No, most mutations do not result in a loss of the original function. The rest is more word games.
This was your only comment worth commenting on so far.
If a new function was created by a mutation that means a function was lost because the information was rearranged. If i am wrong document a mutation that added a new function without losing another function ?
I am sure it is the only one you can think of a comment for, but anyway most mutations neither add a function nor take one away because DNA polymerase repairs mistakes by adding or removing nucleotides. Often times, this results in the same function. Though, a lot of species carry duplicate genes. Recently, it was found that P. aeruginosa actually has a tendency to make duplicate genes when they are in a biofilm. The reason for this is not known, but it is quite interesting because bacteria in a biofilm do not live a unicellular lifestyle. If you have more than one copy of a gene and one gets mutated, it would not destroy any function at all.
Most mutations are neutral that is why you want to make the claim that mutations don't change a function or add a function. But you are so full of crap and this is the last response i will make to you. First you tried to say the genetic code is not a language which overwhelming data suggests it is. Now you're claiming mutations don't cause a loss of a function or gain of a new function ,if that is the case how do you get evolution
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Don't ever question my education and may i suggest you take more classes in biology before you attempt to debate it.
Chapter 16Molecular pathology
16.1Introduction
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Molecular pathology seeks to explain why a given genetic change should result in a particular clinical phenotype. We have already reviewed the nature and mechanisms of mutations in Chapter 9 (briefly summarized in Box 16.1); this chapter is concerned with their effects on the phenotype. Molecular pathology requires us to work out the effect of a mutation on the quantity or function of the gene product, and to explain why the change is or is not pathogenic for any particular cell, tissue or stage of development.
Box 16.1
The main classes of mutation. Deletions ranging from 1 bp to megabases. Insertions including duplications.
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Not surprisingly, given the complexity of genetic interactions, molecular pathology is at present a very imperfect science. The greatest successes to date have been in understanding cancer, where the phenotype to be explained, uncontrolled cell proliferation, is relatively simple. For most other genetic diseases we would like to explain complex clinical findings. Often these are the end result of a long chain of causation, and all too often they are not predictable or even readily comprehensible in our present state of knowledge. Nevertheless, as the emphasis of the Human Genome Project moves from cataloging genes to understanding their function, the study of molecular pathology has moved to center stage.
One of the major advantages of studying humans rather than laboratory organisms is that the healthcare systems worldwide act as a gigantic and continuous mutation screen. Any human phenotype that occurs with a frequency greater than 1 in 109 is probably already described somewhere in the literature, and for most inherited diseases where the gene responsible has been identified, many different mutations are known. We cannot do experiments on humans or breed them to order, but humans provide unique opportunities to observe the clinical effects of many different changes in a given gene. This generates hypotheses, which must then be tested in animals. Thus investigations of naturally occurring human mutations are complemented by studies of specific mutations in transgenic animals (see Chapter 21).
16.2There are rules for the nomenclature of mutations and databases of mutations
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The preferred nomenclature of genes is laid down by the Genome Database Nomenclature Committee (
http://www.gene.ucl.ac.uk/nomenclature/; printed version: White et al., 1997). A valuable summary of genetic nomenclature for many different organisms including man was published as a supplement to Trends in Genetics in 1998 (see Further reading).
Mutations can be described in two ways: by their effects or by detailing the sequence change. Box 16.2 shows one possible nomenclature for effects, currently more widely used for laboratory organisms than humans. Box 16.3 summarizes the recommended conventions for describing sequence changes (Antonarakis et al., 1998). Systematic attempts are now being made to establish disease-specific databases of mutations (Krawczak and Cooper, 1997). These can be accessed through central points such as the Human Gene Mutation Database (
http://www.uwcm.ac.uk/uwcm/mg/hgmd0.html). For some but not all genes, allelic variants are also listed in the OMIM database (
http://www.hgmp.mrc.ac.uk/omim/). Cooper and Krawczak (1993) have performed a number of useful meta-analyses on diferent types of human mutation.
Box 16.2
A nomenclature for describing the effect of an allele. Null allele or amorph: an allele that produces no product. Hypomorph: an allele that produces a reduced amount or activity of product.
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Box 16.3
Nomenclature for describing mutations (see Antonarakis et al. (1998) for full details). Use the one-letter codes: A, alanine; C, cysteine; D, aspartic acid; E, glutamic acid; F, phenylalanine; G, glycine; H, histidine; I, isoleucine; (more...)
