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In a 1983 paper, Harvard University geneticists James Gusella and Nancy Wexler reported that Huntington’s disease, a fatal inherited disease where brain cells progressively decay, was caused by a gene mutation on chromosome 4. This was the first time a single gene had been implicated in a disease.
Since then, scientists have discovered about 5,000 genes whose mutations can increase our susceptibility to afflictions ranging from obesity to schizophrenia, and bipolar disorder.
Concomitant with the rise in genetic discoveries is the rise of commercial genetic testing. The U.S.-based company 23andMe, for example, offers a saliva-based test priced at around Rs. 20,000 that promises “insights into [people’s] ancestry, traits and health that can help make it easier for [them] to take action on [their] health.”
Similarly, Hyderabad-based MapMyGenome offers a “Genomepatri” service for Rs. 5,999. A play on janampatri, a Vedic birth chart purporting to forecast a person’s destiny, Genomepatri offers to help consumers uncover their “authentic self” and enhance their health, according to their website.
But according to six geneticists this reporter spoke to, an individual’s genetic composition is not their destiny.
“Mutations in our genes predispose us to specific traits and diseases, but it doesn’t mean that if you have a mutation, you’re going to get this disease,” Tata Institute of Fundamental Research, Hyderabad, molecular geneticist Manish Jaiswal said.
What then does it mean to find a gene for a trait or disease — and what happens when we carry them?
Genes, mutations, disease
Genes are segments of DNA that provide the body a blueprint for building proteins, which eventually help define traits like eye colour or blood type.
When cells in our body divide, specialised proteins make copies of the DNA. This process, while largely accurate, can introduce errors in the duplicated DNA. These changes are called mutations and the corresponding gene is said to have an allele — a variant.
Only a small fraction of an organism’s genome — which is the entire length of its DNA — has genes that its body uses to build proteins. For human beings, this coding region comprises about 2% of the genome. The rest of the DNA is non-coding, i.e. not involved in producing proteins, but regulates gene expression.
If a mutation in the coding region impairs the protein product, it may lead to a disease. For example, in Huntington’s disease, a small section of the HTT gene is repeated more times than in an average individual. This produces a longer version of the protein, whose toxic fragments accumulate in brain cells and eventually kill them. As brain cells continue to die, people begin showing symptoms of the disease.
Sometimes, mutations in non-coding regions of the DNA can also change an individual’s risk of a disease. For example, four independent studies in 2007 found that mutations in a particular non-coding region of the DNA were associated with a higher risk of coronary artery disease and type 2 diabetes. Later, in 2011, researchers found that the region contained certain enhancers, short DNA sequences that boost the expression of certain genes.
Identifying genes
To identify genes associated with a trait or disease, scientists until recently took two kinds of approaches: candidate-gene studies and linkage studies.
In candidate-gene studies, scientists use existing information about the disease to identify potential gene candidates that, when mutated, may lead to the disease. For example, because schizophrenia is treated with drugs that regulate the amount of dopamine in the human brain, scientists assumed until 2007 that mutations in genes related to dopamine regulation were linked to schizophrenia.
While such studies were successful in some cases, like Alzheimer’s disease, in others they could not reliably identify genes associated with the disease. In the case of schizophrenia, for example, 21 of 25 candidate genes scientists historically studied were found to have little “empirical support … as genetic risk factors for schizophrenia,” a 2015 review in Molecular Psychiatry reported.
Linkage studies on the other hand begin by identifying a population or a family where the incidence of a trait or disease is particularly high. Then, scientists study how known markers in their DNA are inherited. If members of the population carrying the trait or disease also inherit the same markers, scientists can claim that the gene variant responsible for the disease and the marker are close on the chromosome, i.e. they are linked. By using statistical techniques, scientists can then pinpoint the gene.
This method works well when diseases are caused by mutations in one or a few genes, National Institute for Mental Health and Neuro Sciences (NIMHANS) genetics researcher Jayant Mahadevan said. Such diseases, like Huntington’s, are called monogenic when their risk is determined by mutations in one gene and oligogenic when it’s determined by mutations in a few genes.
However, most monogenic diseases are rare: they occur in less than 1% of the population, Dr. Mahadevan added. Most common diseases, including diabetes, obesity, coronary artery disease, and schizophrenia, are polygenic: they are determined by mutations in several genes.
For example, mutations in more than a 100 genes have been implicated in typical obesity. For type 2 diabetes, the most common form of the disease, recent studies place the number at approximately 250 genes. For schizophrenia, scientists suggest that the number could run into several hundreds.
