Genetic variation

Causes

There are many sources of genetic variability in a population:

• Homologous recombination is a significant source of variability. During meiosis in sexual organisms (sexual reproduction), two homologous chromosomes cross over one another and exchange genetic material. This random process of exchanging genetic material is known as recombination, and it is governed by its own set of genes.^[19] Being controlled by genes means that recombination is variable in frequency. Generally, it is more common in areas on the chromosome where there are a higher number of genes. It creates more combinations of genes.^[19] After this occurs, the chromosomes are split apart and are ready to contribute to forming an offspring.
• Immigration, emigration, and translocation – each of these is the movement of an individual into or out of a population. When an individual enters a new population after coming from a genetically isolated one, they will increase the genetic variability of the next generation, provided that they reproduce.^[20]
• Polyploidy – having more than two homologous chromosomes. This allows for more recombination during meiosis and more genetic variability in one's offspring. However, this phenomenon can also prove difficult for cell division.^[21]
• Diffuse centromeres – in asexual organisms where the offspring is an exact genetic copy of the parent, there are limited sources of genetic variability. One thing that increases variability, however, is having diffused centromeres instead of localized centromeres. Being diffused allows the chromatids to split apart in many different ways, which produces chromosome fragmentation and polyploidy.^[22]
• Genetic mutations – contribute to the genetic variability within a population and can have positive, negative, or neutral effects on a fitness.^[23] This variability can be easily propagated throughout a population by natural selection if the mutation increases the affected individual's fitness and its effects will be minimized/hidden if the mutation is deleterious. If the individual can survive with the mutations they have, those mutations will likely be passed down to offspring. However, the smaller a population and its genetic variability are, the more likely the recessive/hidden deleterious mutations will show up causing genetic drift.^[23]

DNA damages are very frequent, occurring more than 60,000 times a day per cell on average in humans. This is due to metabolic or hydrolytic processes as summarized in DNA damage (naturally occurring). Most DNA damages are accurately repaired by various natural DNA repair mechanisms. However, some DNA damages remain and give rise to mutations.

Additionally, not all types of mutations occur as much as others do. Some mutations might have a huge impact on the human body, and some might not. It depends on what combination of base pairs is changed.^[24]

Most spontaneously arising mutations result from error prone replication (translesion synthesis) past a DNA damage in the template strand. For example, in yeast more than 60% of spontaneous single-base pair substitutions and deletions are likely caused by translesion synthesis.^[25] Another significant source of mutation is an inaccurate DNA repair process, non-homologous end joining, that is often employed in repair of DNA double-strand breaks.^[26] (Also see Mutation.) Thus, it seems that DNA damages are the underlying cause of most spontaneous mutations, either because of error-prone replication past damages or error-prone repair of damages.

Pre-Darwinian concepts of heritable variation

In the mid-1700s, Pierre Louis Maupertuis, a French scholar now known primarily for his work in mathematics and physics, posited that while species have a true, original form, accidents during the development of nascent offspring could introduce variations that could accumulate over time.^[27] In his 1750 Essaie de Cosmologie, he proposed that the species we see today are only a small fraction of the many variations produced by "a blind destiny", and that many of these variations did not "conform" to their needs, thus did not survive.^[28] In fact, some historians even suggest that his ideas anticipated the laws of inheritance further developed by Gregor Mendel.^[29]

Simultaneously, French philosopher Denis Diderot proposed a different framework for the generation of heritable variation. Diderot borrowed Maupertuis' idea that variation could be introduced during reproduction and the subsequent growth of offspring,^[30] and thought that production of a "normal" organism was no more probable than production of a "monstrous" one.^[31] However, Diderot also believed that matter itself had lifelike properties and could self-assemble into structures with the potential for life.^[30] Diderot's ideas on biological transformation, introduced in his 1749 work Letter on the Blind, were thus focused on variability of spontaneously generated forms, not variability within existing species.^[32]

Both Maupertuis and Diderot built on the ideas of Roman poet and philosopher Lucretius, who wrote in De rerum natura that all the universe was created by random chance, and only the beings that were not self-contradictory survived.^[33] Maupertuis' work is distinguished from the work of both Lucretius and Diderot in his use of the concept of conformity in explaining differential survival of beings, a new idea among those who believed that life changed over time.^[33]

Like Diderot, two other influential minds of the 18th century—Erasmus Darwin and Jean-Baptiste Lamarck—believed that only very simple organisms could be generated by spontaneous generation, so another mechanism was necessary to generate the great variability of complex life observed on earth.^[27] Erasmus Darwin proposed that changes acquired during an animal's life could be passed to its offspring, and that these changes seemed to be produced by the animal's endeavors to meet its basic needs.^[34] Similarly, Lamarck's theory of the variability among living things was rooted in patterns of use and disuse, which he believed led to heritable physiological changes.^[27] Both Erasmus Darwin and Lamarck believed that variation, whether it arose during development or during the animal's life, was heritable, a key step in theories of change over time extending from individuals to populations.

