The Experts below are selected from a list of 15858 Experts worldwide ranked by ideXlab platform
Robert I. Richards - One of the best experts on this subject based on the ideXlab platform.
-
Ciba Foundation Symposium 197 - Variation in the Human Genome - Unusual inheritance patterns due to Dynamic Mutation in fragile X syndrome.
Ciba Foundation symposium, 2007Co-Authors: Grant R. Sutherland, Robert I. RichardsAbstract:Fragile X syndrome is the most common form of familial mental retardation and is one of the world's most common genetic diseases. The inheritance patterns of the disease have many unusual features. It is an X-linked disorder yet there are asymptomatic carrier males. The disease is expressed only when the gene is inherited from the mother. The risk of a carrier woman having a child with the syndrome depends upon her position in the pedigree (the Sherman paradox) and her own intellectual status. The discovery that the disease is due to Dynamic Mutation (which is a multistage process) that inactivates FMR1 has provided an explanation for the unusual inheritance patterns. The finding of linkage disequilibrium between the fragile X Mutations and closely linked DNA markers (haplotype) has required a reinterpretation of this phenomenon for Dynamic Mutations. Only a small number of normal alleles at the fragile X locus have long stretches of perfect repeat (2% with more than 24 copies) and these form a reservoir of alleles that can increase in length into the preMutation range. Dynamic Mutation is, so far, an exclusively human phenomenon, but this is probably because it has yet to be discovered in other species. Unusual inheritance patterns are a hallmark of Dynamic Mutation diseases.
-
Dynamic Mutations: a decade of unstable expanded repeats in human genetic disease
Human molecular genetics, 2001Co-Authors: Robert I. RichardsAbstract:The term 'Dynamic Mutation' was introduced to distinguish the unique properties of expanding, unstable DNA repeat sequences from other forms of Mutation. The past decade has seen Dynamic Mutations uncovered as the molecular basis for a growing number of human genetic diseases and for all of the characterized 'rare' chromosomal fragile sites. The common properties of the repeats in different diseases and fragile sites have given insight into this unique form of DNA instability. While the Dynamic Mutation mechanism explains some unusual genetic characteristics, unexpected findings have raised new questions and challenged some assumptions about the pathways that lead from Mutation to disease. This review will address the current understanding of the molecular mechanisms involved in the Dynamic Mutation process and elaborate on the pathogenic pathways that lead from expanded repeats to the diseases with which they are associated.
-
FRA10B Structure Reveals Common Elements in Repeat Expansion and Chromosomal Fragile Site Genesis
Molecular cell, 1998Co-Authors: Duncan R. Hewett, Marie Mangelsdorf, Helen J. Eyre, Lynne Hobson, Elizabeth Baker, Oliva Handt, Grant R. Sutherland, Simone Schuffenhauer, Jen-i Mao, Robert I. RichardsAbstract:Abstract A common mechanism for chromosomal fragile site genesis is not yet apparent. Folate-sensitive fragile sites are expanded p(CCG)n repeats that arise from longer normal alleles. Distamycin A or bromodeoxyuridine-inducible fragile site FRA16B is an expanded AT-rich ∼33 bp repeat; however, the relationship between normal and fragile site alleles is not known. Here, we report that bromodeoxyuridine-inducible, distamycin A–insensitive fragile site FRA10B is composed of expanded ∼42 bp repeats. Differences in repeat motif length or composition between different FRA10B families indicate multiple independent expansion events. Some FRA10B alleles comprise a mixture of different expanded repeat motifs. FRA10B fragile site and long normal alleles share flanking polymorphisms. Somatic and intergenerational FRA10B repeat instability analogous to that found in expanded trinucleotide repeats supports Dynamic Mutation as a common mechanism for repeat expansion.
