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7 Types Of Pleiotropy


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#1 Nitai

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Posted 27 May 2005 - 07:24 AM

Hello,

I am not really a trained up scientist but I like to read about it. I found an interesting article about pleitropy on

http://www.ijdb.ehu.....9803/ft501.pdf

I would like to request somebody of you in this forum, an expert in this scientific jargon to briefly explain the main points of this different types of pleiotropy (in the lay man's language). As far as I understood these are constrains to evolution?

Thank you in advance.
Nitai




Type 1. Artefactual pleiotropy
Sometimes a single mutation can affect more than one process, simply because two genes happen to be located next door to each other in the genome. A classic example is provided by the Drosophila claret-non-disjunction alleles, which affect both eye-color (the claret phenotype) and meiosis (increased non-disjunction). Most claret alleles do not have any effect on meiosis, however. The explanation for this behavior became clear when the claret gene was cloned: there is an adjacent gene which encodes a kinesin molecule, required for normal chromosome disjunction at meiosis, and the pleiotropic alleles are small deletions that affect both transcription units (Yamamoto et al., 1989). A very comparable situation occurred with the C. elegans gene unc-86, which encodes a POU-domain transcription factor required for many terminal cell divisions and differentiation events (further discussed below, un-der Type 6). In addition, some alleles of unc-86 also have a meiotic nondisjunction phenotype, although most do not (Hodgkin et al.,1979; Finney et al., 1988). Again, when the locus was cloned it became clear that the non-disjunction alleles were all small deletions affecting not only unc-86 but also two adjacent transcription units, one of which is presumably required for normal meiosis(Finney et al., 1989).The multiple effects of such mutations are therefore artefacts of the process of mutagenesis, hence the name. Most commonly, such artefacts will be associated with small deletions rather than point mutations, but obviously situations may exist where two genes share a regulatory region, and therefore even a single base change might affect both genes. Also, position effects can potentially lead to artefactual pleiotropies, because changes at one localized point in the genome might affect the expression of a whole chromosomal region containing many genes, as a result of altered chromatin organization. Organisms with compact, gene-dense genomes will be especially susceptible to artefactual pleiotropies. Both Drosophila andC. elegans are animals of this type, and may have descended fromancestors with larger genomes which have shrunk in size during evolution, for unknown reasons. Many genes in C. elegans are organized in operons, transcribed as polycistronic units but then broken up into monocistronic messenger RNAs by a process of trans-splicing (Zorio et al., 1994). In contrast to bacterial operons, the linked genes in these operons often lack any discernible functional connection, so the suspicion arises that many of the operons are simply a secondary consequence of genome compression. Perhaps, adjacent genes that were initially independently transcribed became closer together over evolutionary time, and eventually came to be co-transcribed, if there was no countervailing selection pressure against their co-expression. However, the arrangement of genes in operons does mean that the likelihood of artefactual pleiotropies is increased, and it is conceivable that this has created additional constraints on the evolutionary options available to organisms such as C. elegans. Alternatively, but less plausibly, one could argue that the operon arrangement provides opportunities for saltatory evolution, in that simultaneous changes in the expression of several different genes could be achieved with a single mutation in the operon promoter.

