Genomic Analysis And SNPs

Photo of Dr. Sharol with a big smile in oval photo frame
Photo of idea of what genes look like.

Understanding Genome Reports and Definitions

Why Do Genome Testing?

Genomic testing allows practioners to further personalize our diagnosis and treatment options. A physician or other practitioner who is seeking to know their patient well with extensive interviews, physical exams and testing now has one more tool at their disposal. This tool of genomic testing allows us to get to know our patient better as it gives us an idea of the blue-print that was used to make the individual.

It allows us to identify genetic variations in individuals in order to predict the risk of that person developing a particular condition or disease when exposed to a particular "environment".

 

Once we understand an individuals personal genomic strengths and weaknesses, practitioners are able to recommend personalized therapeutic treatments such as lifestyles changes, environmental changes, dietary and supplement changes.

Indiduals themselves have the ability to test themselves via 23andme (see below) or other websites and then use various software to gain understandings of their blueprint.

What can you learn with the tests current knowledge of the genome and Single Nucleotide Polymorphism's (SNPs)?

I have listed a few areas that are currently examined by practitioners who use genomic analysis. You can learn much more than this, but these are commonly examined areas via the use of SNPs.

  • Bone formation/resorption/inflammation: Osteoblast/osteoclast activity, hormones and the regulation of calcium and the role of inflammation in stimulating bone breakdown.
  • Cardiovascular Risk: Examine methylation, inflammation and yes if you wish cholesterol.
  • Cholesterol regulation: Breakdown and metabolism of cholesterol
  • Chronic Inflammation
    • Chronic up-regulation duration/intensity, Examination of TH-1 cytokines which are involved in cell-mediated responses and important in viral illness and cancer.
    • Examination of TH-2 cytokines which are involved in antibody response and are important in atopic illness.
  • Coagulation: Variants that increase the risk of blood clotting.
  • Detoxification:
    • Phase 1 cytochrome P450: Phase 1 detoxification enzymes provide hydroxyl groups to make molecules more soluble
    • Phase 2 detoxification pathways offer processes that add small molecules onto larger molecules to make them more soluble.
  • Estrogen metabolism/Breast Cancer Risk: Examine Phase 1 and 2 detox enzymes
  • Hypercoagulation: Clotting factors, inhibition to clotting
  • Neruomodulation
    • Methylation effects modulation of neurotransmitter function.
    • Detoxification ability effects detoxification of particular neurotoxins.
    • Oxidative stress modifies types and numbers of free radicals.
  • Osteoporosis
  • Vitamin D,
    • bone formation
    • inflammation
  • Oxidative Stress: Toxic intermediate metabolites of Phase 1 detoxification can cause free radical formation and this increases oxidative stress.
  • Hypertension: Angiotensin's role in sodium and water balance
  • Methylation: Methylation is a common epigenetic modification. - methylation effects a lot of things. See my page on methylation.

This kind of data above can be procured through easy to understand tests such as you get from Genova Diagnostics or you can get your whole genome tested by some place such as 23andme and then look up any and all SNPs you wish on your own or use various software programs on the internet to look them up for you. See this data below.

 

Definitions You Will See Regarding Genome Testing.

Since this is a new field, I find I need to spend hours and even days reading research to understand some of the genome data I get on tests. If you are new to this, you will want to save this page and come back to it to look up information.

Genotype: Your genotype is basically a blueprint of who you are. Your phenotype is what you present to the world from the blueprint. By looking at your genome and specifically looking at SNPs, you can optimize the expression of your genotype. By eliminating certain foods from your diet and substances or supplements that you cannot handle, or making environmental changes as well as providing substances that you cannot make on your own via dietary changes or ingestion of supplements we you can effect your phenotype.

Genomic Analysis: Genetic sequence variations exist at defined positions within genomes and are responsible for individual phenotypic characteristics, including a person's likelihood of having a complex disorder such as heart disease and cancer. Techniques used to determine and compare a persons genetic sequence or genetic variations with a compiled database of known genomes is called genomic analysis.

