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Gene and alleles

Gene and alleles


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This is a multiple choice question:

Consider a gene, ABC, which codes for an enzyme involved in the metabolism of sugars. There are two known alleles of this gene, ABC1 and ABC2. Which statement correctly describes the relationship between the ABC gene and the ABC1 and ABC2 alleles?

a. The gene is a sequence of amino acids and the alleles are a very similar sequence of amino acids.

b. The gene is a trait and the alleles are a sequence of amino acids.

c. The gene is a trait and the alleles are a nucleotide sequence.

d. The gene is a nucleotide sequence and the alleles are a sequence of amino acids.

e. Both the gene and the alleles are a nucleotide sequence.

I thought the answer is b, but the correct answer is e. I can't figure out why so. Does anyone know?


Alleles are basically subtypes of a gene. At the time of Mendel, the molecular nature of inheritance was not known so the original definition of gene refers to "some" inheritable molecular entity inside the organism that is responsible for a trait. Alleles are different "flavours" of a given gene. For example there is a gene for flower colour, there can be different alleles which give rise to different colours (this is a highly simplified example). Genotype is a configuration of alleles whereas the phenotype is the effect that is seen.

With the knowledge of molecular genetics superimposed on these basic concepts a gene would basically be a well defined part of the genome (DNA) which is responsible for a molecular trait. Alleles are the actual sequence variants of this genomic region (not considering translocations here).

This is my justification on correctness and incorrectness of different points, based on current knowledge of molecular genetics:

a. Incorrect. Genes need not necessarily code for proteins. There are non-coding RNAs

b. Incorrect. Trait is a qualitative feature. Phenotype is the manifestation of a trait. Genes and genotypes are the causes of a trait and not traits themselves.

c. Incorrect. Same as above.

d. Incorrect. As per the definition, alleles are variants of a gene and they have to be of the same molecular nature as the genes. However, if we forget the semantics then this may seem like a more apt definition because the variations in traits arise not just because of the gene sequence but also the amino acids. However there is a flaw in this logic and the counter points be:

  1. This scheme would not be inheritable (RNA editing/alternative splicing/PTM etc).
  2. It has been shown that even synonymous mutations can have different phenotypes. (Plotkin and Kudla. 2011)
  3. This does not consider non-coding RNAs

e. More or less correct (not in a very strict sense but fine for most discussions. Gene is not really a nucleotide sequence. Gene is an annotated region of a genome which has a defined sequence. This is similar to saying that object is mass. Object has a mass; object is not mass. This is just semantics and, as I said, not too important for general discussions.)


Both genes and alleles are sequences of DNA. A gene will code for a trait, say hair colour, while an allele will be the variants of that gene (say the alleles coding for blonde, brown, black, and red hair).

It's almost like cookbooks: two cookbooks (the DNA) might have a recipe (gene) for bread but they use slightly different instructions (alleles) resulting in different breads (traits).


Gene and alleles - Biology

Mendel implied that only two alleles, one dominant and one recessive, could exist for a given gene. We now know that this is an oversimplification. Although individual humans (and all diploid organisms) can only have two alleles for a given gene, multiple alleles may exist at the population level such that many combinations of two alleles are observed. Note that when many alleles exist for the same gene, the convention is to denote the most common phenotype or genotype among wild animals as the wild type (often abbreviated “+”) this is considered the standard or norm. All other phenotypes or genotypes are considered variants of this standard, meaning that they deviate from the wild type. The variant may be recessive or dominant to the wild-type allele.

An example of multiple alleles is coat color in rabbits (Figure 1). Here, four alleles exist for the c gene. The wild-type version, C + C + , is expressed as brown fur. The chinchilla phenotype, c ch c ch, is expressed as black-tipped white fur. The Himalayan phenotype, c h c h, has black fur on the extremities and white fur elsewhere. Finally, the albino, or “colorless” phenotype, cc, is expressed as white fur. In cases of multiple alleles, dominance hierarchies can exist. In this case, the wild-type allele is dominant over all the others, chinchilla is incompletely dominant over Himalayan and albino, and Himalayan is dominant over albino. This hierarchy, or allelic series, was revealed by observing the phenotypes of each possible heterozygote offspring.

Figure 1. Four different alleles exist for the rabbit coat color (C) gene.

Figure 2. As seen in comparing the wild-type Drosophila (left) and the Antennapedia mutant (right), the Antennapedia mutant has legs on its head in place of antennae.

The complete dominance of a wild-type phenotype over all other mutants often occurs as an effect of “dosage” of a specific gene product, such that the wild-type allele supplies the correct amount of gene product whereas the mutant alleles cannot. For the allelic series in rabbits, the wild-type allele may supply a given dosage of fur pigment, whereas the mutants supply a lesser dosage or none at all. Interestingly, the Himalayan phenotype is the result of an allele that produces a temperature-sensitive gene product that only produces pigment in the cooler extremities of the rabbit’s body.

Alternatively, one mutant allele can be dominant over all other phenotypes, including the wild type. This may occur when the mutant allele somehow interferes with the genetic message so that even a heterozygote with one wild-type allele copy expresses the mutant phenotype. One way in which the mutant allele can interfere is by enhancing the function of the wild-type gene product or changing its distribution in the body.

One example of this is the Antennapedia mutation in Drosophila (Figure 2). In this case, the mutant allele expands the distribution of the gene product, and as a result, the Antennapedia heterozygote develops legs on its head where its antennae should be.

Multiple Alleles Confer Drug Resistance in the Malaria Parasite

Malaria is a parasitic disease in humans that is transmitted by infected female mosquitoes, including Anopheles gambiae (Figure 3a), and is characterized by cyclic high fevers, chills, flu-like symptoms, and severe anemia. Plasmodium falciparum and P. vivax are the most common causative agents of malaria, and P. falciparum is the most deadly (Figure 3b). When promptly and correctly treated, P. falciparummalaria has a mortality rate of 0.1 percent. However, in some parts of the world, the parasite has evolved resistance to commonly used malaria treatments, so the most effective malarial treatments can vary by geographic region.

Figure 3. The (a) Anopheles gambiae, or African malaria mosquito, acts as a vector in the transmission to humans of the malaria-causing parasite (b) Plasmodium falciparum, here visualized using false-color transmission electron microscopy. (credit a: James D. Gathany credit b: Ute Frevert false color by Margaret Shear scale-bar data from Matt Russell)

In Southeast Asia, Africa, and South America, P. falciparum has developed resistance to the anti-malarial drugs chloroquine, mefloquine, and sulfadoxine-pyrimethamine. P. falciparum, which is haploid during the life stage in which it is infectious to humans, has evolved multiple drug-resistant mutant alleles of the dhps gene. Varying degrees of sulfadoxine resistance are associated with each of these alleles. Being haploid, P. falciparum needs only one drug-resistant allele to express this trait.

