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The genotype of an organism is its complete set of genetic material.[1] Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location.[2] The number of alleles an individual can have in a specific gene depends on the number of copies of each chromosome found in that species, also referred to as ploidy. In diploid species like humans, two full sets of chromosomes are present, meaning each individual has two alleles for any given gene. If both alleles are the same, the genotype is referred to as homozygous. If the alleles are different, the genotype is referred to as heterozygous.

Genotype contributes to phenotype, the observable traits and characteristics in an individual or organism.[3] The degree to which genotype affects phenotype depends on the trait. For example, the petal color in a pea plant is exclusively determined by genotype. The petals can be purple or white depending on the alleles present in the pea plant.[4] However, other traits are only partially influenced by genotype. These traits are often called complex traits because they are influenced by additional factors, such as environmental and epigenetic factors. Not all individuals with the same genotype look or act the same way because appearance and behavior are modified by environmental and growing conditions. Likewise, not all organisms that look alike necessarily have the same genotype.

The term genotype was coined by the Danish botanist Wilhelm Johannsen in 1903.[5]

Phenotype

[edit]
Main article: Phenotype

Any given gene will usually cause an observable change in an organism, known as the phenotype. The terms genotype and phenotype are distinct for at least two reasons:

  • To distinguish the source of an observer's knowledge (one can know about genotype by observing DNA; one can know about phenotype by observing outward appearance of an organism).
  • Genotype and phenotype are not always directly correlated. Some genes only express a given phenotype in certain environmental conditions. Conversely, some phenotypes could be the result of multiple genotypes. The genotype is commonly mixed up with the phenotype which describes the result of both the genetic and the environmental factors giving the observed expression (e.g. blue eyes, hair color, or various hereditary diseases).

A simple example to illustrate genotype as distinct from phenotype is the flower colour in pea plants (see Gregor Mendel). There are three available genotypes, PP (homozygous dominant), Pp (heterozygous), and pp (homozygous recessive). All three have different genotypes but the first two have the same phenotype (purple) as distinct from the third (white).

A more technical example to illustrate genotype is the single-nucleotide polymorphism or SNP. A SNP occurs when corresponding sequences of DNA from different individuals differ at one DNA base, for example where the sequence AAGCCTA changes to AAGCTTA.[6] This contains two alleles : C and T. SNPs typically have three genotypes, denoted generically AA Aa and aa. In the example above, the three genotypes would be CC, CT and TT. Other types of genetic marker, such as microsatellites, can have more than two alleles, and thus many different genotypes.

Penetrance is the proportion of individuals showing a specified genotype in their phenotype under a given set of environmental conditions.[7]

Mendelian inheritance

[edit]
Main article: Mendelian inheritance
Here the relation between genotype and phenotype is illustrated, using a Punnett square, for the character of petal colour in a pea plant. The letters B and b represent alleles for colour and the pictures show the resultant flowers. The diagram shows the cross between two heterozygous parents where B represents the dominant allele (purple) and b represents the recessive allele (white).

Traits that are determined exclusively by genotype are typically inherited in a Mendelian pattern. These laws of inheritance were described extensively by Gregor Mendel, who performed experiments with pea plants to determine how traits were passed on from generation to generation.[8] He studied phenotypes that were easily observed, such as plant height, petal color, or seed shape.[8] He was able to observe that if he crossed two true-breeding plants with distinct phenotypes, all the offspring would have the same phenotype. For example, when he crossed a tall plant with a short plant, all the resulting plants would be tall. However, when he self-fertilized the plants that resulted, about 1/4 of the second generation would be short. He concluded that some traits were dominant, such as tall height, and others were recessive, like short height. Though Mendel was not aware at the time, each phenotype he studied was controlled by a single gene with two alleles. In the case of plant height, one allele caused the plants to be tall, and the other caused plants to be short. When the tall allele was present, the plant would be tall, even if the plant was heterozygous. In order for the plant to be short, it had to be homozygous for the recessive allele.[8][9]

