Download Introduction of genomics and more Lecture notes Genomics in PDF only on Docsity!
Complex diseases:
caused mainly by obesity type 2 diabetes/ parkinson’s diseases and neurological diseases. How does the environment function the gene by causing the molecular basis of the environment that influences the gene such as gene expression and protein modification( histone) , such as methylation and acetylation, where non-coding RNA has a functional role such as gene expression. T urner syndrome( 45, X) ● affects 1 in 50,000 of the live female births, caused by the near absence of the X chromosome of the many features as well as congenital heart disease, lack of characteristics. Individuals with Turner syndrome ● Caused by the near or complete absence of the X chromosome ● Effects 1/50, 000 of live female births, caused by the near absence of the X chromosome as well as heart disease and lack of characteristics ● Lymphedema ● Heart disease ● Kidney disease ● Infertility CIS regulatory sequences (regions of non-coding DNA) ● Found in promoters, enhancers, silencers and insulators ● Regulates the transcription of the nearby genes- Thalassaemia, haemophilia and atherosclerosis trans cis regulatory sequences
- Modifies the expression of the distant genes that combine the target sequences.
- Key is to control and recruit the transcription factor. Chromatin looping Stretches the genomic sequences that lie on the same chromosomes that are closer to the physical proximity of the sequence. Important as they intervene in the sequences that regulate the gene expression through the transcriptional activation.
Encode Project : ● Identifies the regulatory regions and contribute the maps of RNA ● The function of the encode identifies the non-coding regions mapping of the transcriptional factor. Is the genome junk? ● 80% of genomes are linked to the biochemical function. ● Junk DNA is the controversial concept as it states that organisms carry the genomes dna that has a positive impact on fitness. Regulome - Part of the ENCODE ● Annotates the human genome( non-coding RNAS and pseudogenes) ● Structure of the chromatin- encodes the transcriptional factor by binding and building up the proteins. DNAse I hypersensitive site mapping plays an important role in expressing the genes such as DNA repair genes. DNAse I hypersensitive are ergonomic regions that are accessible for enzymatic cleavage.
● 22 pairs of the autosome XY males and XX females which use the mitotic metaphase chromosome. ● The different methods that have been used to identify the methods of the different chromosomes such as Giemsa staining. A type of method that is used to identify the methods for different chromosomes (Giemsa) staining also known as banding shown in the ideogram. Karyotype complete sets of chromosomes are characteristics of the individual, with each 46 structures replicated chromosomes after the resolution.
Aneuploidy - change in chromosomes due to the addition of the chromosomes and subtraction of the pair of the homologs ( three copies that causes Down Syndrome). It is affected due to the set of the chromosomes that arises due to the nondisjunction of the pairs such as deletions, duplications, insertions and translocations.
Multiplex-ligation amplification ● quantitative PCR method replaces the applications of FISH, pured DNA are identified under the FISH method. ● Changes in chromosomes that are found during the loss/ gain of the aneuploidy that gains the sets of those chromosomes. Monoploids ● set of chromosomes such as loss of the entire set of the chromosomes. ● Polyploidy is rare between 1 in 10,000 that do not survive long enough. 1% of the polyploidy with 1% of the human conception that mostly die. ● They can occur in several different ways such as failure of the reduction meiosis diploid gametes. Aneuploidy 46 chromosomes (23 pairs of the chromosome deviation) /nondisjunction of the chromosomes at meiosis) with the abnormal chromosomes counted as 46 (consists of 23 pairs)/ nondisjunction. Trisomy 12 (Patau syndrome) / trisomy 18( Edwards syndrome) and trisomy 21 ( Down Syndrome). Sex chromosomes aneuploidy- to remember important. Presence of an extra chromosome does not compromise embryonic survival. Complications of Mendelian Inheritance Single gene inheritance such as autosomal inheritance. Single-gene ( mendelian inheritance) caused by error of the single genes of different patterns. The inheritance of the single gene is monitored from one generation to the other. ● Inheritance of the single gene shows the monitoring of the generation to other of the family trees which gives you the reason to study the patterns of inheritance. Single-gene- mendelia: Characterises the chromosomal single-gene ( less than 16,000) caused by the error of the chromosomal single-gene. Terminology to remember position of the locus shows that site of the chromosome where the gene is located. Alleles-alternate forms of the same gene. Heterozygote - different alleles at the same locus. Homozygous-identical alleles affect the same locus. Homozygous -identical alleles at the same locus. Genotype - individuals genetic constitution.
