Medical Diagnostics

The ability to sequence DNA has led to a major revolution in the way we diagnose diseases. Since the discovery that mutations in DNA are the causes of genetic disorders, diagnosing has become more and more advanced. Decoding the DNA would allow us to see any differences in the sequence, and if those mutations cause any adverse effects. With information from a DNA sequence, diagnosing would be precise and accurate, and it may even save your life. 

The early years 

First Genetic Disease linked to a DNA mutation

1949 Sickle-cell disease was discovered to occur as a result of an abnormality in the hemoglobin, by Linus Pauling. It was published in their paper “Sickle Cell Anemia, a Molecular Disease”.  Pauling, Linus  (1949 -11-01) Science 110 (2865): 543–548. This was the first time that a genetic disorder was linked to a mutation of a specific protein, hemoglobin. This was an important discovery in molecular biology, because it proved that a disease was related to a genetic abnormality. 

1957 Vernon Ingram actually identifies the exact mutation that causes the sickle-cell anemia. The point mutation causes a single amino acid substitution. This is the first characterization of the molecular concenquences of mutation on proteins. (68)

Figure at right: The mutation in the DNA sequence which causes sickle cell anemia (68) 
Diseased Blood Cells Figure (67) 

The Genetics Code, Translation of mRNA to Protein 

1966  Three scientists, Marshall Nirenberg, Robert Holley, and Har Gobind Khorana crack the code of DNA. They discover the concept that codons, consisting of three nucleotides, code for one of the 20 amino acids used to make up proteins.  "RNA Codewords and Protein Synthesis" (with Philip Leder) in Science, 1964.

The genetic code consists of 64 triplets of nucleotides. These triplets are called codons. With three exceptions, each codon encodes for one of the 20 amino acids used in the synthesis of proteins. That produces some redundancy in the code: most of the amino acids are encoded by more than one codon. 



Chromosomes played a huge part in medical diagnostics. In 1956, the normal number of human chromosomes is discover to be 46, XX female, and XY male. That same year down syndrome was identified as a chromosome 21 trisomy (x3 copies of chromosome 21)  by Dr. Jerome Lejeune 
Click on the picture for a link to the National Association of Down Syndrome (NADS), to learn more about down syndrome. 

Figure (71) 
A normal humans chromosomes vs. one with down syndrome. Notice the three chromosomes of 21.

DNA SEquencing's direct impact 

Single Gene Defects 

As genetic sequencing technologies evolved, the amount of diseases for which genetic testing became available expanded. This had a major impact on medical  diagnostics and genetic counseling of individuals with genetic disorders. 

1983 Breakthrough discovery of the approximate location of Huntington's Disease gene

1989 The discovery of the Cystic Fibrosis gene  — the single most important discovery in CF research — was the result of an international research collaboration. (69)

1992 Huntington Disease gene (HTT) identified, making it the first autosomal disease gene identified using linkage analysis. Over 50 investigators from nine different institutions, working together as The Huntington's Disease Collaborative Research Group, isolated an expandable, unstable DNA segment on chromosome 4 that can vary from generation to generation and even among affected siblings. (74) The genetic mutation is a multiple repeat phenomenon (Triplet Repeat Disorder) similar to the defects responsible for Fragile-X syndrome, Myotonic Dystrophy, and Spino-Bulbar Muscular Atrophy.

1992 the  FMR1 gene that causes Fragile X was identified. Almost 50 years later after Martin and Bell investigated a family with multiple male members who had mental retardation and  were able to link the cognitive disorders to an unidentified mode of X-linked inheritance. 

Microarrays and their role in diagnosing

Microarrays revolutionized medicine by being able to pinpoint a very specific disease or the susceptibility to it. Having previously only detecting structural variations of around 100 base pairs, today this technology uses high-resolution arrays to accurately detect structural variations  at resolutions of fewer than 25 base pairs.

Doctors use microarray panel testing for multiple genes for specific disorders: OtoChip for Sensorineural Hearing Loss, Cardiomyopathy Panel for hereditary heart muscle diseases; and Cancer Array which tests for multiple genes for various cancers.  

DNA sequencing changing the way we think 

In 1941 it was thought that one gene would code for one protein.  George Beadle and Edward Tatum proved through their experiments with bread mold that one gene directs the synthesis of one enzyme. (72) Beadle and Tatum's concept of "one gene, one enzyme" won a noble prize and for the longest time was accepted as the truth. When DNA sequencing came around, that idea was proved false. We now know this is inaccurate, because humans produce more than 100,000 proteins and there are less the 25,000 genes. Some genes must be capable of producing more than one protein. Alternative splicing is the explanation for how this might be achieved. 

A schematic representation of alternative splicing (73) 


How DNA sequencing saves lives 

For the first time ever, DNA sequencing technologies saved the life of a child in 2010. A  young boy named Nicholas Volker had an extreme form of inflammatory bowel disease that was threatening his life. (75) His doctors were unable to diagnose what was causing it, so they decided to have his DNA sequenced. This was a chance for them to take because DNA sequencing had never been proven to lead to treatment. The mutation they found was something no one expected, but it led them to find the necessary treatment. One bone marrow transplant later, and Nicholas is now 6 years old, doing very well. This was an extremely significant moment in the history of DNA sequencing, because before it had generally been thought of as a research tool. Now it can also be used as a diagnostics tool also. 

Nicholas Volker, age 6, was the first child to be diagnosed and treated by DNA sequencing. Figure (75) 

One of the other cases involves two brothers, ages 22 and 24, with profound intellectual disability and autism.  The actual cause of their condition was unknown for over 20 years.  Ambry Genetics’ Clinical Diagnostic Exome test revealed that their condition is a form of autosomal recessive intellectual disability precisely caused by mutations in the ELP2 gene.  Because this gene was only recently discovered and routine testing was not available, this diagnosis would have been impossible to identify without exome sequencing.

In 2011, a gene mutation was identified through Whole Genome Sequencing in twins suffering from an unknown neurologic condition; detection of the mutation led to a correct clinical diagnosis, and  the molecular diagnosis offered proper treatment.

The 1000 Genomes Project- an international collaboration to produce an extensive public catalog of human genetic variation.

According to the 1000 Genomes Project, (76) recent improvements in sequencing technology ("next-gen" sequencing platforms) have sharply reduced the cost of sequencing. The 1000 Genomes Project is the first project to sequence the genomes of a large number of people, to provide a comprehensive resource on human genetic variation. The goal of the 1000 Genomes Project is to find most genetic variants that have frequencies of at least 1% in the populations studied. (76) 

Data from the 1000 Genomes Project will be available to the  scientific community worldwide by a freely accessible public database. Click on the image above to learn more. 


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