Null allele

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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]

Contents

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

Polymerase chain reaction (PCR)

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

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

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

Related Research Articles

An allele, or allelomorph, is a variant of the sequence of nucleotides at a particular location, or locus, on a DNA molecule.

A microsatellite is a tract of repetitive DNA in which certain DNA motifs are repeated, typically 5–50 times. Microsatellites occur at thousands of locations within an organism's genome. They have a higher mutation rate than other areas of DNA leading to high genetic diversity. Microsatellites are often referred to as short tandem repeats (STRs) by forensic geneticists and in genetic genealogy, or as simple sequence repeats (SSRs) by plant geneticists.

<span class="mw-page-title-main">Dominance (genetics)</span> One gene variant masking the effect of another in the other copy of the gene

In genetics, dominance is defined as the interactions between alleles at the same locus on homologous chromosomes and the associated phenotype. In the case of complete dominance, one allele in a heterozygote individual completely overrides or masks the phenotypic contribution of the other allele. The overriding allele is referred to as dominant and the masked one recessive. Complete dominance, also referred to as Mendelian inheritance, follow Mendel's laws of segregation. The first law states that each allele in a pair of genes is separated at random and have an equal probability of being transferred to the next generation, while the second law states that the distribution of allele variants is done independently of each other. However, this is not always the case as not all genes segregate independently and violations of this law are often referred to as "non-Mendelian inheritance".

Gene knockouts are a widely used genetic engineering technique that involves the targeted removal or inactivation of a specific gene within an organism's genome. This can be done through a variety of methods, including homologous recombination, CRISPR-Cas9, and TALENs.

<span class="mw-page-title-main">Human leukocyte antigen</span> Genes on human chromosome 6

The human leukocyte antigen (HLA) system or complex of genes on chromosome 6 in humans which encode cell-surface proteins responsible for regulation of the immune system. The HLA system is also known as the human version of the major histocompatibility complex (MHC) found in many animals.

A heterozygote advantage describes the case in which the heterozygous genotype has a higher relative fitness than either the homozygous dominant or homozygous recessive genotype. Loci exhibiting heterozygote advantage are a small minority of loci. The specific case of heterozygote advantage due to a single locus is known as overdominance. Overdominance is a rare condition in genetics where the phenotype of the heterozygote lies outside of the phenotypical range of both homozygote parents, and heterozygous individuals have a higher fitness than homozygous individuals.

<span class="mw-page-title-main">Equine coat color genetics</span> Genetics behind the equine coat color

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<span class="mw-page-title-main">Non-Mendelian inheritance</span> Type of pattern of inheritance

Non-Mendelian inheritance is any pattern in which traits do not segregate in accordance with Mendel's laws. These laws describe the inheritance of traits linked to single genes on chromosomes in the nucleus. In Mendelian inheritance, each parent contributes one of two possible alleles for a trait. If the genotypes of both parents in a genetic cross are known, Mendel's laws can be used to determine the distribution of phenotypes expected for the population of offspring. There are several situations in which the proportions of phenotypes observed in the progeny do not match the predicted values.

<span class="mw-page-title-main">Pleiotropy</span> Influence of a single gene on multiple phenotypic traits

Pleiotropy occurs when one gene influences two or more seemingly unrelated phenotypic traits. Such a gene that exhibits multiple phenotypic expression is called a pleiotropic gene. Mutation in a pleiotropic gene may have an effect on several traits simultaneously, due to the gene coding for a product used by a myriad of cells or different targets that have the same signaling function.

Genetics, a discipline of biology, is the science of heredity and variation in living organisms.

<span class="mw-page-title-main">Haploinsufficiency</span> Concept in genetics

Haploinsufficiency in genetics describes a model of dominant gene action in diploid organisms, in which a single copy of the wild-type allele at a locus in heterozygous combination with a variant allele is insufficient to produce the wild-type phenotype. Haploinsufficiency may arise from a de novo or inherited loss-of-function mutation in the variant allele, such that it yields little or no gene product. Although the other, standard allele still produces the standard amount of product, the total product is insufficient to produce the standard phenotype. This heterozygous genotype may result in a non- or sub-standard, deleterious, and (or) disease phenotype. Haploinsufficiency is the standard explanation for dominant deleterious alleles.