In order to identify gene variants responsible for such diseases, researchers now typically undertake genome-wide association studies (GWAS). By comparing entire DNA sequences of a large number of individuals who carry a disease with that of individuals who don’t, scientists can identify hundreds of variations associated with the disease through the entire length of an individual’s DNA. This gives researchers a more holistic picture of the gene variations underlying the disease.
No ‘obesity gene’
But possessing one or more gene variants implicated in a disease does not mean that one is doomed.
For one, not all gene mutations implicated in a disease have the same effect size. This is a measure of how strongly a gene variant can affect a trait. For example, most gene variants implicated in schizophrenia are thought to have small effect sizes: for an individual’s schizophrenia risk to increase substantively, they need to have mutations in several of these genes.
Studies have shown similar results in the case of gene variants associated with obesity. In a 2010 study, scientists studied the effect sizes of 12 implicated. These have “small effects on obesity measures,” they reported. Even mutations in the FTO gene, known to have the largest effect on an individual’s obesity risk and is commonly dubbed the “obesity gene”, predisposes a person to only a modest increase in weight compared with individuals who do not carry these mutations, the study added.
Even though a combination of mutations in these genes could compound the risk, “their predictive value for obesity risk is limited,” the researchers concluded.
This means scientists cannot reliably predict whether an individual carrying these gene variants will eventually end up obese. Put another way, there is no “obesity gene”. And for similar reasons, there is no “fat gene”, “lazy gene” or “hunger gene”.
Genetics is also only one part of the story behind a certain disease. The other part is epigenetics: a that refers to how physical, behavioural, and social factors affect the gene expression and, eventually, an individual’s risk of a disease.
“Think of the genome as a piano, where each key represents a gene,” said epigenetics researcher Ullas Kolthur-Seetharam, director of the Centre for DNA Fingerprinting and Diagnostics, Hyderabad, and a professor at the Tata Institute of Fundamental Research, Mumbai. “If a key is faulty, it can produce discordant notes — reflecting a potential disease risk. However, the system has flexibility: by adjusting how other keys are played, you can often compensate and still produce harmonious music.”
“In the case of certain inherited diseases caused by critical mutations, some keys may be so impaired that no amount of adjustment can fully restore the intended melody,” he added.
“In those situations, the limitation lies in the instrument itself. But for many complex conditions/diseases, how the piano is played (or how the genes are expressed) become as important as the keys themselves.”
Indeed, behavioural and lifestyle interventions can actually reduce the risk of diseases. There is mounting evidence that in individuals with FTO variants that increase their risk of obesity, high-intensity exercise can reduce the gene’s expression, potentially attenuating their risk of developing obesity. One 2015 study that investigated about 16,000 children and adolescents also found that “lower dietary protein intake attenuates the association between the FTO genotype and adiposity [the way fat is distributed] in children and adolescents.”
Merits of genetic testing
In this context, what does it mean when scientists report identifying a new gene variant for a disease or a trait?
“All you’ve discovered is its pattern of occurrence in the population or the pattern of its transmission in a family,” NIMHANS senior professor Sanjeev Jain, who works on the genetics of several neurological and psychiatric disorders, explained.
But figuring out whether the variant corresponds to the actual disease — and by how much — requires scientists to undertake more research involving diverse model systems, he added.
This doesn’t mean genetic pursuit is itself useless, both Dr. Jain and Dr. Mahadevan cautioned. Genetic studies do help researchers identify the physiological mechanisms underlying a disease, which can help clinicians design more effective therapeutics. Scientists also often end up finding gene variants that are actually beneficial.
Starting in the 2000s, researchers discovered that some mutations in the PCSK9 gene can drastically reduce the risk of coronary artery disease. Since then, clinicians have developed ways to silence the gene, thus reducing patients’ cholesterol levels and mitigating the risk of stroke and heart attacks.
Some scientists also see merit in genetic testing — but only in certain contexts. Dimple Notani, a gene regulation researcher at the National Centre for Biological Sciences, Bengaluru, said women who conceive late could consider getting themselves screened for mutations linked to rare genetic disorders, which are often monogenic. But for traits that are not monogenic, “I wouldn’t worry much,” she added.
Genetic tests should always be followed by genetic counselling, Dr. Jaiswal, the TIFR Hyderabad geneticist, said. Genetic counsellors are specialists who help people assess their risk of developing genetic disorders, and help manage them.
In other words, genetics provides us with a helpful but incomplete picture. Between a mutation and its manifestation is a far messier story.
The reporter thanks Dr. Suhas Ganesh (NIMHANS) for his inputs.
Sayantan Datta is an independent science journalist and a faculty member at Alliance University, Bengaluru.
