What are the possible causes of genetic variation?

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Genetic variation is the difference in DNA sequences between individuals within a population. Variation occurs in germ cells i.e. sperm and egg, and also in somatic (all other) cells. Only variation that arises in germ cells can be inherited from one individual to another and so affect population dynamics, and ultimately evolution. Mutations and recombination are major sources of variation.

What are mutations?

Mutations are the original source of genetic variation. A mutation is a permanent alteration to a DNA sequence. De novo (new) mutations occur when there is an error during DNA replication that is not corrected by DNA repair enzymes. It is only once the error is copied by DNA replication, and fixed in the DNA that it is considered to be a mutation (Figure 1). Mutations may be beneficial to the organism; deleterious (harmful) to the organism; or neutral (have no effect on the fitness of the organism). 

Somatic mutations can accumulate in our cells and are mostly harmless. They can lead to local changes in tissues such as moles appearing on the skin, and can also have more serious effects – for example leading to cancer. To learn more about the role of somatic mutations in cancer have a look at this paper by Martincorena and Campbell1. In this course we focus on heritable genetic variation, i.e. variation that occurs in germ cells.

What is recombination?

Recombination is another major source of genetic variation Each of us has a mixture of genetic material from our parents. The mixing of this genetic material occurs during recombination when homologous DNA strands align and cross over. Recombination effectively ‘shuffles’ maternal and paternal DNA, creating new combinations of variants in the daughter germ-cells (Figure 2).

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Evolution is the process by which populations of organisms change over generations. Genetic variations underlie these changes. Genetic variations can arise from gene variants (also called mutations) or from a normal process in which genetic material is rearranged as a cell is getting ready to divide (known as genetic recombination). Genetic variations that alter gene activity or protein function can introduce different traits in an organism. If a trait is advantageous and helps the individual survive and reproduce, the genetic variation is more likely to be passed to the next generation (a process known as natural selection). Over time, as generations of individuals with the trait continue to reproduce, the advantageous trait becomes increasingly common in a population, making the population different than an ancestral one. Sometimes the population becomes so different that it is considered a new species.

Not all variants influence evolution. Only hereditary variants, which occur in egg or sperm cells, can be passed to future generations and potentially contribute to evolution. Some variants occur during a person’s lifetime in only some of the body’s cells and are not hereditary, so natural selection cannot play a role. Also, many genetic changes have no impact on the function of a gene or protein and are not helpful or harmful. In addition, the environment in which a population of organisms lives is integral to the selection of traits. Some differences introduced by variants may help an organism survive in one setting but not in another—for example, resistance to a certain bacteria is only advantageous if that bacteria is found in a particular location and harms those who live there.

So why do some harmful traits, like genetic diseases, persist in populations instead of being removed by natural selection? There are several possible explanations, but in many cases, the answer is not clear. For some conditions, such as the neurological condition Huntington disease, signs and symptoms occur later in life, typically after a person has children, so the gene variant can be passed on despite being harmful. For other harmful traits, a phenomenon called reduced penetrance, in which some individuals with a disease-associated variant do not show signs and symptoms of the condition, can also allow harmful genetic variations to be passed to future generations. For some conditions, having one altered copy of a gene in each cell is advantageous, while having two altered copies causes disease. The best-studied example of this phenomenon is sickle cell disease: Having two altered copies of the HBB gene in each cell results in the disease, but having only one copy provides some resistance to malaria. This disease resistance helps explain why the variants that cause sickle cell disease are still found in many populations, especially in areas where malaria is prevalent.

Mating patterns are important

When a population interbreeds, nonrandom mating can sometimes occur because one organism chooses to mate with another based on certain traits. In this case, individuals in the population make specific behavioral choices, and these choices shape the genetic combinations that appear in successive generations. When this happens, the mating patterns of that population are no longer random.