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16.3A first classification of mutations is into loss of function vs gain of function mutations
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16.3.1The convenient nomenclature of A and a alleles hides a vast diversity of DNA sequence changes
Over 750 different cystic fibrosis mutant alleles have been described, and a similar number of different mutations in the β-globin gene. There is no reason why these should all fit into a few tidy categories. In principle however, mutation of a gene might cause a phenotypic change in either of two ways:
the product may have reduced or no function (loss of function mutation - an amorph or hypomorph in the terminology of Box 16.2);
the product may do something positively abnormal (gain of function mutation - a hypermorph or neomorph).
Loss of function mutations most often produce recessive phenotypes. For most gene products the precise quantity is not crucial, and we can get by on half the normal amount. Thus most inborn errors of metabolism are recessive. For some gene products, however, 50% of the normal level is not sufficient for normal function, and haploinsufficiency produces an abnormal phenotype, which is therefore inherited in a dominant manner (see Section 16.4.3). Sometimes also a nonfunctional mutant polypeptide interferes with the function of the normal allele in a heterozygous person, giving a dominant negative effect (an antimorph in the terminology of Box 16.2 - see Section 16.4.4).
Gain of function mutations usually cause dominant phenotypes, because the presence of a normal allele does not prevent the mutant allele from behaving abnormally. Often this involves a control or signaling system behaving inappropriately - signaling when it should not, or failing to switch a process off when it should. Sometimes the gain of function involves the product doing something novel - a protein containing an expanded polyglutamine repeat forming abnormal aggregates, for example.
Inevitably some mutations cannot easily be classified as either loss or gain of function. Has a permanently open ion channel lost the function of closing or gained the function of inappropriate opening? A dominant negative mutant allele has lost its function but also does something positively abnormal. Nevertheless, the distinction between loss of function and gain of function is a useful first tool for thinking about molecular pathology.
16.3.2Loss of function is likely when point mutations in a gene produce the same pathological change as deletions
Purely genetic evidence, without biochemical studies, can often suggest whether a phenotype is caused by loss or gain of function. When a clinical phenotype results from loss of function of a gene, we would expect any change that inactivates the gene product to produce the same clinical result. We should be able to find point mutations which have the same effect as mutations that delete or disrupt the gene. Waardenburg syndrome Type 1 (MIM 193500) provides an example. As Figure 16.1 shows, causative mutations in the PAX3 gene include amino acid substitutions, frameshifts, splicing mutations, and in some patients complete deletion of the PAX3 sequence. Since all these events produce the same clinical result, its cause must be loss of function of PAX3. Similarly, among diseases caused by unstable trinucleotide repeats (see Box 16.7), Fragile-X and Friedreich ataxia are occasionally caused by other types of mutation in their respective genes, pointing to loss of function, whereas Huntington disease is never seen with any other type of mutation, suggesting a gain of function.
Figure 16.1
Loss of function mutations in the PAX3 gene. The 10 exons of the gene are shown as boxes, with the connecting introns not to scale. The shaded areas show the sequences encoding (more...)
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Box 16.7
Unstable expanding repeats - a novel cause of disease. Unstable expanding trinucleotide repeats were an entirely novel and unprecedented disease mechanism when first discovered in 1991, and they (more...)
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16.3.3Gain of function is likely when only a specific mutation in a gene produces a given pathology
Gain of function is likely to require a much more specific change than loss of function. The mutational spectrum in gain-of-function conditions should be correspondingly more restricted, and the same condition should not be produced by deletion or disruption of the gene. Likely examples include Huntington disease (see Box 16.7), and achondroplasia (MIM 100800: short-limbed dwarfism). Virtually all achondroplastics have one of two mutations in the fibroblast growth factor receptor gene FGFR3, both of which cause the same amino acid change, G380R (Bellus et al., 1995). Other mutations in the same gene produce other syndromes (Section 16.7.3). For unknown reasons, the mutation rate for G380R is extraordinarily high, so that achondroplasia is one of the commoner genetic abnormalities, despite requiring a very specific DNA sequence change.
