Investigating Juunan Syndrome: Unveiling Gene and Mutation - Essay Sample

Introduction

This essay aims to outline how the researcher will identify and experimentally validate the gene and mutation in Juunan Syndrome (JS). JS, a rare monogenic disorder has been diagnosed in seven families, families A, B, C, D, E, F, and G as shown in figure1. The main early symptoms of the disorder include the tendency to become severely hypoglycaemic after fasting for eight hours, coupled with glucose intolerance, which means showing higher and sustained circulating glucose levels after feeding. Circulating insulin levels in Godber's syndrome patients are low in response to feeding glucose. All affected individuals are unable to sustain vigorous exercise for more than two minutes. They show an unusual fat distribution for their BMI. However, there is no particular tendency to obesity. Among the middle-aged people, heart failure is the main manifestation coupled with hypoglycaemia, hypoglycaemic collapse. and hyperglycemia. The paper discusses the whole gene and whole-exome sequencing approach, and the filtration steps to determine the gene and mutation in the gene. The customer filtration steps to be followed in the analysis of the data from the WES sample of the consanguineous population and non-consanguineous population. The filtration method will then be used to narrow down the number of candidate variants that required classification

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How would you avoid replicating work that has already been done by others?

Each study is unique, and the research design is determined by the subjects under study, the gene, and the resources available. To avoid replicating the work, the researcher must design a study to add novel ideas to the existing literature taking into consideration the study specific factors such as study goals, and materials available.

Family Study

Briefly explain the essential ethical principles in working with human subjects that must be applied in your study.

For studies involving human subjects, there are ethical considerations such as informed consent and approval from an ethical committee. In this study, the researchers acquired ethical approval from IRB to conduct the study. The researcher sampled a group of 2 subjects from the university hospital. The subjected who met the inclusion criteria are recruited into the study with the permission of their next of kin for those who are not competent to contract. The hospital permission is also sought. The patient educated about the purpose of the study, the potential risks of participating in the study and how the data collected during the study will be used. After the education, the few who agreed to participate in the study were allowed to sign the informed consent form agreeing to participate in the study. After recruiting the subjects not, the study, clinical assessment is done, followed by taking the family history. Once the subjects are diagnosed to be suffering from the genetic disease, the geneticists will be visited.

Which other professionals, apart from laboratory geneticists would be involved This project will be carried out by a group of researchers including a laboratory geneticist, bio information professional, a clinician, a geneticist as well as an ethics specialist. The ethics professional appointed by the IRB will oversee the project to ensure that the right of the subjects is not violated. The geneticist will study the pattern of gene inheritance, mutation, education, and inactivation as well as the role played by the genes in the health of the subjects As well as the disease affecting them. The bioinformatician is the professional who will be in charge of developing the systems for gathering data. He will construct the survey methodology, design the clinical trial, and program the status tidal model that will be used to study the patterns. The bioinformatician will also develop the database for compiling the information from the project, such as gene expression.

The researchers will first conduct a clinical assessment and investigate family history. The clinician and the geneticists will investigate the main causes of the disease. In this case, the cause is genetic, and the geneticists will study the family history to determine the pattern of disease I inheritance in the lineage of the subject. The family pedigree is as shown in the future 1.

In family A, two grandchildren (third generation boy 8, and girl 10) are affected while in family, the father and one son are affected. In family C the father and one daughter (I/1, and II/2) affected while family D, the father, and their only daughter are affected. The daughter of the families C, and D are all affected since the fathers have heart failure. In family E, the father and one son are affected while in family F, the father and two sons are affected. Finally, in family G, the father and the mother are both affected, and the daughter of the father and the stepmother are affected. In this case, the father is a carrier. In family B, C, D, E, F, G's condition is hereditary (genetic) as the first and second generation are affected and not spontaneous. In the first family, the inheritance is autosomal dominant, but in the family C to G, the inheritance is autosomal recessive (1). Blood samples will be drawn from A (III8 and III 10), family B II1, family CII2, family D I1, and II1, family E I1, and II2. The sample will also be taken from F I1, and II2, and family G3, II1.

From which individuals would you choose to take samples (for all subsequent work)?

In this case, blood samples will be extracted from the affected family members and sent to the laboratory technologist, after which the next-gen sequencing will be used to identify any pathogenic mutation. The target region of the normal allele will be PCR-amplified then sequenced following the interpretation of the results (2). The 13 family members selected for the study will be used for the study to approve the affected gene due to the similarity of the mutative gene. Over 85% of mutation related diseases are coded in protein (6).

