图2. 溯祖和人口结构变化。来自同一位点的6个基因样本（白色圆圈）在三个具有不同历史的群体中被用于谱系研究，图中的灰色方框代表了群体的规模:规模不变（左）、瓶颈后的近期扩张（中）和更早的扩张（右）。时间（以代为单位）可以追溯到位于图表顶部的过去。突变用黑色圆形（“内部”分支的突变，和样本中的几个基因是相同的）或黑色星形（ “外部”分支的突变，在样本中是独一无二的，因为它们导致样本中单个基因的出现）表示。我们看到，样本中共同祖先的年龄分布因不同条件而有较大差异。系谱的外部（末端）分支与内部分支的长度比是不同的。对于一个恒定的突变率，随着时间的推移，外部和内部突变的相对比例将会不同。样本中罕见/频繁突变的比例是用来重建种群历史的指标之一。其他多态性指标（包括文中看到的H和π）也具有这个属性（temps passé 过去的时间）
图3. 选择性扫描。重组使得基因组上相邻区域的进化有可能被分离。如果没有选择，中性多态性将通过一个非常缓慢的平衡过程沿着染色体达到一个可比值。当一个突变在某个区域具有优势且频率变为1时，这个过程会非常快，并且它会扫除该区域的中性多态性，但不会扫除相邻区域的中性多态性。通过对比扫描区域和中性区域的中性多态性水平，可以肯定确实是选择在前者中起了作用，并排除了认为“适应的就是我们所看到的”的循环推理。本例显示了模拟果蝇X染色体上两个相邻区域的选择性扫描。它们使识别基因的这两个复合体成为可能，这两个复合体同时作用于改变果蝇后代的孟德尔基因比例（参见 [6]）（所谓的“自私”基因）。在这两个区域（SR1和SR2），选择消除了中性多态性。 （régions codantes 编码区；déficit de polymorphisme neutre 中性多态性缺乏；polymorphisme neuter(π) 中性多态性(π)；position des genes sur le chromosome 基因在染色体上的位置） 瞬时多态性是指一个有利突变通过消除可选等位基因而逐渐自我“修复”，这个过程可能导致该基因频率为1。例如，蚊子的杀虫剂抗性基因、细菌的抗生素抗性基因和疟疾寄生虫的抗疟药物抗性基因。这些突变在自然条件下也许没有优势，但在施加药物的环境下，这些等位基因的频率就会增加。调节乳糖酶表达的三种等位基因也是如此，乳糖酶不仅能让人类像其他哺乳动物一样，在新生儿时期消化乳糖，在成人时期也能消化乳糖。这些突变在牲畜群体中变得有益，而我们的狩猎-采集祖先只有在成年后才有机会消化果糖（蔗糖）。在所有这些瞬时多态性的案例中，与选择相关的位点遭到基因组中的一个分子标签的“背叛”：其频率迅速扩大，这让染色体上相邻的中性突变消失。这是一个选择性扫描的例子，我们可以确定等位基因的固定不是基于随机漂变，而是基于选择（图3，[4]）。
[2] 这个公式在这里非常普遍，根据其所使用的遗传模型有几种形式和名称：Wright的FST（两个等位基因），Nei的GST（FST的推广，上面公式5的变体），ΦST，ρST，等等。它可以被类似性质的统计数据所替代：DXY， AMOVA。这种冗余首先表明了“F-统计学”在生态学中的成功。由于估计值依赖于样本量，无偏估计值的使用也必须考虑到观测设计的特殊性。Cf: Weir B.S. & Cockerham C.C. (1984) Estimating F-statistics for the analysis of population structure. Evolution 38:1358-1370
[3] Kingman J.F.C. (1982) On the genealogy of large populations. Journal of Applied Probability 19A:27-43; Hudson R.R. (1983) Properties of a neutral allele model with intragenic recombination. Theoretical Population Biology 23:183-201; Tajima F. (1983) Evolutionary relationship of DNA sequences in finite populations. Genetics 105:437-460.
