Single gene disorder Alexander endler
Single gene disorder Alexander Endler
Number of genes in eucaryotic cells (E coli) 4.6Mb 4, 288 genes cerevisiae 13.5Mb 6,034 genes D. melanogaster 165Mb 12.000 genes C. elegans 97 Mb 19,099 genes H. Sapiens 3, 300 Mb 40,000 genes 28,000-34000 genes 25.947 genes Retroviruses 10 Kb about 10 genes
28,000−34,000 genes 25,947 genes ( E. coli ) 4.6 Mb 4,288 genes S. cerevisiae 13.5 Mb 6,034 genes D. melanogaster 165 Mb 12,000 genes C. elegans 97 Mb 19,099 genes H. Sapiens 3,300 Mb 40,000 genes Number of genes in Eucaryotic cells Retroviruses 10 Kb about 10 genes
Gene abundance number of different m-RNA's molecules/cell Mouse liver cytoplasmic 12000 700 300 11500 15 Chicken oviduct 100000 4000 12500
Gene abundance number of different m-RNA’s molecules/cell Mouse liver cytoplasmic 9 12000 700 300 11500 15 Chicken oviduct 1 100000 7 4000 12500 5
Over 5 of human babies born have recognizable malformations some of them mild some of them severe. Some birth defects are produced by mutant genes or chromosomal abnormalities, while others are produced by environmental factors Genetic defects: malformations often appear as syndromes Use of animal models to identify genetic, cellular and molecular basis of human syndromes Environmental defects: disruptions Responsible agents: teratogens-chemicals, viruses, radiation
Over 5 % of human babies born have recognizable malformations, some of them mild some of them severe. Some birth defects are produced by mutant genes or chromosomal abnormalities, while others are produced by environmental factors. Genetic defects: malformations – often appear as syndromes Use of animal models to identify genetic, cellular and molecular basis of human syndromes. Environmental defects: disruptions Responsible agents: teratogens – chemicals, viruses, radiation
In medicine, the term syndrome refers to the association of several clinically recognizable features, signs, symptoms, phenomena or characteristics that often occur together so that the presence of one feature alerts the physician to the presence of the others Pleiotropy The production of several effects by one gene is called pleiotropy (A)Mosaic pleiotropy (B)Relational pleiotropy Gene a Gene A 60-( igure 21.7 Mosaic and relational pleiotropy.(A)In mosaic pleiotropy, a gene is independently expressed in several tissues. Each tissue needs the gene product and develops abnormally in its absence. (B) In relational pleiotropy, a gene product is needed by only one particular tissue. However, a second tissue needs a signal from the first tissue in order to develop properly. If the first tissue develops abnormally, the signal is not given, so the second tissue develops abnormally as wel
Pleiotropy In medicine, the term syndrome refers to the association of several clinically recognizable features, signs , symptoms, phenomena or characteristics that often occur together, so that the presence of one feature alerts the physician to the presence of the others The production of several effects by one gene is called pleiotropy
Single gene disorder Mendelian traits caused by mutant alleles Exhibit obvious and charactetrisic pedigree pattern Autosomal versus sex-linked Dominant versus recessive(versus co dominant ( Black and white=grey Autosomal Dominant Inheritance Autosomal Recessive Inheritance (One Parent Affected) (Both Parents Carriers Affected Father Mother Carrier Father Carrier Mother D d dd Dd dd dd Rr R Affected Normal Affected Normal Son DaughterDaughter Son Normal Carrier Affected (25%)(25%)(25%)(25%) (25%) (50%) (25%) Occurrence of one disease rare( less than 1/500) But many different kinds of genetic disorder( 13000-20000)
Single gene disorder Mendelian traits caused by mutant alleles Exhibit obvious and charactetrisic pedigree pattern Autosomal versus sex-linked Dominant versus recessive (versus co dominant (Black and white=grey) Occurrence of one disease rare ( less than 1/500) But many different kinds of genetic disorder ( 13000-20000 )
AUG GCC TGc AAA CGC TGG normal met ala cys lys arg trp Single nucleotide polymorphisms (SNP)are the most common type genetic variation. A SNP is AUG GCT TGC AAA CGC TGG silent single base pair mutation at a met ala cys lys arg trp specific locus SNPs are often found to be the etiology of many human diseases and are AUG GCC TGA AAA CGC TGG becoming of particular interest in nonsense met ala pharmacogenetics AUG GCC GGC AAA CGC TGG missense met ala arg lys arg trp AUG GC. TGC AAA CGC TGG frameshift (deletion-1) met ala glu asn ala AUG GCC C TGC CGC TGG frameshift insertion +1) met ala leu ghn thrleu insertion +1, AUG GCC C TGC AAA -GC TGG met ala leu gIn thr p
Single nucleotide polymorphisms (SNP) are the most common type of genetic variation. A SNP is a single base pair mutation at a specific locus. SNPs are often found to be the etiology of many human diseases and are becoming of particular interest in pharmacogenetics
How to detect the gene responsible for a single gene disorder
How to detect the gene responsible for a single gene disorder ?