Mutational homogeneity is a good first indicator of a gain of function, but there are other reasons why a single mutation may account for all or most cases of a disease:
diseases where what one observes is directly related to the gene product itself, rather than a more remote consequence of the genetic change, may be defined in terms of a particular variant product, as in sickle cell disease (see Box 16.5);
a molecular mechanism may make a certain sequence change in a gene much more likely than any other change - e.g. the CGG expansion in Fragile-X syndrome (see Box 16.8);
there may be a founder effect - for example, certain disease mutations are common among Ashkenazi Jews, presumably reflecting mutations present in a fairly small number of founders of the present Ashkenazi population (Motulsky, 1995);
selection favoring heterozygotes (Section 3.3.2) enhances founder effects and often results in one or a few specific mutations being common in a population.
Box 16.5
Hemoglobinopathies. Hemoglobinopathies occupy a special place in clinical genetics for many reasons. They are by far the most common serious mendelian diseases on a worldwide scale. Globins illuminate important (more...)
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Box 16.8
Laboratory diagnosis of fragile X. Cytogenetic testing - the fragile site is seen only when cells are grown under conditions of folate or thymidine depletion. For unknown reasons, (more...)
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16.3.4Deciding whether a DNA sequence change in a gene is pathogenic can be difficult
Not every sequence variant seen in an affected person is necessarily pathogenic. If the genome-wide average heterozygosity of 0.0032 is applied to coding sequences, then screening a panel of 100 patients for mutations in a 3-kb coding sequence would reveal about 500 sequence changes. Even allowing for the much higher conservation of coding sequences, screening on such a scale will almost certainly reveal some rare nonpathogenic sequence variants, as well as pathogenic changes. If each variant occurs in one person in 10 000 in the population, it will not show up in any panel of normal controls of realistic size. How does one decide whether a sequence variant is pathogenic?
If the pathogenic mechanism is gain of function, then as explained above (Section 16.3.3), the mutation is likely to be very specific. Any sequence change different from the standard mutation is probably not pathogenic, at least for the disease in question. Loss of function mutations are usually much more heterogeneous. Only a functional test, either in vitro (Chapter 20) or in vivo (Chapter 21), can definitively show whether a DNA sequence change in a gene affects the function, but useful clues can be obtained by considering the nature of the sequence change (Box 16.4).
Box 16.4
Guidelines for deciding whether a DNA sequence change is pathogenic. Deletions of the whole gene, nonsense mutations and frameshifts are almost certain to destroy the gene function. Mutations that (more...)
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16.4Loss of function mutations
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16.4.1Many different changes to a gene can cause loss of function
Not surprisingly, there are many ways of reducing or abolishing the function of a gene product (Table 16.1 and Figure 16.2). Some of these have been discussed in Section 9.4. The hemoglobinopathies (Box 16.5) exemplify many of these mechanisms especially well. In fact, globin mutations can be found to illustrate virtually every process described in this book. Readers with a particular interest in these diseases are recommended to consult one of the excellent reviews of this topic (e.g. Weatherall et al., 1995; see further reading).
Table 16.1
Eleven ways to reduce or abolish the function of a gene product (see Table 9.5 for a classification of mutations by their nature and location in the gene).
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Figure 16.2
Deletions of α-globin genes in α-thalassemia. Normal copies of chromosome 16 carry two active α-globin genes and an inactive pseudogene arranged in tandem. Repeat blocks (labeled (more...)
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When considering the likely result of a mutation on the gene product, some points to bear in mind are as follows:
Small deletions and insertions have a much more drastic effect on the gene product if they introduce a frameshift (that is, if they add or remove a number of nucleotides that is not an exact multiple of 3). Deletions in the dystrophin (DMD) gene provide striking examples (Figure 16.3). Almost regardless of the size of the deletion, frameshifting deletions produce the lethal Duchenne muscular dystrophy, in which no dystrophin is produced, whereas nonframeshifting mutations cause the milder Becker form, in which dystrophin is present but abnormal.
Nonsense mutations often trigger mRNA instability (see Section 9.4.6 and Hentze and Kulozik, 1999) rather than cause production of a truncated protein.
Base substitutions in coding sequences may be pathogenic because of an effect on splicing or because they destroy an embedded signal (a nuclear localization signal, for example), rather than because of their effect on the amino acids encoded. Activation of a cryptic splice site is particularly hard to predict - see Section 9.4.5 and Berget (1995).
Figure 16.3
Deletions in the central part of the dystrophin gene associated with Becker and Duchenne muscular dystrophy. Numbered boxes represent exons 4355. Deletions that generate frameshifts cause
Molecular pathology - Human Molecular Genetics - NCBI Bookshelf
