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Genetic distance is a measure of the genetic divergence between species or between populations within a species, whether the distance measures time from common ancestor or degree of differentiation.^[2] Populations with many similar alleles have small genetic distances. This indicates that they are closely related and have a recent common ancestor.

Genetic distance is useful for reconstructing the history of populations, such as the multiple human expansions out of Africa.^[3] It is also used for understanding the origin of biodiversity. For example, the genetic distances between different breeds of domesticated animals are often investigated in order to determine which breeds should be protected to maintain genetic diversity.^[4]

Biological foundation

Life on earth began from very simple unicellular organisms evolving into most complex multicellular organisms through the course of over three billion years.^[5] Creating a comprehensive tree of life that represents all the organisms that have ever lived on earth is important for understanding the evolution of life in the face of all challenges faced by living organisms to deal with similar challenges in future. Evolutionary biologists have attempted to create evolutionary or phylogenetic trees encompassing as many organisms as possible based on the available resources. Fossil dating and molecular clock are the two means of generating evolutionary history of living organisms. Fossil record is random, incomplete and does not provide a continuous chain of events like a movie with missing frames cannot tell the whole plot of the movie.^[5]

Molecular clocks on the other hand are specific sequences of DNA, RNA or proteins (amino acids) that are used to determine at molecular level the similarities and differences among species, to find out the timeline of divergence,^[6] and to trace back the common ancestor of species based on the mutation rates and sequence changes being accumulated in those specific sequences.^[6] The primary driver of evolution is the mutation or changes in genes and accounting for those changes overtime determines the approximate genetic distance between species. These specific molecular clocks are fairly conserved across a range of species and have a constant rate of mutation like a clock and are calibrated based on evolutionary events (fossil records). For example, gene for alpha-globin (constituent of hemoglobin) mutates at a rate of 0.56 per base pair per billion years.^[6] The molecular clock can fill those gaps created by missing fossil records.

In the genome of an organism, each gene is located at a specific place called the locus for that gene. Allelic variations at these loci cause phenotypic variation within species (e.g. hair colour, eye colour). However, most alleles do not have an observable impact on the phenotype. Within a population new alleles generated by mutation either die out or spread throughout the population. When a population is split into different isolated populations (by either geographical or ecological factors), mutations that occur after the split will be present only in the isolated population. Random fluctuation of allele frequencies also produces genetic differentiation between populations. This process is known as genetic drift. By examining the differences between allele frequencies between the populations and computing genetic distance, we can estimate how long ago the two populations were separated.^[7]

Let’s suppose a sequence of DNA or a hypothetical gene that has mutation rate of one base per 10 million years. Using this sequence of DNA, the divergence of two different species or genetic distance between two different species can be determined by counting the number of base pair differences among them. For example, in Figure 2 a difference of 4 bases in the hypothetical sequence among those two species would indicate that they diverged 40 million years ago, and their common ancestor would have lived at least 20 million years ago before their divergence. Based on molecular clock, the equation below can be used to calculate the time since divergence.^[8]

Number of mutation ÷ Mutation per year (rate of mutation) = time since divergence

Process of determining genetic distance

Recent advancement in sequencing technology and the availability of comprehensive genomic databases and bioinformatics tools that are capable of storing and processing colossal amount of data generated by the advanced sequencing technology has tremendously improved evolutionary studies and the understanding of evolutionary relationships among species.^[9][10]

Markers for genetic distance

Different biomolecular markers such DNA, RNA and amino acid sequences (protein) can be used for determining the genetic distance.^[11][12]

The selection criteria^[13] of appropriate biomarker for genetic distance entails the following three steps:

1. choice of variability
2. choice of specific region of DNA or RNA
3. the use of technique

The choice of variability depends on the intended outcome. For example, very high level of variability is recommended for demographic studies and parentage analyses, medium to high variability for comparing distinct populations, and moderate to very low variability is recommended for phylogenetic studies.^[13] The genomic localization and ploidy of the marker is also an important factor. For example, the gene copy number is inversely proportional to the robustness with haploid genome (mitochondrial DNA) more prone to genetic drift than diploid genome (nuclear DNA).