Epigenetics: Epigenetics refers to changed in the function and/or regulation of DNA, RNA and not changes in the primary sequences of the genetic code. It is the study of cellular and physiological traits that are heritable by daughter cells and not caused by changes in the DNA sequence. Epigenetics, refers to lifestyle choices and environmental exposures that can affect gene expression. Environmental changes that cause physiological traits would be an epigenetic change. You could say the genetics is the "nature" we are born with and epigenetics is the "nurture" we receive.

Nutrigenomics: The type of genomic analysis I am interested in is the study of genetic variances that lead to various health conditions and via manipulation of diet or addition of supplements/herbs can be remedied. You can study this area of medicine by looking at what are called single nucleotide polymorphisms (SNPs). You run your SNPs through various computer software programs that will locate those SNP variants that are associated with susceptibility to environmental factors such as toxins due to specific alterations in how the body can process them, or there may be variations that cause an imbalance in specific biochemical pathways leading to dysfunction and health issues. Sometimes this can be corrected by supplying missing nuitritional ingredients that are necessary for these bodily processes. By using dietary manipulations or adding a needed nutrient as a supplement based on these findings, it may make a big difference in a person's health. You can see more details on the Nutrigenomics page.

Nucleotides: Nucleotides are the structural units of RNA, DNA, and several cofactors - CoA, flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), adenosine triphosphate and nicotinamide adenine dinucleotide phosphate. In the cell they have important roles in metabolism, and signaling.

Single Nucleotide Polymorphism (SNP) testing examines a single nucleotide variation at a specific location on the chromosome. This can be benign and cause no changes or it can completely change the protein that is ultimately made from this template. (DNA is just a template or pattern.) There are currently over 3 million SNPs known.

SNPs (pronounced “snips”), are the most common type of genetic variation among people. Each SNP represents a difference in a single DNA building block, called a nucleotide. For example, a SNP may replace the nucleotide cytosine (C) with the nucleotide thymine (T) in a certain stretch of DNA.

A SNP can change an amino acid in the protein coding sequence and thereby alter an enzyme binding site and/or the substrate binding site, which may affect the overall function.

SNPs occur normally throughout a person’s DNA. They occur once in every 300 nucleotides on average, which means there are roughly 10 million SNPs in the human genome. Most commonly, these variations are found in the DNA between genes. They can act as biological markers, helping scientists locate genes that are associated with disease. When SNPs occur within a gene or in a regulatory region near a gene, they may play a more direct role in disease by affecting the gene’s function.

Most SNPs have no effect on health or development. Some of these genetic differences, however, have proven to be very important in the study of human health. Researchers have found SNPs that may help predict an individual’s response to certain drugs, susceptibility to environmental factors such as toxins, and risk of developing particular diseases. SNPs can also be used to track the inheritance of disease genes within families. Future studies will work to identify SNPs associated with complex diseases such as heart disease, diabetes, and cancer.

I have listed some definitions below to help you understand genetic testing lingo that you might see as you read about it in other places or on this website.

Chromosomes: For data on understanding Genome Reports and Definitions: In their body cells, humans have 46 chromosomes, made up of 23 pairs. There are 44 chromosomes called autosomes that are numbered from 1 to 22 according to size from the smallest to the largest as well as the two sex chromosomes: X and Y. Women’s chromosomes are described as 46,XX; men’s as 46,XY. A mother passes 23 chromosomes to her child through her egg and a father passes 23 chromosomes through his sperm. The chromosomes are made up of DNA. Each chromosome consist of two very long thin strands of DNA chains twisted into the shape of a double helix and are located in the nucleus (the ‘control centre’) of our body cells . The chromosomes can be thought of as long strings of genes. Since the chromosomes in the cell’s nucleus come in pairs, the genes in the nucleus also come in pairs

Genes: Each chromosome contains many genes. A gene is the basic physical and functional unit of heredity. Genes, which are made up of DNA, act as instructions to make molecules called proteins. Genes are specific sequences of bases that encode instructions on how to make proteins. Genes are located in very small compartments called mitochondria that are randomly scattered in the cytoplasm of the cell outside the nucleus.