[4] Derome N., K. Métayer, C. Montchamp-Moreau & M. Veuille (2004) Signature of selective sweep associated with the evolution of sex-ratio drive in Drosophila simulans. Genetics 166: 1357-1366; Derome N., E. Baudry, D. Ogereau, M. Veuille & C. Montchamp-Moreau (2008) Selective sweeps reveal a two-locus model for sex-ratio meiotic drive in Drosophila simulans. Molecular Biology and Evolution, 25:409-416.
[5] Yassin A., Bastide H., Chung H., Veuille M., David J.R. & Pool J.E. (2016) Ancient Balancing Selection at tan Underlies Female Colour Dimorphism in Drosophila erecta. Nature Communications DOI: 10.1038/ncomms10400.
[6] Malecot G. (1948) The mathematics of heredity. Masson et Cie; Nagylaki T. (1989) Gustave Malécot and the transition from classical to modern population genetics. Genetics 122, 253-268.
[7] Lewontin R.C. & Hubby J.L. (1966) Molecular Approach to the Study of Genic Heterozygosity in Natural Populations. II. Amount of Variation and Degree of Heterozygosity in Natural Populations of Drosophila pseudoobscura, Genetics 54: 595-609; Lewontin R.C. (1974) The Genetic Basis of Evolutionary Change. Columbia Univ. Press, New York.
[8] Kimura M. (1969) The Rate of Molecular Evolution Considered from the Standpoint of Population Genetics. Proceedings of the National Academy of Sciences, 63:1181-1188.
Polymorphism has caused controversy about its role in evolution. But if it essentially follows a neutral evolution, it serves as a reference, in contrast, for the study of natural selection. It is also used by ecologists in conservation biology to reconstruct the past history of species.
Polymorphism consists of mutations that escape DNA repair systems over cell divisions. Their rate of appearance is therefore a biological variable. In humans and chimpanzees, it is µ ≈ 10-8 mutations by nucleotideBasic element of a nucleic acid such as DNA or RNA. It is composed of a nucleic base (or nitrogenous base), a ose with five carbon atoms, called pentose, whose association forms a nucleoside, and finally one to three phosphate groups. and by generation. The considerable amount of sperm produced by male mammals means that there is much more cell division in male germ lineAll cells from stem cells to gametes than in female germ line: 380 against 23 at age 30 (i.e. 16 times more), and even more so when men age (840 against 23 at age 50, i.e. 36 times more). This means that in these species the mutations are mainly produced in male lines and depend on the age of the father. Each birth produces about 100 new mutations per genomeGenetic material of a living organism. It contains genetic information encoding proteins. In most organisms, the genome corresponds to DNA. However, in some viruses called retroviruses (e.g. HIV), the genetic material is RNA., but because only a small part of the genome is codingDescribes the part of the DNA or RNA of a gene translated into protein. Represents only a part of the gene from which it originates, as well as the mRNA in which it is registered., 99% of them have no effect on survival or fertility. They are called neutral. A new allelTwo homologous genes are called alleles when they have different shapes, distinguishable at a given level of observation. An allele can therefore correspond to a single sequence, or to a set of sequences that are different but not distinguishable at the phenotype level. (e.g. blue/brown/green eye colour but at the nucleotide level there are many more different alleles, several per colour). can be neutral, harmful or advantageous. Neutral mutations are the most studied, as they allow predictive models to be written to explore population history. Their distribution also serves as a null hypothesisRefers to the basic point of view, to the default position regarding a given phenomenon. In general, hypotheses opposing the null hypothesis have the burden of proof. to interpret, by comparison, that of deleterious or beneficial mutations.
