A Common Genome
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Discovering information about genes enables the development of effective medical treatments
How disease genes in dogs are relevant in humans
As the National Human Genome Research Institute (NHGRI), of the National Institutes of Health (NIH) cites, the sequencing of the dog genome began in June of 2003, led by Kerstin Lindblad-Toh, PhD, Scientific Director of Vertebrate Genome Biology of the Broad Institute of MIT and Harvard, founded on the beliefs of the opportunity and responsibility this generation has to transform medicine by utilizing novel types of research institutes tackling the critical challenges in biology and medicine, to "accelerate the understanding and treatment of disease." One novel approach is the Canine Genome Sequencing Project, producing a high-quality draft sequence of Tasha, a female Boxer.
As Dr. Lindblad-Toh states, it was in early 2004 where the first high-quality dog genome sequence was completed, consisting of approximately 2.4 billion letters, meticulously analyzed to discover genes and variation among dog breeds. The dog and human genome share approximately 20,000 genes, similar at the nucleotide level; because of the large similarity, information from one genome to the other can easily be transferred. If a disease mutation in a gene in dogs is found, that corresponding gene can be studied in humans.
Many common diseases affecting humans also affect dogs, including cancers (breast cancer, lymphoma, bone cancer), epilepsy, cardiomyopathy, and many immunological disorders, as well as heart disease, neurological diseases, even behavior (compulsive disorders, shyness); diseases difficult to study in humans. "Many of these diseases have very similar clinical presentation, molecular mechanisms and treatment strategies in humans and dogs'" where the disease genes found in dogs are relevant in humans, particularly in discovering effective treatments.
The project compiled a comprehensive set of SNPs (single nucleotide polymorphisms) by comparing Tasha with other breeds, where the genomic landmarks are crucial for disease mapping. As the Broad Institute explains, SNPs are variations in the DNA (deoxyribonucleic acid) code; DNA is composed of 3 billion pairs of chemical nucleotides, or "letters" (A: adenine, C: cytosine), where approximately one in 1,000 letters of human DNA can vary in the form of a SNP, using the example, "If the human genome were a string of 3 billion colored beads, a SNP would be like substituting a blue bead for a red one." SNPs are a part of the natural genetic variation, creating diversity, influence factors such as eye color, or contributing to certain diseases, where the SNPs can be utilized to generate coordinates to survey genetic adjustments. Dr. Lindblad-Toh states, finding disease mutations or markers which tag the SNPs will help in generating better disease diagnostics, utilized for "diagnosis or guiding prevention or breeding programs. By finding the cause of disease, we may be able to develop more targeted and effective treatment strategies."
At the Broad Institute, blood samples are primarily used to prepare DNA and for genetic studies, also utilizing tumor material for study. What is examined is the clinical characteristics and how it matches human diseases, particularly examining mutations, comparing the genome of 100 healthy dogs to 100 dogs with a disease, of the same breed; a detailed study is done on the mutation, as pathways to the disease mechanism is discovered. A better understanding of the disease genes and mechanisms will allow for better development for treatment through a combination of diagnostics.
According to the American Cancer Society (ACS), cancer originates when abnormal cells grow out of control. Normal body cells grow, divide, and die routinely, where most cells divide only to replace worn-out or dying cells, or to repair injuries. Rather than dying, cancer cells continue to grow and form new, abnormal cells, also invading or growing into, other tissues (something normal cells cannot do); the growing and invasion of other tissues makes the cell a cancer cell, which result from DNA damage, which directs all cell action; in normal cells, when the DNA is damaged (due to mistakes while the normal cell is reproducing, or due to environmental factors), the cell will either repair the damage or the cell will die; in cancer cells, the cell will continue making new cells the body does not need, producing the same abnormal DNA as the first cell.
According to the Morris Animal Foundation (MAF), a foundation for the sole purpose of addressing animal health and welfare, cancer is the number one cause of death in dogs over the age of two. According to the National Canine Cancer Foundation (NCCF), a nationwide non-profit, contribution funded corporation devoted to eliminating canine cancer, canine cancer affects one of three dogs, where half of those will die from it.
The Broad Institute has been study Osteosarcoma (bone cancer), identifying 33 risk factors in Greyhounds and Rottweilers. Dr. Lindblad-Toh continues, these factors include bone growth, where in different breeds, some have cells which become cancerous, some have a good immune response; the hope is to learn how these cells communicate with one another, and the effect of that communication on the potential of cancerous cells. Another goal is to discover what different mechanisms can contribute to the abnormal growth.