Phenotype- observed effect of the action of gene/genes. Dominant and recessive- effects of the gene rather than the gene itself. Autosomal dominant inheritance ● a way that a genetic trait can be passed down from parent to child. ● The child that has a parent of the mutated gene has a 50% higher chance of inheriting the mutated gene. ● Men and women are equally likely to have the mutations where they can inherit them. Homozygosity autosomal dominant trait- which has more severe heterozygotes. What are the 4 types of phenotypes? Aa, ao, bb, bo, ab, oo. The absence of antigen has shown to be associated with the formation of the antibodies that are against the antigen. Alpha 1 antitrypsin is a protein that is produced by the liver to the lungs that protects the lungs from the inflammation caused by inhaling tobacco/smoke. Causes mutations in SERPINA ● encodes the alpha-1 antitrypsin-most prevalent mendelian disorders, caused by the environmental factors such as exposure to tobacco smoke, chemicals dust and that may also cause the condition worse. ● The mutations that can be seen in SERPINA1- can lead to shortage of the alpha- antitrypsin as an abnormal form of the protein that cannot be controlled as a neutrophil elastase. Aut osomal codominant inheritance ● where each allele contributes to the phenotype- these three alleles of the serpina can produce the normal amounts, s- moderate amounts, z- little amounts. ● Disease phenotype can be used according to a mix of alleles, such as parents with or without the faculty of the AAT genes. Genes such as SERPINA1 gene are found on the chromosome 14q32.13. HLA- also known as human leukocyte antigen , has three classes where the genes are involved in the immune cell function. The six gene locus are: HLA-A, HLA-B, HLA-F, HLA-F ● All highly morphic why? Presence of two or more variants occurring in many different populations and individuals.
Complications of Mendelian inheritance Autosomal inheritance-single gene inheritance: pedigree patterns of the complications./ Single gene mendelian inheritance- single caused by error, different patterns of the inheritance by depending on the location of the gene, whether the disorder is caused by mutation in one gene or both copies: dominant/recessive. What are the diseases linked to autosomal inheritance and the most common one in the UK? Familial hypercholesterolemia, hypertrophic cardiomyopathy, adult polycystic kidney disease. X- linked dominant inheritance- way that the genetic trait condition can be passed down from one parent to the child through the mutations( changes) in the gene on the single X chromosome. Y-linked inheritance has few genes mostly involved in the determination of the spermatogenesis. Pseudoautosomal x and y chromosomes are transmitted by mothers that are equally children of the both sexes and fathers of the predominant one. Maternal inheritance is a small circular chromosome with 13 subunits of the oxidative phosphorylation. The maternal mitochondrial inheritance comes from the ovum that is eternally inherited, soon after the fertilisation. Cells : 1000s copies of mtDNA, same sequence; homoplasmy. Mutations accumulate in the proportion heteroplasmy that causes the proportion of the mitochondria( heteroplasmy- causes problems in the mitochondria, affects tissues such as muscle and nervous tissue. Maternal inheritance - primary conditions that can vary among family. Inheritance of the heteroplasmy- variable and unpredictable. The ATP ( adenosine triphosphate) provides the power muscles of the contraction. Mendelian rules do not occur during epistasis , multiple allele, anticipation, germline mosaicism, imprinting and uniparental disomy. Atypical mendelian inheritance - imprinting of alleles occurs during the small number of genes on chromosome 6,7,11,14 and 15. A or A-like that are complex on chromosome 16 which has 3 pseudogenes and one unknown gene function. The haemoglobin genes are the y chains that are encoded in the foetal life. The B-globin chain begins after birth and normal adults after birth. Normal haemoglobin( HbA + HbA2) states the haemoglobin mutation of 5% of the world’ s population. e. Most of the inheritance genes are inherited such as the type of the mutation a/b globulin confirmation/expression. Patients that have B-haemoglobinopathies have a lower rate of
