Hubbry Logo
Null alleleNull alleleMain
Open search
Null allele
Community hub
Null allele
logo
7 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
Null allele
Null allele
Null allele
View on Wikipedia
from Wikipedia

A null allele is a nonfunctional allele (a variant of a gene) caused by a genetic mutation. Such mutations can cause a complete lack of production of the associated gene product or a product that does not function properly; in either case, the allele may be considered nonfunctional. A null allele cannot be distinguished from deletion of the entire locus solely from phenotypic observation.[1]

A mutant allele that produces no RNA transcript is called an RNA null (shown by Northern blotting or by DNA sequencing of a deletion allele), and one that produces no protein is called a protein null (shown by Western blotting). A genetic null or amorphic allele has the same phenotype when homozygous as when heterozygous with a deficiency that disrupts the locus in question. A genetic null allele may be both a protein null and an RNA null, but may also express normal levels of a gene product that is nonfunctional due to mutation.

Null alleles can have lethal effects depending on the importance of the mutated gene. For example, mice homozygous for a null allele for insulin die 48 to 72 hours after birth.[2] Null alleles can also have beneficial effects,[3] such as the elevated harvest index of semi-dwarf rice of the green revolution caused by null alleles in GA20ox-2. [4]

Evidence

[edit]

Polymerase chain reaction (PCR)

[edit]

A microsatellite null allele is an allele at a microsatellite locus that does not amplify to detectable levels in a polymerase chain reaction test.[5] Microsatellite regions are usually characterized by short, repeated sequences of nucleotides.[5] Primers that are specific to a particular locus are used in PCR amplification to bind to these nucleotide sequence repeats and are used as genetic markers.[6][5] The primers anneal to either end of the locus and are derived from source organisms in a genomic library. Divergence from the reference sequences (from genetic mutations) results in poor annealing of the primers so that the marker cannot be used, representative of a null allele.[6]

Parentage analysis

[edit]

Strong evidence of null alleles was first seen in analysis of bears in 1995.[7] In this analysis, a known parent was determined to be homozygous at a certain locus, but produced offspring that expressed a different "homozygous" genotype.[5] This result led to the inference that the parent and offspring were both heterozygous for the locus being studied.[7]

Examples

[edit]

Null alleles or genes have been studied in different organisms from the red pines of Minnesota to Drosophila melanogaster and mice. Null alleles are difficult to identify because a heterozygous individual for one null allele and one active allele is phenotypically indistinguishable from a homozygous individual with both active alleles.[8] In other words, a null allele can only be identified from the phenotypic standpoint if the individual is homozygous for the null allele. Researchers have been able to work around this problem by using detailed Electrophoresis, gel assays, and chromosomal manipulation.[8][9][10]

  1. Allendorf et al. studied the enzyme activity of the same species of red pine seeds collected from two different tree stands in Minnesota. The two groups of trees were treated as one population because no deviations from expected genotype frequencies were observed, as would be expected if the populations were diverging from one another.[8] Many different loci were tested for enzyme activity using a specific gel electrophoresis technique.[11] Alleles that produced an enzyme lacking catalytic activity were denoted as null alleles. A total of 27 loci were tested in red pines and null alleles were found at 3 of those loci.[8]
  2. A population of Drosophila melanogaster from Raleigh, NC were genetically manipulated by Voelker et al. in 1980 to determine existence and frequency of null alleles. The experiment consisted of making the chromosome of a wild fly heterozygous by using the mobility variants at the locus being observed. If the manipulated allele (now heterozygous) did not present a heterozygous phenotype, the allele was suspected to be null. These potential null alleles were then confirmed when they failed to produce a heterozygous electrophoretic pattern. A total of 25 loci were tested with 5 loci being X-linked and the remaining 20 autosomal. No null alleles were detected at the X-linked loci, but 13 of the 20 autosomal loci contained null alleles.[9]
  3. Multiple different experiments have used genetic manipulation to induce null allele mutants in mice populations in order to observe the consequences of different allele combinations at specific loci. Two such experiments investigated the role of insulin-like growth factor (Igf) in mouse embryonic development. The experiments only differed in the gene being investigated, Igf-1[10] and Igf-2.[12] Both experiments used the process of mutageneis, whereby the genetic content of the organism is changed, to produce individuals with different combinations of null mutations.[10][12] By observing the consequences of different inactive allele combinations, the researchers were able to deduce the roles of insulin-like growth factors in the development of mice. The experiment involving Igf-1 revealed that, in addition to its role after birth, it is also fundamental in the development of the embryo and the differentiation of cells.[10]
  4. One example of a null allele is the 'O' blood type allele in the human A, B and O blood type system. The alleles for the A-antigen and B-antigen are co-dominant, thus they are both phenotypically expressed if both are present. The allele for O blood type, however, is a mutated version of the allele for the A-antigen, with a single base pair change due to genetic mutation. The protein coded for by the O allele is enzymatically inactive and therefore the O allele is expressed phenotypically in homozygous OO individuals as the lack of any blood antigen. Thus we may consider the allele for the O blood type as a null allele.[13]