One way this can be illustrated is using a Punnett square. In a Punnett square, the genotypes of the parents are placed on the outside. An uppercase letter is typically used to represent the dominant allele, and a lowercase letter is used to represent the recessive allele. The possible genotypes of the offspring can then be determined by combining the parent genotypes.[10] In the example on the right, both parents are heterozygous, with a genotype of Bb. The offspring can inherit a dominant allele from each parent, making them homozygous with a genotype of BB. The offspring can inherit a dominant allele from one parent and a recessive allele from the other parent, making them heterozygous with a genotype of Bb. Finally, the offspring could inherit a recessive allele from each parent, making them homozygous with a genotype of bb. Plants with the BB and Bb genotypes will look the same, since the B allele is dominant. The plant with the bb genotype will have the recessive trait.

These inheritance patterns can also be applied to hereditary diseases or conditions in humans or animals.[11][12][13] Some conditions are inherited in an autosomal dominant pattern, meaning individuals with the condition typically have an affected parent as well. A classic pedigree for an autosomal dominant condition shows affected individuals in every generation.[11][12][13]

An example of a pedigree for an autosomal dominant condition

Other conditions are inherited in an autosomal recessive pattern, where affected individuals do not typically have an affected parent. Since each parent must have a copy of the recessive allele in order to have an affected offspring, the parents are referred to as carriers of the condition.[11][12][13] In autosomal conditions, the sex of the offspring does not play a role in their risk of being affected. In sex-linked conditions, the sex of the offspring affects their chances of having the condition. In humans, females inherit two X chromosomes, one from each parent, while males inherit an X chromosome from their mother and a Y chromosome from their father. X-linked dominant conditions can be distinguished from autosomal dominant conditions in pedigrees by the lack of transmission from fathers to sons, since affected fathers only pass their X chromosome to their daughters.[13][11][14] In X-linked recessive conditions, males are typically affected more commonly because they are hemizygous, with only one X chromosome. In females, the presence of a second X chromosome will prevent the condition from appearing. Females are therefore carriers of the condition and can pass the trait on to their sons.[13][11][14]

An example of a pedigree for an autosomal recessive condition

Mendelian patterns of inheritance can be complicated by additional factors. Some diseases show incomplete penetrance, meaning not all individuals with the disease-causing allele develop signs or symptoms of the disease.[13][15][16] Penetrance can also be age-dependent, meaning signs or symptoms of disease are not visible until later in life. For example, Huntington disease is an autosomal dominant condition, but up to 25% of individuals with the affected genotype will not develop symptoms until after age 50.[17] Another factor that can complicate Mendelian inheritance patterns is variable expressivity, in which individuals with the same genotype show different signs or symptoms of disease.[13][15][16] For example, individuals with polydactyly can have a variable number of extra digits.[15][16]

Non-Mendelian inheritance

[edit]
Main article: Non-Mendelian inheritance

Many traits are not inherited in a Mendelian fashion, but have more complex patterns of inheritance.

Incomplete dominance

[edit]

For some traits, neither allele is completely dominant. Heterozygotes often have an appearance somewhere in between those of homozygotes.[18][19] For example, a cross between true-breeding red and white Mirabilis jalapa results in pink flowers.[19]

Codominance

[edit]

Codominance refers to traits in which both alleles are expressed in the offspring in approximately equal amounts.[20] A classic example is the ABO blood group system in humans, where both the A and B alleles are expressed when they are present. Individuals with the AB genotype have both A and B proteins expressed on their red blood cells.[20][18]

Epistasis

[edit]
Main article: Epistasis

Epistasis is when the phenotype of one gene is affected by one or more other genes.[21] This is often through some sort of masking effect of one gene on the other.[22] For example, the "A" gene codes for hair color, a dominant "A" allele codes for brown hair, and a recessive "a" allele codes for blonde hair, but a separate "B" gene controls hair growth, and a recessive "b" allele causes baldness. If the individual has the BB or Bb genotype, then they produce hair and the hair color phenotype can be observed, but if the individual has a bb genotype, then the person is bald which masks the A gene entirely.