In humans, genes vary in size from a few hundred DNA bases to more than 2 million bases. All of the DNA in the cell (in the nucleus and the mitochondria) make up the genome The Human Genome Project has estimated that the human genome is estimated to have between 20,000 and 25,000 genes. Genes comprise only about 1-2% of the human genome; the remainder consists of noncoding regions, whose functions may include providing chromosomal structural integrity and regulating where, when, and in what quantity proteins are made.

Every person has two copies of each gene, one inherited from each parent. Most genes are the same in all people, but a small number of genes (less than 1 percent of the total) are slightly different between people. Alleles are forms of the same gene with small differences in their sequence of DNA bases. These small differences contribute to each person’s unique physical features.

Genome: A genome is an organism’s complete set of DNA, including all of its genes. Each genome contains all of the information needed to build and maintain that organism. In humans, a copy of the entire genome—more than 3 billion DNA base pairs—is contained in all cells that have a nucleus. Except for mature red blood cells, all human cells contain a complete genome.

DNA: DNA from all organisms consists of the same chemical and physical components. The DNA sequence is the particular side-by-side arrangement of bases along the DNA strand (e.g., ATTCCGGA). This order spells out the exact instructions required to create a particular organism with its own unique traits.

DNA in the human genome is arranged into 24 distinct chromosomes—physically separate molecules that range in length from about 50 million to 250 million base pairs. A few types of major chromosomal abnormalities, including missing or extra copies or gross breaks and rejoinings (translocations), can be detected by microscopic examination. Most changes in DNA, however, are more subtle and require a closer analysis of the DNA molecule to find perhaps single-base differences.

Genetic Code: The genetic information contained in the DNA is in the form of a chemical code, called the genetic code. The genetic information guides our growth, development and health. The DNA’s genetic code is virtually identical across all living organisms and is like a recipe book for the body to make proteins and control how the genes work. The DNA code is made up of very long amino acid chains of four chemical ‘letters’: Adenine (A), Guanine (G), Thymine (T) and Cytosine (C)

In the DNA information, each ‘word’ is a combination of three of these four chemical ‘letters’ A, G, C and T

Each three-letter word (triplet) tells the cell to produce a particular amino acid, the building blocks of proteins.

The sequence of three-letter words in the gene enables the cells to assemble the amino acids in the correct order to make up a protein.

Different cell types, tissues and organs have specific roles and so produce specific proteins for that role. The genes that contain the information to make the necessary proteins are therefore ‘switched on’ in these cells while the remaining genes are ‘switched off’. For example, the genes that are ‘switched on’ in liver cells are different to those that are ‘switched on’ in brain cells because the cells have different roles and make different proteins.

We all have variations in the genetic code which is why we are all unique.

Mutations: Most variations are harmless. However, variations to the genetic information can sometimes make the gene faulty which means that a particular protein is not produced properly, produced in the wrong amounts or not produced at all. Variations that make the gene faulty are called mutations.

Variations that make a gene faulty can result in a genetic condition, affecting our growth, development and how our bodies work

In other cases, the variation in the genetic code makes a person more susceptible to developing a genetic condition.

You can find more details on genetic mutations here.

You can find details on gene nomenclature here.

The Human Genome Project: The Human Genome Project was an international research effort to determine the sequence of the human genome and identify the genes that it contains. The Project was coordinated by the National Institutes of Health and the U.S. Department of Energy. Additional contributors included universities across the United States and international partners in the United Kingdom, France, Germany, Japan, and China. The Human Genome Project formally began in 1990 and was completed in 2003, 2 years ahead of its original schedule.
The work of the Human Genome Project has allowed researchers to begin to understand the blueprint for building a person. As researchers learn more about the functions of genes and proteins, this knowledge is having a major impact in the fields of medicine, biotechnology, and the life sciences.

Places to get SNP test (genome analysis for polymorphisms) and places to further anaylize the test:

23andme

This is relatively inexpensive and has been useful for many lay folks and docs.