<span class="mw-page-title-main">Locus (genetics)</span> Location of a gene or region on a chromosome

In genetics, a locus is a specific, fixed position on a chromosome where a particular gene or genetic marker is located. Each chromosome carries many genes, with each gene occupying a different position or locus; in humans, the total number of protein-coding genes in a complete haploid set of 23 chromosomes is estimated at 19,000–20,000.

The Kidd antigen system are proteins found in the Kidd's blood group, which act as antigens, i.e., they have the ability to produce antibodies under certain circumstances. The Jk antigen is found on a protein responsible for urea transport in the red blood cells and the kidney. They are important in transfusion medicine. People with two Jk(a) antigens, for instance, may form antibodies against donated blood containing two Jk(b) antigens. This can lead to hemolytic anemia, in which the body destroys the transfused blood, leading to low red blood cell counts. Another disease associated with the Jk antigen is hemolytic disease of the newborn, in which a pregnant woman's body creates antibodies against the blood of her fetus, leading to destruction of the fetal blood cells. Hemolytic disease of the newborn associated with Jk antibodies is typically mild, though fatal cases have been reported.

In medical genetics, compound heterozygosity is the condition of having two or more heterogeneous recessive alleles at a particular locus that can cause genetic disease in a heterozygous state; that is, an organism is a compound heterozygote when it has two recessive alleles for the same gene, but with those two alleles being different from each other. Compound heterozygosity reflects the diversity of the mutation base for many autosomal recessive genetic disorders; mutations in most disease-causing genes have arisen many times. This means that many cases of disease arise in individuals who have two unrelated alleles, who technically are heterozygotes, but both the alleles are defective.

Lethal alleles are alleles that cause the death of the organism that carries them. They are usually a result of mutations in genes that are essential for growth or development. Lethal alleles may be recessive, dominant, or conditional depending on the gene or genes involved.

The infinite alleles model is a mathematical model for calculating genetic mutations. The Japanese geneticist Motoo Kimura and American geneticist James F. Crow (1964) introduced the infinite alleles model, an attempt to determine for a finite diploid population what proportion of loci would be homozygous. This was, in part, motivated by assertions by other geneticists that more than 50 percent of Drosophila loci were heterozygous, a claim they initially doubted. In order to answer this question they assumed first, that there were a large enough number of alleles so that any mutation would lead to a different allele ; and second, that the mutations would result in a number of different outcomes from neutral to deleterious.

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The stepwise mutation model (SMM) is a mathematical theory, developed by Motoo Kimura and Tomoko Ohta, that allows for investigation of the equilibrium distribution of allelic frequencies in a finite population where neutral alleles are produced in step-wise fashion.

In the rabbit, lethal dwarfism occurs in individuals homozygous for the dwarf allele (dwdw). Homozygosity for the dwarf allele results in a lethal autosomal recessive mutation. This is caused by a loss of function (LOF) mutation in the High mobility AT-hook 2 (HMGA2) gene, spanning 12.1Kb from 44,709,089 bp to 44,721,236 bp that removes the gene promotor as well as multiple exons. This mutation greatly affects growth of homozygous embryos and homozygous kits once born. These individuals homozygous for the dwarf allele are viable in the womb but die days after being born. Individuals that are heterozygous for the dwarf allele are healthy and unaffected by the lethality of the mutation, but are smaller than individuals homozygous for the wild type allele.

