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Overview

DNA

What is DNA?

Advancements in our understanding of the basic building blocks of life has led to an exponential increase in the widespread awareness of DNA… but how well do you really know DNA?

You probably know that differences in DNA directly determine the differences between you and I, between you and your pet or the microbes living inside you, and even between your plants you lovingly called Clara and Phyll.

DNA is a molecular code or template that when “read,” instructs cells of the body on what to make, how to make it, and how to behave.​ Information in the DNA code contains genes, which perform unique functions in your cells.

Genes and Variants

Within a species we all have the same genes but the exact code in them can be different. ​Differences of the same genes are called alleles.  Some you can see, such as eye color and hair color.

Sometimes alleles known as variants can lead to problems in your body that you can’t see. Those problems may affect your health, response to foods, and response to drugs.

Genes and Variants

Within a species we all have the same genes but the exact code in them can be different. ​Differences of the same genes are called alleles.  Some you can see, such as eye color and hair color.

Sometimes alleles known as variants can lead to problems in your body that you can’t see. Those problems may affect your health, response to foods, and response to drugs.

What is important about your genes?

Genetic testing looks for alleles or variants that may change the activity of your immune system and how your body uses food and drugs. These variants may impact lifestyle and change disease risk. ​

Genetic testing is useful in many areas of medicine and can change the medical care you or your family member receives to get you the best treatment possible.

Genome and Exome

What is the Genome and Exome?

When someone references a genome they are referring to the entire DNA code of a person, which includes genes and other DNA. All of your chromosomes from both parents are considered in this and it includes 3 billion nucleotides. If nucleotides were letters being read, it would be over 1000 copies of War and Peace in length.

While we have a lot of DNA code, not all of it encodes our genes. Only ~1-2 % of our genome is “coded” to make the genes that we are familiar with and these coded sequences are called the exome.

The exome captures much of the variants that we associate with diseases, which is why many scientists analyze the Whole Exome Sequence (WES) and not the Whole Genome Sequence (WGS). However, since improvements in technology have enabled more whole genomes to be sequenced, we are seeing diseases that associate with regions in the genome that are “intergenic” or between genes and coding areas. Chromosome structures and intergenic regions have important roles to play in the function of a healthy cell.  

Therefore, the genome comprises everything, the exome is a subset of “everything” and both are becoming increasingly valuable in health research and diagnostics. 

The exome captures much of the variants that we associate with diseases, which is why many scientists analyze the Whole Exome Sequence (WES) and not the Whole Genome Sequence (WGS). However, since improvements in technology have enabled more whole genomes to be sequenced, we are seeing diseases that associate with regions in the genome that are “intergenic” or between genes and coding areas. Chromosome structures and intergenic regions have important roles to play in the function of a healthy cell.  

Therefore, the genome comprises everything, the exome is a subset of “everything” and both are becoming increasingly valuable in health research and diagnostics. 

Next Generation Sequencing

The DNA code is represented by the first letter of the base of the nucleotide molecule in the sequence: A for adenine, T for thymine, C for cytosine, and G for guanine. A stretch of DNA is called an oligonucleotide and would be represented by these bases to make a “word”.  You can think of our chromosomes as very, very long words. 

As was mentioned earlier, we have differences in our codes to cause different alleles and variants in our bodies. Consider it to be a string of ATCGs  that are “spelled” differently with letter changes that change the letters in the word for different ones (A to T), delete letters, add letters, and copy and paste groups of letters to different parts of chromosome or onto another. The changes arose from mutations in the histories of our families and  were propagated by our ancestors until we were born. We are at least 50 % likely to have that change in our children too (if you and your partner are from the same population, there is a greater chance you share ancestral genes).

DNA codes are “read” by the laboratory technique known as sequencing that allows the scientists to identify each base in a sequence. The field of study started by being able to identify only short reads of one type of DNA sequence at a time (think of lots of copies of the same word ). It then progressed to be able to identify many words at a time. This is what is known as Massive Parallel Sequencing (MPS) or the more commonly known term: Next Generation Sequencing (NGS). 

NGS technology started with only selecting targeted parts of the genome to look at for determining if there is a genetic cause or contribution to a certain disease. Now, the technology has grown to allow sequencing of the whole exome and whole genome.

DNA codes are “read” by the laboratory technique known as sequencing that allows the scientists to identify each base in a sequence. The field of study started by being able to identify only short reads of one type of DNA sequence at a time (think of lots of copies of the same word ). It then progressed to be able to identify many words at a time. This is what is known as Massive Parallel Sequencing (MPS) or the more commonly known term: Next Generation Sequencing (NGS).

NGS technology started with only selecting targeted parts of the genome to look at for determining if there is a genetic cause or contribution to a certain disease. Now, the technology has grown to allow sequencing of the whole exome and whole genome.

Genome sequencing as a diagnostic test

There are over 6000 diseases known to be directly linked to the genetics of an individual. These diseases may be monogenic disorders (single gene change) causing cystic fibrosis, Huntington’s disease, sickle cell anemia, or they could be polygenic disorders (multiple genes changed) such as coronary heart disease, diabetes, cancers, or Alzheimer’s. There are also genes that are pleiotropic – in which a single gene can be responsible for the development of several different diseases.