Principle of linkage( pedigree)analysis Gives a hint about the position of a genetic disorder associated with a different phenotype The top diagram shows paternal (blue)and maternal(red) chromosomes aligned in a germ cell, a cell that gives rise to eggs or sperm. Three DNA sequences are shown, labelled A, B and C. The capital letters represent the patemal alleles and the lower case letters represent the maternal alleles. The middle panel shows the physical process of recombination, which involves crossing over of DNA strands between the paired chromosomes. The bottom panel shows what happens when the crossover is resolved. The maternal and paternal alleles are mixed(recombined)and these mixed chromosomes are passed to the sperms or eggs A is the disease gene and B and c are genetic markers, recombination is likely to occur much more frequently between A and c than it is between A and B. this allows the disease gene to be mapped relative to the markers b and c
The top diagram shows paternal (blue) and maternal (red) chromosomes aligned in a germ cell, a cell that gives rise to eggs or sperm. Three DNA sequences are shown, labelled A, B and C. The capital letters represent the paternal alleles and the lower case letters represent the maternal alleles. The middle panel shows the physical process of recombination, which involves crossing over of DNA strands between the paired chromosomes. The bottom panel shows what happens when the crossover is resolved. The maternal and paternal alleles are mixed (recombined) and these mixed chromosomes are passed to the sperms or eggs. If A is the disease gene and B and C are genetic markers, recombination is likely to occur much more frequently between A and C than it is between A and B. This allows the disease gene to be mapped relative to the markers B and C Principle of linkage ( pedigree) analysis. Gives a hint about the position of a genetic disorder associated with a different phenotype
Aniridia Present in people without Figure 21.5 aniridia; absent in people Positional cloning of the human PAX6 gene with aniridia netics, to be located in a certain region of the po A)Principles of positional cloning a gene is termined, by pedigree analysis and somatic cell ge- genome--in this case, band 13 of the short arm of chromosome 11. Overlapping cloned sequences that span this region are compared between pec ple who have the condition of interest and people who do not. In this case, certain people with aniridia lacked a particular region of DNA. This region was sequenced and found to contain the human homologue of the Pax6 gene known in nice. Comparisons of the sequences found in controls with those found in people with aniridia indicated that the people with aniridia either Human chromosome 11 DNA segment lacked a copy of this gene or had mutations in one of their copies.( B)In situ hybridization of anan tisense RNA probe with a human fetal eye shows PAX6 expression(yellow)in the retina, presum Overlapping PAX6 gene: tive iris, and surface ectoderm. from Ton et al cloned sequences compare between 1991; photograph courtesy of G E. Saunders. patients and Positional Cloning Aniridia gene, if absent people develop no or little iris in their eyes (B)Make probe for in situ hybridization
Positional Cloning Aniridia gene, if absent people develop no or little iris in their eyes. Aniridia