We could think that in a genome comprising only neutral alleles, the drift of allelic frequencies would compensate for one fluctuation on the other and that the allelic diversity H would remain stable in the long term. But this impression is false. Gradually, diversity is eroding. This phenomenon is very similar to the loss of diversity of family names, a slow but significant phenomenon in human isolates such as remote villages. When a family does not have a boy, it does not pass on its surname. The same surname can be transmitted by related families, but the smaller the population, the greater the probability of names being lost. This is obviously not due to any biological property of the Y chromosome, which accompanies male births. Chance is enough to explain it. This property reflects the fact that the constitution of a daughter generation from a parental population follows the principle of a draw with replacementDrawing successively with delivery of tokens in an urn containing n tokens, means taking a first token, reading its value, putting it in the urn, taking a second token, reading its value, putting it in the urn, etc. until the p-th token. This means choosing p objects among n with repetition (you can choose the same object several times) and in order (the order in which you choose the objects is important). The number of successive draws with tokens among n is: n × n × n × … × n = np..
Like the Y chromosomes, some genes of the parental generation are not derived, and are not found in the daughter population. If the genes of the progeny are randomly drawn in a population of constant size, the probability that genes are not drawn is given by a Poisson’s law of parameter 1 as q(0) = e-1 = 0.367. These undrawn genes (more than a third) disappear without offspring. Their absence is compensated by parental genes which, by chance, have left more descendants. If this were not the case, the ancestral lines would remain parallel without ever meeting. The grouping of ancestral lines when going back in time is no different from a loss of diversity when going down to the present, nor is it different from what is called consanguinity.
The measurement of the diversity of formula (1) has a useful property: it depends on the sample size on which it is estimated. When a daughter population “t+1” is sampled by drawing n genes from a parental generation “t” the daughter generation shows a loss of variation equal to 1/n, according to the formula E(Hs) = Ht (1 – 1/n). This is true even if the daughter population is larger than the mother population, since it is a draw with replacement, but the larger the population, the less diversity is eroded. It is sufficient that the population be finite in size, which is what all real populations are. By convention, geneticists refer to this loss of variation as 1/Ne, where Ne is referred to as the effective number of chromosomes [1]. Thus from a generation 1 to a generation 2:
E(H2) = H1 (1 – 1/Ne) (3)
The effective size is almost always much smaller than the actual size of the chromosomes, for reasons that will be discussed later. For example, it is estimated that in the past of the human lineage, the effective number of chromosomes was in the order of 10,000. If there were no mutations, it is shown that the population would become monomorphic after a time T, of hope:
E(T) = 2 Ne (4)
There are two consequences to this: first, the polymorphism of a species is always “recent” on the scale of the duration of a species, since it depends on mutations that have restored the polymorphism despite the erosion of diversity that accompanies the drift of allelic frequencies. Second, the level of polymorphism is a compromise between two opposing mechanisms, creating the neutral mutation-drift balance.
The disappearance of polymorphism over time can be expressed in the opposite direction: when we go back in time, there is always a last common ancestor between two genes of the same locusPosition of the gene on the chromosome. In population genetics, all homologous genes (homology class). Two chromosomes or two genes are homologous if they match and exclude each other at meiosis.. This is what John Kingman called the coalescence process. The ancestor is not the same for different locus, because sexuality multiplies the number of ancestors, therefore also the common ancestors of genes. If the probability of having an ancestor common to the previous generation q = 1/Ne, remains constant over time, the distribution of ancestors follows an exponential law t = q. e-qt. The age expectation of these ancestors is equal to Ne. Two genes will be genetically similar if no mutation has occurred since then. But it is enough that a mutation has occurred in one of the lines leading from the ancestor to each of the two genes for both genes to be alleles. It can be deduced that the number of nucleotide differences between these two genes is θ = Ne x 2µ, where µ is the neutral mutation rate. This θ value, defined as θ = 2Neµ, is a fundamental parameter of population genetics.
Figure 1. Some models of population structure. The continuous arrows represent migration rates between populations, represented by ellipses. The interrupted arrows represent the differentiation between populations due to random drift. In star phylogeny and the founding effect, the divergence is continuous over time. In other models, there is a balance between random drift within populations and homogenization of populations by migration. Observed patterns of genetic variation and TSFs between population pairs indicate whether the history of a given species is more or less similar to one of these scenarios.