See also

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Null allele

View on Grokipedia
from Grokipedia
A null allele is a mutant form of a gene that produces no functional product, resulting in the complete absence or non-detectability of the gene's or protein output at the molecular level, and consequently no normal phenotypic effect. These alleles typically arise from mutations such as deletions, mutations, or frameshifts that disrupt entirely. In , null alleles, also known as amorphs, serve as loss-of-function variants that help researchers study essentiality by eliminating protein activity, as seen in model organisms like and mice. In molecular , particularly with PCR-based methods like microsatellites or short tandem repeats (STRs), a null allele refers to a variant present in the but undetectable due to failure in amplification, often caused by in primer-binding sites that prevent efficient annealing. Such technical null alleles lead to allelic dropout, where heterozygotes are misidentified as homozygotes, thereby underestimating and heterozygosity in population studies. This phenomenon is common in and conservation , where null allele frequencies rarely exceed 0.20 but can bias parentage exclusion probabilities and relatedness estimates if unaccounted for. Detection often involves inferring deficits in heterozygosity or redesigning primers to mitigate amplification failures.

Fundamentals

Definition

A null allele is a mutant at a genetic locus that results in no functional , such as a protein or , being produced from that allele, or produces a product that is entirely non-functional, thereby causing a complete loss of the 's normal activity. This contrasts with the wild-type , which supports normal function, and distinguishes null alleles as a specific category of loss-of-function variants in . The concept of null alleles was first conceptualized in the early during foundational studies in Mendelian , particularly through observations of inheritance patterns that implied complete absence of certain traits. Formal recognition in molecular terms occurred by the 1980s, as advances in allowed identification of specific types leading to non-functional products. Key characteristics of null alleles include their complete lack of contribution to function, which can manifest differently based on : in homozygous individuals, both are null, resulting in a total absence of functional product and often severe phenotypic effects; in heterozygous individuals, the presence of a dominant wild-type allele typically compensates, leading to partial or normal function. In genetic notation, null alleles are commonly represented as "null" or with a superscript zero, such as gene0. Null alleles thus play a critical role in producing loss-of-function phenotypes, especially in homozygous states.

Distinction from Other Allele Types

Null alleles are distinguished from wild-type alleles, which encode a fully functional capable of normal . In contrast, null alleles result in the complete absence of functional activity from the affected copy, often leading to no detectable protein function when homozygous. Unlike hypomorphic alleles, which produce a partially functional with reduced but residual activity compared to wild-type, null alleles cause a total loss of function, amplifying phenotypic effects in homozygous states. Hypomorphic mutations may allow for milder, sometimes viable phenotypes, whereas null alleles typically result in more severe outcomes. Hypermorphic alleles represent the opposite spectrum, encoding a gene product with enhanced activity or expression levels exceeding that of the wild-type, potentially leading to gain-of-function phenotypes. Null alleles, by eliminating all function, underscore the baseline requirement for gene activity without any such augmentation. The terms null and amorphic are often used synonymously to describe complete loss-of-function alleles. This distinction arises from classical genetic analyses, such as in Drosophila, where phenotypic equivalence to deficiencies defines amorphic alleles. Null alleles generally exhibit recessive inheritance patterns due to their passive loss of function. Neomorphic alleles differ fundamentally by conferring a molecular function or expression pattern not present in the wild-type , resulting in gain-of-function effects that null alleles entirely lack. These novel activities can produce dominant phenotypes unrelated to simple loss. Antimorphic alleles, in opposition to the passive absence of function in null alleles, produce a that actively antagonizes or interferes with the wild-type counterpart, often through dominant-negative mechanisms in multimeric complexes. This interference reduces overall function beyond what a null allele would achieve in heterozygotes.
Allele TypeFunction Level Relative to Wild-TypeExample Phenotype Impact
Wild-typeFull (100%)Normal, baseline
NullNone (0%)Severe recessive loss-of-function, e.g., complete deficiency
HypomorphicReduced (<100%)Partial loss, e.g., milder disease severity than null
HypermorphicIncreased (>100%)Gain-of-function, e.g., overactive pathway leading to excess trait
NeomorphicNovel (new activity)Dominant novel trait, e.g., altered substrate specificity
AntimorphicAntagonistic (interferes)Dominant-negative, e.g., reduced total activity in heterozygotes despite wild-type presence