In Southeast Asia, different sulfadoxine-resistant alleles of the dhps gene are localized to different geographic regions. This is a common evolutionary phenomenon that occurs because drug-resistant mutants arise in a population and interbreed with other P. falciparum isolates in close proximity. Sulfadoxine-resistant parasites cause considerable human hardship in regions where this drug is widely used as an over-the-counter malaria remedy. As is common with pathogens that multiply to large numbers within an infection cycle, P. falciparum evolves relatively rapidly (over a decade or so) in response to the selective pressure of commonly used anti-malarial drugs. For this reason, scientists must constantly work to develop new drugs or drug combinations to combat the worldwide malaria burden. [1]


4.1 Chromosomes, Genes, Alleles and Mutations

Sickle Cell Anemia: A Mutation Story from the excellent Evolution Library.

30-Minute Inquiry: Base-substitution mutations

Question: What do HBB, PAH, PKD1, NF1, CFTR, Opn1Mw and HEXA have in common?

Answer: They are all disorders causes by base-substitution mutations.

  1. Assign groups by handing out cards with the codes above (we had already studied HBB, so didn’t include it) and asking them to find each other.
  2. Give them the instructions – to produce a simple poster & 1-minute overview of their disorder, using the guidance in the image below.
  3. Go. Lots of discussion, lots of questioning. If students get stuck, they need to look it up, evaluate their sources and keep on going.
  4. Students will need to use the NCBI gene database to get going: http://www.ncbi.nlm.nih.gov/gene

Check they’re on the right track: HBB (sickle cell), PAH (PKU), PKD1 (polycystic kidney disease), NF1 (neurofibromatosis), CFTR (cystic fibrosis), Opn1Mw (medium-wave sensitive colour-blindness), HEXA (Tay-Sachs disease).


Dominant allele and recessive allele

Now we know that an allele is best thought of as one letter, it&rsquos easy to see which is the dominant letter and which is the recessive letter.

The capital B dominates (dominant) the lower case b, so the lower case b retires to a small recess (recessive).

Dominant and recessive alleles can be shown in a punnet square.

In this example the mother has brown eyes but carries one brown eye allele and one blue eye allele. The father also has brown eyes but again carries one brown eye allele and one blue eye allele.

If you have two different alleles, one will be stronger/ more dominant than the other. The stronger allele will overrule the recessive allele. When it comes to eye genotypes, the dominant brown allele will overrule the recessive blue allele:

BB = brown eyes (Both alleles are the same so no overruling here)

Bb = brown eyes (B dominates b to give brown eyes)

bB = brown eyes (B dominates b to give brown eyes)

bb = blue eyes (Both alleles are the same so no overruling here)

Further example

Cystic fibrosis is a common inherited disorder of cell membranes. It is caused by inheriting two recessive alleles (ff). People who have the heterozygous genotype (Ff) are said to be carriers, with no ill effects. Only people who have the homozygous (ff) are affected. The recessive allele must be inherited from both parents.


Discussion

Restoration of tumour suppressor gene function in cancer cells in vivo has proven to be a powerful means to identify context-specific programmes of tumour suppression. However, the widespread practice of restoring gene function in established tumours within their natural setting has been greatly limited by previous approaches that are incompatible with specific genes of interest or by strategies that require multiple technically challenging steps to implementation 1,2,3,4,5,31 .

We and others have used genetically engineered alleles in which a loxP-flanked transcription/translation stop cassette (loxP-STOP-loxP LSL) is inserted into the first intron of a gene of interest 1,2 . An LSL allele is a null allele until Cre-mediated recombination deletes the STOP cassette, thus allowing normal expression of the targeted genes. For example, the p53 LSL allele is a functionally null allele of p53 and p53 LSL/LSL mice develop spontaneous lymphomas and sarcomas at the same frequency and rate as p53 KO mice 1 . Initially, p53 LSL/LSL mice were used to study the consequences of p53 restoration in T-cell lymphomas and soft tissue sarcomas that naturally arise in p53-deficient mice 1 . Most genetically engineered mouse cancer models rely on Cre to activate or inactivate genes of interest, but because LSL approaches require Cre for gene restoration they are not compatible with these existing models. Because of this major limitation, we made use of a lung cancer model (Kras LA2/+ ) where Kras G12D is activated spontaneously due to a stochastic recombination event 32 . These mice develop lung adenocarcinomas with 100% penetrance at an early age. This afforded us the opportunity to generate Kras LA2/+ p53 LSL/LSL mice and to restore p53 in these early-to-moderate stage lung cancers 2 . Performing this restoration in large cohorts of mice was frustrating, owing to the mortality associated with the frequent and rapid development of sarcomas and lymphomas in p53-deficient mice. Extensive ageing of the mice was not possible and we were unable to assess the effects of p53 restoration on the most clinically relevant advanced stages of primary lung tumours and metastases.

The most critical limitation of the LSL system is that LSL alleles cause germline deficiency. Thus, LSL alleles cannot be used to study genes that are required for embryonic development. Unfortunately, the vast majority of tumour suppressor genes are embryonic lethal (for example, Rb1, Pten, Apc, Nf1, Nf2, Ptc, Vhl, Smad4, Atr, Smarca4, Arid1a, Snf5, Nkx2-1, Nkx3-1, Tsc1, Tsc2 and so on), thus leaving very few tumour suppressor genes with which to use this system (for example, p53, Cdkn2a and Atm). This fact, together with its incompatibility with other Cre-based systems, has severely limited the utility of this approach.

Fusion of an ER fragment to proteins may, in some instances, allow for tamoxifen-dependent activity of the fused protein. In the limited cases where this has proven effective, it has been a robust method. A p53 ERTam knock-in allele has been used to model p53 restoration in Myc-induced lymphomas and in Kras G12D -induced lung adenocarcinomas 3,4 . Although, unlike the LSL approach, the ER-fusion alleles are compatible with Cre-based cancer models, ER fusions are still limited to non-essential genes, as mice with homozygous knock-in would still be expected to recapitulate the embryonic lethality of null mice. In addition, not all proteins will tolerate carboxy and/or amino-terminal fusions with the ER and there can be concern of unknown alterations in function of the ER fusion protein. Finally, this approach is limited to proteins that carry out their functions in the nucleus, as the mechanism of induction is based on tamoxifen-induced nuclear translocation of the fusion protein.