The neutral evolution of natural populations is very important in conservation biology, as it allows the history of species to be reconstructed. Geneticists have long known that random genetic drift allows them to infer models of population differentiation and species structure in space (Figure 1). During the second half of the 20th century, the most commonly used indicator to study the structuring of a population into sub-populations was the FST of the formula:
FST = 1-HS/HT (5)
where HS is the average of the diversities of the sub-populations and HT is the diversity of the total population [2].
Figure 2. Coalescence and demographic changes. The genealogy of a sample of 6 genes (white circles) from the same locus is examined in three populations with different demographic histories where the framing represents the size of the population: constant size (left), recent expansion after a bottleneck (centre) and old expansion (right). Time (in generations) goes back to the past at the top of the diagram. Mutations are represented by black circles (mutations of the “internal” branches, common to several genes in the sample) or by black stars (mutations of the “external” branches, unique in the sample because they lead to a single gene in the sample). We see that the age distribution of the common ancestors in the sample is very different depending on the conditions. The length ratio between the external (terminal) and internal branches of genealogy is different. This will result, for a constant mutation rate over time, in a different relative proportion of external and internal mutations. This ratio of rare/frequent mutations in the sample is one of the indicators used to reconstruct the history of the population. Other sets of polymorphism indicators (including H and π, seen in the text) also have this property.
In the 21st century, the age of numerical genome analysis, the theory of coalescence [3], independently developed by Kingman, Hudson and Tajima in 1982-83, makes it possible, in addition to studying structuring, to determine whether populations have remained stable or have undergone demographic changes (Figure 2).
2. Neutral model and biodiversity management
Figures 1 and 2 illustrate how genetic variation profiles are affected by population history: spatial structuring, colonization, migration, population change are all events that impart a specific signature in the molecular polymorphism of species, and allow ecologistswork in ecology. The job of an ecologist is to study the relationships between organisms and the surrounding world. Should not be confused with the ecologist, who campaigns to protect ecology. to trace its history. During the Quaternary era – the current geological period – the world’s climates changed cyclically, resulting in periodic changes in the coastline, a north-south shift of biological associations and glaciers, and periods of wet or dry climate at all latitudes. The resulting movements, decreases, increases, invasions of populations, indices of species’ responses to changes in their environment, are systematically recorded by population biologists before any natural population management initiative is undertaken. Most of the applications of population genetics today are in conservation biology.
3. Harmful mutations
Because genes code for proteins, most mutations in coding regions modify the protein sequence (about 3/4 of the mutations, a proportion that varies according to the composition of the sequence). In the human lineage, about 40% of these changes are deleterious, i.e. they are missing when the evolution of the genome of this species is assessed since its separation from the chimpanzee lineage. If a mutation were neutral, it would have a 1/Ne chance of replacing the other genes present at this locus one day (in a population of effective size Ne, the other genes taken together are in a 1-1/Ne proportion, and each also has a 1/Ne chance of replacing all the others). But a mutation can be harmful and affect the health or fertility of the individuals who carry it. Its frequency may fluctuate for a few generations by random drift before disappearing by selection (forty generations on average in Drosophila). All members of a species are carriers of deleterious mutations. You and I are. They are almost always in the heterozygousstate. This characterizes an organism that has two different alleles of the same gene at the same locus for each of its homologous chromosomes., because if a mutation has a frequency, for example, of 1/1000, it will have a thousand times fewer representatives in the homozygotestate, characterized by an organism that has two identical alleles of this gene at the same locus for each of its homologous chromosomes. than in the heterozygote state. It is the slight disadvantage of heterozygotes that eliminates the mutation rather than the often much greater disadvantage of the homozygous. Since the effects of deleterious mutations on several locus are cumulative, the mutation burden becomes a quantitative variable like any other whose additive effects may be undetectable, but nevertheless effective over the long term to purge the genome permanently. This explains why proteins remain functional and harmful mutations remain of low frequency. They are probably one of the factors that explain the maintenance of genetic recombination. This makes it possible both to group harmful mutations together to eliminate them and to limit the consequences of their elimination on adjacent regions of the chromosomes.