death such as dying before the age of 5. This also goes back to the structure of the chains of the haemoglobin ( a and two none ) The globin genes are expressed initially after the yolk sac and the oliver in the embryonic life and the spleen. ● Different ages of the onset of the various forms of the haemoglobinopathies. Some abnormalities include: instability of the tetramer, formation of the abnormal 3-dimensional structure. ● Prevention of the ferric iron reduction and the normal haem binding. Abnormal hemoglobins that result in mutations of the change sequences, mispairs and crossover between the two genes. ● Variants recognise the variants of the type point mutations of the instability of the formation for the dimensional structure. ● Abnormalities of the structure depend on recognising point mutations such as instability of the tetramer and formation of the abnormal 3-dimensional structure. Variants recognise the type of point mutations by having the instability of the formation of the dimensional structure. ● Abnormalities of the structure depends on recognising the point mutations such as tetramer and formation of abnormal 3-dimensional that further prevents the normal haem binding. ● Some of the disorders of the haemoglobin are: abnormalities of it like thalassaemia and inheritance disorder which is associated with the reduction of the globin chain. It is highly divided in two parts: A-thalassemia-caused by large deletion and B-thalassaemia-mutational heterogeneity ( point mutations, small deletions and insertions) Thalassaemias are the diseases that are caused by mutations in the haemoglobin chains that result in reduced expression. ● Mutations in haemoglobinopathies show the mutations that resulted in abnormal proteins during loss of functions and property. ● Mutations can interrupt the RNA/ the splicing of the RNA by altering the levels of the proteins. The alteration of the protein causes the disease in critical alterations. Some of those mutations are a result of expression where the haemoglobin can lead to SICKLE CELL ANAEMIA where the oxygen carries the normal designated state. Sickle-Cell disease is a common form of haemoglobinopathy that gives a prime example of the inherited disorder of heterozygous advantages , one of the most common forms of haemoglobinopathies that gives an example of the inherited disorder.
● It has been proven that low levels of carbon monoxide are released after the infection to protect against the development. For thalassemias, the blood disorder affects the production of the haemoglobin and the red blood cells. What are the treatments for hemoglobinopathies? ● Folic acid supplementation ● bone marrow transplantation ● stem-cell transplantation. There are different types of a-thalassaemia: ● a-globin chain synthesis(deletion/both globin genes). ● SB-thalassaemia - hereditary foetal haemoglobin ( HPFPH). Cooley’s anaemia: thalassaemia major ( B-thalassaemia) severe anaemia, that results in transfusion dependency. Thalassaemia intermedia (B+ thalassaemia) minor or thalassaemia trait also known as heterozygous carrier. B-Thalassaemia- carrier frequency observed in the mediterranean islands such as Cyprus and Rhodes. 3-10% of the frequency in the indian and south-east asia. Excessive levels of a -globin chains can be unstable and precipitate to the red cell precursors as well as treatment - the immunisation of the pneumococcal infection , regular prophylactic treatment of the penicillin, folic acid supplementation. Hydroxyurea and butyrate can lead to increase in foetal haemoglobin production. Thalassaemia: is also known as the sea water in blood. A thalassemia is the deficiency of the a-globin chain synthesis( deletion of the both globin gene) B-thalassaemia: persistence of the foetal haemoglobin (HPFH) : double heterozygote: both a- and b-thalassaemia. B thalassaemia/haemoglobin is depended on the transfusion B-Thalassaemia : Two types of disorders that don't make enough globulin,they are major and minor. Treatment for B-thalassemia and SCD -T (sickle cell trait) / inherited haematological disorder that is categorised by the decrease number or absence of the globin chains synthesis. ● The patients of high level production of the foetal haemoglobin (Hbf) can have a milder clinical course. ● The S-phase cell-cycle can trigger the increase in erythroid precursors that have HbF with a milder course. ● The S-phase can have an impact on increasing the precursors that has HbF, can decrease the blood leukocyte count, reduce the severity of the pain and the hospitalisation.