Polygenic traits

[edit]
Main article: Polygene

A polygenic trait is one whose phenotype is dependent on the additive effects of multiple genes. The contributions of each of these genes are typically small and add up to a final phenotype with a large amount of variation. A well studied example of this is the number of sensory bristles on a fly.[23] These types of additive effects is also the explanation for the amount of variation in human eye color.

Genotyping

[edit]
Main article: Genotyping

Genotyping refers to the method used to determine an individual's genotype. There are a variety of techniques that can be used to assess genotype. The genotyping method typically depends on what information is being sought. Many techniques initially require amplification of the DNA sample, which is commonly done using PCR.

Some techniques are designed to investigate specific SNPs or alleles in a particular gene or set of genes, such as whether an individual is a carrier for a particular condition. This can be done via a variety of techniques, including allele specific oligonucleotide (ASO) probes or DNA sequencing.[24][25] Tools such as multiplex ligation-dependent probe amplification can also be used to look for duplications or deletions of genes or gene sections.[25] Other techniques are meant to assess a large number of SNPs across the genome, such as SNP arrays.[24][25] This type of technology is commonly used for genome-wide association studies.

Large-scale techniques to assess the entire genome are also available. This includes karyotyping to determine the number of chromosomes an individual has and chromosomal microarrays to assess for large duplications or deletions in the chromosome.[24][25] More detailed information can be determined using exome sequencing, which provides the specific sequence of all DNA in the coding region of the genome, or whole genome sequencing, which sequences the entire genome including non-coding regions.[24][25]

Genotype encoding

[edit]

In linear models, the genotypes can be encoded in different manners. Let us consider a biallelic locus with two possible alleles, encoded by and . We consider to correspond to the dominant allele to the reference allele . The following table details the different encoding.[26]

Genotype
Additive encoding 0 1 2
Dominant encoding 1 1 0
Recessive encoding 0 0 1
Codominant encoding 0,0 0,1 1,0

See also

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Genotype

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The genotype of an is its complete heritable genetic makeup, encompassing the full set of genes or, more specifically, the particular combination of alleles at one or more genetic loci inherited from its parents. This genetic information is encoded in the 's DNA and serves as the blueprint for its biological characteristics. Unlike the , which represents the observable traits resulting from the interaction between genotype and environmental factors, the genotype remains relatively stable throughout an 's life, barring mutations. Genotypes can be described at various levels of detail, from the entire to specific loci, and are classified based on combinations, such as homozygous (identical at a locus) or heterozygous (different at a locus). For instance, in , a controlling flower color in sweet peas might have a dominant F for and a recessive f for white, yielding genotypes FF (homozygous dominant, flowers), Ff (heterozygous, flowers), or ff (homozygous recessive, white flowers). Similarly, in animals, genotypic variations like those affecting ear shape in cats—where a dominant produces curled ears and a recessive produces normal ears—demonstrate how specific genotypes influence traits. The study of genotypes is fundamental to , enabling researchers to predict patterns, identify risks, and understand ary processes through changes in genotypes over generations. Techniques such as , which determine an organism's genetic composition, have advanced fields like and by revealing how genotypes underpin phenotypic diversity and adaptability.

Core Concepts

Definition

The genotype of an organism refers to its complete genetic constitution, consisting of the full set of genes or alleles inherited from its parents. This encompasses the genetic information that forms the basis of heredity, distinguishing it from environmental influences. At the molecular level, the genotype is defined by the specific nucleotide sequences of DNA at particular genetic loci in eukaryotic organisms and most prokaryotes, which encode the instructions for hereditary traits. In RNA viruses, the genotype instead comprises the RNA sequences at analogous genomic positions. These sequences represent the variants present at each locus, often denoted by symbols for analysis. The term "genotype" was coined in 1909 by Danish botanist Wilhelm Johannsen to describe the underlying genetic factors separate from observable traits. For a single gene locus, genotypes are categorized by allele combinations: homozygous, with two identical alleles (e.g., AA for homozygous dominant or aa for homozygous recessive); heterozygous, with two different alleles (e.g., Aa); and hemizygous, with only one allele, as seen in sex-linked traits on the X chromosome in males.