4. Advantageous mutations
What are the 60% of mutations affecting proteins without deleterious effect? Like mutations affecting other regions of the genome, they can be “neutral”, i.e. without any effect on health or fertility in a particular environment and in a particular communication system of a species. Their frequency fluctuates randomly in natural populations. But if conditions change, they can be advantageous. They are then part of the natural selection and sexual selection imagined by Darwin, but also of the selection in the first sense of the word, i.e. the selection made by man on his domestic species. There are two types of polymorphism selected: transient polymorphism and balanced polymorphism.
Figure 3. Selective scanning. Recombination makes it possible to decouple the evolution of adjacent regions of the genome. If there was no selection, neutral polymorphism would reach comparable values along the chromosome through a very slow equilibrium process. When a mutation is advantageous in a region and sets at the frequency of 1, the process is very fast, and it sweeps away the neutral polymorphism of that region, but not that of adjacent regions. The contrast of the level of neutral polymorphism in the scanned regions and in the neutral regions makes it possible to affirm that it is indeed the selection that has acted in the former, and excludes the circular reasoning that would admit that “what is adapted is what we see”. This example shows two contiguous areas of selective scanning on the X chromosome of Drosophila simulans. They make it possible to identify two complexes of genes that act simultaneously to modify for their benefit the Mendelian proportions in the offspring of fruit flies (see ref [6]) (so-called “selfish” genes). In these two zones (SR1 and SR2), selection has eliminated neutral polymorphism.Transient polymorphism is the case of an advantageous mutation that gradually “fixes” itself by eliminating alternative alleles, which can lead to a frequency of 1. This is the case, for example, of insecticide resistance genes in mosquitoes, antibiotic resistance in bacteria and antimalarial drug resistance in the malaria parasite: these mutations would probably not have had an advantage under natural conditions, but in the environmental context imposed by medicine, these alleles increase in frequency. This is also the case for the three alleles that regulate the expression of lactase, an enzyme that allows humans to digest milk sugar (lactose) not only in the newborn state, as in other mammals, but also in adults. These mutations have become beneficial in livestock populations, while our hunter-gatherer ancestors only had the opportunity to digest fruit sugar (sucrose) as adults. In all these cases of transient polymorphism, the locus to which the selection relates is “betrayed” by a signature in the genome: the rapid expansion of its frequency makes the adjacent neutral variation on the chromosome disappear. This is a case of selective scanning, which makes it possible to affirm that the fixation of an allele is not due to random drift, but to selection (Figure 3, [4]).
Figure 4. Balanced polymorphism. When natural selection maintains the coexistence of two alleles, their sequences diverge more and more, to the point of accumulating more mutations between them than the neutral model for the rest of the genome predicts. This is the case for two alleles of the Drosophila tan gene (coordinate 0), whose two alleles have maintained the coexistence of females with light or black abdomen for about three million years. These patterns of coloration are involved in communication between males and females during mating, but neither can eliminate the other, probably because their selective advantage decreases when they become too frequent. Interrupted line: expected value of the divergence between chromosomes; in blue: value actually observed (see ref [7]).Balanced polymorphism refers to situations where two alleles coexist because each is favoured under certain conditions, but where neither can prevail over the other in all circumstances of time or space. An example is given by cases where the selective advantage of a genotype increases due to its inverse frequency. This is called frequency-dependent selection. Such situations of balanced polymorphism are frequent in cases of sexual selection (Figure 4, [5]).