-
Dynamic Mutation: possible mechanisms and significance in human disease
Trends in biochemical sciences, 1997Co-Authors: Robert I. Richards, Grant R. SutherlandAbstract:Increases in repeat-DNA copy number are the molecular basis of a growing list of human genetic diseases, including fragile X syndrome, myotonic dystrophy, Huntington disease and a form of epilepsy. Repeat-DNA sequences undergo a unique process of Dynamic Mutation, the common properties of which probably reflect common molecular events. This form of Mutation is no longer restricted to trinucleotide repeats, because repeats of different length have been found to undergo expansion.
-
REVIEWS Dynamic Mutation: possible mechanisms and si ificance in human disease
1997Co-Authors: Robert I. Richards, Grant R. SutherlandAbstract:Increases in repeat-DNA copy number are the molecular basis of a growing list of human genetic diseases, including fragile X syndrome, myotonic dystro- phy, Huntington disease and a form of epilepsy. Repeat-DNA sequences undergo a unique process of Dynamic Mutation, the common properties of which probably reflect common molecular events. This form of Mutation is no longer restricted to trinucleotide repeats, because repeats of different length have been found to undergo expansion= Dynamic Mff[ATIOI~, ' is a term that has been introduced to distinguish differ- ences in the number of copies of DNA re- peat sequences from other types of mu- tationL Repeat-sequence motifs involved in d~mamic Mutation range in length from 3 bp (trinucleotides) up to 33 bp ~ig. 1). Such repeats occur normally within the genome and can either be perfect repeats, that is, with no variation in the base composition of the repeat motif, or imperfect repeats, where there are some copies that vary from the canonical repeat motif. Many repeats are composites of perfect and intperfect units. When located within or near tran- scribed sequences the expanded repeat can have an effect on either the gene transcrlpt or gene product, which might manifest in disease. At each Dynamic- Mutation locus there is a normal range of copy numbers above which the repeat becomes unstable, that is, copy number can be increased to a point where the repeat manifests in a disease and/or a fragile site (Table I). (Fragile sites are identified as non-staining gaps on chromo- somes that are inducible by certain con- ditions of tissue culture.)
Grant R. Sutherland - One of the best experts on this subject based on the ideXlab platform.
-
Simple tandem DNA repeats and human genetic disease (fragile X syndrome/trinucleotide repeats/chromosomal fragile sites/spinocerebellar ataxias/myotonic dystrophy)
2016Co-Authors: Grant R. SutherlandAbstract:The human genome con- tains many repeated DNA sequences that vary in complexity of repeating unit from a single nucleotide to a whole gene. The repeat sequences can be widely dispersed or in simple tandem arrays. Arrays of up to 5 or 6 nt are known as simple tandem repeats, and these are widely dispersed and highly polymorphic. Members of one group of the simple tandem repeats, the trinucleotide repeats, can undergo an in- crease in copy number by a process of Dynamic Mutation. Dynamic Mutations of the CCG trinucleotide give rise to one group of fragile sites on human chromo- somes, the rare folate-sensitive group. One member of this group, the fragile X (FRAXA) is responsible for the most com- mon familial form of mental retardation. Another member of the group FRAXE is responsible for a rarer mild form of men- tal retardation. Similar Mutations of AGC repeats give rise to a number of neurological disorders. The expanded re- peats are unstable between generations and somatically. The intergenerational instability gives rise to unusual patterns of inheritance-particularly anticipation, the increasing severity and/or earlier age of onset of the disorder in successive generations. Dynamic Mutations have been found only in the human species, and possible reasons for this are considered. The mechanism of Dynamic Mutation is discussed, and a number of observations of simple tandem repeat Mutation that could assist in understanding this phe- nomenon are commented on.
-
Ciba Foundation Symposium 197 - Variation in the Human Genome - Unusual inheritance patterns due to Dynamic Mutation in fragile X syndrome.