References

  1. ↑ Peter., Snustad, D. (2012). Genetics. Simmons, Michael J. (6th ed., International student version ed.). Singapore: Wiley. ISBN   978-1118092422. OCLC   770517281.{{cite book}}: CS1 maint: multiple names: authors list (link)
  2. ↑ Accili, Domenico; Drago, John; Lee, Eric; Johnson, Mark; Cool, Martha; Salvatore, Paola; Asico, Laureano; Jose, Pedro; Taylor, Simeon; Westphal, Heiner (January 12, 1996). "Early neonatal death in mice homozygous for a null allele of the insulin receptor gene". Nature Genetics. 12 (1): 106–9. doi:10.1038/ng0196-106. PMID   8528241. S2CID   5610177.
  3. ↑ Monroe, J Grey; McKay, John; Weigel, Detlef; Flood, Padraic (February 11, 2021). "The population genomics of adaptive loss of function". Heredity. 126 (3): 383–395. doi: 10.1038/s41437-021-00403-2 . PMC   7878030 . PMID   33574599.
  4. ↑ Sasaki; Ashikari; Ueguchi-Tanaka; Itoh; Nishimura; Swapan; Ishiyama; Saito; Kobayashi; Khush; Kitano (2002). "A mutant gibberellin-synthesis gene in rice". Nature. 416 (6882): 701–702. doi:10.1038/416701a. PMID   11961544. S2CID   4414560.
  5. 1 2 3 4 Dakin, E E; Avise, J C (2004-08-04). "Microsatellite null alleles in parentage analysis" (PDF). Heredity. 93 (5): 504–509. doi: 10.1038/sj.hdy.6800545 . ISSN   1365-2540. PMID   15292911.
  6. 1 2 Primmer, C. R.; Møller, A. P.; Ellegren, H. (August 1995). "Resolving genetic relationships with microsatellite markers: a parentage testing system for the swallow Hirundo rustica". Molecular Ecology. 4 (4): 493–498. doi:10.1111/j.1365-294x.1995.tb00243.x. ISSN   0962-1083. PMID   8574445. S2CID   28574614.
  7. 1 2 Paetkau, D.; Strobeck, C. (1995-08-01). "The molecular basis and evolutionary history of a microsatellite null allele in bears". Molecular Ecology. 4 (4): 519–520. doi:10.1111/j.1365-294x.1995.tb00248.x. ISSN   1365-294X. PMID   8574449. S2CID   33072622.
  8. 1 2 3 4 Allendorf, Fred W.; Knudsen, Kathy L.; Blake, George M. (March 1982). "Frequencies of Null Alleles at Enzyme Loci in Natural Populations of Ponderosa and Red Pine". Genetics. 100 (3): 497–504. doi:10.1093/genetics/100.3.497. ISSN   0016-6731. PMC   1201825 . PMID   17246067.
  9. 1 2 Voelker, R. A.; Langley, C. H.; Brown, A. J.; Ohnishi, S.; Dickson, B.; Montgomery, E.; Smith, S. C. (February 1980). "Enzyme null alleles in natural populations of Drosophila melanogaster: Frequencies in a North Carolina population". Proceedings of the National Academy of Sciences of the United States of America. 77 (2): 1091–1095. Bibcode:1980PNAS...77.1091V. doi: 10.1073/pnas.77.2.1091 . ISSN   0027-8424. PMC   348430 . PMID   16592770.
  10. 1 2 3 4 Liu, J. P.; Baker, J.; Perkins, A. S.; Robertson, E. J.; Efstratiadis, A. (1993-10-08). "Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r)". Cell. 75 (1): 59–72. doi: 10.1016/s0092-8674(05)80084-4 . ISSN   0092-8674. PMID   8402901. S2CID   42023430.
  11. ↑ Clayton, J. W.; Tretiak, D. N. (1972-08-01). "Amine-Citrate Buffers for pH Control in Starch Gel Electrophoresis". Journal of the Fisheries Research Board of Canada. 29 (8): 1169–1172. doi:10.1139/f72-172. ISSN   0015-296X.
  12. 1 2 Wraight, Christopher J.; Werther, George A. (1995-10-01). "Insulin-Like Growth Factor-I and Epidermal Growth Factor Regulate Insulin-Like Growth Factor Binding Protein-3 (IGFBP-3) in the Human Keratinocyte Cell Line HaCaT". Journal of Investigative Dermatology. 105 (4): 602–607. doi: 10.1111/1523-1747.ep12323716 . PMID   7561166.
  13. ↑ Dean, Laura (2005). The ABO blood group. National Center for Biotechnology Information (US).
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