Regulatable small hairpin RNA (shRNA) is a very different method that overcomes several of the limitations associated with LSL and ER fusion-based approaches. However, the techniques involved are challenging and, to date, the generation of regulatable RNA interference transgenic mice has been employed by few laboratories. This approach has been used to regulate the expression of three tumour suppressor genes (Apc, Pten and p53) in relevant cancer models 5,6,31,33,34 . To effectuate potent knockdown of the target gene and recreate phenotypes equivalent to null alleles, multiple specialized techniques, mouse strains and ES cell lines are required 35 . The success of the regulatable shRNA to recapitulate phenotypes associated with gene loss requires the ability to generate a sufficiently potent shRNA. Screening of dozens of shRNAs is therefore required and specialized protocols to ascertain whether an shRNA is likely to be effective as a single-copy integrated transgene is necessary 35,36 . Despite this, potent shRNAs have been identified that approximate null alleles in certain experimental systems 5,31,37,38 .

Off-target effects associated with shRNA expression are also potentially problematic 39 . High expression of a heterologous shRNA could obscure biological readouts by knocking down the expression of unintended messenger RNA targets or by overwhelming the RNA interference processing machinery to such an extent that naturally expressed micro RNAs are not normally produced 40,41,42 . Each of these technical issues may have profound consequences on the biology of cells in question that will have an impact on data interpretation.

Currently, regulatable shRNA strategies rely on tet-based systems which limits their functionality within other systems that also utilize tet-regulated transgenes. For example, multiple cancer models rely on tet-inducible oncogenes to drive tumour formation and these models rely on continual expression of the oncogenic driver to maintain the cancer 43,44,45,46 . Although the regulated shRNA can be easily added into this approach to ascertain the added effect of target gene knockdown, the ability to cleanly determine the effect of target gene restoration is not possible due to the simultaneous loss of oncogene expression on doxycyclin removal.

The simplicity and functionality of the XTR allele system offers several significant advantages over existing strategies, to interrogate gene function in the mouse. Similar to conventional approaches to create conditional alleles in the mouse, XTR integration relies on gene targeting in ES cells. Creation of XTR alleles uses the same methods that are standard protocols in academic and commercial ES cell/transgenic mouse facilities and thus requires no specialized technical hurdles. As outlined in Supplementary Fig. 3, generation of XTR alleles requires a neoXTR allele intermediate that necessitates secondary selection of either ES cell clones or pups that lost the FRT-Neo-FRT. For p53 and Rb, this was achieved by either electroporation with Flp-expressing plasmids or by crossing with germline Flp-expressing mice 47 . Further use of the XTR system at other loci will be necessary to determine whether locus-dependent effects exist that could limit this strategy. CRISPR-based approaches to generate conditional alleles by directly injecting zygotes with modified XTR vectors lacking the FRT-Neo-FRT cassette could obviate the need for this step 48,49 .

XTR combines three separate tools into one discrete genetic element to conditionally inactivate a gene of interest, accurately report host gene expression once inactivated and facilitate precise gene restoration in an inducible manner. Bringing these tools together into one strategy offers unparalleled functionality to a single genetically engineered allele. With the increased functionality to mark gene inactivation and report accurate gene expression levels of the targeted gene, as well as the ability to rescue gene function, XTR is positioned to greatly expand current capabilities to interrogate gene function within in vivo systems. Thus far, our experience targeting XTR to p53 and Rb loci suggest a ‘plug and play’ simplicity that abrogates the need for development, testing and optimization that is associated with ER fusion and regulatable shRNA strategies. However, targeting of additional loci will be required to affirm the generalizable nature of the XTR approach with respect to preserving proper host gene regulation and robustness of gene inhibition. Although the XTR system would not be compatible with the few examples of Flp-dependent alleles that exist 50,51 , its seamless integration into the numerous Cre-based model systems available should facilitate its widespread utility. Similar to most conditional approaches to inactivate gene function in the mouse, XTR alleles require specialized methods or mouse strains to deliver Cre recombinase to specific cell types of interest. Our data suggest that either promoter-specific transgenes or viral based approaches to deliver Cre to tissues of interest is a robust strategy to inactivate genes of interest in the mouse with XTR. Finally, restoration of gene function using XTR alleles requires strategies to regulate Flp activity. As demonstrated, we used a tamoxifen-inducible Rosa26 FlpO-ER allele that is widely expressed and therefore suitable for a broad range of applications using the XTR system 30 . However, additional strategies to regulate FlpO may augment the utility of the XTR system in specialized scenarios.

Here we have targeted the XTR cassette to two important tumour suppressor genes to address cancer-relevant questions. However, we envision XTR as a powerful approach to investigate gene function in diverse biological settings to gain important insight into mechanisms at the tissue, cellular or molecular level. In addition, XTR alleles have the potential to model therapeutic interventions in disease settings, where temporarily inactivating a putative drug target through the genetic means intrinsic to XTR could predict efficacy or identify unforeseen complications of future therapies. More broadly, the ability to restore gene function using the XTR system offers a major opportunity in conditional genetic methods to facilitate the widespread application of in vivo gene restoration approaches.


TMEM173 mutations in SAVI (STING-associated vasculopathy with onset in infancy)

Activating mutations in the TMEM173 gene lead to a newly classified rare auto-inflammatory disease call SAVI [38] (Table 1). It is an autosomal-dominant disease characterized by systemic inflammation, interstitial lung disease, cutaneous vasculitis, and recurrent bacterial infection [38, 39]. Both inherited, and de novo TMEM173 mutations were found in SAVI patients (Table 1). SAVI with the de novo TMEM173 mutations tended to have an early-onset (<8 weeks) and severe phenotype [38, 40], whereas familial TMEM173 mutations had late-onset (teenager or adulthood) and milder clinical manifestations [39, 41]. For instance, SAVI patients with the inherited V155M mutation had a less severe disease penetration than patients with the de novo V155M mutation [38, 39, 42]. Jeremiah et al. [39], first found that the V155M mutation, at the steady state, localized mainly in the Golgi and in perinuclear vesicles of patient fibroblasts, which is a hallmark of the STING activation.

SAVI as a unique interferonopathy with lung manifestation

SAVI is considered as a type I Interferonopathy that includes chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature, Aicardi-Goutieres syndrome, and TREX1-SAMHD1-mediated familial chilblain lupus [40, 43, 44]. For example, familial SAVI mutations caused familial chilblain lupus [39, 41]. However, SAVI is unique because it is the only known type I Interferonopathy with pulmonary involvement [40, 43, 44]. In fact, all three reported fatalities from SAVI patients were due to the pulmonary complications [38, 40]. We showed that activating STING in the mouse lung by intranasal administration of CDNs, induced lung production of IFNγ and IFNλ but not IFNβ [45]. Interestingly, IFNγ + CD4 + T cells and serum IFNγ were markedly increased in a recent SAVI patient [46]. Notably, serum IL-18, a known IFNγ inducer, was also elevated in several SAVI patients [47]. Whether the increased IFNγ production contributes to the lung symptoms in SAVI patients is worth further investigation.