What general approach (in 2019) would you take to identify the mutated gene? Why is your approach likely to work?

Next-Generation Sequencing Approach to identify gene mutations is used. The high throughput sequencing method will be used as opposed to sanger sequencing, which is expensive and laborious. The high throughput method will be effective because the experiment will involve sequencing the entire genome. The candidate gene approach will be used to study the overall genetic architecture of any complex traits (4). In this case, the researcher will rely on the biology of the phenotype being investigated

Why the same technique will not be applied to the same techniques to samples from all the family members

The same technique will not be applied to the samples from all the family members because the mode of mutation inheritance varies among the family members. In case the researchers fail to identify any mutation in the 13 affected family members, the researcher will conduct a whole-genome sequencing for the second generation and third family members who are affected (5).

Findings That Might Immediately Provide the Most Compelling Evidence Identified

The outcomes from the third-generation families or grandchildren will be useful in predicting the results of other family members displaying a similar phenotype. The syndrome that displays a similar or overlapping set of disease signs as GS includes cystic fibrosis (CF) and type 2 diabetes. Failure to identify the mutation in the affected families will lead to the conclusion of the study as non-genetic. Otherwise, the second stage of the study is initiated if a mutation is identified.

What genetic changes might you find in some sporadic cases whose phenotype resembles JS?

The genetic changes such as microdeletion of the key region and the microduplication of the region may also cause the same syndromes. In some case, reciprocal syndromes do manifest.

How many genetic variants are you likely to find in these experiments?

The whole-genome sequence method would, therefore, be effective in identifying the substitution mutation within the exons that lead to monogenic disorders. The WES will identify over 60,000 structural variants or genomes that the bioinformatician will filter based on the reported variant and the mode of inheritance (8).

How will you select those that might be interesting? Outline the scale of the problem of screening and the logical steps that can be used to select appropriate gene variants.

The researcher will exclude the non-assistive variants but include the causative variants with the frequency of the alleles and the possible disease. This will be based on the disease-causing mutations to predict the mendelian disease-causing non-consanguineous single nucleotide variant in the exome sequencing studies. It is important to note that minor allele frequency (MAF) filtering approach will be effective in determining the pathogenic mutation (9). The researcher may also combine multiple functional prediction methods to improve the accuracy of the production. The logit model may be combined with other methods to determine an unbiased probability of the variant causing disease

Who would assess individuals for JS? What is the most likely mode of inheritance of JS in these families?

The filtering approach has been the most effective approach for reducing the candidate gene variants. In this case, the subjects have rare recessive diseases, which means that compound heterozygosity of the pathogenic mutation is the probable inheritance model as the parents are non-consanguineous (7). The compound filter will be suited for this project and more useful for the bioinformatician and non-bioinformaticians. The power of the compound heterozygous mutation filtering will be analyzed using the background of healthy individuals. There are over 30 genes that have the potential compound heterozygotes in an exome.

The number of genes can be reduced by each additional member of the family pedigrees in the analysis. Compound filtering will, therefore, be efficient in reducing the number of candidate mutations that focuses on identifying the recessive disease gene in the non-consanguineous families (10). In the first family (Family A), a quarter (25%) of individual III8 genes and individual III10 genes are similar as they share some of the variance the two copies of the genes that is why the fileting approach will begin with the study of family A. with studying the gene because of the phylogenetic similarity and correlations between the metabolite and transcript abundance profiles.

After the candidate gene filtration, the genes are stratified into their function, and third impacts estimated. The genes are categorized into specific phenotypes to help in identifying the key candidate for the disease. The variants within the chosen candidate genes will be evaluated quantitatively to determine if they affect the protein functions (11). The rate importance correlation is the most successfully used method for predicting the functionality of the noncoding DNA sequences. Experimental validation relies on the conservation properties of the sequences. The highly conserved sequences have a higher estimate of affecting protein function (12). PolyPhen-2 can be used to predict the functional effects of human Un-SNAPS. This way, the pathogenicity or non-pathogenicity of the impact can be determined. Those candidate genes that are not categorized are not included in the estimation. The mutation co-segregated for three generations in family A with the by being asymptomatic. The exon duplication is likely not clinically relevant. The exon represents a true gene mutation that leads to functional haploinsufficiency without...