The choice and examples of molecular markers for evolutionary biology studies.^[13]

Application of genetic distance

• Phylogenetics: Exploring the genetic distance among species can help in establishing evolutionary relationships among them, the time of divergence between them and creating a comprehensive phylogenetic tree that connect them to their common ancestors.
•  Accuracy of genomic prediction: Genetic distance can be used to predict unobserved phenotypes which has implication in medical diagnostics, and breeding of plants and animals.^[14]
• Population Genetics: Genetic distance can help in studying population genetics, understanding intra and inter-population genetic diversity.
• Taxonomy and Species Delimitation: Determining genetic distance through DNA barcoding is an effective tool for delimiting species especially identifying cryptic species.^[15] An optimized percentage threshold genetic distance is recommended based on the data and species being studied to improve and enhance the reliability and applicability of delimitation^[16][17][18] that can delineate species boundaries and identify cryptic species that look similar but are genetically distinct.

Evolutionary forces affecting genetic distance

Evolutionary forces such as mutation, genetic drift, natural selection, and gene flow drive the process of evolution and genetic diversity. All these forces play significant role in genetic distance within and among species.^[19]

Measures

Figure 3: Image depicts speciation stemmed from geographic isolation where a starting population is separated. Over vast amounts of time, isolated groups of a particular taxa may diverge into distinct species.

Different statistical measures exist that aim to quantify genetic deviation between populations or species. By utilizing assumptions gained from experimental analysis of evolutionary forces, a model that more accurately suits a given experiment can be selected to study a genetic group. Additionally, comparing how well different metrics model certain population features such as isolation can identify metrics that are more suited for understanding newly studied groups^[20] The most commonly used genetic distance metrics are Nei's genetic distance,^[7] Cavalli-Sforza and Edwards measure,^[21] and Reynolds, Weir and Cockerham's genetic distance.^[22]

Jukes-Cantor Distance

One of the most basic and straight forward distance measures is Jukes-Cantor distance. This measure is constructed based on the assumption that no insertions or deletions occurred, all substitutions are independent, and that each nucleotide change is equally likely. With these presumptions, we can obtain the following equation:^[23]

${\displaystyle d_{AB}=-{\frac {3}{4}}\ln(1-{\frac {4}{3}}f_{AB})}$

where ${\displaystyle d_{AB}}$ is the Jukes-Cantor distance between two sequences A, and B, and ${\displaystyle f_{AB}}$ being the dissimilarity between the two sequences.

Nei's standard genetic distance

In 1972, Masatoshi Nei published what came to be known as Nei's standard genetic distance. This distance has the nice property that if the rate of genetic change (amino acid substitution) is constant per year or generation then Nei's standard genetic distance (D) increases in proportion to divergence time. This measure assumes that genetic differences are caused by mutation and genetic drift.^[7]

${\displaystyle D=-\ln {\frac {\sum \limits _{\ell }\sum \limits _{u}X_{u}Y_{u}}{\sqrt {\left(\sum \limits _{u}X_{u}^{2}\right)\left(\sum \limits _{u}Y_{u}^{2}\right)}}}}$

This distance can also be expressed in terms of the arithmetic mean of gene identity. Let ${\displaystyle j_{X}}$ be the probability for the two members of population ${\displaystyle X}$ having the same allele at a particular locus and ${\displaystyle j_{Y}}$ be the corresponding probability in population ${\displaystyle Y}$. Also, let ${\displaystyle j_{XY}}$ be the probability for a member of ${\displaystyle X}$ and a member of ${\displaystyle Y}$ having the same allele. Now let ${\displaystyle J_{X}}$, ${\displaystyle J_{Y}}$ and ${\displaystyle J_{XY}}$ represent the arithmetic mean of ${\displaystyle j_{X}}$, ${\displaystyle j_{Y}}$ and ${\displaystyle j_{XY}}$ over all loci, respectively. In other words,

${\displaystyle J_{X}=\sum _{u}{\frac {{X_{u}}^{2}}{L}}}$

${\displaystyle J_Y=\underset{u}{\sum <!--\; \sum \; -->}\frac{{{}_{}}^{}}{}}$Zdroj:https://en.wikipedia.org?pojem=Genetic_distance
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