5. Is polymorphism useful?
In the 1930s to 1960s, natural population geneticists discovered an increasing number of polymorphisms in nature. They wanted to assess its extent and discover its potential utility in terms of evolution. Debates opposed researchers who considered that genetic diversity conferred an advantage in itself and that selection maintained it at high levels, to researchers who considered that selection led to a phenotypeAll the observable characteristics of a fairly homogeneous wild individual, the remaining variations being rather harmful. None of them were right. The Frenchman Gustave Malécot had already demonstrated in the 1950s that neutral polymorphism was a consequence of Mendel’s {tooltip}laws{ind-text}Lois concerning the principles of biological heredity, set out by the Czech monk and botanist Gregor Mendel (1822-1884). in a finite size population [6]. It was finally the discovery in 1966 of extremely high levels of molecular polymorphism, which could not be explained by natural selection alone [7], that allowed the Japanese Kimura and Ohta to put forward the neutralist theory [8]. It was realized that the alternative to Darwin’s theory of natural selection was not the fixity of species (as thought by Darwin’s opponents, for example) but a continuous genetic change predicted by the neutral model, similar to the random walk of a diffusion phenomenon in physics. This vision was definitively accepted in the 1980s. However, the very low value of the effective population size measured in all species, compared to the reproductive population size, indicates that forces are eroding genetic diversity much more than neutralist models predict. This erosion is due in part, still poorly estimated, to natural selection, which eliminates harmful mutations and fixes advantageous variations, and thus increases the effects of drift on the neutral variation. Although extremely important for the future of the species, the selected polymorphisms certainly represent only a small fraction of the cases of polymorphism.
Neutral molecular polymorphism provides the basic theory, the reference model, from which the selection and history of populations are studied. The paradox is that, from now on, the molecular signatures of natural selection are sought in the genome using neutralist theory.
The existence of selective forces that maintain the recombination system, Mendel’s laws [9], and the genetic mixing of sexuality is an argument for considering that polymorphism, which they maintain in this way, has a short-term advantage in natural populations.
References and notes
[1] Until about 2000, the effective size was expressed in individuals and not in chromosomes, so the effective size of the chromosomes was 2Ne for autosomes, 1.5Ne for ,X chromosomes, and 0.5Ne for Y chromosomes and mitochondria, provided that the number of males and females at breeding is the same. These formulas can be found in manuals.
[2] This formula, here very general, takes several forms and denominations according to the genetic model used: Wright’s FST (for two alleles), Nei’s GST (its generalization, of which formula 5 above is a variant), ΦST,ρST, etc. It can be replaced by statistics with similar properties: DXY, AMOVA. This redundancy shows above all the success of “F-statitics” in ecology. Because of the dependence of the estimate on the sample size, the use of unbiased estimators must also take into account the particularities of the observation design. Cf: Weir B.S. & Cockerham C.C. (1984) Estimating F-statistics for the analysis of population structure. Evolution 38:1358-1370
[3] Kingman J.F.C. (1982) On the genealogy of large populations. Journal of Applied Probability 19A:27-43; Hudson R.R. (1983) Properties of a neutral allele model with intragenic recombination. Theoretical Population Biology 23:183-201; Tajima F. (1983) Evolutionary relationship of DNA sequences in finite populations. Genetics 105:437-460.
[4] Derome N., K. Métayer, C. Montchamp-Moreau & M. Veuille (2004) Signature of selective sweep associated with the evolution of sex-ratio drive in Drosophila simulans. Genetics 166: 1357-1366; Derome N., E. Baudry, D. Ogereau, M. Veuille & C. Montchamp-Moreau (2008) Selective sweeps reveal a two-locus model for sex-ratio meiotic drive in Drosophila simulans. Molecular Biology and Evolution, 25:409-416.
[5] Yassin A., Bastide H., Chung H., Veuille M., David J.R. & Pool J.E. (2016) Ancient Balancing Selection at tan Underlies Female Colour Dimorphism in Drosophila erecta. Nature Communications DOI: 10.1038/ncomms10400.
[6] Malecot G. (1948) The mathematics of heredity. Masson et Cie; Nagylaki T. (1989) Gustave Malécot and the transition from classical to modern population genetics. Genetics 122, 253-268.
[7] Lewontin R.C. & Hubby J.L. (1966) Molecular Approach to the Study of Genic Heterozygosity in Natural Populations. II. Amount of Variation and Degree of Heterozygosity in Natural Populations of Drosophila pseudoobscura, Genetics 54: 595-609; Lewontin R.C. (1974) The Genetic Basis of Evolutionary Change. Columbia Univ. Press, New York.
[8] Kimura M. (1969) The Rate of Molecular Evolution Considered from the Standpoint of Population Genetics. Proceedings of the National Academy of Sciences, 63:1181-1188.
