The Human Nuclear Genome - Essay Example

The human nuclear genome consists of 24 widely different chromosomal DNA molecules The human nuclear genome consists of 24 widely different chromosomal DNA molecules The size of human nuclear genome is 3100 Mb and it is widely spread on 24 X shaped aggregated molecules of DNA which are called as Chromosomes. These aggregated DNA molecules i.e. chromosomes further consists of two major types of proteins i.e. Histone and non-histone proteins. Out of these 24 Chromosomes, the first 22 chromosomes are called autosomes as they carry genes for general characteristics and the rest of the 2 chromosomes are called as Sex Chromosomes. These are called so because they carry genes for the determination of the sex of the newborn and they are also of two types i.e. X & Y chromosomes where X is for female and Y for Male. The chromosomes are mainly classified either on the basis of their banding or on the basis of the position of the centromere i.e. the central point of every chromosome. The basic constitutive component of these DNA molecules, euchromatin and heterochromatin is the main factor on which the DNA on all these chromosomes differ from each other. Still, on some of the chromosomes e.g. 1, 9 and 16 show heterochromatin in their centromere region where as Chromosome Y is also considered to contain more heterochromatin. (T. STRACHAN and A. READ, 2004,p19) Mitochondrial genes There usually are two strands in mitochondrial genome i.e. H and L strand. The H strand is supposed to encode more genes i.e. 28 out of 37 where as the L strand encodes the remaining number of genes. The mitochondrial genome is not very much similar to the nuclear genome as it does not contain any introns as well as it is very much compact and tightly packed as compared to the loosely packed nuclear genome. Most of the coding sequences are separated by one or two of the non coding bases while overlapping is observed in only some of the coding sequences. In some genes post transcription introduction of of UAA codon i.e. termination codon is necessary since they lack their own termination codons. (T. STRACHAN and A. READ, 2004,p19) Figure 9.3 The organization of the human mitochondrial genome. The H strand is transcribed from two closely spaced promoter regions fl anking the tRNAPhe gene (grouped here as PH); the L strand is transcribed from the PL promoter in the opposite direction. In both cases, large primary transcripts are produced and cleaved to generate RNAs for individual genes. All genes lack introns and are closely clustered. The symbols for protein-coding genes are shown here without the prefi x MT- that signifi es mitochondrial gene. The genes that encode subunits 6 and 8 of the ATP synthase (ATP6 and ATP8) are partly overlapping. Other polypeptide-encoding genes specify seven NADH dehydrogenase subunits (ND4L and ND1–ND6), three cytochrome c oxidase subunits (CO1–CO3), and cytochrome b (CYB). tRNA genes are represented with the name of the amino acid that they bind. The short 7S DNA strand is produced by repeat synthesis of a short segment of the H strand (see Figure 9.2). COMPARISON OF NUCLEAR AND MITOCHONDRIAL GENOME (T. STRACHAN and A. READ, 2004,p21) Single gene disorders These mainly include autosomal, X linked and Y linked. These disorders are called as Mendelian disorders as they follow the mendelian order of inheritance. Some other disorders such as Non mendelians ones are also included in the list. (AKUL MEHTA.2012) Both the sperm and the egg contribute to the formation nuclear genome in the zygote whereas the mitochondrial is supposed to take the sequence from the egg only.(T. STRACHAN and A. READ, 2004) Autosomal dominant These disorders are usually common in the offsprings who have one of the two parents with the abnormality. These disorders are mainly caused by mutation in one of the genes only with the 50 % possibility of getting the mutated gene. The disease usually develops later in the life or it would even not appear at all as the penetrance of these disorders is considered to be very low and the inheritance is very low too. E.g. Huntingtons disease, Neurofibromatosis 1, Marfan Syndrome Autosomal recessive These disorders usually occur in offsprings who have both the parents affected with the disorder or the disease. As compared to dominant disorders, they require mutation in both the copies of the genes. There is only a chance of 25% transfer of the mutated gene and the development of the disease in a child who’s both the parents are affected. E.g. Cystic fibrosis, Sickle cell anemia, Tay‐Sachs disease, Spinal muscular atrophy. X‐linked dominant They are present in a very small number of populations as their inheritance rate is very low. The main cause of these disorders is the mutation in the genes that are present on the X chromosome. Males getting the only X chromosome from the female are supposed to get these disorders more commonly as compared to the female population who are considered to be carriers. The inheritance is as follows: all the daughters of an affected father will get the disease whereas the sons will have no affect as they will receive Y chromosome as compared to the abnormal X chromosome which is transferred in case of