At the start of this century, genomic sequencing for a single person cost millions of dollars, now only two decades into the century you can not only purchase personal genome sequencing, but also have it analyzed for a few thousand dollars. Currently, most referrals for genomic testing are those with multiple unexplained pathologies or with severe developmental problems, however this is rapidly changing. BioAro aims to build preventative healthcare infrastructure, which will build wellness and identify risks before they become pathological.

Genomic testing can reveal information about your risk for disease and inherited genes from your parents. Some may wish to not know about their risk for certain diseases, which is why we have ensured that you can customize your analysis. Regardless of your results, it is important to meet with a genetic counselor to discuss what they may mean for your life. Our AI and person powered analysis works tirelessly to provide accurate and rapid diagnostics that are easy to understand, however we know it is always better to have someone to talk to. Our genetic counselors on staff are ready to meet with you and review how you can leverage your genomic data to prevent disease and lead the best life you can.

Not everyone who gets their genome sequenced will have a positive result flagging something of concern, which does not mean you will not develop the analyzed disease, it simply means that you are at lower risk than others in the population. The development of disease is a result of not only your genetics, but also the environment you live in and how you live your life. For the same reason, a negative result does not preclude you from the possibility of developing a certain disease.

Analysis

Why is genomic analysis important?

Genomic data is vast and is of little meaning without processing and analysis to make sense of it. The data is large (3 billion base pairs for WGS) and humans are all different, so to understand what one person’s DNA sequence is indicating, it must be handled by a computer to give an output of value.

After sequencing, the next step is to analyze the output data from the sequencer. This analysis can be divided into two parts: Secondary analysis and tertiary analysis. The desired result from the combination of these steps is a report informing the patient of what their genomic makeup means with regards to disease association. 

The analysis that follows primary analysis (which is where the reads are produced during the sequencing process), is secondary analysis. This is the stage at which the produced reads, i.e. the nucleotides, are aligned to the set reference genome (see the human genome project (link)). This allows for the visualization of where differences, often referred to as variants, can be highlighted and listed in a Variant Calling Format, VCF.

Tertiary analysis is when the generated VCF is allocated clinical significance based on knowledge databases that aggregate literature and published findings within the medical field, globally. Based on the strength of evidence for a variant-disease association, a pathogenicity score/category is allocated to each variant. The number of variants found can often be too large (4-5 million) to report on and is also of little benefit to overall clinical reporting. Therefore, heavy filters are applied to exclude findings that are currently of little to no supporting evidence and that fall outside the specified metrics. This process results in a report stating found variants that are relevant to the phenotype of interest or purpose of the test, for the purpose of informing the patient and/or their healthcare provider of their likelihood of developing a condition or that their already existing condition may be due to the found varia.

Tertiary analysis is when the generated VCF is allocated clinical significance based on knowledge databases that aggregate literature and published findings within the medical field, globally. Based on the strength of evidence for a variant-disease association, a pathogenicity score/category is allocated to each variant. The number of variants found can often be too large (4-5 million) to report on and is also of little benefit to overall clinical reporting. Therefore, heavy filters are applied to exclude findings that are currently of little to no supporting evidence and that fall outside the specified metrics. This process results in a report stating found variants that are relevant to the phenotype of interest or purpose of the test, for the purpose of informing the patient and/or their healthcare provider of their likelihood of developing a condition or that their already existing condition may be due to the found varia.

Microbiome Education

What is microbiome?

Our microbiome is composed of communities of bacteria, archaea, viruses, protozoans and fungi. It has greater complexity as well as a higher number of genes than the human genome itself. This community of microbes has even been described as a supporting organ in the human body.

Microbes and our human cells live in a mutually beneficial symbiotic relationship. However, the microbiome is dynamic and susceptible to changes such as diet, use of antibiotics and changes in homeostasis of the human body. Such changes affect the symbiotic relationship that exists between our body and microbiota. Pathogenic or ‘bad’ microbes are typically unable to gain control or large numbers until there is a change in our microbiome for the worse, which makes the human body more susceptible to diseases.

What is microbiome?

Our microbiome, composed of communities of bacteria, archaea, viruses, protozoans and fungi, have greater complexity as well as higher number of genes than the human genome itself. This community of microbes is even described as a supporting organ in human body.

Microbes and our human cells live in a mutually beneficial, also called as symbiotic relationship. However, the microbiome is dynamic and susceptible to changes such as diet, use of antibiotics and changed homeostatic state of human body. Such changes affect the symbiotic relationship that exist between our body and microbiota. This situation is used by pathogenic microbes, who were kept in check by our microbiota. This could then lead to our human body being more susceptible to diseases.

Where is the microbiome?

The majority of these microbes live in our gut with the second largest group being in our mouth. Microbial communities also reside on our skin and even in our genital tracts. All microbiome communities have the ability to affect our health, our partner’s health and even our future children’s health. The microbes in our gut, referred to as the gut microbiome, can be sampled using our feces ie. poop. The oral and skin microbiome can be sampled using a swab. Similarly, the vaginal microbiome in women can be self-collected using a swab and can be analyzed to understand their contribution to our health.