Genotype versus Phenotype

The refers to an organism's observable traits, such as physical characteristics, biochemical properties, and behavioral patterns, which arise from the interaction between its genotype and environmental influences. Unlike the genotype, which represents the fixed genetic composition inherited from parents, the is dynamic and can vary even among individuals with identical genotypes due to external factors. A key feature of the genotype-to-phenotype relationship is its one-to-many mapping, where a single genotype can produce multiple phenotypes influenced by environmental conditions, as well as genetic phenomena like incomplete —where not all individuals with a disease-causing genotype exhibit the trait—and variable expressivity, where the trait's severity differs among affected individuals. This mapping underscores that the genotype provides the potential blueprint, but its realization into observable traits is not deterministic. The norm of reaction describes the range of phenotypes that a specific genotype can produce across a spectrum of environmental conditions, illustrating the plasticity inherent in genetic expression. For instance, a genotype may yield robust growth in optimal environments but stunted development under stress, highlighting how environmental variation shapes phenotypic outcomes without altering the underlying DNA sequence. Gene-environment interactions (G×E) further exemplify this by demonstrating how external factors modulate phenotypic expression through mechanisms that do not change the genotype itself, such as altering gene regulation or metabolic pathways. These interactions are a primary driver of phenotypic diversity, as they allow the same genetic makeup to adaptively respond to differing habitats or stressors. A classic example is the flower color in hydrangea plants (), where the same genotype produces blue sepals in acidic soil (pH 4.5–5.5) due to enhanced aluminum uptake that stabilizes blue pigments, but pink or red sepals in alkaline soil (pH 5.5–7.5) where aluminum availability is reduced.

Mendelian Inheritance

Basic Principles

Mendelian inheritance is governed by two fundamental laws proposed by based on his experiments with pea plants. The law of segregation states that during gamete formation, the two for a separate, so each carries only one , ensuring that inherit one from each parent. The law of independent assortment further specifies that of different assort independently during formation, provided the genes are on different chromosomes. In a monohybrid cross involving a single with complete dominance, crossing two heterozygous individuals (e.g., Aa × Aa) produces offspring with a genotypic of 1:2:1 (homozygous dominant : heterozygous : homozygous recessive) and a phenotypic of 3:1 (dominant : recessive). This outcome arises because each parent contributes one of two possible alleles equally likely, leading to predictable segregation in the progeny. For traits controlled by two genes, a between two heterozygous individuals (e.g., AaBb × AaBb) yields a phenotypic of 9:3:3:1 among offspring, assuming independent assortment. This reflects the combined probabilities from each : nine individuals show both dominant phenotypes, three show dominant for the first and recessive for the second, three the reverse, and one both recessive. The serves as a graphical tool to visualize and calculate the probabilities of genotypes and phenotypes in such crosses by listing possible gametes from each parent along the axes and filling in the resulting combinations. Developed later but rooted in Mendel's principles, it facilitates of patterns for one or more genes. These principles rely on key assumptions, including complete dominance where one fully masks the other, no between genes on the same , and random mating without environmental influences on segregation.