In the subsequent century, William Herschel's telescopic observations of diverse nebulae across the night sky suggested to him that different nebulae could each be in different stages in the process of condensation. This idea, which came to be known as the nebular hypothesis, suggested that natural processes could both create order out of matter and introduce variation, and that these processes could be observed over time.^[27] While it may seem to the modern reader that astronomical theories are irrelevant to theories of organic variation, these ideas became significantly conflated with ideas of biological transformation—what we now know as evolution—in the mid-19th century, laying important groundwork for the work of subsequent thinkers such as Charles Darwin.^[35]

Darwin's concept of heritable variation

Charles Darwin's ideas of heritable variation were shaped by both his own scientific work and the ideas of his contemporaries and predecessors.^[36] Darwin ascribed heritable variation to many factors, but particularly emphasized environmental forces acting on the body. His theory of inheritance was rooted in the (now disproven) idea of gemmules - small, hypothetical particles, which capture the essence of an organism and travel from all over the body to the reproductive organs, from which they are passed to offspring.^[37] Darwin believed that the causal relationship between the environment and the body was so complex that the variation this relationship produced was inherently unpredictable.^[38] However, like Lamarck, he acknowledged that variability could also be introduced by patterns of use and disuse of organs.^[39] Darwin was fascinated by variation in both natural and domesticated populations, and his realization that individuals in a population exhibited seemingly purposeless variation was largely driven by his experiences working with animal breeders.^[40] Darwin believed that species changed gradually, through the accumulation of small, continuous variations, a concept that would remain hotly contested into the 20th century.^[41]

Post-Darwinian concepts of heritable variation

In the 20th century, a field that came to be known as population genetics developed. This field seeks to understand and quantify genetic variation.^[41] The section below consists of a timeline of selected developments in population genetics, with a focus on methods for quantifying genetic variation.

• 1866 - Heterozygosity: Gregor Mendel's hybridization experiments introduced the concept that in the 1950s came to be recognized as heterozygosity.^[39] In a diploid species, one that contains two copies of DNA within each cell (one from each parent), an individual is said to be a heterozygote at a particular location in the genome if its two copies of DNA differ at that site. Heterozygosity, the average frequency of heterozygotes in a population, became a fundamental measure of the genetic variation in a population by the mid-20th century.^[42] If the heterozygosity of a population is zero, every individual is homozygous; that is, every individual has two copies of the same allele at the locus of interest and no genetic variation exists.
• 1918 - Variance: In a seminal paper entitled "The correlation between relatives on the supposition of Mendelian inheritance", R.A. Fisher introduced the statistical concept of variance; the average of squared deviations of a collection of observations from their mean (${\textstyle \sigma ^{2}={\frac {1}{I}}\sum _{i=1}^{I}(x_{i}-\mu )^{2}}$), where ${\displaystyle \sigma ^{2}}$ is the variance and ${\displaystyle \mu }$ is the mean of the population from which the observations ${\displaystyle x_{i}}$ are drawn).^[43] R.A. Fisher's work in population genetics was not just important to population genetics; these ideas would also form the foundations of modern statistics.
• 1918, 1921 - Additive and dominant genetic variance: R.A. Fisher subsequently subdivided his general definition of variance into two components relevant to population genetics: additive and dominant genetic variance.^[44] An additive genetic model assumes that genes do not interact if the number of the genes affecting the phenotype is small and that a trait value can be estimated simply by summing the effect of each gene on the trait. Under Fisher's model, the total genetic variance is the sum of the additive genetic variance (the variance in a trait due to these additive effects) and the dominant genetic variance (which accounts for interactions between genes).^[43]
• 1948 - Entropy: Unlike variance, which was developed with the purpose of quantifying genetic variance, Claude Shannon's measure of diversity, now known as Shannon entropy, was developed as part of his work in communication theory as a way to quantify the amount of information contained in a message. However, the method quickly found use in population genetics, and was the central method used to quantify genetic diversity in a seminal paper by Richard Lewontin, "The Apportionment of Human Genetic Diversity".^[45]
• 1951 - F-statistics: F-statistics, also known as fixation indices, were developed by population geneticist Sewall Wright to quantify differences in genetic variation within and between populations. The most common of these statistics, F_ST, considers in its simplest definition two different versions of a gene, or alleles, and two populations that contain one or both of these two alleles. F_ST quantifies the genetic variability among these two populations by computing the average frequency of heterozygotes across the two populations relative to the frequency of heterozygotes if the two populations were pooled.^[46] F-statistics introduced the idea of quantifying hierarchical concepts of variance and would become the foundation of many important population genetic methods, including a set of methods that tests for evidence of natural selection in the genome.^[47]