In September of 2013, the Broad Institute had done a study on canine mast cell tumors, an aggressive cancer accounting for approximately one-third of all skin tumors in dogs; it is a disease closely related to mastocytosis, a painful condition in humans, triggered by an excess of mast cells, resulting in skin lesions to anaphylaxis, according to the Broad Institute. As Dr. Lindblad-Toh states, the studies are on-going, studying Labradors, Boxers, and Golden Retrievers, where in dogs, they can frequently develop mast cells on the skin, which can lead to anaphylaxis. "By looking for genetic risk factors in multiple dog breeds we will be able to identify what the key disease mechanism is for this devastating disease' Determining the underlying genetics for canine cancers like mast cell tumors can lead to better diagnostics, prevention and treatment for both canine and human disease," by discovering risk factors, and pinpointing the gene mutations.
As The American Heart Association (AHA) states, heart disease, cardiovascular disease, or coronary heart disease, is the general term to describe the problems associated to the plaque buildup in the walls of the arteries, or atherosclerosis; as the plaque builds, the arteries narrow, resulting in the difficulty for blood to flow, creating the risk for heart attack or stroke; other types of heart disease include heart failure, an irregular heartbeat, or arrhythmia, and heart valve problems.
Kansas State University Associate Professor of Cardiology, Michele Borgarelli, has been studying canine heart disease for over fifteen 15 years, discovering chronic mitral valve disease in dogs, the most common acquired cardiovascular disease in dogs (most commonly affecting geriatric dogs), as similar to the same disease in humans, according to Kansas State University. Chronic mitral valve disease is a heart condition where the mitral valve, one of the four valves in the heart, deteriorates; as it deteriorates, more blood backflows through the value, which can lead to congestive heart failure. Approximately 70 percent of dogs who are affected by the disease do not experience heart failure and do not die from the disease; "That's very similar to people. There are some people who don't progress to heart failure even without treatment," states Borgarelli. Since it is a common disease, and dogs are natural models for studying the disease in humans, Borgarelli continues studying this disease.
The Broad Institute has been studying Dilated Cardiomyopathy (DCM), a disease of the heart muscle, resulting in enlarged heart chambers, valve leakage, resulting in weakened contractions and difficulty pumping blood to the body and lungs. According to the Cornell University College of Veterinary Medicine, DCM is characterized by the dilation of the ventricles with ventricular wall thinning, where the ability of the heart to pump blood through the vascular system is diminished. The Broad Institute is studying Boxers, Doberman Pinchers, Great Danes, Irish Wolfhounds, and Newfoundland (large breed dogs are generally more prone). As Dr. Lindblad-Toh states, the more breeds the institute can study, they can discover the different mechanisms for the reason behind the enlarging of the heart; it was discovered in Doberman Pinchers a predisposing gene mutation for DCM.
As the Mayo Clinic, a nonprofit worldwide leader in medical care, research, and education for all people, describes, Parkinson's disease is a progressive disorder of the nervous system which affects movement; the disease develops gradually, beginning with perhaps a tremor in one hand; the symptoms worsen as the condition progresses over time. In early stages, your arms may not swing as you walk, speech may become soft or slurred. The cause of Parkinson's disease is unknown; however several factors may play a role, which include genetics and environmental triggers. Researchers have identified specific gene mutations which may cause the disease, including gene variations (polymorphisms) which increase the risk. Exposure to certain toxins or environmental factors can increase the risk of later Parkinson's disease.
The University of Missouri has also discovered a gene mutation found in Tibetan Terriers, which can also be found in a fatal human neurological disorder related to Parkinson's disease, according to the University of Missouri, which was found by doctoral candidate in Area Genetics, Fabiana Farias, as a part of her thesis research. The disease in the terriers, adult-onset neuronal ceroid-lipofuscinosis (NCL), affects the cells in the brain and eye, where "material that should be 'recycled' builds up and interferes with nerve cell function." What results from the build up (approximately at the age of five) is in the dog exhibiting dementia, impaired visual behavior, loss of coordination, and unwarranted aggression; other symptoms include loss of muscle control and seizures.
There are numerous forms of NCL in humans, where the symptoms of NCL are similar in people and dogs, as the disease is fatal for both. In utilizing the canine genome map and DNA samples from dogs diagnosed with NCL, researchers were able to ascertain the specific gene which causes NCL; the mutation discovered in dogs causes a hereditary form of Parkinson's disease in humans, suggesting that the "recycling that goes awry in the NCL may also be involved in degenerative diseases like Parkinson's."