Nonrandom mating can occur in two forms, with different consequences. One form of nonrandom mating is inbreeding, which occurs when individuals with similar genotypes are more likely to mate with each other rather than with individuals with different genotypes. The second form of nonrandom mating is called outbreeding, wherein there is an increased probability that individuals with a particular genotype will mate with individuals of another particular genotype. Whereas inbreeding can lead to a reduction in genetic variation, outbreeding can lead to an increase.

Random forces lead to genetic drift

Sometimes, there can be random fluctuations in the numbers of alleles in a population. These changes in relative allele frequency, called genetic drift, can either increase or decrease by chance over time.

Typically, genetic drift occurs in small populations, where infrequently-occurring alleles face a greater chance of being lost. Once it begins, genetic drift will continue until the involved allele is either lost by a population or is the only allele present at a particular gene locus within a population. Both possibilities decrease the genetic diversity of a population.

Genetic drift is common after a population experiences a population bottleneck. A population bottleneck arises when a significant number of individuals in a population die or are otherwise prevented from breeding, resulting in a drastic decrease in the size of the population. Genetic drift can result in the loss of rare alleles, and can decrease the size of the gene pool. Genetic drift can also cause a new population to be genetically distinct from its original population, which has led to the hypothesis that genetic drift plays a role in the evolution of new species.

Distribution

How does the physical distribution of individuals affect a population? A species with a broad distribution rarely has the same genetic makeup over its entire range. For example, individuals in a population living at one end of the range may live at a higher altitude and encounter different climatic conditions than others living at the opposite end at a lower altitude. What effect does this have? At this more extreme boundary, the relative allele frequency may differ dramatically from those at the opposite boundary. Distribution is one way that genetic variation can be preserved in large populations over wide physical ranges, as different forces will shift relative allele frequencies in different ways at either end.

If the individuals at either end of the range reconnect and continue mating, the resulting genetic intermixing can contribute to more genetic variation overall. However, if the range becomes wide enough that interbreeding between opposite ends becomes less and less likely, and the different forces acting at either end become more and more pronounced, and the individuals at each end of the population range may eventually become genetically distinct from one another.

Migration

Migration is the movement of organisms from one location to another. Although it can occur in cyclical patterns (as it does in birds), migration when used in a population genetics context often refers to the movement of individuals into or out of a defined population. What effect does migration have on relative allele frequencies? If the migrating individuals stay and mate with the destination individuals, they can provide a sudden influx of alleles. After mating is established between the migrating and destination individuals, the migrating individuals will contribute gametes carrying alleles that can alter the existing proportion of alleles in the destination population.

Here is an example of migration affecting relative allele frequency:

The overall effect

How do populations respond to all these forces? As relative allele frequencies change, relative genotype frequencies may also change. Each genotype in the population usually has a different fitness for that particular environment. In other words, some genotypes will be favored, and individuals with those genotypes will continue to reproduce. Other genotypes will not be favored: individuals with those genotypes will be less likely to reproduce. What type of genotype would be unfavorable? Unfavorable genotypes take many forms, such as increased risk of predation, decreased access to mates, or decreased access to resources that maintain health. Overall, the forces that cause relative allele frequencies to change at the population level can also influence the selection forces that shape them over successive generations.

For example, if moths with genotype aa migrate into a population composed of AA and Aa individuals, they will increase the relative allele frequency of a. However, if the aa genotype has a clear disadvantage to survival (e.g. vulnerability to predation), eventually the changes brought about by the initial migration will be reversed.

Here is an example of how a specific genotype is less favorable than another genotype:

Summary

Genetic variation in a population is derived from a wide assortment of genes and alleles. The persistence of populations over time through changing environments depends on their capacity to adapt to shifting external conditions. Sometimes the addition of a new allele to a population makes it more able to survive; sometimes the addition of a new allele to a population makes it less able. Still other times, the addition of a new allele to a population has no effect at all, yet the new allele will persist over generations because its contribution to survival is neutral.