daughters. In case of an affected mother, the sons will get the disease whereas daughters have 50-50 chance of getting affected. Some X‐linked dominant conditions, like Aicardi Syndrome, are mortal to boys, consequently only girls have them. E.g Hypophosphatemia, Aicardi Syndrome. X‐linked recessive These disorders are very much similar to the Dominant disorders as they are also caused due to a mutation in genes on the X chromosome. The only difference is their order of inheritance. A woman carrying the affected gene will have the same 50-50 chance of transferring the affected/mutated gene both to her sons or her daughters. Here again males are supposed to be more oftenly affected E.g Hemophilia A, Duchenne muscular dystrophy, Color blindness, Muscular dystrophy, Androgenetic alopecia and  also includes G‐6‐PD (Glucose‐6‐phosphate dehydrogenase) deficiency. Y‐linked These are present only in the males as the Y chromosome which carries the mutated gene is transferred to male offsprings only and females have no chance of getting the disorders. E.g.Male Infertility Mitochondrial (maternal inheritance) These disorders are transferred by females/mother only. As explained earlier, mitochondrial genome gets DNA from the egg only so only females can pass these traits. They are mainly transferred by mutated genes present in the mitochondrial genome (AKUL MEHTA.2012) Autosomal dominant inheritance model: (any parent can be dominant “D”, and normal gene is labeled as “n”, here just for the example, the father is dominant i.e. affected, it is possible to create a pattern with the possibility of mother behaving as a dominant too) Autosomal recessive inheritance pattern: (recessive gene is “d” and normal gene is “N”) X‐linked dominant inheritance pattern: (either parent can be the one who is affected) (AKUL MEHTA.2012) PROSPECTS FOR NUCLEAR AND MITOCHONDRIAL GENOME MUTATION TREATMENT USING GENETIC STRATEGIES Nuclear genome mutation 1) Marfan syndrome (MFS) (autosomal dominant disorder) The birth of an affected child can be avoided by counselling the couple when the mutation is detected by the testing of the FBN1 gene. This test has to be done in the prenatal phase (LOEYS, L. NUYTINCK, P. VAN ACKER, S. WALRAEDT, M. BONDUELLE, K. SERMON, B. HAMEL, A. SANCHEZ, L. MESSIAEN and A. DE PAEPE. 2002) 2) Sickle‐cell disease (autosomal recessive) Highly specific and lineage restricted gene silencing can be carried out by coregulating transgene expression and RNA in hemetopoitic stem cells. (SELDA SAMAKOGLU, LESZE LISOWSKI, TULIN BUDAK – ALPDOGAN, YELENA USACHENO, SANTINA ACUTO, ROSALBA DI MARZO, AURELIO MAGGIO, PING ZHU, JOHN F TISDALE, ISABELLE RIVIERE et al.. 2006) Gene-transfer vectors that are used to treat hereditary disorders (TIMOTHY P. O’CONNOR and RONALD G. CRYSTAL.2006) Mitochondrial genome mutation The 37 genes enclosed in the mitochondria (around 0.1 per cent of our genes in total) are thought to be restricted in administering the dealings of the mitochondria. Thirteen of the genes in mitochondria are protein-encoding genes which are associated with the generation of cellular energy. The remaining 24 genes (22 tRNAs and 2 rRNAs) in the mitochondria support the 13 protein genes to manufacture proteins.( HUMAN MOLECULAR GENETICS 3, 2004,p19) Mitochondrial disorders can occur from two basis: mutations of DNA in mitochondria, or mutations of DNA in nuclear genes. Mitochondrial DNA has a mutation speed of approximately ten times as compared to nuclear DNA. This is attributed to the fact that there are so many more mitochondria per cell are there in contrast to the two pairs of nDNA genes per cell. Secondly, the system of replication of mitochondria is inclined to inaccuracies due to less efficient systems for DNA repair.( T. STRACHAN and A. READ, 2004,p21) Mitochondrial disorders Mitochondrial disorders have been described as “…a cruel class of inherited disease, because serious, even life threatening conditions are coupled with great unpredictability about how future children will be affected.” (HUI LI and ZE-HUI HONG. 2012). They progress with the span of time and on occasions can lead to disabilities. There is a possibility that they can become a cause for miscarriage and stillbirth, in few cases babies can even die because of it. In children and young people it can also lead to death. If the onset is not in young age it can cause severe symptoms in adults. Diagnosis is difficult as the symptoms and the age and extent at which they appear differ extensively between patients. In few situations affect is only on one organ by mitochondrial disorders – like blindness or heart failure – or many parts of the body are at sake on the same time. There is a possibility that mothers never themselves experience symptoms but they can pass on mitochondrial disorders to their children. (HUI LI and ZE-HUI HONG. 2012). The organs of the body that need high amount of Oxygen are more at stake as this compromised supply of oxygen damages them the most. Therefore severe symptoms are experienced in the brain, heart, kidneys and major muscle groups. Mitochondrial disorder’s symptoms when caused by mitochondrial DNA and nuclear DNA will include: deprived growth, disturbed muscle coordination, weakness of muscle, intolerance