As defined by the National Library of Medicine (NLM), of the NCBI, an autoimmune disorder is a condition which occurs when "the immune system mistakenly attacks and destroys healthy body tissue." Normally, the immune system's white blood cells protect the body from harmful substances, antigens (which include bacteria, toxins, blood or tissue transferred from another person or species), as the immune system produces antibodies to destroy the harmful antigens. Those afflicted with an autoimmune disorder, the immune system cannot differentiate between the healthy body tissue and the antigens, where the immune response is to destroy the normal, healthy tissue.
What was interesting to Dr. Lindblad-Toh was the study of Nova Scotia Duck-Tolling Retrievers, looking at five genetic loci, suggesting a predisposition of T-cell activation, where the over activation of the cells can result in tumors, as well as attacking healthy tissue. Dr. Lindblad-Toh cites the early 1900s, when there was an outbreak of canine distemper virus; only 4-5 dogs survived. According to the Cornell University College of Veterinary Medicine, Baker Institute for Animal Health, the canine distemper virus is a highly contagious, largely incurable, often fatal disease which attacks the respiratory and gastrointestinal tracts, and nervous system. Dr. Lindblad-Toh continues, the dogs who survived had a strong T-cell immune response, suggesting the contemporary breed of Nova Scotia Duck-Tolling Retrievers (who originated from the surviving population of the distemper outbreak), are predisposed to the T-cell over activation due to their ancestors who survived with the strong immune system. However, that strong response may now lead to autoimmune disease.
Josh Liddy, Founder of SwayLove.Org, in tribute to Sway, the Pit Bull who was always by his side, discovered the severity behind the autoimmune disease, Autoimmune Hemolytic Anemia (AIHA). According to VCA Animal Hospitals, operating in over 600 animal hospitals in 42 states across the nation, AIHA is an immune system disease where the body kills its own red blood cells; the red blood cells are being produced in the bone marrow, but after its release into the bloodstream, they have a shorter-than-normal lifespan.
AIHA may be primary, where the dog's immune system is working improperly, incorrectly making antibodies that target its own red blood cells (3/4 of cases of AIHA are primary); or secondary, where the surface of the red blood cells are altered by an underlying condition (triggered by cancer, infections, parasites) or a drug reaction, chemicals, or toxins, as the dog's immune system recognizes the altered red blood cells as "foreign" that must be destroyed. The red blood cells will be destroyed within the blood vessels or when circulated through the liver or spleen, where hemoglobin is released; the liver then attempts to break down the excess hemoglobin, increasing its workload.
Liddy accounts, the normal red blood count in dogs is 50-55 percent, where Sway's count was at 29 percent; she was diagnosed with AIHA after the second test yielded a similar count. Within a few months, Sway's red blood cell count was routinely dropping into the teens, requiring blood transfusions to sustain her life. Sway's case of AIHA was in the extreme, as her bone marrow was not regenerating red blood cells; Sway's body was not only killing the adult blood cells, but also the baby cells from the bone marrow. Sway's muscle was wasting away, as she experienced appetite loss; Sway's lowest weight was 17 pounds. Despite the weakness of her body, Sway's spirit was strong, where "you could see it in her eyes [that] she wanted to live."
Sway experienced numerous rebounds and declines, developing inoperable liver shunts and Pancreatitis, further complicating her health. The liver shunts diverted vital nutrients as well as not cleansing the blood of toxins. Sway's battle ended in late July 2009. However, AIHA is not a death sentence. According to VCA Animal Hospitals, "The prognosis for dogs with AIHA is based on the specific diagnosis, as well as the patient's general condition at the time of diagnosis."
Dr. Lindblad-Toh looks ahead towards the future, as goals for the study of the dog genome include improving the genome map in order to discover additional information about the genes, making that information available to the community. What is exciting to Dr. Lindblad-Toh is, in discovering more information about the genes, it creates a greater opportunity to understand the spectrum, enabling the development of genetic tests, ascertaining the effectiveness of treatments, which specific treatments are most beneficial, as well as learning more about alternative treatments, as certain mutations will reveal which treatments will be most effective. Dr. Lindblad-Toh believes the studies benefit both canine and human health, where we should "take advantage of the dog genome," utilizing the "power of their genome" to build a better understanding of developing efficient treatments for both canines and humans. To Dr. Lindblad-Toh, we should embrace and engage in genetic research, as the available information derived from the genome is greatly beneficial.
The Broad Institute is comprised of talented scientists, collaborating and working across disciplines and institutions in biomedical research, with the goal of a better understanding and treatment of diseases. It is the generous support of donors who help to advance their work.
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Louisa Lew, Contributing Writer: Louisa Lew graduated from the University of Washington with a Bachelor’s Degree in the Liberal Arts, double majoring in Political Science and Film. She is currently a Freelance Copy Editor and Writer, living in Seattle with her two dogs. (more...)