Genotype Determination in Mendelian Traits

In , determining the genotype of an individual exhibiting a dominant requires experimental crosses to reveal hidden s, as the alone cannot distinguish between homozygous dominant (AA) and heterozygous (Aa) states. A , involving breeding the unknown individual with a homozygous recessive (aa) partner, produces offspring ratios that indicate the genotype: a 1:1 phenotypic ratio of dominant to recessive suggests heterozygosity, while all dominant offspring indicate homozygosity. This method, originally employed by in his pea plant experiments, allows direct inference of the genotype by observing the segregation of s in the progeny. Backcrossing, a related technique, involves crossing an individual of interest with one of its al lines, often the recessive parent, to trace and recover specific genotypes while minimizing . In pedigree analysis, family trees are constructed to map patterns across generations, enabling probabilistic assignment of genotypes based on observed phenotypes and known Mendelian ratios; for instance, the absence of recessive phenotypes in multiple generations may indicate homozygous dominant status. These approaches are particularly useful in controlled breeding programs for and animals, where direct observation of multiple clarifies allele transmission. Predicting genotypic outcomes from known parental genotypes relies on the segregation of alleles during formation, as described by Mendel's law of segregation. For a self-cross of a heterozygote (Aa × Aa), the expected genotypic ratio among offspring is 1/4 AA : 1/2 Aa : 1/4 aa, reflecting the equal probability of each allele combination. This 1:2:1 ratio arises from the random union of , each carrying A or a with 50% probability, and can be visualized using Punnett squares for monohybrid crosses. In larger populations under random mating and without evolutionary forces, genotype frequencies stabilize according to the Hardy-Weinberg equilibrium, providing a baseline for estimating allele frequencies from observed phenotypes. If the frequency of the dominant allele A is p and the recessive allele a is q (where p + q = 1), the equilibrium genotype frequencies are p² for AA, 2pq for Aa, and q² for aa, satisfying the equation: p2+2pq+q2=1p^2 + 2pq + q^2 = 1 This principle, independently formulated by G.H. Hardy and Wilhelm Weinberg, allows calculation of expected genotype proportions; for example, if q = 0.3 (recessive allele frequency), then the homozygous recessive frequency is 0.09, or 9% of the population. Deviations from these expectations can signal non-random mating or selection, but under equilibrium assumptions, they predict genotype distributions reliably.

Non-Mendelian Inheritance

Incomplete Dominance

Incomplete dominance refers to a pattern of inheritance in which neither of a gene pair is fully dominant over the other, leading to a heterozygous phenotype that represents an intermediate blend between the two homozygous phenotypes. This occurs because the gene products from each interact or combine to produce a novel trait expression, rather than one masking the other completely. Unlike complete dominance in , where heterozygotes express only the dominant trait, incomplete dominance results in a modified that deviates from both parental forms. In genetic crosses exhibiting incomplete dominance, the genotypic ratios follow the standard Mendelian 1:2:1 segregation (one homozygous for A, two heterozygous, one homozygous for B), but the phenotypic ratios also become 1:2:1, reflecting three distinct observable traits instead of the typical 3:1 ratio. This pattern arises from the self- of heterozygotes, where the intermediate heterozygous form is clearly distinguishable from the homozygotes. For instance, a between two pink-flowered snapdragons (Rr) yields 25% red (RR), 50% pink (Rr), and 25% white (rr) offspring, demonstrating how the genotype directly correlates with a blended without . A classic example of incomplete dominance is observed in the flower color of snapdragons (), where the red (R) and white (r) produce pink flowers in heterozygotes (Rr) due to partial pigmentation. When true-breeding red (RR) and white (rr) plants are crossed, all F1 offspring display pink flowers, and the F2 shows the 1:2:1 phenotypic ratio of red:pink:white. This phenomenon was first noted in similar plants by in his early 20th-century experiments, highlighting non-Mendelian deviations in trait expression. At the molecular level, incomplete dominance in snapdragons stems from semi-dominant alleles at the Nivea locus, which encodes chalcone synthase (CHS), a key enzyme in anthocyanin pigment biosynthesis. The red allele produces high levels of functional CHS, leading to full pigmentation, while the white allele yields little to no activity; in heterozygotes, the combined partial output results in intermediate pigment levels and pink coloration. This dosage effect of gene products exemplifies how allelic variations in production can blend to generate intermediate phenotypes. Incomplete dominance differs from codominance in that the heterozygous arises from a physical or biochemical blending of allelic effects, producing a uniform intermediate trait, rather than the simultaneous and distinct expression of both alleles as separate entities.

