theory has become known as the neutral theory of molecular evolution.^[3]

As technology has allowed for better analysis of genomic data, research has continued in this area. While natural selection may encourage adaptation to a changing environment, neutral mutation may push divergence of species due to nearly random genetic drift.^[2]

Impact on evolutionary theory[edit]

Neutral mutation has become a part of the neutral theory of molecular evolution, proposed in the 1960s. This theory suggests that neutral mutations are responsible for a large portion of DNA sequence changes in a species. For example, bovine and human insulin, while differing in amino acid sequence are still able to perform the same function. The amino acid substitutions between species were seen therefore to be neutral or not impactful to the function of the protein. Neutral mutation and the neutral theory of molecular evolution are not separate from natural selection but add to Darwin‘s original thoughts. Mutations can give an advantage, create a disadvantage, or make no measurable difference to an organism‘s survival.^[4]

A number of observations associated with neutral mutation were predicted in neutral theory including: amino acids with similar biochemical properties should be substituted more often than biochemically different amino acids; synonymous base substitutions should be observed more often than nonsynonymous substitutions; introns should evolve at the same rate as synonymous mutations in coding exons; and pseudogenes should also evolve at a similar rate. These predictions have been confirmed with the introduction of additional genetic data since the theory’s introduction.^[2]

Types of neutral mutation[edit]

Synonymous mutation of bases[edit]

When an incorrect nucleotide is inserted during replication or transcription of a coding region, it can affect the eventual translation of the sequence into amino acids. Since multiple codons are used for the same amino acids, a change in a single base may still lead to translation of the same amino acid. This phenomenon is referred to as degeneracy and allows for a variety of codon combinations leading to the same amino acid being produced. For example, the codes TCT, TCC, TCA, TCG, AGT, and AGC all code for the amino acid serine. This can be explained by the wobble concept. Francis Crick proposed this theory to explain why specific tRNA molecules could recognize multiple codons. The area of the tRNA that recognizes the codon called the anticodon is able to bind multiple interchangeable bases at its 5‘ end due to its spacial freedom. A fifth base called inosine can also be substituted on a tRNA and is able to bind with A, U, or C. This flexibility allows for changes in bases in codons leading to translation of the same amino acid.^[5] The changing of a base in a codon without the changing of the translated amino acid is called a synonymous mutation. Since the amino acid translated remains the same a synonymous mutation has traditionally been considered a neutral mutation.^[6] Some research has suggested that there is bias in selection of base substitution in synonymous mutation. This could be due to selective pressure to improve translation efficiency associated with the most available tRNAs or simply mutational bias.^[7] If these mutations influence the rate of translation or an organism’s ability to manufacture protein they may actually influence the fitness of the affected organism.^[6]

^A The codon ATG both codes for methionine and serves as an initiation site: the first ATG in an mRNA‘s coding region is where translation into protein begins.^[8]

Neutral amino acid substitution[edit]

While substitution of a base in a noncoding area of a genome may make little difference and be considered neutral, base substitutions in or around genes may impact the organism. Some base substitutions lead to synonymous mutation and no difference in the amino acid translated as noted above. However, a base substitution can also change the genetic code so that a different amino acid is translated. This sort of substitution usually has a negative effect on the protein being formed and will be eliminated from the population throughpurifying selection. However, if the change has a positive influence, the mutation may become more and more common in a population until it becomes a fixed genetic piece of that population. Organisms changing via these two options comprise the classic view of natural selection. A third possibility is that the amino acid substitution makes little or no positive or negative difference to the affected protein.^[9] Proteins demonstrate some tolerance to changes in amino acid structure. This is somewhat dependent on where in the protein the substitution takes place. If it occurs in an important structural area or in the active site, one amino acid substitution may inactivate or substantially change the functionality of the protein. Substitutions in other areas may be nearly neutral and drift randomly over time.^[10]

Identification and measurement of neutrality[edit]