Molecular Basis

Mutations Causing Null Alleles

Null alleles arise from a variety of genetic alterations at the DNA level that completely abolish gene function, resulting in no functional protein product. These mutations disrupt essential aspects of gene expression or protein structure, leading to a loss-of-function phenotype. Common types include large-scale deletions that remove entire genes or critical exons, thereby preventing any transcription or translation of functional sequences. For instance, deletions encompassing the full coding region eliminate the possibility of producing a viable protein. Nonsense mutations introduce premature stop codons within the coding sequence, typically through single substitutions, causing transcription of a truncated mRNA that is often degraded by (NMD), yielding no stable protein. Frameshift mutations, caused by insertions or deletions of not divisible by three, alter the downstream of the mutation site, leading to a garbled sequence and usually a premature termination codon, again resulting in non-functional or absent protein via NMD. Splice-site mutations affect the conserved sequences at intron-exon boundaries, disrupting proper mRNA splicing and producing aberrant transcripts that either lack essential exons or include intronic sequences, both of which preclude functional protein synthesis. Promoter mutations, often involving point changes or small deletions in regulatory regions upstream of the coding sequence, impair binding or recruitment, drastically reducing or eliminating mRNA production and thus generating a null state at the transcriptional level. In rare instances, epigenetic mechanisms such as promoter hypermethylation can induce heritable equivalent to a null allele by blocking transcription without altering the DNA sequence; this has been observed in cases like epialleles in hybrid incompatibilities, though it is not a true sequence-based . Null alleles typically emerge spontaneously at mutation rates ranging from 10^{-6} to 10^{-9} per locus per , depending on the and locus size, with higher rates for larger due to more target sites. These rates reflect the cumulative probability of deleterious changes like or frameshift events across the . Evolutionarily, most null alleles are strongly deleterious and subject to purifying selection, often being purged from populations unless masked in heterozygous carriers; however, they can persist at low frequencies in recessive forms or become fixed if they confer rare adaptive advantages, such as in metabolic adaptations. To illustrate, consider a of a typical eukaryotic : an upstream promoter region followed by (coding blocks) interspersed with . A might span multiple , removing them entirely (marked as a gap in the ). In contrast, a in an could introduce a codon (shown as a red "STOP" symbol), while a frameshift in another shifts the (indicated by altered codon alignment). Splice-site disruptions at boundaries would be depicted as broken splice signals, leading to unspliced or skipped mRNA. This visualization highlights how at different sites converge on the null outcome of absent functional protein.