Ciba Foundation symposium, 2007Co-Authors: Grant R. Sutherland, Robert I. RichardsAbstract:Fragile X syndrome is the most common form of familial mental retardation and is one of the world's most common genetic diseases. The inheritance patterns of the disease have many unusual features. It is an X-linked disorder yet there are asymptomatic carrier males. The disease is expressed only when the gene is inherited from the mother. The risk of a carrier woman having a child with the syndrome depends upon her position in the pedigree (the Sherman paradox) and her own intellectual status. The discovery that the disease is due to Dynamic Mutation (which is a multistage process) that inactivates FMR1 has provided an explanation for the unusual inheritance patterns. The finding of linkage disequilibrium between the fragile X Mutations and closely linked DNA markers (haplotype) has required a reinterpretation of this phenomenon for Dynamic Mutations. Only a small number of normal alleles at the fragile X locus have long stretches of perfect repeat (2% with more than 24 copies) and these form a reservoir of alleles that can increase in length into the preMutation range. Dynamic Mutation is, so far, an exclusively human phenomenon, but this is probably because it has yet to be discovered in other species. Unusual inheritance patterns are a hallmark of Dynamic Mutation diseases.
-
FRA10B Structure Reveals Common Elements in Repeat Expansion and Chromosomal Fragile Site Genesis
Molecular cell, 1998Co-Authors: Duncan R. Hewett, Marie Mangelsdorf, Helen J. Eyre, Lynne Hobson, Elizabeth Baker, Oliva Handt, Grant R. Sutherland, Simone Schuffenhauer, Jen-i Mao, Robert I. RichardsAbstract:Abstract A common mechanism for chromosomal fragile site genesis is not yet apparent. Folate-sensitive fragile sites are expanded p(CCG)n repeats that arise from longer normal alleles. Distamycin A or bromodeoxyuridine-inducible fragile site FRA16B is an expanded AT-rich ∼33 bp repeat; however, the relationship between normal and fragile site alleles is not known. Here, we report that bromodeoxyuridine-inducible, distamycin A–insensitive fragile site FRA10B is composed of expanded ∼42 bp repeats. Differences in repeat motif length or composition between different FRA10B families indicate multiple independent expansion events. Some FRA10B alleles comprise a mixture of different expanded repeat motifs. FRA10B fragile site and long normal alleles share flanking polymorphisms. Somatic and intergenerational FRA10B repeat instability analogous to that found in expanded trinucleotide repeats supports Dynamic Mutation as a common mechanism for repeat expansion.
-
Dynamic Mutation: possible mechanisms and significance in human disease
Trends in biochemical sciences, 1997Co-Authors: Robert I. Richards, Grant R. SutherlandAbstract:Increases in repeat-DNA copy number are the molecular basis of a growing list of human genetic diseases, including fragile X syndrome, myotonic dystrophy, Huntington disease and a form of epilepsy. Repeat-DNA sequences undergo a unique process of Dynamic Mutation, the common properties of which probably reflect common molecular events. This form of Mutation is no longer restricted to trinucleotide repeats, because repeats of different length have been found to undergo expansion.
-
REVIEWS Dynamic Mutation: possible mechanisms and si ificance in human disease
1997Co-Authors: Robert I. Richards, Grant R. SutherlandAbstract:Increases in repeat-DNA copy number are the molecular basis of a growing list of human genetic diseases, including fragile X syndrome, myotonic dystro- phy, Huntington disease and a form of epilepsy. Repeat-DNA sequences undergo a unique process of Dynamic Mutation, the common properties of which probably reflect common molecular events. This form of Mutation is no longer restricted to trinucleotide repeats, because repeats of different length have been found to undergo expansion= Dynamic Mff[ATIOI~, ' is a term that has been introduced to distinguish differ- ences in the number of copies of DNA re- peat sequences from other types of mu- tationL Repeat-sequence motifs involved in d~mamic Mutation range in length from 3 bp (trinucleotides) up to 33 bp ~ig. 1). Such repeats occur normally within the genome and can either be perfect repeats, that is, with no variation in the base composition of the repeat motif, or imperfect repeats, where there are some copies that vary from the canonical repeat motif. Many repeats are composites of perfect and intperfect units. When located within or near tran- scribed sequences the expanded repeat can have an effect on either the gene transcrlpt or gene product, which might manifest in disease. At each Dynamic- Mutation locus there is a normal range of copy numbers above which the repeat becomes unstable, that is, copy number can be increased to a point where the repeat manifests in a disease and/or a fragile site (Table I). (Fragile sites are identified as non-staining gaps on chromo- somes that are inducible by certain con- ditions of tissue culture.)