Treating SAVI with JAK inhibitors

Current anti-inflammatory treatments corticosteroid, DMARDs, anti-TNF, steroids, anti-CD20, IVIG, were ineffective in SAVI patients [42, 47]. SAVI patients died of lung complication, and lung damage was irreversible [40, 47]. In fact, one SAVI patient died after double lung transplantation due to acute complications [40]. Thus, any SAVI treatment should result in improved lung function and prevent the irreversible lung damage.

Encouragingly, in a 2-year study with three SAVI children, ruxolitinib dramatically improved pulmonary function, resolved the cutaneous lesions and led to a better overall well-being of the patients [42, 48]. In a separate study, after a 3-month tofacitinib treatment, Seo et al. [46], saw an improved skin lesion in a SAVI teenager but the pulmonary defect remained. Eli Lilly is currently conducting a clinical trial (ClinicalTrials.gov number, NCT01724580) to examine the efficacy of baricitinib in SAVI patients.

Ruxolitinib and baricitinib are JAK1 and JAK2 inhibitors while tofacitinib is a JAK3 and to a lesser degree, JAK2 inhibitor. IFNα/β signals via JAK1/Tyk2 while IFNγ activates JAK1/JAK2. Thus, ruxolitinib and baricitinib are more suitable for treating SAVI than tofacitinib. Notably, baricitinib, at a high dose, also inhibits Tyk2, which mediates IL-10, IL-12/23, IL-6, and IL-4/13 signaling. Proper dosing may be important when treating SAVI patients with baricitinib.

Loss-of-function human TMEM173 allele as a natural inhibitor of SAVI

SAVI is caused by gain-of-function human TMEM173 mutations [38] (Table 1). An intriguing question is whether the loss-of-function TMEM173 alleles could serve as natural genetic inhibitors [49]. Cerboni et al. [49] found that in vitro, introducing HAQ into the V155M SAVI mutation (HAQ-V155M) relocated STING back to ER, restored T cell proliferation, and corrected NF-κB activation . Recently, a de novo SAVI patient was identified in a HAQ family [46]. In this case, the activating TMEM173 mutation acts in trans with the HAQ allele [46]. The patient exhibited SAVI symptoms but with a late-onset (3 years) [46]. Thus, the presence of the HAQ allele could be advantageous to SAVI patients.


Contents

The concept of dominance was introduced by Gregor Johann Mendel. Though Mendel, "The Father of Genetics", first used the term in the 1860s, it was not widely known until the early twentieth century. Mendel observed that, for a variety of traits of garden peas having to do with the appearance of seeds, seed pods, and plants, there were two discrete phenotypes, such as round versus wrinkled seeds, yellow versus green seeds, red versus white flowers or tall versus short plants. When bred separately, the plants always produced the same phenotypes, generation after generation. However, when lines with different phenotypes were crossed (interbred), one and only one of the parental phenotypes showed up in the offspring (green, or round, or red, or tall). However, when these hybrid plants were crossed, the offspring plants showed the two original phenotypes, in a characteristic 3:1 ratio, the more common phenotype being that of the parental hybrid plants. Mendel reasoned that each parent in the first cross was a homozygote for different alleles (one parent AA and the other parent aa), that each contributed one allele to the offspring, with the result that all of these hybrids were heterozygotes (Aa), and that one of the two alleles in the hybrid cross dominated expression of the other: A masked a. The final cross between two heterozygotes (Aa X Aa) would produce AA, Aa, and aa offspring in a 1:2:1 genotype ratio with the first two classes showing the (A) phenotype, and the last showing the (a) phenotype, thereby producing the 3:1 phenotype ratio.

Mendel did not use the terms gene, allele, phenotype, genotype, homozygote, and heterozygote, all of which were introduced later. He did introduce the notation of capital and lowercase letters for dominant and recessive alleles, respectively, still in use today.

In 1928, British population geneticist Ronald Fisher proposed that dominance acted based on natural selection through the contribution of modifier genes. In 1929, American geneticist Sewall Wright responded by stating that dominance is simply a physiological consequence of metabolic pathways and the relative necessity of the gene involved. Wright's explanation became an established fact in genetics, and the debate was largely ended. Some traits may have their dominance influenced by evolutionary mechanisms, however. [4] [5] [6]

Chromosomes, genes, and alleles Edit

Most animals and some plants have paired chromosomes, and are described as diploid. They have two versions of each chromosome, one contributed by the mother's ovum, and the other by the father's sperm, known as gametes, described as haploid, and created through meiosis. These gametes then fuse during fertilization during sexual reproduction, into a new single cell zygote, which divides multiple times, resulting in a new organism with the same number of pairs of chromosomes in each (non-gamete) cell as its parents.

Each chromosome of a matching (homologous) pair is structurally similar to the other, and has a very similar DNA sequence (loci, singular locus). The DNA in each chromosome functions as a series of discrete genes that influence various traits. Thus, each gene also has a corresponding homologue, which may exist in different versions called alleles. The alleles at the same locus on the two homologous chromosomes may be identical or different.

The blood type of a human is determined by a gene that creates an A, B, AB or O blood type and is located in the long arm of chromosome nine. There are three different alleles that could be present at this locus, but only two can be present in any individual, one inherited from their mother and one from their father. [7]

If two alleles of a given gene are identical, the organism is called a homozygote and is said to be homozygous with respect to that gene if instead the two alleles are different, the organism is a heterozygote and is heterozygous. The genetic makeup of an organism, either at a single locus or over all its genes collectively, is called its genotype. The genotype of an organism, directly and indirectly, affects its molecular, physical, and other traits, which individually or collectively are called its phenotype. At heterozygous gene loci, the two alleles interact to produce the phenotype.

Complete dominance Edit

In complete dominance, the effect of one allele in a heterozygous genotype completely masks the effect of the other. The allele that masks the other is said to be dominant to the latter, and the allele that is masked is said to be recessive to the former. [8] Complete dominance, therefore, means that the phenotype of the heterozygote is indistinguishable from that of the dominant homozygote.

A classic example of dominance is the inheritance of seed shape (pea shape) in peas. Peas may be round (associated with allele R) or wrinkled (associated with allele r). In this case, three combinations of alleles (genotypes) are possible: RR and rr are homozygous and Rr is heterozygous. The RR individuals have round peas and the rr individuals have wrinkled peas. In Rr individuals the R allele masks the presence of the r allele, so these individuals also have round peas. Thus, allele R is completely dominant to allele r, and allele r is recessive to allele R.