Biochemical and Phenotypic Consequences

Null alleles, also known as amorphic , result in the complete loss of function, producing no functional protein product at the molecular level. This absence typically arises from mechanisms such as deletions, premature stop codons, or frameshift that prevent or yield a nonfunctional polypeptide. Biochemically, null alleles eliminate , disrupt structural protein assembly, or abolish regulatory factor activity, leading to stalled metabolic pathways or unregulated cellular processes. For instance, the lack of a functional can cause accumulation of unprocessed substrates or toxic intermediates, as seen in disruptions to or signaling cascades. At the cellular level, the consequences of null alleles depend on gene dosage sensitivity. In heterozygotes, a single wild-type often suffices for normal function, but occurs when the remaining copy cannot compensate, resulting in reduced protein levels and impaired cellular . This can manifest as altered profiles, defective function, or disrupted , such as elevated phosphoinositide levels impairing in synaptic vesicles. Homozygous null cells, however, exhibit profound defects, including pathway blockages that trigger compensatory responses like upregulation of alternative genes or cellular stress pathways. Null alleles in dosage-sensitive genes may evade mechanisms like X-chromosome inactivation in mammals, leading to unbalanced expression without full compensation. Phenotypically, null alleles generally follow recessive inheritance patterns, where heterozygotes remain unaffected, but homozygotes display the full loss-of-function , often including severe developmental abnormalities or . For example, homozygous null mutations frequently cause embryonic or postnatal death due to essential disruptions, as evidenced by high mortality rates in model organisms like mice lacking critical orthologs. In viable cases, phenotypes include morphological defects or physiological impairments arising from uncompensated protein loss. Evolutionarily, null alleles facilitate studies of essentiality by revealing minimal functional requirements, contributing to understanding adaptive loss-of-function variants that enhance fitness in specific environments without causing .

Detection Methods

PCR-Based Techniques

In (PCR)-based , null alleles often manifest as allelic dropout, where mutations in the primer-binding sites prevent amplification of the affected allele, resulting in heterozygotes appearing as homozygotes for the amplifiable allele. This phenomenon arises primarily from sequence variations, such as single nucleotide polymorphisms or insertions/deletions, in the flanking regions of the target locus that disrupt primer annealing. Allelic dropout (ADO) is a critical issue in molecular genetics, leading to diagnostic and forensic errors by masking pathogenic mutations (false-negatives) or creating the appearance of a homozygous state that does not exist (false-positives). It is especially hazardous in preimplantation genetic diagnosis (PGD), forensic evidence analysis of degraded DNA, and clinical screening for dominant disorders like hereditary hemorrhagic telangiectasia. Detection of null alleles in PCR assays is indicated by consistent homozygous patterns in individuals expected to be heterozygous based on pedigree or , as well as an excess of homozygotes at specific loci that deviates from Hardy-Weinberg equilibrium expectations. Such deviations can be quantified using (F_IS) calculations, where significantly positive values signal potential null allele presence. To mitigate allelic dropout, researchers employ strategies such as using multiple primer sets targeting different flanking regions to achieve concordance across assays, redesigning primers to accommodate known sequence variants, or integrating PCR with for direct confirmation of null alleles. Additionally, robust multi-platform validation is essential to ensure the integrity of genetic data and reduce false homozygote calls. These approaches improve accuracy, particularly in multiplex reactions. In forensic and applications, null alleles significantly impact short (STR) analysis by causing allele mismatches in parentage testing and database comparisons. Null allele frequencies rarely exceed 0.20 but can bias results if unaccounted for. This issue was first noted in the early during the development and application of markers for genetic studies. Recent advances include the use of next-generation sequencing (NGS) to directly identify sequence variants in primer-binding sites, enabling redesign of locus-specific primers and reducing null allele occurrence in high-throughput as of 2025.

Population and Pedigree Analysis

In , null alleles can be inferred through deviations from Hardy-Weinberg equilibrium (HWE), where they produce an apparent excess of homozygotes because individuals heterozygous for a null allele and a visible allele are scored as homozygous for the visible allele. This homozygote excess signals potential null alleles, and software such as MICRO-CHECKER estimates their presence by simulating frequencies under a null allele model and comparing them to observed data to test if the disequilibrium is explained by nulls rather than other factors like . In pedigree and parentage analysis, null alleles lead to mismatches where appear not to inherit an from a , as the parent's null allele fails to amplify, resulting in the being scored as homozygous while the parent shows only the other . Likelihood-based models address this by incorporating null allele frequencies into parentage assignment probabilities, often using to jointly infer - relationships and null frequencies across loci. A common estimator for null allele frequency at a locus is qnull=1−HoHeq_{\text{null}} = 1 - \sqrt{\frac{H_{o}}{H_{e}}}
Add your contribution
Related Hubs
User Avatar
No comments yet.