to exercise, neuromuscular system will have diseases and malfunctions, puzzlement, perplexity and loss of memory, problems related to neurology, seizures, autism, delay is development, disabled learning, loss of hearing and/or vision, heart, liver, kidney or respiratory disease (leading to heart and/or liver failure), disorders of gastrointestinal system, diabetes, thyroid and/or adrenal dysfunction, lactic acidosis, and problems of immune system which may lead to augmented susceptibility to infections. (T. STRACHAN and A. READ, 2004,p21) As varieties of mitochondrial diseases are there so the exact determination of prevalence is troublesome. Secondly, to determine whether the mitochondrial disorder is caused by hitch in nuclear genes or mitochondrial genes is also difficult. An estimated figure for the total frequency of populace affected by mitochondrial DNA disorders and mitochondrial disorders originated from nuclear genes is 1 in 5,000,30. In a research on a cohort of patients drew attention to the following issues: a) Out of all children with mitochondrial disease 50-60 per cent do not have a genetic identification and 40 per cent of them have a widespread defect of mtDNA expression. If the genetic reason in these patients is identified it will show the way to specific genetic advice and the smooth the progress of the process of suggestion of new approaches to cure. (XIAOYU ZHU, XUERUI PENG, MIN-XIN GUAN, and QINGFENG YAN. 2009) In respect of mitochondrial disorders and of their unfortunate outcomes for a few of the children and young people affected, procedures have been hunted that could avoid the communication of mutated mtDNA this includes pronuclear transfer (PNT) and maternal spindle transfer (MST). It would consequent in children born free from inherited mitochondrial disorders caused by mutated mtDNA. PNT and MST could be recommended with IVF to women who yearn to use their own eggs to have a baby but who risk passing on a disease-causing level of mutated mitochondria to their children. (T. STRACHAN and A. READ, 2004,p23) Current options for preventing the transmission of inherited mitochondrial DNA disorders Women who have incidence of living with mitochondrial disorders themselves, or who have affected family members may not fancy risking having a child who could be similarly affected. For this group, the only way of avoiding having an affected child would be to desire not to use their own eggs to conceive. Therefore, women in this place may, for example, choose to look for egg donation, surrogacy with egg donation, or to apply for adoption. (DR TIM LEWENS. 2012) Current options for minimising the risk of transmission of inherited mitochondrial DNA disorders At present, heteroplasmic women who chose to use their own eggs to have a baby have a number of alternatives vacant to them in order to minimise their peril of passing on mitochondrial DNA disorders to their infant. This group of women may, for example, be proposed PGD (Preimplantation genetic diagnosis) as a component of IVF cycle preceding to pregnancy, and/or prenatal diagnosis (PND) once a pregnancy is ascertained. Neither performance would be recommended to homoplasmic women due to the unavoidability that the embryo or fetus would also be homoplasmic for the mutation. (T. STRACHAN and A. READ, 2004,p25) (MICHAEL LYNCH. 2010) (VERELLEN-DUMOULIN. 2012).  Nuclear gene mutations causing oxidative phosphorylation defects Non-oxidative phosphorylation nuclear-encoded mitochondrial proteins and disease, by protein Bibliography T. STRACHAN and A. READ (2004). Human Molecular Genetics 3. New York: Garland Publishing. p19-25. DR TIM LEWENS (2012). Discussion event: Novel techniques for the prevention of mitochondrial DNA disorders: an ethical review. London: amazon.co.uk. p31-42. HUI LIand ZE-HUI HONG. (2012). Mitochondrial DNA mutations in human tumor cells (Review). Oncology Letters . 4, 868-872. AKUL MEHTA. (2012). Genetic disorders and hereditary disorders. Available: http://pharmaxchange.info/notes/clinical/genetic_disorders.pdf. Last accessed 25th Nov 2012. VERELLEN-DUMOULIN. (2012). The Treatment of Genetic Disease. Available: http://www.beshg.be/2011_course_slides/2011_Verellen_Dumoulin.pdf. Last accessed 25th Nov 2012. LOEYS, L. NUYTINCK, P. VAN ACKER, S. WALRAEDT, M. BONDUELLE, K. SERMON, B. HAMEL, A. SANCHEZ, L. MESSIAEN and A. DE PAEPE . (2002). Strategies for prenatal and preimplantation genetic diagnosis in Marfan syndrome (MFS). Prenat Diagn . 22, 22-28. SELDA SAMAKOGLU, LESZE LISOWSKI, TULIN BUDAK – ALPDOGAN, YELENA USACHENO, SANTINA ACUTO, ROSALBA DI MARZO, AURELIO MAGGIO, PING ZHU, JOHN F TISDALE, ISABELLE RIVIERE ET AL. . (2006). A genetic strategy to treat sickle cell anemia by coregulating globin transgene expression and RNA interference. Nature Biotechnology . 24 (1), 89-94. TIMOTHY P. O’CONNOR and RONALD G. CRYSTAL . (2006). Genetic medicines: treatment strategies for hereditary disorders. Genetics. 7, 261-295. XIAOYU ZHU, XUERUI PENG, MIN-XIN GUAN, and QINGFENG YAN. (2009). Pathogenic mutations of nuclear genes associated with mitochondrial disorders. Acta Biochim Biophys Sin ., 179-187. MICHAEL LYNCH. (2010). Evolution of the mutation rate. Trends in Genetics. 26 (8), 345-352. Read More