● BCL11A and SOX6 c ooperates the adult erythroid cells that represses the Y-globin gene expression. The gene therapy slows down the progression of the disease, by producing in adequate amounts, therefore there won’t be any infective viruses that can be produced by targeting the cells. Gene therapy vectors can be retroviruses, removes the three protein-coding gene as well as replaces the transfer of the gene, coinfects thehelper virus as a result of the integration of the transgene. The only difference of the retrovirus is that it cannot enter the nucleus of the nondividing cells and accommodate larger transgenes that can offer and control the target of the genes. The adenoviruses or adenoviruses can integrate at the specific human chromosome 19. The adenoviruses: lysis of the infected cells can be powerful due to immunogenicity. Non-viral vectors / injection of the naked plasmid DNA to the tissue muscle(18% of the trias) , electroporation, wrapping of the DNA -7.6% of the other polymers and others. What are the number of the trials- they can be over 1985 trials, concerned as regarding the potential dangers of the procedure. The targeted disease of the gene therapy can be addressed as cancer, cardiovascular disease and inherited monogenic disease. Two thirds of the trials , also non-viral approaches, can become much more common. Why are viral vectors the most popular? Because they are more effective due to the gene transfer modification of the specific cell type. SCID- severe combined immune deficiency : T cells are collected , stem cells of the bone marrow that have been collected that carry the correct human gene. The first BE/B0-thalassaemia major( transfusion of the patient has been treated by the globin lentiviral independent that also has the global amelioration of the thalassemia phenotype. Lentiviral vectors ● They are important therapy for B-haemoglobinopathies used for clinical genes .. ● These lentiviral vectors can disrupt the normal regulation of the development of the cell that proliferates. ● Lenti-vector inactivates the NON-VIRAL VECTOR that limits the risk of the genotoxicity by Lenti vector, limits the risk of the genotoxicity by inserting the mutagenesis and the transcriptional adjacent oncogenes of the patient.
it is the affinity of the haemoglobin for oxygen that thas the oxygen-binding protein called haemoglobin. Position cloning : identify the trait-associated gene technique that identifies the trait associated with the gene, linkage analysis and association mapping and bioinformatics are involved. Glucose homeostasis : Low glucose levels stimulate these into the bloodstream and that will help the liver of glucagon so they are stored glucose in the liver by glucagon. Diabetes is the commonest glucose metabolism, where 4.9 million cases in the uk are diagnosed with diabetes, so around a million are not diagnosed because they haven’t approached( hyperglycaemia),
Metabolism disorders: carbohydrate metabolism, amino acid, urea cycle , lipid metabolism, porphyrin metabolism, treatment. Biochemical features: hyperglycemia- high levels of glucose), glycosuria( abnormal presence of the sugar-especially glucose found in urine and then ketonuria( excessive concentration of the ketone bodies in the urine. ● There are two types of diabetes: diabetes type 1 - chronic childhood disease-results in lack of production, linkage to the pancreatic infection, type 2 formerly NIDDM (also known as dependent diabetes mellitus which is associated with obesity. ● Diabetes differs by ethnicity that can occur in all groups. They are highly polymorphic, lacking insulin. It causes its own cell to produce less production of insulin. Type 2 diabetes genes found an association of the studies with an increased susceptibility to the disease. ● Majority of the loci can influence the capacity of the beta-cells that increases the insulin resistance for the body weight. ● TCF7L2 is one of the most strongest candidates therefore it is associated with each risk of the small variant, it also improves on understanding the pathogenesis. Glycogen storage disease ● Is a rare condition that changes how the body use and stores and catalyses the glycogen ( form of the sugar) that causes the deficiency in enzymes. ● 1/100,000 glucose 6 phosphate , also marked as a muscle weakness. It is autosomal recessive , can lead to poor growth/ low treatment ● Treatment: frequency of the feeding during the day, infusion and glucose Diagnosis: age onset, clinical manifestation and the severity of the type. Suspected diagnosis by history, examination and detection of the glycogen. Prognosis and the treatment varies depending on the involvement of the supplementation of the cornflour and its hepatic forms Galactosemia ● also caused by the inherited deficiency in enzymes that convert galactose to glucose. Some of those important symptoms are hepatic, renal dysfunction, cataracts and premature ovarian failure.