Neutral mutations are measured in population and evolutionary genetics often by looking at variation in populations. These have been measured historically by gel electrophoresis to determine allozyme frequencies.^[11] Statistical analyses of this data is used to compare variation to predicted values based on population size, mutation rates and effective population size. Early observations that indicated higher than expected heterozygosity and overall variation within the protein isoforms studied, drove arguments as to the role of selection in maintaining this variation versus the existence of variation through the effects of neutral mutations arising and their random distribution due to genetic drift.^[12][13][14] The accumulation of data based on observed polymorphism led to the formation of the neutral theory of evolution.^[12] According to the neutral theory of evolution, the rate of fixation in a population of a neutral mutation will be directly related to the rate of formation of the neutral allele.^[15]

In Kimura’s original calculations, mutations with |2 Ns|<1 or |s|≤1/(2N) are defined as neutral.^[12][14] In this equation, N is the effective population size and is a quantitative measurement of the ideal population size that assumes such constants as equal sex ratios and no emigration, migration, mutation nor selection.^[16] Conservatively, it is often assumed that effective population size is approximately one fifth of the total population size.^[17] s is the selection coefficient and is a value between 0 and 1. It is a measurement of the contribution of a genotype to the next generation where a value of 1 would be completely selected against and make no contribution and 0 is not selected against at all.^[18] This definition of neutral mutation has been criticized due to the fact that very large effective population sizes can make mutations with little selection coefficients appear non neutral. Additionally, mutations with high selection coefficients can appear neutral in very small populations.^[14] The testable hypothesis of Kimura and others showed that polymorphism within species are approximately that which would be expected in a neutral evolutionary model.^[14][19][20]

For many molecular biology approaches, as opposed to mathematical genetics, neutral mutations are generally assumed to be those mutations which cause no appreciable effect on gene function. This simplification eliminates the effect of minor allelic differences in fitness and avoids problems when selection has only a minor effect.^[14]

Early convincing evidence of this definition of neutral mutation was shown through the lower mutational rates in functionally important parts of genes such as cytochrome c versus less important parts^[21] and the functionally interchangeable nature of mammalian cytochrome c in in vitro studies.^[22] Nonfunctional pseudogenes provide more evidence for the role of neutral mutations in evolution. The rates of mutation in mammalian globin pseudogenes has been shown to be much higher than rates in functional genes.^[23][24] According to neo-Darwinian evolution, such mutations should rarely exist as these sequences are functionless and positive selection would not be able to operate.^[14]

The McDonald-Kreitman test^[25] has been used to study selection over long periods of evolutionary time. This is a statistical test that compares polymorphism in neutral and functional sites and estimates what fraction of substitutions have been acted on by positive selection.^[26] The test often uses synonymous substitutions in protein coding genes as the neutral component, however, synonymous mutations have been shown to be under purifying selection in many instances.^[27][28]

Molecular clocks[edit]

Molecular clocks can be used to estimate the amount of time since divergence of two species and for placing evolutionary events in time.^[29] Pauling and Zuckerkandl, proposed the idea of the molecular clock in 1962 based on the observation that the random mutation process occurs at an approximate constant rate. Individual proteins were shown to have linear rates of amino acid changes over evolutionary time.^[30] Despite controversy from some biologists arguing that morphological evolution would not proceed at a constant rate, many amino acid changes were shown to accumulate in a constant fashion. Kimura and Ohta explained these rates as part of the framework of the neutral theory. These mutations were reasoned to be neutral as positive selection should be rare and deleterious mutations should be eliminated quickly from a population.^[31] By this reasoning, the accumulation of these neutral mutations should only be influenced by the mutation rate. Therefore, the neutral mutation rate in individual organisms should match the molecular evolution rate in species over evolutionary time. The neutral mutation rate is affected by the amount of neutral sites in a protein or DNA sequence versus the amount of mutation in sites that are functionally constrained. By quantifying these neutral mutations in protein and/or DNA and comparing them between species or other groups of interest, rates of divergence can be determined.^[29][32]

Molecular clocks have caused controversy as to their dates derived on events such as explosive radiations seen after extinction events like the Cambrian explosion and the radiations of mammals and birds. Two fold differences exist in dates from molecular clocks and the fossil record. While some paleontologists argue that molecular clocks are systemically inaccurate, others attribute the discrepancies to lack of robust fossil data and bias in sampling.^[33] While not without constancy and discrepancies with the fossil record, the data from molecular clocks has shown how evolution is dominated by the mechanisms of a neutral model and is less influenced by the action of natural selection.