Codominance

Codominance is a form of genetic in which both alleles of a are fully and equally expressed in the heterozygous individual, resulting in a that displays traits from both alleles simultaneously without blending or dilution. This contrasts with incomplete dominance, where the heterozygous represents an intermediate blend of the two homozygous phenotypes. In codominance, the genotypic ratio from a between two heterozygotes follows the classic Mendelian 1:2:1 pattern (homozygous dominant : heterozygous : homozygous recessive), but the phenotypic ratio also yields three distinct categories, as the heterozygote exhibits a unique combined rather than one dominated by a single . For instance, if alleles A and B are codominant, the offspring would appear as 1 A : 2 A and B : 1 B. A prominent example of codominance is the human ABO blood group system, controlled by the ABO gene on chromosome 9. Individuals with genotype I^A I^A or I^A i express blood type A, I^B I^B or I^B i express type B, I^A I^B express type AB (with both A and B antigens present on red blood cells), and i i express type O (no A or B antigens). The I^A and I^B alleles are codominant, while the i allele is recessive. At the molecular level, codominance in the ABO system arises because each produces a distinct that independently modifies the on surfaces: the I^A adds N-acetylgalactosamine to form the A , the I^B adds to form the B , and the i encodes a nonfunctional . In heterozygotes (I^A I^B), both enzymes are produced without interference, leading to the co-expression of A and B antigens. This independent action of allelic products exemplifies the lack of typical in codominance. Codominance plays a key role in by preserving genetic polymorphism within populations, as both alleles remain viable and expressed, preventing the fixation of a single variant and promoting in certain contexts, such as resistance associated with ABO diversity.

Epistasis

refers to the interaction between s at different loci, where the alleles of one (the epistatic ) mask or modify the phenotypic expression of alleles at another (the hypostatic ). This arises when the product of the epistatic is required for the expression of the hypostatic 's effects, leading to deviations from the expected Mendelian ratios in dihybrid crosses. One common type is recessive epistasis, in which the homozygous recessive genotype at the epistatic locus suppresses the expression of the hypostatic locus, resulting in a modified dihybrid ratio of 9:3:4 instead of the standard 9:3:3:1. For instance, in coat color , the recessive c/c genotype at the C locus ( gene) prevents production, masking the effects of the B locus (which determines vs. ), yielding mice regardless of B alleles. Dominant epistasis occurs when a dominant at the epistatic locus overrides the hypostatic locus, producing a 12:3:1 ratio in dihybrid crosses. An example is seen in squash fruit color, where the dominant W at the W locus inhibits color expression from the Y locus, resulting in white fruit for genotypes with W-, colored for ww Y- , and for ww yy. A well-known example of recessive epistasis is coat color in Labrador retrievers, controlled by the E locus (MC1R gene) and B locus (TYRP1 gene). The dominant E allele allows expression of eumelanin pigments determined by B (black for B- , chocolate for bb), while the homozygous recessive ee blocks melanin deposition in hair follicles, resulting in yellow coats regardless of the B genotype and a 9:3:4 phenotypic ratio. At the molecular level, epistasis often involves regulatory genes that control downstream pathways, such as transcription factors or enzymes that enable or inhibit the function of other genes in a . In the example, the MC1R protein (encoded by E) acts as a receptor for , activating the pathway for (encoded by B) to produce eumelanin; loss-of-function in MC1R (ee) halts this pathway upstream, epistatically masking TYRP1 variants. These interactions highlight how epistasis complicates genotype-to-phenotype predictions by altering the independent assortment outcomes assumed in basic Mendelian principles.