Albinism: complete lack of pigment in the skin and hair together with photophobia, autosomal recessive. Sensitivity to the light and no pigment on the skin, hair and ti is autosomal recessive Homocystinuria ● cystathionine b-synthase (CBS) , characterised by the delay /intellectual disability. The gene is affected, symptoms that the individuals play such as b6 homocystinuria, ● Some forms are responsive in terms of the treatment protein. It is a protein restricted diet and individuals are given correlation for the beta supplementations. ● In adults there is also deposition of pigment in cartilage acid in the urine where in the phenylalanine pathway the deficiency of acid in urine. Alkaptonuria- historic distinction of the first conditions in the mendelian recessive, connective tissue that can cause higher amounts of arthritis. Maple Syrup Urine disorder - characterised by the odour of the urine from patients, mostly caused by drinking too much fenugreek tea. Biochemical defect:
Types of MSUD ( maple syrup urine disorder)
characterised by the symptoms: mental and physical retardation that feeds the problems, vomiting, seizures and coma. ● Types of MSUD: intermittent (mild) low signs of MSUD, intermediate (rare with 3-30% active enzyme and thiamine responsive improvement during the improvement of thiamine supplements. E3-deficient MSUD, rare additional deficient metabolic enzymes, ● BCKDH: has three catalytic sulphates, branched-chain alpha keto acid decarboxylase and the other activity that regulates the specific kinase. ● Some of the classical types of MSUD are caused by the deficiency of the bckdh subunit-78 bp deletion in the mRNA. ● Maple syrup urin e is caused by the mutation in the E1 alpha subunit gene that causes the mutation in the E1 type II phenotype causage of the mutation. ● E3 deficiency - rare presents the combined deficiency of the branched-chain alpha-keto acid dehydrogenase, pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complex.
Isovaleric acidemia autosomal recessive : caused by the deficiency enzyme, short for coenzyme dehydrogenase, caused by the deficiency of the enzyme metabolic due to dietary information, this prevents toxic metabolites from accumulation. Disorders of the urea cycle ● 1/20,000 to 1/80,000 leads to coma and the treatment is to reduce the circulation level of the ammonia. ● Lipid metabolism transport can have two types that can present in two forms: that can precipitate by energy crises or by coronary artery disease, cerebral vascular disorder. Glutaric acidemia type I ● autosomal recessive of the individual's gliosis and neuronal loss of the basal ganglia and the progressive movement of the disorder. ● 1 in 250, 000 births is the inborn error branched as chain amino acid leucine dehydrogenase. ● There are at least three aspects of the therapy: prevention of metabolic crisis, restriction of protein and medication of carnitine that can be used to reduce the level of ammonia.
Familial hypercholesterolaemia
autosomal dominant disorder, incidence 1/50, caused by the mutations in the gene that encodes the LDL receptor on the chromosome 19. Heterozygote and homozygote T, much more intense when it is homozygous. Heart failure, progressive and other neurological diseases. Treatment: statins. mal disorders- defective enzyme activity leads to accumulation of the substrate, stored in various organs and tissues. Tay Sachs Disease : Autosomal recessive/ no treatment. The treatment of the biochemical disorders: galactosemia( substrate restriction), enzyme inhibition. Results in an effective reading frame and alters the reading frame outcome. A screening test would be helpful. Diseases of porphyrins by reduced activity in one eight enzymes of both the pathways, they are carbon structures that build the haem molecule, these disorders have defect or reduced activity of the pathways of the haemoglobin. Autosomal dominant or recessive substances that are precipitated by drugs and progesterone can lead to certain accumulations. One of the best treatments is to stop taking the drug. Therefore all of the biochemical disorders that give the restrictions such as galactosemia, vegetable and fruits.