Márcia Mattos Gonçalves Pimentel - One of the best experts on this subject based on the ideXlab platform.
-
Dynamic Mutation and human disorders: the spinocerebellar ataxias (review).
International Journal of Molecular Medicine, 2004Co-Authors: Marcelo Aguiar Costa Lima, Márcia Mattos Gonçalves PimentelAbstract:: A completely new Mutational event associated with human diseases - the Dynamic Mutation - was discovered in the last decade. The molecular mechanism underlying Dynamic Mutation involves the expansion and intergenerational instability of a tandem-arrayed nucleotide sequence that acquire a pathological size, despite its polymorphic occurrence in normal individuals. To date, at least fourteen neurological disorders are associated with this phenomenon, including Huntington's disease (HD), dentatorubral and palidoluysian atrophy (DRPLA), spinobulbar and muscular atrophy (SBMA), myotonic dystrophy (DM), fragile X syndrome, FRAXE mental retardation and spinocerebellar ataxias (SCA) types 1-3, 6-8, 12 and 17. The spinocerebellar ataxias comprise a heterogeneous group of severe neurodegenerative-late onset disorders characterized by loss of balance and coordination. Most of the spinocerebellar ataxias exhibit an autosomal dominant pattern of inheritance and are promoted by the intergenerational expansion of a trinucleotide repeat (CAG)n inside the coding region of the respective gene. The expanded segment is translated into an abnormal polyglutamine tract in the protein, leading to the formation of nuclear aggregates that have been considered the basis of the pathogenesis in most of SCA types. One striking characteristic of these diseases is that the gene is expressed throughout the brain and also in other tissues but no pathological consequences are observed, despite the specific cellular degeneration. The characterization of the Mutational event has led to the development of specific and sensitive molecular tests for direct DNA analysis, which allow confirmation of clinical diagnostic and an adequate therapeutic indication as well as genetic counseling.
-
Dynamic Mutation and human disorders: the spinocerebellar ataxias (review).
International journal of molecular medicine, 2004Co-Authors: Marcelo Aguiar Costa Lima, Márcia Mattos Gonçalves PimentelAbstract:A completely new Mutational event associated with human diseases - the Dynamic Mutation - was discovered in the last decade. The molecular mechanism underlying Dynamic Mutation involves the expansion and intergenerational instability of a tandem-arrayed nucleotide sequence that acquire a pathological size, despite its polymorphic occurrence in normal individuals. To date, at least fourteen neurological disorders are associated with this phenomenon, including Huntington's disease (HD), dentatorubral and palidoluysian atrophy (DRPLA), spinobulbar and muscular atrophy (SBMA), myotonic dystrophy (DM), fragile X syndrome, FRAXE mental retardation and spinocerebellar ataxias (SCA) types 1-3, 6-8, 12 and 17. The spinocerebellar ataxias comprise a heterogeneous group of severe neurodegenerative-late onset disorders characterized by loss of balance and coordination. Most of the spinocerebellar ataxias exhibit an autosomal dominant pattern of inheritance and are promoted by the intergenerational expansion of a trinucleotide repeat (CAG)n inside the coding region of the respective gene. The expanded segment is translated into an abnormal polyglutamine tract in the protein, leading to the formation of nuclear aggregates that have been considered the basis of the pathogenesis in most of SCA types. One striking characteristic of these diseases is that the gene is expressed throughout the brain and also in other tissues but no pathological consequences are observed, despite the specific cellular degeneration. The characterization of the Mutational event has led to the development of specific and sensitive molecular tests for direct DNA analysis, which allow confirmation of clinical diagnostic and an adequate therapeutic indication as well as genetic counseling.
Erkki Makinen - One of the best experts on this subject based on the ideXlab platform.