Incomplete dominance Edit

Incomplete dominance (also called partial dominance, semi-dominance or intermediate inheritance) occurs when the phenotype of the heterozygous genotype is distinct from and often intermediate to the phenotypes of the homozygous genotypes. For example, the snapdragon flower color is homozygous for either red or white. When the red homozygous flower is paired with the white homozygous flower, the result yields a pink snapdragon flower. The pink snapdragon is the result of incomplete dominance. A similar type of incomplete dominance is found in the four o'clock plant wherein pink color is produced when true-bred parents of white and red flowers are crossed. In quantitative genetics, where phenotypes are measured and treated numerically, if a heterozygote's phenotype is exactly between (numerically) that of the two homozygotes, the phenotype is said to exhibit no dominance at all, i.e. dominance exists only when the heterozygote's phenotype measure lies closer to one homozygote than the other.

When plants of the F1 generation are self-pollinated, the phenotypic and genotypic ratio of the F2 generation will be 1:2:1 (Red:Pink:White). [9]

Co-dominance Edit

Co-dominance occurs when the contributions of both alleles are visible in the phenotype.

For example, in the ABO blood group system, chemical modifications to a glycoprotein (the H antigen) on the surfaces of blood cells are controlled by three alleles, two of which are co-dominant to each other (I A , I B ) and dominant over the recessive i at the ABO locus. The I A and I B alleles produce different modifications. The enzyme coded for by I A adds an N-acetylgalactosamine to a membrane-bound H antigen. The I B enzyme adds a galactose. The i allele produces no modification. Thus the I A and I B alleles are each dominant to i (I A I A and I A i individuals both have type A blood, and I B I B and I B i individuals both have type B blood), but I A I B individuals have both modifications on their blood cells and thus have type AB blood, so the I A and I B alleles are said to be co-dominant.

Another example occurs at the locus for the beta-globin component of hemoglobin, where the three molecular phenotypes of Hb A /Hb A , Hb A /Hb S , and Hb S /Hb S are all distinguishable by protein electrophoresis. (The medical condition produced by the heterozygous genotype is called sickle-cell trait and is a milder condition distinguishable from sickle-cell anemia, thus the alleles show incomplete dominance with respect to anemia, see above). For most gene loci at the molecular level, both alleles are expressed co-dominantly, because both are transcribed into RNA.

Co-dominance, where allelic products co-exist in the phenotype, is different from incomplete dominance, where the quantitative interaction of allele products produces an intermediate phenotype. For example, in co-dominance, a red homozygous flower and a white homozygous flower will produce offspring that have red and white spots. When plants of the F1 generation are self-pollinated, the phenotypic and genotypic ratio of the F2 generation will be 1:2:1 (Red:Spotted:White). These ratios are the same as those for incomplete dominance. Again, this classical terminology is inappropriate – in reality such cases should not be said to exhibit dominance at all.

Addressing common misconceptions Edit

While it is often convenient to talk about a recessive allele or a dominant trait, dominance is not inherent to either an allele or its phenotype. Dominance is a relationship between two alleles of a gene and their associated phenotypes. A "dominant" allele is dominant to a particular allele of the same gene that can be inferred from the context, but it may be recessive to a third allele, and codominant to a fourth. Similarly, a "recessive" trait is a trait associated with a particular recessive allele implied by the context, but that same trait may occur in a different context where it is due to some other gene and a dominant allele.

Dominance is unrelated to the nature of the phenotype itself, that is, whether it is regarded as "normal" or "abnormal," "standard" or "nonstandard," "healthy" or "diseased," "stronger" or "weaker," or more or less extreme. A dominant or recessive allele may account for any of these trait types.

Dominance does not determine whether an allele is deleterious, neutral or advantageous. However, selection must operate on genes indirectly through phenotypes, and dominance affects the exposure of alleles in phenotypes, and hence the rate of change in allele frequencies under selection. Deleterious recessive alleles may persist in a population at low frequencies, with most copies carried in heterozygotes, at no cost to those individuals. These rare recessives are the basis for many hereditary genetic disorders.

Dominance is also unrelated to the distribution of alleles in the population. Both dominant and recessive alleles can be extremely common or extremely rare.

In genetics, symbols began as algebraic placeholders. When one allele is dominant to another, the oldest convention is to symbolize the dominant allele with a capital letter. The recessive allele is assigned the same letter in lower case. In the pea example, once the dominance relationship between the two alleles is known, it is possible to designate the dominant allele that produces a round shape by a capital-letter symbol R, and the recessive allele that produces a wrinkled shape by a lower-case symbol r. The homozygous dominant, heterozygous, and homozygous recessive genotypes are then written RR, Rr, and rr, respectively. It would also be possible to designate the two alleles as W and w, and the three genotypes WW, Ww, and ww, the first two of which produced round peas and the third wrinkled peas. The choice of "R" or "W" as the symbol for the dominant allele does not pre-judge whether the allele causing the "round" or "wrinkled" phenotype when homozygous is the dominant one.

A gene may have several alleles. Each allele is symbolized by the locus symbol followed by a unique superscript. In many species, the most common allele in the wild population is designated the wild type allele. It is symbolized with a + character as a superscript. Other alleles are dominant or recessive to the wild type allele. For recessive alleles, the locus symbol is in lower case letters. For alleles with any degree of dominance to the wild type allele, the first letter of the locus symbol is in upper case. For example, here are some of the alleles at the a locus of the laboratory mouse, Mus musculus: A y , dominant yellow a + , wild type and a bt , black and tan. The a bt allele is recessive to the wild type allele, and the A y allele is codominant to the wild type allele. The A y allele is also codominant to the a bt allele, but showing that relationship is beyond the limits of the rules for mouse genetic nomenclature.

Rules of genetic nomenclature have evolved as genetics has become more complex. Committees have standardized the rules for some species, but not for all. Rules for one species may differ somewhat from the rules for a different species. [10] [11]

Multiple alleles Edit

Although any individual of a diploid organism has at most two different alleles at any one locus (barring aneuploidies), most genes exist in a large number of allelic versions in the population as a whole. If the alleles have different effects on the phenotype, sometimes their dominance relationships can be described as a series.