Type 2. Secondary pleiotropy
This is roughly equivalent to “relational pleiotropy”, as defined by Hadorn (1961), and describes situations where a simple bio-chemical abnormality has multiple phenotypic consequences, sometimes with little superficial connection to the initiating mutation. Complex, long-lived organisms, especially those with advanced abilities to compensate for physiological dysfunction, are especially likely to exhibit secondary pleiotropies.An old example, indeed one of the first human mutants to beunderstood at a biochemical level, is provided by the disease PKU(phenylketonurea). Here, a defect in the liver enzyme phenylalanine hydroxylase leads to excess plasma levels of phenylalanine. This in turn affects myelination of axons in the brain, and ultimately to mental retardation. Similar or more complex chains of physiological and developmental consequence can be seen in many human genetic disorders, such as the complex syndromes arising from thalassaemias. In Drosophila, a familiar example is provided by rudimentary mutations, affecting pyrimidine biosynthesis. Some of these lead to defective development of the wing, but not of the rest of the fly, because pyrimidine levels become rate-limiting for cell division in the rapidly proliferating tissues of the wing disc, but not elsewhere. Sometimes, the connection between a biochemical defect and a distinctive phenotype is far from obvious, and the possibility of other kinds of pleiotropy should be considered (Types 4-7 below).For example, the human Lesch-Nyhan syndrome, arising from loss of the enzyme HPRT, is associated with dramatic self-mutilating behavior. This has been ascribed to abnormal levels of purine in the brain, but exactly how or why this should lead to such a specific behavioral change is not yet known. More obscure yet is the connection between melanin synthesis and the formation of a normal optic nerve projection (reviewed by Guillery et al., 1995). Albino mutants are known in many mammalian species, usually resulting from mutations of tyrosinase. These mutants have low levels of retinal melanin, but also exhibit incorrect projections from retina tobrain, with abnormalities in the optic chiasm, as in cross-eyed Siamese cats (and cross-eyed tigers too!). As we understand more about developmental mechanisms, some of these pleiotropies may become explicable in terms of secondary effects, but some may not.

Type 3. Adoptive pleiotropy
One might also use the term “exaptational pleiotropy” for this category, because it describes cases where a pre-existing protein has clearly been co-opted, or “exapted”, in evolutionary terminology (Gould and Vrba, 1981), to execute an additional function unrelated to its original biochemical role. The best example of this kind of effect is provided by crystalline proteins, which constitute the most abundant proteins in lens tissue, and play a structural and refractive role (reviewed by Tomarev and Piatigorsky, 1996).Remarkably, in many cases these are familiar metabolic enzymes such as LDH (e-crystallin) and enolase (t-crystallin).It seems likely that cases like this, where the same gene productis used for totally different purposes in different tissues, are likelyto be transient on an evolutionary timescale. If gene duplication occurs, there will be an opportunity for the two functions to be optimized independently, and the two copies will rapidly diverge in regulation, protein sequence, or both. In the example of d-crystal-lin, which corresponds to the enzyme arginosuccinate lyase, thelens-specific version of the protein is encoded by a different gene from the major metabolic versions, so pleiotropy has been lost. Many protein families provide possible examples of this effect -for example, a-lactalbumin and lysozyme, which are clearly related in sequence and structure, but have very different physiological functions. Sometimes gene duplication may have preceded theadoption of a new functional role, but the example of e-crystallins demonstrates that genuinely bifunctional genes can arise without duplication, and can persist for significant periods of evolutionary time.

Type 4. Parsimonious pleiotropy
This type encompasses cases where the same enzyme catalyzes the same chemical reaction in multiple different pathways. Loss of this enzyme will then have complex metabolic consequences. For example, the same proteins are used at several steps in the biosynthesis of isoleucine and of valine (acting on different substrates), so knocking out any of these enzymes in bacterialeads to simultaneous prototrophy for both amino acids. In such cases, there has presumably been no pressure to evolve independent regulation of the two pathways, either at the gene level or at the enzyme level, so the organism employs the same protein in each pathway. Some regulatory proteins also exhibit parsimonious pleiotropy, such as the ß subunit of G proteins in C. elegans. There are many genes encoding G a subunits in the nematode, each with specific roles and patterns of expression, but apparently only one gene for the ß subunit, gpb-1. A knockout of this gene, achieved by reverse genetics, leads to multiple phenotypic consequences, because of the involvement of G protein signaling in so many different processes (Zwaal et al., 1996). All the specificity is achieved by use of different a subunits; as far as is known, the ß subunit is executing an identical biochemical function in all these cases, so a single gene suffices.

Type 5. Opportunistic pleiotropy
This is related to the two preceding types, and describes cases where a regulatory protein appears to have been recruited to perform an additional role in a different tissue, distinct from its major and more ancient role. Illustrations are provided by the genes acting as “numerator elements” on the X chromosome of Drosophila. s@x in Drosophila is determined by the ratio of X chromo-some dosage to autosomal dosage, and a small number of sites on the X chromosome act early in development as major numerators in setting this ratio (reviewed by Cline and Meyer, 1996). At least two of the numerator sites, sisB and runt, encode transcription factors that play important roles later in development, and one can assume that their action as numerators, acting as transcriptional activators of the target gene Sxl, is a relatively recent evolutionary acquisition. The distinction from Type 3 is that the biochemistry is basically the same; the distinction from Type 4 is that the interacting partners are different. Also, as compared to Type 4, one role is secondary, and perhaps more subject to rapid evolutionary change.