Polygenic Traits

Polygenic traits, also known as quantitative traits, are phenotypic characteristics influenced by the combined effects of multiple genes, each contributing a small additive effect, along with environmental factors. This form of inheritance, termed polygenic inheritance, results in a continuous range of variation rather than the discrete categories observed in Mendelian traits. For instance, is determined by thousands of genetic variants (over 12,000 identified in large-scale genome-wide association studies as of 2022) across the , producing a spectrum of outcomes influenced by and other environmental inputs. Similarly, skin color in humans arises from the additive contributions of several genes regulating production, leading to diverse pigmentation levels. In polygenic inheritance, the phenotypic distribution typically follows a bell-shaped curve, reflecting the cumulative impact of many loci rather than simple dominant-recessive ratios. (h²), a key measure in , quantifies the proportion of phenotypic variance (V_P) in a attributable to genetic variance (V_G), expressed as h² = V_G / V_P. For polygenic traits like , estimates often range from 0.7 to 0.8 in well-nourished populations, indicating that genetic factors explain a substantial portion of the observed variation, though environmental influences remain significant. This contrasts sharply with , where traits segregate in predictable 3:1 or 1:1 ratios due to single-gene control. Polygenic risk scores (PRS) provide a method to estimate an individual's genetic liability to a polygenic trait by summing the effects of numerous genetic variants, weighted by their estimated effect sizes from genome-wide association studies (GWAS). These scores aggregate common variants across the to predict trait outcomes, such as susceptibility or quantitative measures like , offering insights into complex genotype-phenotype relationships. By capturing the polygenic , PRS highlight how small effects from many alleles deviate from discrete Mendelian patterns, enabling probabilistic rather than categorical predictions.

Genotype Analysis

Genotyping Methods

Genotyping methods encompass a range of techniques designed to identify specific genetic variants, such as single nucleotide polymorphisms (SNPs) or mutations, at targeted loci in an organism's DNA. These approaches have evolved from labor-intensive classical procedures to high-throughput modern technologies, enabling precise determination of genotypes for research and clinical applications. Early methods relied on physical differences in DNA fragments, while contemporary techniques leverage amplification, sequencing, and hybridization for scalability and accuracy. Classical genotyping methods, such as restriction fragment length polymorphism (RFLP), involve digesting genomic DNA with restriction enzymes that recognize specific sequences, producing fragments of varying lengths based on the presence or absence of polymorphisms at restriction sites. The fragments are then separated by gel electrophoresis and visualized, often through Southern blotting with radioactive or fluorescent probes, to distinguish alleles; for instance, a polymorphism disrupting a restriction site results in longer uncut fragments. This technique, foundational for genetic mapping, was first proposed for constructing human linkage maps using polymorphic DNA markers. RFLP's resolution depends on enzyme selection and probe specificity but is limited by the need for known restriction site variations and its labor-intensive nature. Polymerase chain reaction (PCR)-based methods have become staples for targeted genotyping due to their specificity and sensitivity in amplifying short DNA regions. Allele-specific PCR (AS-PCR) employs primers designed with a 3' terminal base complementary to one allele of a SNP or mutation, allowing selective amplification only when the primer perfectly matches the template; mismatched primers fail to extend efficiently under stringent conditions, enabling discrimination between homozygous and heterozygous states in a single reaction. Real-time PCR, or quantitative PCR (qPCR), extends this by monitoring amplification via fluorescent probes or dyes during cycles, quantifying allele ratios through melting curve analysis or endpoint fluorescence to detect genotypes with high throughput. These methods are particularly effective for validating known variants and require minimal DNA input, though primer design is critical to avoid cross-reactivity. Direct DNA sequencing technologies provide unambiguous genotype determination by reading sequences at loci of interest. , the gold standard for short-read accuracy, uses chain-terminating dideoxynucleotides to generate fragments of varying lengths during , which are separated by to produce a chromatogram revealing base calls; it is ideal for confirming variants in amplicons up to 1,000 base pairs, such as in targeted screening. For broader applications, next-generation sequencing (NGS) platforms, exemplified by Illumina's sequencing-by-synthesis, enable analysis of millions of fragments, allowing high-throughput across entire genomes or exomes by aligning short reads to sequences and calling variants via bioinformatics pipelines. NGS has revolutionized by reducing costs per base and increasing speed, though it requires computational resources for error correction in repetitive regions. Microarray hybridization methods, particularly SNP chips, facilitate simultaneous of thousands to millions of predefined loci through allele-specific oligonucleotide probes immobilized on a solid surface. In platforms like Illumina's Infinium assays, genomic DNA is fragmented, amplified, and hybridized to bead-bound probes that capture specific alleles; enzymatic single-base extensions or ligation reveal genotypes via fluorescent signals scanned by systems, enabling genome-wide association studies with high . These arrays probe fixed sets of SNPs, offering cost-effective for population-level analysis but limited flexibility for novel variants. In research applications, genotyping methods are crucial for identifying causative mutations in Mendelian diseases, such as , where variants in the CFTR gene are detected using targeted PCR, sequencing, or arrays to distinguish disease-associated alleles like the ΔF508 deletion from wild-type sequences. For example, as of 2023, ACMG-recommended panels combine AS-PCR and sequencing to screen 100 CFTR variants, aiding diagnosis and carrier detection with near-complete coverage of common variants in diverse populations. These techniques underscore the transition from single-locus to multiplexed , enhancing precision in studies.