How does the microbiome affect us?

The first exposure to microorganisms for a human is in the birth canal during vaginal delivery. Most microbes that the infant is exposed to in the early days of life solely come from the mother through milk and contact through skin. As the infant grows, environmental exposures and diet changes can lead to the development of their own unique microbiome, which is very instrumental in training a child’s immune cells and eventually dictates many facets of adult human health.

Microbes also have a broader affect on our health, contributing to our nutrition by producing metabolites, nutrients, and vitamins. They also affect metabolic functions by influencing our fat storage, they can protect our body against pathogens and even help in the education of our immune system. They have also been shown to affect our physiological functions directly and indirectly by influencing brain function and human behaviour, making it an indispensable organ of our body.

However, pathogenic microbes can displace beneficial microbes over time, changing metabolic processes that could result in an abnormal immune response against our body. Hence, even autoimmune diseases such as diabetes, rheumatoid arthritis, muscular dystrophy, multiple sclerosis, and fibromyalgia have been associated with dysfunction in the microbiome. Inheritance of autoimmune diseases is described less by human DNA inheritance and more by inheritance of a familial microbiome.

Healthy Microbiome, Healthy You – Advantages to having your microbiome sequenced

Gut Microbiome

Microbiomes have been implicated in many health conditions, but the microbiome in our gut has the most influence on our health. Gut microbiome affects our gut health, brain function through gut-brain axis [2], heart health [3], even health of our lungs [4] and our skin [5]. In certain gastrointestinal diseases such as irritable bowel syndrome, inflammatory bowel disease, Crohn’s disease and ulcerative colitis, one might benefit from a combination of WGS with gut microbiome characterization. As described previously, gut microbiome is associated with autoimmune and metabolic diseases like obesity and diabetes. The gut-brain axis is also increasingly associated with autism spectrum disorder. Gut microbes and the metabolites they produce is described to have an impact on joints, liver, and heart health. Gut microbial metabolites are also known to affect the prognosis of colon cancer. One of the microbiome-centric interventions in a clinical condition that have shown extraordinary efficacy is in treatment of recurrent Clostridium difficile infection. Clostridium difficile infection occurs after or during the use of antibiotics for other clinical conditions. Recurrence of Clostridium difficile infection is very common and can occur in about 15-35% of CDI patients.

Vaginal microbiome

The vaginal microbiome changes in composition throughout a woman’s lifetime. In reproductive years, the vaginal microbiome is dominated by one species of bacteria called Lactobacillus [6], with the vagina being the only site that is described to be healthy/normal with low diversity. Human vaginal microbiota is described to be causative of bacterial vaginosis, yeast infections, and urogenital diseases. Dysbiosis of vaginal microbiome could potentially increase a person’s risk of contracting sexually transmitted infections and urinary tract infections. Misdiagnosis for various vaginal conditions and recurrence of conditions like bacterial vaginosis (BV) is a huge problem for women who suffer this discomfort. Bacterial vaginosis, the most common vaginal dysbiotic condition, is thought to affect 1 in 3 women of reproductive-age [7]. BV is also considered to be a risk factor for subfertility and infertility in women. Therefore, vaginal microbiome testing might be useful in the following conditions: recurrent bacterial vaginosis, aerobic vaginitis, yeast infection, Trichomonas, STIs (sexually transmitted diseases), menopause and vaginal dryness.

Vaginal microbiome and fertility

A specific class of microbiome, called Mollicutes are implicated in causing fertility issues. Increased presence of specific bacterial taxa along with higher abundance of Candida (yeast) and reduced Lactobacillus in vaginal microbiome, is often present in women with fertility problems. Research also confirms the vaginal microbiome as being a component that influences outcome with IVF and assisted reproductive technology (ART).

Microbiome and Pregnancies

In a healthy pregnancy, the mucous plug at the cervix blocks bacteria from ascending into the uterus. However, a subset of vaginal microbiome organisms are able to ascend to the upper genital tract and gain access to the uterus and amniotic sac during pregnancy. The subset of bacteria that do this are able to degrade hyaluronan and other amino sugars that form the matrix of cervical mucous plug. By degrading the mucous plug of cervix, and thereby gaining access to uterus, the microbiome can act on the amniotic sac and cause preterm birth and other prenatal and postpartum complications. Microbiome testing can be useful in cases with history of preterm birth, spontaneous abortions, preterm labor, chorioamnionitis, amnionitis, PPROM (Preterm premature rupture of membrane during pregnancy).

Oral microbiome

The oral microbiome refers to the community of microbes that reside in our oral cavity and is the second largest community (with over 700 kinds) that resides in/on our body [9]. The normal microbiome consists of bacteria, fungi, viruses, archaea and protozoa. Oral microbiota is now recognized to be able to engage the brain by producing metabolites that can influence the brain. The oral microbiome is known to work closely with gut microbiome, influencing conditions like IBD, liver diseases, heart diseases, metabol