Type 6. Combinatorial pleiotropy
This term applies to the large number of cases where a single protein product interacts with a variety of different partners in different cell types, and as a result has altered specificity and/or biochemical activity in each different situation. Mutations affecting this protein will therefore have multiple and potentially diverse effects on a variety of tissues. Many, perhaps most, transcription factors in multicellular organisms fall into this category. Even in unicellular eukaryotes, the same combinatorial strategy is observed. For example, the proteins that control yeast mating type include the DNA binding protein encoded by MAT?2, which has different functions in ??cells and in diploids (reviewed by Herskowitz et al., 1992). By itself, in haploid ??cells, it acts to repress ?-specific genes, but in diploid cells, it acts in combination with MAT?1 to repress an additional set of haploid specific genes.
The nervous system seems to be a realm where combinatorial strategies are especially important, since there are a very large number of closely related cell types to be generated in nervous tissue, each with distinctive anatomy, connectivity and physiological properties. An illustration is provided by the simple and well-studied nervous system of C. elegans, with 302 neurons and about 115 definable cell types. The POU-domain transcription factor encoded by the gene unc-86 is expressed in 57 out of the 302 neurons, and as a result affects the development of multiple cell types and physiological functions: touch sensitivity, locomotion, egg-laying and so on (Finney et al., 1988; Finney and Ruvkun, 1990). Its action is necessary but not sufficient to generate the various neuron types -for example, the mec-3 gene, another transcription factor, contains UNC-86 binding sites in its promoter, but mec-3 is only transcribed in ten cells, and only six of these ten differentiate into mechanosensory neurons. Other factors must act combinatorially with UNC-86 and MEC-3 to achieve the necessary specificity (Mitani et al., 1993).
The distinction between Type 6 and Type 4 (Parsimonious pleiotropy) is that in the combinatorial situation, the biochemistry of the protein changes from context to context, sometimes radically (for example, from transcriptional activator to transcriptional repressor). The distinction from Type 5 (Opportunistic) is less clear-cut, and probably much combinatorial pleiotropy evolved from an initially opportunistic state. Opportunistic proteins can act in isolation, however, whereas the emphasis in Type 6 is on the diversity that can be generated by heteromeric combinations of
different proteins in different cell types.
Other kinds of protein can also be deployed combinatorially, for example the subunits of membrane receptors. The mammalian receptors for the lymphokines IL-3 and GM-CSF have the same ??subunit, but different ??subunits, and as a result the ??subunit probably has different properties in the two receptors (Kitamura et al., 1991).