For example, coat color in domestic cats is affected by a series of alleles of the TYR gene (which encodes the enzyme tyrosinase). The alleles C, c b , c s , and c a (full colour, Burmese, Siamese, and albino, respectively) produce different levels of pigment and hence different levels of colour dilution. The C allele (full colour) is completely dominant over the last three and the c a allele (albino) is completely recessive to the first three. [12] [13] [14]

Autosomal versus sex-linked dominance Edit

In humans and other mammal species, sex is determined by two sex chromosomes called the X chromosome and the Y chromosome. Human females are typically XX males are typically XY. The remaining pairs of chromosome are found in both sexes and are called autosomes genetic traits due to loci on these chromosomes are described as autosomal, and may be dominant or recessive. Genetic traits on the X and Y chromosomes are called sex-linked, because they are linked to sex chromosomes, not because they are characteristic of one sex or the other. In practice, the term almost always refers to X-linked traits and a great many such traits (such as red-green colour vision deficiency) are not affected by sex. Females have two copies of every gene locus found on the X chromosome, just as for the autosomes, and the same dominance relationships apply. Males, however, have only one copy of each X chromosome gene locus, and are described as hemizygous for these genes. The Y chromosome is much smaller than the X, and contains a much smaller set of genes, including, but not limited to, those that influence 'maleness', such as the SRY gene for testis determining factor. Dominance rules for sex-linked gene loci are determined by their behavior in the female: because the male has only one allele (except in the case of certain types of Y chromosome aneuploidy), that allele is always expressed regardless of whether it is dominant or recessive. Birds have opposite sex chromosomes: male birds have ZZ and female birds ZW chromosomes. However, inheritance of traits reminds XY-system otherwise male zebra finches may carry white colouring gene in their one of two Z chromosome, but females develop white colouring always. Grasshoppers have XO-system. Females have XX, but males only X. There is no Y chromosome at all.

Epistasis Edit

Epistasis ["epi + stasis = to sit on top"] is an interaction between alleles at two different gene loci that affect a single trait, which may sometimes resemble a dominance interaction between two different alleles at the same locus. Epistasis modifies the characteristic 9:3:3:1 ratio expected for two non-epistatic genes. For two loci, 14 classes of epistatic interactions are recognized. As an example of recessive epistasis, one gene locus may determine whether a flower pigment is yellow (AA or Aa) or green (aa), while another locus determines whether the pigment is produced (BB or Bb) or not (bb). In a bb plant, the flowers will be white, irrespective of the genotype of the other locus as AA, Aa, or aa. The bb combination is not dominant to the A allele: rather, the B gene shows recessive epistasis to the A gene, because the B locus when homozygous for the recessive allele (bb) suppresses phenotypic expression of the A locus. In a cross between two AaBb plants, this produces a characteristic 9:3:4 ratio, in this case of yellow : green : white flowers.

In dominant epistasis, one gene locus may determine yellow or green pigment as in the previous example: AA and Aa are yellow, and aa are green. A second locus determines whether a pigment precursor is produced (dd) or not (DD or Dd). Here, in a DD or Dd plant, the flowers will be colorless irrespective of the genotype at the A locus, because of the epistatic effect of the dominant D allele. Thus, in a cross between two AaDd plants, 3/4 of the plants will be colorless, and the yellow and green phenotypes are expressed only in dd plants. This produces a characteristic 12:3:1 ratio of white : yellow : green plants.

Supplementary epistasis occurs when two loci affect the same phenotype. For example, if pigment color is produced by CC or Cc but not cc, and by DD or Dd but not dd, then pigment is not produced in any genotypic combination with either cc or dd. That is, both loci must have at least one dominant allele to produce the phenotype. This produces a characteristic 9:7 ratio of pigmented to unpigmented plants. Complementary epistasis in contrast produces an unpigmented plant if and only if the genotype is cc and dd, and the characteristic ratio is 15:1 between pigmented and unpigmented plants. [15]

Classical genetics considered epistatic interactions between two genes at a time. It is now evident from molecular genetics that all gene loci are involved in complex interactions with many other genes (e.g., metabolic pathways may involve scores of genes), and that this creates epistatic interactions that are much more complex than the classic two-locus models.

Hardy–Weinberg principle (estimation of carrier frequency) Edit

The frequency of the heterozygous state (which is the carrier state for a recessive trait) can be estimated using the Hardy–Weinberg formula: p 2 + 2 p q + q 2 = 1 +2pq+q^<2>=1>

This formula applies to a gene with exactly two alleles and relates the frequencies of those alleles in a large population to the frequencies of their three genotypes in that population.

For example, if p is the frequency of allele A, and q is the frequency of allele a then the terms p 2 , 2pq, and q 2 are the frequencies of the genotypes AA, Aa and aa respectively. Since the gene has only two alleles, all alleles must be either A or a and p + q = 1 . Now, if A is completely dominant to a then the frequency of the carrier genotype Aa cannot be directly observed (since it has the same traits as the homozygous genotype AA), however it can be estimated from the frequency of the recessive trait in the population, since this is the same as that of the homozygous genotype aa. i.e. the individual allele frequencies can be estimated: q = √ f (aa) , p = 1 − q , and from those the frequency of the carrier genotype can be derived: f (Aa) = 2pq .

This formula relies on a number of assumptions and an accurate estimate of the frequency of the recessive trait. In general, any real-world situation will deviate from these assumptions to some degree, introducing corresponding inaccuracies into the estimate. If the recessive trait is rare, then it will be hard to estimate its frequency accurately, as a very large sample size will be needed.

Dominant versus advantageous Edit

The property of "dominant" is sometimes confused with the concept of advantageous and the property of "recessive" is sometimes confused with the concept of deleterious, but the phenomena are distinct. Dominance describes the phenotype of heterozygotes with regard to the phenotypes of the homozygotes and without respect to the degree to which different phenotypes may be beneficial or deleterious. Since many genetic disease alleles are recessive and because the word dominance has a positive connotation, the assumption that the dominant phenotype is superior with respect to fitness is often made. This is not assured however as discussed below while most genetic disease alleles are deleterious and recessive, not all genetic diseases are recessive.

Nevertheless, this confusion has been pervasive throughout the history of genetics and persists to this day. Addressing this confusion was one of the prime motivations for the publication of the Hardy–Weinberg principle.

The molecular basis of dominance was unknown to Mendel. It is now understood that a gene locus includes a long series (hundreds to thousands) of bases or nucleotides of deoxyribonucleic acid (DNA) at a particular point on a chromosome. The central dogma of molecular biology states that "DNA makes RNA makes protein", that is, that DNA is transcribed to make an RNA copy, and RNA is translated to make a protein. In this process, different alleles at a locus may or may not be transcribed, and if transcribed may be translated to slightly different versions of the same protein (called isoforms). Proteins often function as enzymes that catalyze chemical reactions in the cell, which directly or indirectly produce phenotypes. In any diploid organism, the DNA sequences of the two alleles present at any gene locus may be identical (homozygous) or different (heterozygous). Even if the gene locus is heterozygous at the level of the DNA sequence, the proteins made by each allele may be identical. In the absence of any difference between the protein products, neither allele can be said to be dominant (see co-dominance, above). Even if the two protein products are slightly different (allozymes), it is likely that they produce the same phenotype with respect to enzyme action, and again neither allele can be said to be dominant.