 

Government Guide to Understanding Genetic Conditions

Genetics Home Reference

Where you can order a variant report. This is basically a comparison of your SNPs with Peoples SNPs with known varient issues. Before you order an interpretation you might want to take a look at a blog that compares a few of these sites.

Genetic Genie: This is a donation site. It does not give very many SNPs but gives some more important ones and ones that more is known about. It is cheap also. Gives some good data along with the SNPs.

mthfrsupport.com : Gives a longer list of SNPs than Genetic Genie. Pulls out many of the SNPs that I want to look at but still missing bits and pieces. Costs $20 at time of writing this. Here is what they say about their report: This Variant Report is a listing of Single Nucleotide Polymorphisms (SNPs), derived from the raw data results of 23andMe saliva testing, and generated via a software tool. The most comprehensive and well researched Variant Report can be obtained via MTHFRsupport.com, using Sterlings App. The Variant Report is organized into groups of SNPs, including Phase I and Phase II liver detoxification SNPs, IgE, IgA, and IgG SNPs, Methylation SNPs, Mitochondrial Electron Transport Chain SNPs, and others.

Promethease : This is inexpensive. As I write it is $5. Gives a lot of data that is based on SNPedia. However, there is the possibility of errors if there is errors in SNPedia.

Interpretome : This allows your to explore your genome by looking up your SNPs. No charge. Kind of like the public SNP database I list below, but easier to use.

Livewello: This is another gene variance report such as you get with MTHFRSupport or genetic genie or promethease. They all vary a bit in what they provide. Check it out.

Public SNPs Database: The Single Nucleotide Polymorphism database (dbSNP) is a public-domain archive for a broad collection of simple genetic polymorphisms. This collection of polymorphisms includes single-base nucleotide substitutions (also known as single nucleotide polymorphisms or SNPs), small-scale multi-base deletions or insertions (also called deletion insertion polymorphisms or DIPs), and retroposable element insertions and microsatellite repeat variations (also called short tandem repeats or STRs).

Details on using this database here.

The SNP database can be queried from the dbSNP homepage , or by using Entrez SNP

Reading Tests

There are two copies of each gene. One from each parent. If the two copies are the same they will be listed as +/+ or -/- and this is called homozygous. If it is listed as +/- it is called heterozygousand means they are two different bases. When you see + this indicates a variation. Sometimes labs may have a different definition of what the norm is. When a person has a homozygous variation (mutation) this generally means any effects from the variation will be more exagerated. However, just because a person has a variation does not necessarily mean that the activity of that gene is going to be impaired. It is simply an indicator that there could be an impairment. Although an impairment may appear from this variation, it may never happen if other genetic influences or environmental influences do not exist. So these variations are simply an indicator of a possible impairment. Often there can be a partial impairment that is not noticed until some environmental factor causes it to become more pronounced.

The relationship between genetic variants and the associated disease phenotype (the condition) can be very complex. In some cases, variants in one gene can be involved in several phenotypes (conditions) and conversely one condition can be due to many genes.

PharmGKB

PharmGKB is a comprehensive resource that curates knowledge about the impact
of genetic variation on drug response for clinicians and researchers.

Example of Mold Sensitivity and Genetics: Aflatoxin B1, a mycotoxin found in some food has a risk for hepatocellular carcinoma, especially when it is combined with hepatitis virus exposure. The biotransformation of aflatoxin B1 involves the CYP450 mediated oxidation and then goes through reactions catalyzed by GST, epoxide hydrolase and/or glucuronosyltransferase to yield an excretable metabolite. If a person exposed to aflatoxin B1 that has GSTM1 and EPHX1 (epoxide hydrolase1) genotypes conferring a lack of enzyme and less active enzyme, respectively, there is an increased hepatocellular carcinoma (HCC) risk. The people with these genetic varients of GSTM1 and EPHX1 will have increased aflatoxin-albumin adducts in peripheral blood thatn those without polymorphisms.

Although research on CYP1A2 and CYP3A4 have not yet been studied for an increase HCC risk, since they both catalyze the phase I metabolism (epoxidation) of aflatoxin B1, any modification in the genes for these enzymes may alter the risk of HCC from aflatoxin B1 exposure.

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