Genotype Encoding and Representation

In computational genetics, genotype data is often encoded numerically to facilitate statistical analyses, particularly in genome-wide association studies (GWAS). The is a common approach, where genotypes at a biallelic (SNP) are coded as 0 for homozygous reference (e.g., AA), 1 for heterozygous (e.g., Aa), and 2 for homozygous alternate (e.g., aa). This encoding assumes an additive effect of alleles on the , allowing models to estimate the impact of each alternate allele copy while simplifying computations across millions of variants. It is widely adopted in tools like PLINK, where genotype matrices store these values in binary format for efficient processing of large datasets. Haplotype representation extends this by capturing the chromosomal phase of alleles, distinguishing which alleles are on the same DNA strand. Phased genotypes are denoted using a pipe symbol (|) to separate alleles on homologous chromosomes, such as 0|1 for a heterozygous where the reference allele is on one haplotype and the alternate on the other. This is crucial for reconstructing ancestry, patterns, and imputation accuracy in . The Variant Call Format (VCF), a standard for storing such data, supports both unphased (/) and phased (|) notations in its genotype (GT) field, along with quality metrics like genotype quality () and read depth (DP) to assess call reliability. For scenarios involving uncertainty, such as imputation from low-coverage sequencing, dosage encoding represents expected counts as continuous values between 0 and 2, calculated as the sum of posterior probabilities for each genotype state (e.g., dosage = 0 × Pr(AA) + 1 × Pr(Aa) + 2 × Pr(aa)). This probabilistic approach improves power in association tests by incorporating imputation uncertainty, especially for rare variants. In software like PLINK, genotype data is organized into matrices where rows represent individuals and columns represent SNPs, with entries as 0, 1, 2, or missing values, enabling scalable analyses such as for population structure. VCF files can be converted to these matrices for integration with downstream tools, ensuring compatibility across workflows.

References

  1. https://www.nature.com/scitable/definition/genotype-234/
  2. https://evolution.berkeley.edu/genotype-versus-phenotype/
  3. https://www.ncbi.nlm.nih.gov/books/NBK225676/
  4. https://cfa.org/breed/american-curl/
  5. https://www.cancer.gov/publications/dictionaries/genetics-dictionary/def/genotype
  6. https://vgl.ucdavis.edu/resources/genetics-glossary
  7. https://plato.stanford.edu/archives/fall2016/entries/genotype-phenotype/
  8. https://www.cdc.gov/flu/php/viruses/genetic-characterization.html
  9. https://www.genome.gov/genetics-glossary/genotype
  10. https://embryo.asu.edu/pages/wilhelm-johannsens-genotype-phenotype-distinction
  11. https://opengenetics.pressbooks.tru.ca/chapter/alleles-hetero-homo-hemizygosity/
  12. https://www.genome.gov/genetics-glossary/Phenotype
  13. https://plato.stanford.edu/archives/spr2019/entries/genotype-phenotype/
  14. https://pmc.ncbi.nlm.nih.gov/articles/PMC9380816/
  15. https://evolution.berkeley.edu/glossary/norm-of-reaction/
  16. https://pmc.ncbi.nlm.nih.gov/articles/PMC3011025/
  17. https://www.genome.gov/genetics-glossary/Gene-Environment-Interaction
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