Type 7. Unifying pleiotropy
This final type is of a different nature from those preceding, because it describes cases where the multiple functions of a locus or gene are all related, in ultimate biological output, but the immediate chemical functions are diverse. The different enzyme activities, binding domains or structural components may all be included in the same polypeptide chain, or they may be encoded by adjacent cistrons under common regulatory control. In either case, mutation of the locus can have complex physiological consequences, which may be hard to explain if the underlying biology is not understood.
Operons in bacteria obviously reflect this kind of modular organization, and achieve common control by using a single promoter for all the components of an enzymatic pathway or structural assembly process. Operons are much less common in multicellular organisms, and unification is often achieved by using multifunctional proteins. There are many cases where two or more enzymes are encoded by separate cistrons in prokaryotes, but assembled into a single polyprotein in eukaryotes.
Such polyproteins offer an additional possible advantage, which is that metabolites may be more efficiently channeled from one catalytic site to the next, if all the sites are connected by the same polypeptide backbone. Even in bacteria, polyproteins occur, though they are less prevalent than in higher organisms. The fatty acid synthetase polypeptide of mammals contains seven enzymatic activities, and a corresponding multienzymatic protein is found in a few bacterial species, although it is broken up into separate monofunctional proteins in most bacteria. Argument continues as to whether channeling is significantly advantageous. Probably each biochemical situation has its own particular properties, favoring channeling to various degrees (for discussion, see Davidson et al., 1993).
These are cases where the function of the locus is unified at the level of an overall biochemical function, such as the synthesis of a particular metabolite, and all the subfunctions correspond to
simple enzymatic steps. More sophisticated assemblies may unite synthesis together with cellular organization. For example, the cha-1 and unc-17 genes of C. elegans encode, respectively,
choline acetyltransferase (the enzyme responsible for acetylcholine synthesis), and the acetylcholine transporter protein, responsible for loading acetylcholine into synaptic vesicles. The two genes overlap, and have identical 5’ non-coding exons, but generate otherwise completely different transcripts and proteins, as a result of alternative splicing (Alfonso et al., 1994). A comparable cholinergic operon also occurs in mammals, indicating that this is a conserved and advantageous organization (Bejanin et al.,1994).
Yet more complicated assemblies bring together genes or activities that affect a great variety of cellular or organismal functions. Loci controlling S@xual phenotype in many organisms provide illustrations, ranging from simple cases like the yeast MAT??locus (encoding an activator for one set of genes, and a separate repressor for another set of genes), to “supergenes” with many clustered genes for different aspects of S@xual phenotype.
The evolutionary forces that result in tight linkage are obvious in these cases. For example, in primroses, the genes controlling flower structure and pollen incompatibility must remain linked,
because recombination would lead to non-functional flower types. In other cases, the advantage of clustering is less obvious. Hox clusters appear ubiquitous in animals, but in both Drosophila and C. elegans, the Hox cluster is partly broken up, and does not seem to depend on linkage for its function -for discussion, see Mann (1997).
As with metabolic pathways, different activities can be built into the same polypeptide chain, or closely related polypeptides generated by alternative splicing. Examples are provided by s@x
determination genes in both flies and worms. The Drosophila Sexlethal gene affects dosage compensation (probably in two different ways), somatic S@xual phenotype, and germ line S@xual
phenotype (reviewed in Cline and Meyer, 1996). The C. elegans gene sdc-3 similarly affects both s@x and dosage compensation, and the two functions appear independently mutable, with the
function-specific mutations mapping to different parts of the SDC-3 protein (Klein and Meyer, 1993). In many cases, however, the different functions presumably involve incompatible biochemistry, and therefore cannot be included in the same polyprotein. Cases of unifying pleiotropy are usually easy to recognize, because the biology is interpretable, but there may be situations where it is not immediately apparent. A case in point is the C. elegans gene encoding cytochrome b, which forms an operon with the cell-death regulator ced-9 (Hengartner and Horvitz, 1994). Initially, this association seemed accidental, but recent work has suggested a possible involvement of cytochrome with apoptosis.

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Posted 27 May 2005 - 08:06 AM

I would like to request somebody of you in this forum, an expert in this scientific jargon to briefly explain the main points of this different types of pleiotropy (in the lay man's language).

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Maybe you could single out the point you find most interesting (or confusing) and we could start by discussing that?


As far as I understood these are constraints to evolution?

The simplest answer would be: "yes". Unfortunately, since this area is anything but simple, exceptions could likely be found to just about any general rule (and even that would be very dependent upon the ability to accurately assess all the implications of a specific change -- no easy task by any means).

#3 Nitai

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Posted 27 May 2005 - 09:23 AM

Tnx, for answer.

I am asking here things because I am layman in scientific jargon. So, could you explain the following paragraph?

A classic example is provided by the Drosophila claret-non-disjunction alleles, which affect both eye-color (the claret phenotype) and meiosis (increased non-disjunction). Most claret alleles do not have any effect on meiosis, however. The explanation for this behavior became clear when the claret gene was cloned: there is an adjacent gene which encodes a kinesin molecule, required for normal chromosome disjunction at meiosis, and the pleiotropic alleles are small deletions that affect both transcription units (Yamamoto et al., 1989).

Nitai

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Posted 27 May 2005 - 10:09 AM

Tnx, for answer.

I am asking here things because I am layman in scientific jargon. So, could you explain the following paragraph?