-
genetic synthesis of software architecture
Simulated Evolution and Learning, 2008Co-Authors: Outi Raiha, Kai Koskimies, Erkki MakinenAbstract:Design of software architecture is intellectually one of the most demanding tasks in software engineering. This paper proposes an approach to automatically synthesize software architecture using genetic algorithms. The technique applies architectural patterns for Mutations and quality metrics for evaluation, producing a proposal for a software architecture on the basis of functional requirements given as a graph of functional responsibilities. Two quality attributes, modifiability and efficiency, are considered. The behavior of the genetic synthesis process is analyzed with respect to quality improve ment speed, the effect of Dynamic Mutation, and the effect of quality attribute prioritization. Our tests show that it is possible to genetically synthesize architectures that achieve a high fitness value early on.
-
SEAL - Genetic Synthesis of Software Architecture
Lecture Notes in Computer Science, 2008Co-Authors: Outi Raiha, Kai Koskimies, Erkki MakinenAbstract:Design of software architecture is intellectually one of the most demanding tasks in software engineering. This paper proposes an approach to automatically synthesize software architecture using genetic algorithms. The technique applies architectural patterns for Mutations and quality metrics for evaluation, producing a proposal for a software architecture on the basis of functional requirements given as a graph of functional responsibilities. Two quality attributes, modifiability and efficiency, are considered. The behavior of the genetic synthesis process is analyzed with respect to quality improve ment speed, the effect of Dynamic Mutation, and the effect of quality attribute prioritization. Our tests show that it is possible to genetically synthesize architectures that achieve a high fitness value early on.
Eberhard Gill - One of the best experts on this subject based on the ideXlab platform.
-
swarm satellite mission scheduling planning using hybrid Dynamic Mutation genetic algorithm
Acta Astronautica, 2017Co-Authors: Zixuan Zheng, Jian Guo, Eberhard GillAbstract:Abstract Space missions have traditionally been controlled by operators from a mission control center. Given the increasing number of satellites for some space missions, generating a command list for multiple satellites can be time-consuming and inefficient. Developing multi-satellite, onboard mission scheduling & planning techniques is, therefore, a key research field for future space mission operations. In this paper, an improved Genetic Algorithm (GA) using a new Mutation strategy is proposed as a mission scheduling algorithm. This new Mutation strategy, called Hybrid Dynamic Mutation (HDM), combines the advantages of both Dynamic Mutation strategy and adaptive Mutation strategy, overcoming weaknesses such as early convergence and long computing time, which helps standard GA to be more efficient and accurate in dealing with complex missions. HDM-GA shows excellent performance in solving both unconstrained and constrained test functions. The experiments of using HDM-GA to simulate a multi-satellite, mission scheduling problem demonstrates that both the computation time and success rate mission requirements can be met. The results of a comparative test between HDM-GA and three other Mutation strategies also show that HDM has outstanding performance in terms of speed and reliability.
-
Swarm satellite mission scheduling & planning using Hybrid Dynamic Mutation Genetic Algorithm
Acta Astronautica, 2017Co-Authors: Zixuan Zheng, Jian Guo, Eberhard GillAbstract:Abstract Space missions have traditionally been controlled by operators from a mission control center. Given the increasing number of satellites for some space missions, generating a command list for multiple satellites can be time-consuming and inefficient. Developing multi-satellite, onboard mission scheduling & planning techniques is, therefore, a key research field for future space mission operations. In this paper, an improved Genetic Algorithm (GA) using a new Mutation strategy is proposed as a mission scheduling algorithm. This new Mutation strategy, called Hybrid Dynamic Mutation (HDM), combines the advantages of both Dynamic Mutation strategy and adaptive Mutation strategy, overcoming weaknesses such as early convergence and long computing time, which helps standard GA to be more efficient and accurate in dealing with complex missions. HDM-GA shows excellent performance in solving both unconstrained and constrained test functions. The experiments of using HDM-GA to simulate a multi-satellite, mission scheduling problem demonstrates that both the computation time and success rate mission requirements can be met. The results of a comparative test between HDM-GA and three other Mutation strategies also show that HDM has outstanding performance in terms of speed and reliability.