Loss of function and haplosufficiency Edit

Dominance typically occurs when one of the two alleles is non-functional at the molecular level, that is, it is not transcribed or else does not produce a functional protein product. This can be the result of a mutation that alters the DNA sequence of the allele. [ citation needed ] An organism homozygous for the non-functional allele will generally show a distinctive phenotype, due to the absence of the protein product. For example, in humans and other organisms, the unpigmented skin of the albino phenotype [16] results when an individual is homozygous for an allele that encodes a non-functional version of an enzyme needed to produce the skin pigment melanin. It is important to understand that it is not the lack of function that allows the allele to be described as recessive: this is the interaction with the alternative allele in the heterozygote. Three general types of interaction are possible:

  1. In the typical case, the single functional allele makes sufficient protein to produce a phenotype identical to that of the homozygote: this is called haplosufficiency. For example, suppose the standard amount of enzyme produced in the functional homozygote is 100%, with the two functional alleles contributing 50% each. The single functional allele in the heterozygote produces 50% of the standard amount of enzyme, which is sufficient to produce the standard phenotype. If the heterozygote and the functional-allele homozygote have identical phenotypes, the functional allele is dominant to the non-functional allele. This occurs at the albino gene locus: the heterozygote produces sufficient enzyme to convert the pigment precursor to melanin, and the individual has standard pigmentation.
  2. Less commonly, the presence of a single functional allele gives a phenotype that is not normal but less severe than that of the non-functional homozygote. This occurs when the functional allele is not haplo-sufficient. The terms haplo-insufficiency and incomplete dominance are typically applied to these cases. The intermediate interaction occurs where the heterozygous genotype produces a phenotype intermediate between the two homozygotes. Depending on which of the two homozygotes the heterozygote most resembles, one allele is said to show incomplete dominance over the other. For example, in humans the Hb gene locus is responsible for the Beta-chain protein (HBB) that is one of the two globin proteins that make up the blood pigment hemoglobin. [16] Many people are homozygous for an allele called Hb A some persons carry an alternative allele called Hb S , either as homozygotes or heterozygotes. The hemoglobin molecules of Hb S /Hb S homozygotes undergo a change in shape that distorts the morphology of the red blood cells, and causes a severe, life-threatening form of anemia called sickle-cell anemia. Persons heterozygous Hb A /Hb S for this allele have a much less severe form of anemia called sickle-cell trait. Because the disease phenotype of Hb A /Hb S heterozygotes is more similar to but not identical to the Hb A /Hb A homozygote, the Hb A allele is said to be incompletely dominant to the Hb S allele.
  3. Rarely, a single functional allele in the heterozygote may produce insufficient gene product for any function of the gene, and the phenotype resembles that of the homozygote for the non-functional allele. This complete haploinsufficiency is very unusual. In these cases, the non-functional allele would be said to be dominant to the functional allele. This situation may occur when the non-functional allele produces a defective protein that interferes with the proper function of the protein produced by the standard allele. The presence of the defective protein "dominates" the standard protein, and the disease phenotype of the heterozygote more closely resembles that of the homozygote for two defective alleles. The term "dominant" is often incorrectly applied to defective alleles whose homozygous phenotype has not been examined, but which cause a distinct phenotype when heterozygous with the normal allele. This phenomenon occurs in a number of trinucleotide repeat diseases, one example being Huntington's disease. [17]

Dominant-negative mutations Edit

Many proteins are normally active in the form of a multimer, an aggregate of multiple copies of the same protein, otherwise known as a homomultimeric protein or homooligomeric protein. In fact, a majority of the 83,000 different enzymes from 9800 different organisms in the BRENDA Enzyme Database [18] represent homooligomers. [19] When the wild-type version of the protein is present along with a mutant version, a mixed multimer can be formed. A mutation that leads to a mutant protein that disrupts the activity of the wild-type protein in the multimer is a dominant-negative mutation.

A dominant-negative mutation may arise in a human somatic cell and provide a proliferative advantage to the mutant cell, leading to its clonal expansion. For instance, a dominant-negative mutation in a gene necessary for the normal process of programmed cell death (Apoptosis) in response to DNA damage can make the cell resistant to apoptosis. This will allow proliferation of the clone even when excessive DNA damage is present. Such dominant-negative mutations occur in the tumor suppressor gene p53. [20] [21] The P53 wild-type protein is normally present as a four-protein multimer (oligotetramer). Dominant-negative p53 mutations occur in a number of different types of cancer and pre-cancerous lesions (e.g. brain tumors, breast cancer, oral pre-cancerous lesions and oral cancer). [20]

Dominant-negative mutations also occur in other tumor suppressor genes. For instance two dominant-negative germ line mutations were identified in the Ataxia telangiectasia mutated (ATM) gene which increases susceptibility to breast cancer. [22] Dominant negative mutations of the transcription factor C/EBPα can cause acute myeloid leukemia. [23] Inherited dominant negative mutations can also increase the risk of diseases other than cancer. Dominant-negative mutations in Peroxisome proliferator-activated receptor gamma (PPARγ) are associated with severe insulin resistance, diabetes mellitus and hypertension. [24]

Dominant-negative mutations have also been described in organisms other than humans. In fact, the first study reporting a mutant protein inhibiting the normal function of a wild-type protein in a mixed multimer was with the bacteriophage T4 tail fiber protein GP37. [25] Mutations that produce a truncated protein rather than a full-length mutant protein seem to have the strongest dominant-negative effect in the studies of P53, ATM, C/EBPα, and bacteriophage T4 GP37.

In humans, many genetic traits or diseases are classified simply as "dominant" or "recessive". Especially with so-called recessive diseases, which are indeed a factor of recessive genes, but can oversimplify the underlying molecular basis and lead to misunderstanding of the nature of dominance. For example, the recessive genetic disease phenylketonuria (PKU) [26] results from any of a large number (>60) of alleles at the gene locus for the enzyme phenylalanine hydroxylase (PAH). [27] Many of these alleles produce little or no PAH, as a result of which the substrate phenylalanine (Phe) and its metabolic byproducts accumulate in the central nervous system and can cause severe intellectual disability if untreated.

To illustrate these nuances, the genotypes and phenotypic consequences of interactions among three hypothetical PAH alleles are shown in the following table: [28]

In unaffected persons homozygous for a standard functional allele (AA), PAH activity is standard (100%), and the concentration of phenylalanine in the blood [Phe] is about 60 μM (= μmol/L). In untreated persons homozygous for one of the PKU alleles (BB), PAH activity is close to zero, [Phe] ten to forty times standard, and the individual manifests PKU.