A classic example is provided by the Drosophila claret-non-disjunction alleles, which affect both eye-color (the claret phenotype) and meiosis (increased non-disjunction). Most claret alleles do not have any effect on meiosis, however. The explanation for this behavior became clear when the claret gene was cloned: there is an adjacent gene which encodes a kinesin molecule, required for normal chromosome disjunction at meiosis, and the pleiotropic alleles are small deletions that affect both transcription units (Yamamoto et al., 1989).

Nitai

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Meiosis refers to the nuclear division in a germ cell (a sperm, or egg) during which the number of chromosomes found in a somatic cell (all cells other than germ cells) is halved.

Nondisjunction refers to a failure of the chromosomes to correctly separate (when it does happen correctly, it is called disjunction).

An allele is a location on the DNA which may carry a gene from either one parent or the other (but not both).

Kinesin you can read about here:
http://www.imb-jena....hm/Kinesin.html

So what's being said there is that the alleles in Drosophila have an effect both on the eye color and on the way chromosomal division takes place. As for the latter, it would help to know what a spindle is in this context...

...Uh, I'm not sure it will help all that much to simply try to translate jargon into layman's terms -- you can't really do that without learning the principles involved anyway. I don't mean it in an insulting way, but if this is the first time you have seen the above terms defined, you might need a little more grounding in the basics before you try to tackle the subtleties of pleiotropy.

#5 Nitai

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Posted 27 May 2005 - 08:25 PM

[I'm not sure it will help all that much to simply try to translate jargon into layman's terms]

It does help, of course it is up to you if you like to continue this. But anyway.
If I very briefly summarize this artefactual pleiotropy is this correct?

This type of pleiotropy occurs when a single mutation affects more than one process, simply because two genes are situated very close to each other in the genome. When genes exhibit pleiotropy, they have multiple affects. E.g. people with Marfan’s syndrome, they usually have the potential for: very tall stature, elongated fingers, curved spine, problems with their retina, heart valve problems. The crucial cause of all this debilitating problems is the modification of fibrilin fibers that surrounds the important areas of connective tissue in the body.

Here i gave other example is this a good one? My question is also is there a specific place (in the DNA) where and when this type of pleiotropy always occur? E.g. only during meiosis? What example you would give for this type of artefactual pleiotropy.

Tnx in advance.
Nitai

PS: I just found an example of pleiotropy. Is this an example for artefactual or some other type of pleiotropy from the above list?

The sickle-cell disease. Effects: 1. breaking down of red blood cells; 2. clumping of cells; 3. accumulation of sickled-cells inspleen.

Now breaking down of red blood cells results in a. physical weakness b. anemia and c. heart failure.

The clumping of the cells and clogging of small blood vessels will cause a. heart failure b. pain and fever c. brain damage and d. damage of other organs.

Accumulation of sickled celles in the spleen causes a. damage to different organs and b. spleen damage.

All these problems in turn will be the cause of other problems like impaired mental function, kidney, failure, rheumatism and even paralysis.

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Posted 27 May 2005 - 10:46 PM

Here i gave other example is this a good one?

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Yes. It often appears on biology exams.

My question is also is there a specific place (in the DNA) where and when this type of pleiotropy always occur?

I don't know how to answer that (unless you insist on the always, in which case I would say no). There appear to be factors which can make specific locations more likely to be the subject of mutations in general. I'm assuming that you mean are there specific alleles that are more likely to be involved, and that you noticed (in the article you linked) the mention of greater prevalance of pleiotropy in denser, more compact genomes (it only makes sense; where compactness in a genome conferred an advantage, you would expect to see such space-saving tricks in play). Answering this sort of question is the subject of much current work in biology.

E.g. only during meiosis?

Don't be confused by the references to meiosis. They were talking about meiosis being affected by pleiotropy, not as a cause of it.

What example you would give for this type of artefactual pleiotropy.

Well, say in the design plans for a submarine, the color of the hull paint somehow got associated with the type of material used for hatch covers, so subs with green hulls always got steel plate, while grey ones got open mesh.


All these problems in turn will be the cause of other problems like impaired mental function, kidney, failure, rheumatism and even paralysis.

I think that is better explained as secondary pleiotropy.




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