In the AB heterozygote, PAH activity is only 30% (not 50%) of standard, blood [Phe] is elevated two-fold, and the person does not manifest PKU. Thus, the A allele is dominant to the B allele with respect to PKU, but the B allele is incompletely dominant to the A allele with respect to its molecular effect, determination of PAH activity level (0.3% < 30% << 100%). Finally, the A allele is an incomplete dominant to B with respect to [Phe], as 60 μM < 120 μM << 600 μM. Note once more that it is irrelevant to the question of dominance that the recessive allele produces a more extreme [Phe] phenotype.

For a third allele C, a CC homozygote produces a very small amount of PAH enzyme, which results in a somewhat elevated level of [Phe] in the blood, a condition called hyperphenylalaninemia, which does not result in intellectual disability.

That is, the dominance relationships of any two alleles may vary according to which aspect of the phenotype is under consideration. It is typically more useful to talk about the phenotypic consequences of the allelic interactions involved in any genotype, rather than to try to force them into dominant and recessive categories.


What is the Difference Between Gene and Allele?

The key difference between gene and allele is that the gene is a specific nucleotide sequence that encodes for a specific protein while the allele is a variant of a gene either the dominant or the recessive variant. Therefore, the gene is the basic functional unit of the heredity while the allele is an alternative form of a gene. One gene possibly has two alleles. And, the allele can be either a dominant allele or a recessive allele.

The below infographic shows the difference between gene and allele as a side by side comparison.


Quick validation of genetic quality for conditional alleles in mice

Site-specific conditional inactivation technologies using Cre-loxP or Flp-FRT systems are becoming increasingly important for the elucidation of gene function and disease mechanism in vivo. A large number of gene knockout mouse models carrying complex conditional alleles have been generated by global community efforts and made available for biomedical researchers. The structures of conditional alleles in these mice are becoming increasingly complex and sophisticated, and so the validation of the genetic quality of these alleles is likewise becoming a laborious task for individual researchers. To ensure the reproducibility of conditional experiments, the researcher should confirm that loxP or FRT is integrated at the correct positions in the genome prior to start of the experiments. We report the successful design of universal PCR primers specific to loxP and FRT for the quick validation of conditional floxed and Flrted alleles. The primer set consists of forward and reverse primers complimentary to the loxP or FRT sequences with partial modifications at the 5' end containing 6-base restriction endonuclease recognition sites. The universal primer set was tested to detect genomic intervals between a pair of cis-integrated loxP or FRT and was useful for quickly validating various floxed or Flrted alleles in conditional mice.

Keywords: Cre-loxP Flp-FRT conditional mice genetic quality reproducibility.

© 2021 The Authors. Genes to Cells published by Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.


Selfish Genes and Gene-Centered Evolution

I doubt that anyone reading Bitesize Bio has never heard of Richard Dawkins. He’s always been controversial in one way or another, ever since the release of arguably his most popular book, The Selfish Gene (Amazon US/UK). But despite Dawkins’ notoriety, maybe there are some readers here who haven’t read The Selfish Gene – I didn’t until two years ago, actually. So, what specifically is The Selfish Gene about?

Dawkins coined the term selfish gene as a way of expressing the gene-centred view of evolution, which holds that evolution is best viewed as acting on genes and that selection at the level of organisms or populations almost never overrides selection based on genes. In chapter three, he explains:

“Genes are competing directly with their alleles for survival, since their alleles in the gene pool are rivals for their slot on the chromosomes of future generations. Any gene that behaves in such a way as to increase its own survival chances in the gene pool at the expense of its alleles will, by definition, tautologously, tend to survive. The gene is the basic unit of selfishness.”

This way of looking at selection, from the perspective of the gene, gets extended to such emergent behaviors as kin selection, eusociality, and altruism, by way of the fact that an allele not only gets propogated through the gene pool by helping the immediate organism survive, it also helps other copies of itself survive in other members of its species. Meaning, altruistic behavior is a natural outcome of selection, even if it is bad for the individual organism, because the genes themselves are acting selfishly by protecting other copies of themselves. Of course most genes don’t directly influence behavior, meaning that most genes are, at best, indirectly selfish – but in the case of parochial altruism (within a family or other inbreeding group), most organisms benefiting from altruism likely carry copies of the same non-behavioral genes anyway.

At a time when the idea of group selection was being shown not to be a stable evolutionary strategy, this model provided one way of explaining why kin selection was a much better description of sociality in animals.

For these reasons, The Selfish Gene has rightfully received wide acclaim. But, it is just a metaphor, and no gene is an island. Each gene must act in concert with the rest of an organisms’ genome, which in turn must act to cooperate and compete with other members of its species and within a given ecosystem. As a result, tradeoffs get made. Many times, it is not the allele that is most effective at performing its usual task that is propogated in the gene pool, but the allele that works best with the rest of its genome to generate a successful phenotype that survives.

As a result, one of the primary scientific criticisms of The Selfish Gene has been on the idea that the gene is the unit of selection. Most even criticize the idea that the genome is the unit of selection, instead arguing that the phenotype is what is being selected. Instead, the gene is the unit of evolution, some argue, viewing evolution as the long-term trend of shifting allele frequencies.

Being a molecular biologist and not having studied evolutionary biology formally, my first reaction was to take these two perspectives at face value. After a thrashing from Larry Moran (see the comments), my conclusion that macroevolution is just a “very long-term trend of shifting allele frequencies” was blown apart. As a result, I’ve since come around to be very critical of the view that the gene is the unit of evolution.

Instead, the population appears to be the best candidate as the unit of evolution, with phyletic change (shifting allele frequencies) of a single population over time being “microevolution”, and isolation/divergence of two or more populations representing “macroevolution”.

All of this means that the impact of The Selfish Gene is very restricted as a metaphor of how evolution occurs, being successful at solving a very specific set of problems relating to social animal behavior, and is limited to discussions of phyletic change.

The implications for social behavior coming out of The Selfish Gene has also directed much of Richard Dawkins’ career since its publication. His follow-up book, The Extended Phenotype, subtitled “The Gene as the Unit of Selection”, and later, “The Long Reach of the Gene”, argued that a gene may effect an organism’s environment through that organism’s behaviour, citing as examples caddis houses and beaver dams.

He also coined the term “meme” (the cultural equivalent of a gene) to describe how Darwinian principles might be extended to explain the spread of ideas and cultural phenomena, an idea that has been developed into a new area of study principally by Susan Blackmore. Dawkins used the word meme to refer to any cultural entity which an observer might consider a replicator. He hypothesised that people could view many cultural entities as capable of such replication, generally through exposure to humans, who have evolved as efficient (although not perfect) copiers of information and behaviour. Most notably in his more recent book, The God Delusion, he argues that religions are basically memes (among other things).

I don’t know if his arguments about religions as memes are all that great, but he sparks discussion either way about how it is useful to view the origins of social behaviors. But that’s a story for another post, some other time.



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